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1.
Thyroid ; 33(1): 91-99, 2023 01.
Article in English | MEDLINE | ID: mdl-35443825

ABSTRACT

Background: Sorafenib and lenvatinib have been widely adopted to treat radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). However, limited data exist regarding a direct comparison of these tyrosine kinase inhibitors (TKIs). We aimed to evaluate the clinical efficacy and safety of two TKIs as first-line therapy in patients with distant metastatic or locally advanced, progressive, RAI-refractory DTC in real-world practice. Methods: In this multicenter, retrospective cohort study, we evaluated 136 patients with progressive distant metastatic or locally advanced, progressive, RAI-refractory DTC or poorly differentiated thyroid carcinoma (PDTC) who received first-line sorafenib or lenvatinib treatment. The primary outcome was progression-free survival (PFS). We also evaluated the objective response rate, disease-control rate, clinical benefit rate, and safety. Results: The median age of the patients was 68 years, and 35% (47/136) were male. Eighty and fifty-six patients were included in the sorafenib and lenvatinib groups, respectively. The median PFS was 13.3 months [95% confidence interval, CI, 9.9-18.1 months] in the sorafenib group and 35.3 months [CI, 18.2 months to upper limit not reported as the median was not reached] in the lenvatinib group (p = 0.001). A significantly prolonged PFS was observed in the lenvatinib group (compared with the sorafenib group) after adjusting for age, sex, pathology, disease-related symptom, lung-only metastasis, cumulative RAI dose, time from diagnosis, treatment duration, and longest diameter of the target lesion (hazard ratio = 0.34, CI, 0.19-0.60, p < 0.001). The partial response rate was 24% and 59% in the sorafenib and lenvatinib groups, respectively (p < 0.001). More common grade 3-4 adverse events were hypertension (16%, 9/56 vs. 1%, 1/80, p = 0.002) and proteinuria (32%, 18/56 vs. 0%, p < 0.001) in the lenvatinib group, and hand-foot skin reaction (24%, 19/80 vs. 4%, 2/56, p = 0.001) in the sorafenib group. Conclusion: In our study of Asian patients, first-line lenvatinib treatment of metastatic or locally advanced, progressive, RAI-refractory DTC or PDTC was associated with a longer PFS compared with sorafenib. However, severe hypertension and proteinuria were observed more frequently after lenvatinib treatment than after sorafenib treatment.


Subject(s)
Adenocarcinoma , Antineoplastic Agents , Hypertension , Quinolines , Thyroid Neoplasms , Humans , Male , Aged , Female , Sorafenib/therapeutic use , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/radiotherapy , Thyroid Neoplasms/pathology , Iodine Radioisotopes/therapeutic use , Antineoplastic Agents/adverse effects , Retrospective Studies , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Hypertension/chemically induced , Proteinuria/chemically induced , Proteinuria/drug therapy , Protein Kinase Inhibitors/adverse effects
2.
Eur J Endocrinol ; 186(5): 561-571, 2022 Apr 01.
Article in English | MEDLINE | ID: mdl-35286279

ABSTRACT

Objective: Thyroid cancer survivors have a high risk of second primary malignancies (SPMs). We aimed to evaluate the site-specific incidence, prognosis, and risk factors for metachronous SPMs following thyroid cancer. Design: A nationwide cohort study. Methods: This study included data from the Korea National Health Insurance Service (between 2002 and 2018). Exposure to diagnostic radiation was defined by the number of computed tomography (CT) and positron emission tomography-CT scans after the index date. A cumulative radioactive iodine (RAI) dose >100 mCi was considered high-dose RAI. Results: During the median 6 years of follow-up, among 291 640 patients, 13 083 (4.5%) developed SPMs. Thyroid cancer survivors had a 26% increased risk of SPMs compared with the general population (standardized incidence ratio: 1.26; 95% CI: 1.22-1.29). Furthermore, those with SPMs had a significantly poorer survival rate than those without SPMs (hazard ratio: 11.85; 95% CI: 11.21-12.54; P < 0.001). Significantly elevated risks were observed in myeloid leukemia and 13 solid cancer sites: lip, salivary gland, small intestine, larynx, lung, mediastinum and pleura, mesothelium, breast, corpus uteri, ovary, prostate, kidney, and bladder. Frequent diagnostic medical radiation exposure and high-dose RAI therapy were independent risk factors for several SPMs, including the cancer of salivary gland, lung, mediastinum and pleura, breast, kidney, and bladder, as well as myeloid leukemia. Conclusions: Frequent diagnostic radiation exposure and high-dose RAI therapy are independent risk factors for SPM following thyroid cancer. Clinicians need to consider minimizing unnecessary diagnostic radiation exposure and administering a high dose RAI only when justified in patients with thyroid cancer.


