Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

BACKGROUND: Iodine is an intrinsic element of thyroid hormone, which is essential for childhood growth and development. The Ideal Breast Milk (IBM) cohort study aims to evaluate the effects of maternal iodine status during pregnancy and lactation on maternal thyroid function, offspring growth and development, and offspring thyroid function. METHODS: The IBM cohort study recruited pregnant women from Seoul National University Hospital between June 2016 and August 2017, followed by enrollment of their offspring after delivery. For the maternal participants, iodine status is evaluated by urinary iodine concentration (UIC) and dietary records in the third trimester and at 3 to 4 weeks and 12 to 15 months postpartum. For the child participants, cord blood sampling and UIC measurements are performed at birth. At 3 to 4 weeks of age, UIC and breastmilk iodine concentrations are measured. At 12 to 15 months of age, growth and development are assessed and measurements of UIC, a thyroid function test, and ultrasonography are performed. RESULTS: A total of 198 pregnant women in their third trimester were recruited. Their mean age was 35.1±3.5 years, and 78 (39.4%) of them were pregnant with twins. Thirty-three (16.7%) of them had a previous history of thyroid disease. CONCLUSION: Korea is an iodine-replete area. In particular, lactating women in Korea are commonly exposed to excess iodine due to the traditional practice of consuming brown seaweed soup postpartum. The study of the IBM cohort is expected to contribute to developing guidelines for optimal iodine nutrition in pregnant or lactating women.
Breast* ; Child ; Cohort Studies* ; Cordocentesis ; Diet Records ; Female ; Growth and Development* ; Humans ; Infant ; Iodine* ; Korea ; Lactation* ; Milk, Human* ; Parturition ; Postpartum Period ; Pregnancy Trimester, Third ; Pregnancy* ; Pregnant Women ; Prospective Studies* ; Seaweed ; Seoul ; Thyroid Diseases ; Thyroid Function Tests ; Thyroid Gland* ; Twins ; Ultrasonography

BACKGROUND: The role of uric acid in cerebrovascular disease is controversial. Uric acid may be an independent risk factor for cerebrovascular diseases but its neuroprotective role as an antioxidant has also been suggested. We studied the effects of uric acid on the early prognosis in acute ischemic stroke. METHODS: The subjects were 721 patients with moderate-to-severe acute stroke who arrived at hospital within 48 hours from the onset of symptoms. Patients were divided into quartiles based on serum uric acid levels at admission. In-hospital stroke outcome were calculated on the National Institutes of Health Stroke Scale (NIHSS) and analyzed by multivariate logistic regression. RESULTS: Differences in NIHSS scores between baseline and discharge in the patients were not significantly related to serum uric acid levels. However, in large artery atherosclerosis group, the proportion of patients with neurological improvement and differences in NIHSS score between baseline and discharge differed between the quartile uric acid groups (p<0.01 and p=0.04, respectively). A multivariate analysis adjusting for known vascular risk factors showed that a higher uric acid level was associated with a higher probability of a good in-hospital outcome (odds ratio, 1.31 per additional 1 mg/dL; 95% confidence interval, 1.07-1.60 per additional 1 mg/dL), but only in those with large-artery atherosclerosis. CONCLUSIONS: Uric acid level is independently correlated with the neurological improvement in patients with acute ischemic stroke caused by large-artery atherosclerosis.
Arteries ; Atherosclerosis ; Humans ; Hyperuricemia ; Logistic Models ; Multivariate Analysis ; National Institutes of Health (U.S.) ; Prognosis ; Risk Factors ; Stroke ; Uric Acid

BACKGROUNDRecent studies have demonstrated the existence of a small fraction of cells with features of primitive neural progenitor cells and tumor-initiating function in brain tumors. These cells might represent primary therapeutic target for complete eradication of the tumors. This study aimed to determine the resistant phenotype of glioblastoma stem cells (GSCs) to temozolomide (TMZ) and to explore the possible molecular mechanisms underlying TMZ resistance.