Subject(s)
Neoplasms, Second Primary , Thyroid Neoplasms , Cohort Studies , Female , Humans , Incidence , Iodine Radioisotopes/therapeutic use , Male , Neoplasms, Second Primary/chemically induced , Neoplasms, Second Primary/etiology , Risk Factors , Thyroid Neoplasms/drug therapy
3.
Endocrinol Metab (Seoul) ; 36(3): 514-524, 2021 06.
Article in English | MEDLINE | ID: mdl-34154310

ABSTRACT

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the parafollicular cells. The diagnostic and therapeutic strategies for the condition are different from those used for well-differentiated thyroid cancer. Since the 2015 American Thyroid Association guidelines for the diagnosis and treatment of MTC, the latest, including the National Comprehensive Cancer Network and European Association for Medical Oncology guidelines have been updated to reflect several recent advances in the management of MTC. Advances in molecular diagnosis and postoperative risk stratification systems have led to individualized treatment and follow-up strategies. Multi-kinase inhibitors, such as vandetanib and cabozantinib, can prolong disease progression-free survival with favorable adverse effects. In addition, potent selective rearranged during transfection (RET) inhibitors (selpercatinib and pralsetinib) have shown a promising efficacy in recent clinical trials. This review summarizes the management of MTC in recent guidelines focused on sporadic MTC.


Subject(s)
Carcinoma, Neuroendocrine , Thyroid Neoplasms , Carcinoma, Neuroendocrine/diagnosis , Carcinoma, Neuroendocrine/drug therapy , Humans , Protein Kinase Inhibitors/therapeutic use , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/drug therapy
4.
Thyroid ; 29(12): 1804-1810, 2019 12.
Article in English | MEDLINE | ID: mdl-31592739

ABSTRACT

Background: Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events. Methods: This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group. Results: The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31-0.99], p = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00-1.03], p = 0.049). Best tumor response was not associated with OS (p = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15-0.53], p < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group. Conclusions: The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.


Subject(s)
Antineoplastic Agents/therapeutic use , Phenylurea Compounds/therapeutic use , Quinolines/therapeutic use , Sorafenib/therapeutic use , Thyroid Neoplasms/therapy , Aged , Cohort Studies , Female , Humans , Iodine Radioisotopes/therapeutic use , Kaplan-Meier Estimate , Male , Middle Aged , Progression-Free Survival , Republic of Korea , Retrospective Studies , Salvage Therapy , Survival Analysis , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/radiotherapy , Treatment Outcome
5.
Physiol Behav ; 210: 112624, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31325512

ABSTRACT

Pyrus ussuriensis Maxim. commonly known as "Sandolbae" in Korean is a pear tree widely distributed across East Asia. Recent studies indicate that P. ussuriensis Maxim. leaves (PUL) have antipruritic effects. This study aimed to determine the effects of PUL extract and its fractions in decreasing the itch sensation and skin lesions in two distinct animal models of atopic dermatitis (AD) induced by dinitrofluorobenzene (DNFB) or house dust mite (HDM). Our results showed that the total ethanol extract of PUL decreased the scratching behavior in mice with DNFB- and HDM-induced AD. Moreover, the ethyl acetate fraction of PUL significantly improved the overall condition of the mice with AD induced by HDM. Further, we used HEK293T cells that express receptors and ion channels for thymic stromal lymphopoietin (TSLP), a potent pruritogen for AD, to determine the mechanisms underlying the antipruritic effects of PUL extract/fractions. Specific subfractions of the PUL strongly inhibited the increase in calcium levels induced by TSLP. In addition, the specific subfraction of PUL inhibited the TSLP-induced increase in calcium levels in cultured mouse dorsal root ganglia neurons. Thus, our results showed that the PUL extract could be effective for alleviating pruritus, and the antipruritic effects were exerted probably via the inhibition of the TSLP pathway in peripheral sensory neurons governing the itch sensation in AD.


Subject(s)
Antipruritics/therapeutic use , Cytokines/drug effects , Dermatitis, Atopic/drug therapy , Plant Extracts/therapeutic use , Pruritus/drug therapy , Pyrus/chemistry , Animals , Antipruritics/pharmacology , Calcium Signaling/drug effects , Cytokines/genetics , Dermatitis, Atopic/genetics , Dinitrofluorobenzene , Ethanol , Ganglia, Spinal/drug effects , HEK293 Cells , Humans , Male , Mice , Mice, Inbred ICR , Neurons/drug effects , Plant Extracts/pharmacology , Pruritus/chemically induced , Pyroglyphidae/immunology , Solvents , Thymic Stromal Lymphopoietin
6.
Cancers (Basel) ; 11(2)2019 Feb 15.
Article in English | MEDLINE | ID: mdl-30781391

ABSTRACT

To evaluate the role of risk-adapted proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients, a total of 243 HCC patients receiving risk-adapted PBT with three dose-fractionation regimens (regimen A [n = 40], B [n = 60], and C [n = 143]) according to the proximity of their gastrointestinal organs (<1 cm, 1⁻1.9 cm, and ≥2 cm, respectively) were reviewed: The prescribed doses to planning target volume 1 (PTV1) were 50 gray equivalents (GyE) (EQD2 [equivalent dose in 2 Gy fractions], 62.5 GyE10), 60 GyE (EQD2, 80 GyE10), and 66 GyE (EQD2, 91.3 GyE10) in 10 fractions, respectively, and those of PTV2 were 30 GyE (EQD2, 32.5 GyE10) in 10 fractions. In all patients, the five-year local recurrence-free survival (LRFS) and overall survival (OS) rates were 87.5% and 48.1%, respectively, with grade ≥3 toxicity of 0.4%. In regimens A, B, and C, the five-year LRFS and OS rates were 54.6%, 94.7%, and 92.4% (p < 0.001), and 16.7%, 39.2%, and 67.9% (p < 0.001), respectively. The five-year OS rates of the patients with the Modified Union for International Cancer Control (mUICC) stages I, II, III, and IVA and Barcelona Clinic Liver Cancer (BCLC) stages A, B, and C were 69.2%, 65.4%, 43.8%, and 26.6% (p < 0.001), respectively, and 65.1%, 40%, and 32.2% (p < 0.001), respectively. PBT could achieve promising long-term tumor control and have a potential role as a complementary or alternative therapeutic option across all stages of HCC.