METHODSFreshly resected glioblastoma specimen was collected and magnetic isolation of GSCs was carried out using the Miltenyi Biotec CD133 Cell Isolation kit. The cytotoxic effect of TMZ on CD133(+) and CD133(-) glioblastoma cells was determined by using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Autophagy-related proteins (Beclin-1, LC3 and Atg5) and cleaved caspase-3 (p17) were analyzed by Western blotting. Immunofluorescent staining was used to detect Atg5, glial fibrillary acidic protein (GFAP) and CD133 expression in glioblastoma cells. Statistical analysis was carried out using SPSS 10.0 software. For all tests, the level of statistical significance was set at P < 0.05.

RESULTSCD133(+) glioblastoma cells exhibited neurosphere-like growth in vitro and high expression of CD133 stem cell marker. The growth-inhibiting rate in CD133(-) glioblastoma cells treated with 5 or 50 micromol/L TMZ was significantly higher than that in CD133(+) glioblastoma cells ((14.36 +/- 3.75)% vs (2.54 +/- 1.36)% or (25.95 +/- 5.25)% vs (2.72 +/- 1.84)%, respectively, P < 0.05). Atg5, LC3-II and Beclin-1 levels were significantly lower in CD133(+) glioblastoma cells than those in autologous CD133(-) cells after TMZ treatment (P < 0.05). Caspase-3 was mildly activated only in CD133(-) glioblastoma cells after exposure to TMZ (P < 0.05). Immunofluorescent staining revealed elevated expression of Atg5 in GFAP(+) cells following TMZ treatment.

CONCLUSIONSThe GSCs display strong capability of tumor's resistance to TMZ. This resistance is probably contributed by the CD133(+) cells with down-regulation of autophagy-related proteins. Future treatment should target this small population of cancer stem cells in tumors to improve survival of patients.

AC133 Antigen ; Antigens, CD ; metabolism ; Antineoplastic Agents, Alkylating ; therapeutic use ; Apoptosis Regulatory Proteins ; metabolism ; Autophagy-Related Protein 5 ; Beclin-1 ; Blotting, Western ; Caspase 3 ; metabolism ; Cells, Cultured ; Dacarbazine ; analogs & derivatives ; therapeutic use ; Drug Resistance, Neoplasm ; physiology ; Glioblastoma ; drug therapy ; pathology ; Glycoproteins ; metabolism ; Humans ; Immunohistochemistry ; Membrane Proteins ; metabolism ; Microtubule-Associated Proteins ; metabolism ; Peptides ; metabolism

This study was undertaken to investigate age-dependent and postmenopausal changes in the serum levels of anti-Mullerian hormone (AMH), inhibin B, insulin-like growth factor (IGF)-I, IGF-binding protein-3 (IGFBP-3), and follicle-stimulating hormone (FSH), and to determine which of these markers best reflects the aging process in women. A total of 144 women aged 20-59 yr were enrolled in this cross-sectional study. Blood samples were obtained on cycle day 3 of regularly menstruating women (n=111), or at random in postmenopausal women (n=33). Data were analyzed with respect to premenopausal women age groups and compared in pre- and postmenopausal women. Area under the receiver operating characteristic curve (ROCAUC) analyses were performed to assess the ability of each marker to discriminate between the pre- and postmenopausal status. Serum levels of AMH, IGF-I, and IGFBP-3 decreased and serum levels of FSH increased significantly with age in premenopausal women. Serum luteinizing hormone (LH) was higher and inhibin B was lower in women in their 20-30's than in 40's. Serum levels of AMH and IGF-I showed a consistent decrease with all age groups. ROCAUC analysis showed that the diagnostic accuracy of AMH for menopausal status was similar to those of FSH, LH, and inhibin B, and was better than that of IGF-I. In conclusion, the serum AMH level appears to be the best marker of the aging process in premenopausal women.
Adult ; Age Factors ; Anti-Mullerian Hormone/*blood ; Female ; Follicle Stimulating Hormone/*blood ; Humans ; Inhibins/*blood ; Insulin-Like Growth Factor Binding Protein 3/*blood ; Insulin-Like Growth Factor I/*analysis ; Menopause/*blood ; Middle Aged ; ROC Curve