7.
Gut Liver ; 13(3): 342-348, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30600675

ABSTRACT

Background/Aims: Sorafenib remains the only approved molecular targeted agent for hepatocellular carcinoma (HCC); however, reliable biomarkers that predict its efficacy are still lacking. The aim of this study was to explore whether cancer stem cell (CSC) markers have a predictive role with regard to the sorafenib response in HCC patients. Methods: We enrolled 47 patients with HCC for whom tumor samples obtained before starting sorafenib treatment were available. RNA was extracted from formalin-fixed, paraffin-embedded samples, and real-time polymerase chain reaction was used to quantify mRNA expression of the CSC genes EpCAM, CD13, CK8, CD24, CD44, CD90, CD133, SALL4, ALDH1A1, ALB, and AFP . Results: Of 47 patients, 14.9% and 74.5% had vascular invasion and extrahepatic spread, respectively. Patients with low CD133 expression tended to have longer progression-free survival (PFS) than those with high CD133 expression (5.5 months vs 4.0 months), although without statistical significance. The expression levels of other markers were not associated with PFS. When examining markers in combination, patients with high CD133 and CD90 expression had shorter PFS rates than those with low expression (2.7 months vs 5.5 months; p=0.04). Patients with low CD133 and EpCAM expression demonstrated better PFS than those with high expression (7.0 months vs 4.2 months; p=0.04). Multivariable analysis indicated that an Eastern Cooperative Oncology Group performance status score of 1 and high CD133/CD90 expression were significantly associated with shorter PFS. Conclusions: Overexpression of the CSC markers CD133 and CD90 in HCC was associated with poorer response to sorafenib. These two genes may serve as predictive biomarkers for sorafenib therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Neoplastic Stem Cells/metabolism , Sorafenib/therapeutic use , Adult , Aged , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Female , Humans , Liver Neoplasms/genetics , Male , Middle Aged , Pharmacogenomic Testing , RNA, Messenger/metabolism , Treatment Outcome
8.
J Hepatol ; 70(4): 684-691, 2019 04.
Article in English | MEDLINE | ID: mdl-30529387

ABSTRACT

BACKGROUND & AIMS: Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC. METHODS: In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, n = 169) or in combination with cTACE on demand (Arm C, n = 170). Sorafenib was started within 3 days and cTACE within 7-21 days of randomization. The primary endpoint was overall survival (OS). RESULTS: For Arms C and S, the median OS was 12.8 vs. 10.8 months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; p = 0.290); median time to progression, 5.3 vs. 3.5 months (HR 0.67; 90% CI 0.53-0.85; p = 0.003); median progression-free survival, 5.2 vs. 3.6 months (HR 0.73; 90% CI 0.59-0.91; p = 0.01); and tumor response rate, 60.6% vs. 47.3% (p = 0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (p = 0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8 months; HR 0.58; 95% CI 0.40-0.82; p = 0.006). CONCLUSION: Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC. LAY SUMMARY: For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Chemoembolization, Therapeutic/methods , Liver Neoplasms/drug therapy , Sorafenib/therapeutic use , Aged , Alanine Transaminase/blood , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Ascites/etiology , Chemoembolization, Therapeutic/adverse effects , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Hyperbilirubinemia/etiology , Male , Middle Aged , Progression-Free Survival , Sorafenib/administration & dosage , Sorafenib/adverse effects , Thrombocytopenia/etiology
10.
Article in English | MEDLINE | ID: mdl-30224929

ABSTRACT

INTRODUCTION: The study was to see whether there were differences in values of facial surface electromyography in subjects of good heath by muscles, age, and sex. METHODS: It draws ratio between lower value and higher value (R-LV/HV) and asymmetry index (AI), based on root mean square (RMS) from measurement of facial surface electromyography (sEMG) in 154 people of healthy people (male:female = 70:84) aging between more than 20 and less than 70. RESULTS: For R-LV/HV, it averages 81.70±14.60% on frontalis muscle, 73.74±19.12% on zygomaticus muscle, and 79.72±14.77% on orbicularis oris muscle. With analysis of the AI average was 10.87±10.14% on frontalis muscle, 16.71±14.79% on zygomaticus muscle, and 12.10±10.05% on orbicularis oris muscle. Both values were statistically significant in three parts of muscles as shown. Both of R-LV/HV and AI show no statistically significant difference on age and sex (p>0.05). CONCLUSIONS: It could provide basic data for the future diagnosis of facial nerve palsy patients by measuring facial sEMG values for healthy people.

11.
Thyroid ; 28(3): 340-348, 2018 03.
Article in English | MEDLINE | ID: mdl-29350109

ABSTRACT

BACKGROUND: Sorafenib, a multi-kinase inhibitor, is approved for the treatment of patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). This study evaluated the efficacy and safety of sorafenib in real-world clinical practice and compared the results to those of the DECISION trial. The clinical features associated with better clinical outcomes after sorafenib treatment were also evaluated. METHODS: This multicenter, retrospective cohort study evaluated 98 patients with progressive RAI-refractory DTC who were treated with sorafenib in six tertiary hospitals in Korea. The primary objective was the progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors v1.1. Overall survival, response rate (defined as the best objective response according to Response Evaluation Criteria In Solid Tumors v1.1), and safety were also evaluated. RESULTS: The median PFS was 9.7 months; median overall survival was not reached during follow-up. Partial responses and stable disease were achieved in 25 (25%) and 64 (65%) patients, respectively. Stable disease of >6 months was achieved in 41 (42%) patients. Subgroup analyses identified several prognostic indicators of a better PFS: absence of disease-related symptoms (hazard ratio [HR] = 0.5; p = 0.041), lung-only metastasis (HR = 0.4; p = 0.048), a daily maintenance dose ≥600 mg (HR = 0.3; p = 0.005), and a thyroglobulin reduction ≥60% (HR = 0.4; p = 0.012). The mean daily dose of sorafenib was 666 ± 114 mg, and drug withdrawals due to adverse events (AEs) occurred in 13% of patients. AEs and serious AEs were reported in 93 (95%) and 40 (41%) patients, respectively. The most frequent AE was hand-foot skin reaction (76%). CONCLUSIONS: The PFS of progressive RAI-refractory DTC patients treated with sorafenib was consistent with the findings of the DECISION trial. Disease-related symptoms, lung-only metastasis, a daily maintenance dose, and thyroglobulin reduction were significantly associated with PFS. These results suggest that sorafenib is an effective treatment option for patients with progressive RAI-refractory DTC.


Subject(s)
Antineoplastic Agents/therapeutic use , Sorafenib/therapeutic use , Thyroid Neoplasms/drug therapy , Aged , Female , Humans , Male , Middle Aged , Progression-Free Survival , Republic of Korea , Retrospective Studies , Survival Analysis , Survival Rate , Tertiary Healthcare , Thyroid Neoplasms/mortality , Thyroid Neoplasms/pathology , Treatment Outcome
12.
Oncotarget ; 6(18): 16449-60, 2015 Jun 30.
Article in English | MEDLINE | ID: mdl-25965825

ABSTRACT

Reliable biomarkers are required to predict the response to sorafenib. We investigated genomic variations associated with responsiveness to sorafenib for patients with unresectable hepatocellular carcinoma (HCC). Blood samples from 2 extreme, 2 strong and 3 poor responders to sorafenib were subjected to whole-genome analysis. Then, we validated candidate genomic variations with another 174 HCC patients, and performed in vitro functional analysis and in silico analyses. Genomic data of >96 gigabases/sample was generated at average of ~34X sequencing depth. In total, 1813 genomic variations were matched to sorafenib responses in clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes. From them, 36 variants were within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2). Validation genotyping confirmed sequencing results and revealed patients genotype for rs2257212 in SLC15A2 showed longer progression-free survival (HR = 2.18). In vitro study displayed different response to sorafenib depending on the genotype of SLC15A2. Structural prediction analysis revealed changes of the phosphorylation levels in protein, potentially affecting sorafenib-associated enzymatic activity. Our finding using extreme responder seems to generate robust biomarker to predict the response of sorafenib treatment for HCC.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm/genetics , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Symporters/genetics , Aged , Antineoplastic Agents/therapeutic use , Base Sequence , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Disease-Free Survival , Female , Genome, Human/genetics , Genotype , Humans , Liver Neoplasms/genetics , Male , Middle Aged , Niacinamide/therapeutic use , Polymorphism, Single Nucleotide/genetics , Sequence Analysis, DNA , Sorafenib , Treatment Outcome
13.
ACS Nano ; 8(1): 650-6, 2014 Jan 28.
Article in English | MEDLINE | ID: mdl-24350996

ABSTRACT

Graphene offers great promise to complement the inherent limitations of silicon electronics. To date, considerable research efforts have been devoted to complementary p- and n-type doping of graphene as a fundamental requirement for graphene-based electronics. Unfortunately, previous efforts suffer from undesired defect formation, poor controllability of doping level, and subtle environmental sensitivity. Here we present that graphene can be complementary p- and n-doped by simple polymer coating with different dipolar characteristics. Significantly, spontaneous vertical ordering of dipolar pyridine side groups of poly(4-vinylpyridine) at graphene surface can stabilize n-type doping at room-temperature ambient condition. The dipole field also enhances and balances the charge mobility by screening the impurity charge effect from the bottom substrate. We successfully demonstrate ambient stable inverters by integrating p- and n-type graphene transistors, which demonstrated clear voltage inversion with a gain of 0.17 at a 3.3 V input voltage. This straightforward polymer doping offers diverse opportunities for graphene-based electronics, including logic circuits, particularly in mechanically flexible form.

14.
J Gastroenterol Hepatol ; 28(12): 1859-68, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23808824

ABSTRACT

BACKGROUND AND AIM: Liver fibrosis is associated with the deposition of the extracellular matrix, and hepatic stellate cells (HSCs) are the major source of these matrix proteins. Guggulsterone has recently been shown to induce apoptosis in several cell lines. Thus, the aim of this study was to evaluate whether guggulsterone has antifibrotic activities by reducing the activation and survival of HSCs. METHODS: Apoptotic and fibrosis-related signaling pathways and nuclear factor kappa B (NF-κB) activity were explored in LX-2 cells, an immortalized human HSC line, and in a mice model of liver fibrosis. RESULTS: Guggulsterone suppressed LX-2 cell growth in a dose- and activation-dependent manner. This growth suppression was due to the induction of HSC apoptosis, which was mediated by the activation of c-Jun N-terminal kinase and mitochondrial apoptotic signaling. Additionally, guggulsterone regulated phosphorylation of Akt and adenosine monophosphate-activated protein kinase, which were subsequently proven responsible for the guggulsterone-induced HSC growth suppression. Guggulsterone inhibited NF-κB activation in LX-2 cells, which is one of the major mediators in HSC activation. Indeed, guggulsterone decreased collagen α1 synthesis and α-smooth muscle actin expression in these cells. Compared with the control mice or mice treated with a low dose of guggulsterone, high dose of guggulsterone significantly decreased the extent of collagen deposition and the percentage of activated HSCs undergoing apoptosis. CONCLUSIONS: These results demonstrate that guggulsterone suppressed HSC activation and survival by inhibiting NF-κB activation and inducing apoptosis. Therefore, guggulsterone may be useful as an antifibrotic agent in chronic liver diseases.


Subject(s)
Apoptosis/drug effects , Hepatic Stellate Cells/drug effects , NF-kappa B/antagonists & inhibitors , Pregnenediones/pharmacology , AMP-Activated Protein Kinases/metabolism , Actins/metabolism , Animals , Cell Survival/drug effects , Cells, Cultured , Collagen/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Enzyme Activation/drug effects , Hepatic Stellate Cells/metabolism , Humans , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/pathology , Liver Cirrhosis, Experimental/prevention & control , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Male , Mice , Mice, Inbred BALB C , Microscopy, Fluorescence , NF-kappa B/metabolism , PTEN Phosphohydrolase/physiology , Pregnenediones/administration & dosage , Pregnenediones/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Thioacetamide
15.
Nucl Med Mol Imaging ; 47(4): 268-72, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24900123

ABSTRACT

PURPOSE: Remnant thyroid ablation and 1-year stimulated thyroglobulin (sTg) measurement are recommended for those who have undergone total thyroidectomy for differentiated thyroid cancer. The serum Tg kinetics in such patients are still unclear. This study was designed to evaluate whether the periablative change in serum markers can predict biochemical remission in papillary thyroid cancer (PTC) patients. METHODS: We reviewed the medical records of 185 patients who were given high-dose radioactive iodine ablation therapy from January 2006 to December 2008. Serum Tg, TSH, and anti-Tg antibody (TgAb) were measured on the day and the following 10th day of radioactive iodine administration. We defined preablative sTg as Tg-1, postablative Tg measured on the 10th day of ablation as Tg-2, and the 1-year sTg as Tg-3. ΔTg means Tg2-Tg1. The same definition was applied to TgAb. RESULTS: A biochemical remission defined as Tg-3 < 2 ng/ml was achieved in 144 patients. Among the patients who achieved biochemical remission, PTC recurred in six during a median follow-up of 54 months. Tg-1 < 3.3 ng/ml (p < 0.0001) predicted biochemical remission. Neither the ΔTg nor ΔTgAb was useful for predicting biochemical remission. On the evaluation of recurrence after biochemical remission, Tg-1 > 5.32 (p < 0.0001) and Tg-3 > 2.9 (p = 0.01) were proven to be statistically significant cutoff values for predicting recurrence. The ΔTg and ΔTgAb were not able to predict recurrence. CONCLUSION: For the prediction of biochemical remission or recurrence after biochemical remission, preablative sTg was demonstrated to be a statistically significant serum marker. However, short-term changes in biochemical markers including Tg and TgAb around the day of ablation could not provide useful clinical information about biochemical remission or disease recurrence. In conclusion, 1-year sTg measurement cannot be omitted with short-term change.

16.
Carcinogenesis ; 32(6): 921-8, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21317303

ABSTRACT

Epidemiological studies suggest that coffee consumption reduces the risk of cancers, including colon cancer, but the molecular mechanisms and target(s) underlying the chemopreventive effects of coffee and its active ingredient(s) remain unknown. Based on serving size or daily units, coffee contains larger amounts of phenolic phytochemicals than tea or red wine. Coffee or chlorogenic acid inhibited CT-26 colon cancer cell-induced lung metastasis by blocking phosphorylation of ERKs. Coffee or caffeic acid (CaA) strongly suppressed mitogen-activated MEK1 and TOPK activities and bound directly to either MEK1 or TOPK in an ATP-noncompetitive manner. Coffee or CaA, but not caffeine, inhibited ERKs phosphorylation, AP-1 and NF-κB transactivation and subsequently inhibited TPA-, EGF- and H-Ras-induced neoplastic transformation of JB6 P+ cells. Coffee consumption was also associated with a significant attenuation of ERKs phosphorylation in colon cancer patients. These results suggest that coffee and CaA target MEK1 and TOPK to suppress colon cancer metastasis and neoplastic cell transformation.


Subject(s)
Adenocarcinoma/prevention & control , Coffee , Colonic Neoplasms/prevention & control , Lung Neoplasms/prevention & control , Mitogen-Activated Protein Kinase Kinases/metabolism , Phenols/therapeutic use , Protein Serine-Threonine Kinases/metabolism , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Blotting, Western , Cell Adhesion/drug effects , Cell Transformation, Neoplastic/drug effects , Chlorogenic Acid/therapeutic use , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Humans , Immunoenzyme Techniques , Luciferases/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Mitogen-Activated Protein Kinase Kinases/chemistry , Models, Molecular , Prospective Studies , Xenograft Model Antitumor Assays
17.
Bioresour Technol ; 102(3): 3639-41, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21144741

ABSTRACT

This paper shows energy-efficiency of microwave-accelerated esterification of free fatty acid with a heterogeneous catalyst by net microwave power measurement. In the reaction condition of 5 wt% sulfated zirconia and 1:20 M ratio of oil to methanol at 60°C and atmospheric pressure, more than 90% conversion of the esterification was achieved in 20 min by microwave heating, while it took about 130 min by conventional heating. Electric energy consumption for the microwave heating in this accelerated esterification was only 67% of estimated minimum heat energy demand because of significantly reduced reaction time.


Subject(s)
Fatty Acids, Nonesterified/chemistry , Fatty Acids, Nonesterified/radiation effects , Oleic Acid/chemistry , Oleic Acid/radiation effects , Soybean Oil/chemistry , Soybean Oil/radiation effects , Catalysis , Esterification , Microwaves
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