PURPOSE: Although computed tomography (CT) is widely used for diagnosing liver metastasis from colorectal cancer, diagnostic accuracy of CT is not satisfactory. Magnetic resonance (MR) imaging and F-18 FDG PET has been reported to be superior to CT. However, studies on direct comparison of PET and MR are scarce. We compared the diagnostic accuracy of FDG PET and MR in detecting liver metastasis from colorectal cancer. MATERIALS AND METHODS: Among 363 colorectcal cancer patients who underwent F-18 FDG PET (ECAT, Siemens-CTI, Knoxville; Gemini, Philips, Milpitas, U.S.), 26 patients (M:F=17:9, age=62+/-11) underwent MR to evaluate suspicious metastatic liver lesions. Finally, 35 liver lesions detected by CT from 26 patients were enrolled for analysis. PET and MR results were compared with pathologic reports, clinical findings or follow-up results. RESULTS: Of the 35 lesions, 18 lesions (51.4%) were diagnosed as liver metastases, while remaining 17 (48.6%) as benign. The sensitivity and the specificity of PET were 94.4% and 94.1%, respectively, compared to 100% and 82.4% for MR. MR and PET was concordant in 30 lesions (85.7%): 17 metastatic (94.4%) and 13 benign (76.5%) lesions. ROC curve analysis revealed maximal SUV of 3.1 as the optimum standard in differentiating metastatic from benign liver lesions (AUC=0.897, p<0.001, sensitivity 83.3%, specificity 94.1%). For small lesions less than 1cm in diameter (n=20), diagnostic accuracy of PET was comparable to that of MR. CONCLUSION: F-18 FDG PET showed good diagnostic performance in detecting liver metastasis from colorectal cancer, which was comparable to MR.
Colonic Neoplasms ; Colorectal Neoplasms* ; Follow-Up Studies ; Humans ; Liver* ; Neoplasm Metastasis* ; Positron-Emission Tomography ; ROC Curve ; Sensitivity and Specificity

PURPOSE: Incidence of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) is known to be higher than that in general population. However, it is difficult to discriminate pulmonary nodule in patients with IPF, because underlying IPF can be expressed as lung nodules. We evaluated the diagnostic performance of FDG PET in discriminating lung nodule in patients with IPF. METHODS: We retrospectively reviewed 28 lung nodules in 16 subjects (age; 67.53+/-9.83, M:F=14:2). Two patients had previous history of malignant cancer (small cell lung cancer and subglottic cancer). The diagnostic criteria on chest CT were size, morphology and serial changes of size. FDG PET was visually interpreted, and maximal SUV was calculated for quantitative analysis. RESULTS: From 28 nodules, 18 nodules were interpreted as benign nodules, 10 nodules as malignant nodules by histopahthology or follow-up chest CT. The sensitivity and specificity of FDG PET were 100% and 94.4%, while those of CT were 70.0% and 44.4%, respectively. Malignant nodule was higher maxSUV than that of benign lung nodules (7.68+/-3.96 vs. 1.22+/-0.65, p<0.001). Inflammatory lesion in underlying IPF was significantly lower maxSUV than that of malignant nodules (1.80+/-0.43, p<0.001). The size of malignant and benign nodule were 23.95+/-10.15 mm and 10.83+/-5.23 mm (p<0.01). CONCLUSION: FDG PET showed superior diagnostic performance to chest CT in differentiating lung nodules in patients with underlying IPF. FDG PET could be used to evaluate suspicious malignant lung nodule detected by chest in patients with IPF.
Follow-Up Studies ; Humans ; Idiopathic Pulmonary Fibrosis* ; Incidence ; Lung ; Lung Neoplasms ; Retrospective Studies ; Sensitivity and Specificity ; Thorax ; Tomography, X-Ray Computed

A 42 years old woman underwent F-18 FDG PET because of the incidentally detected lung mass on chest X-ray. PET/CT showed hypermetabolic lesion in the lung right upper lobe and the lung cancer was suspected because of the high FDG uptake. However, pathologic diagnosis was sclerosing hemangioma. There are few reports on the evaluation of sclerosing hemangioma using FDG PET. A report showed a slightly increased uptake (standardized uptake ratio of 1.8) (1), and another report showed unsatisfactory result (2). We suggest that sclerosing hemangioma could be seen as hypermetabolic lesion on the FDG PET.
Adult ; Diagnosis ; Female ; Histiocytoma, Benign Fibrous* ; Humans ; Lung ; Lung Neoplasms ; Positron-Emission Tomography and Computed Tomography ; Thorax

PURPOSE: Current evidence of the benefits of early intensive behavioral intervention (EIBI) in children with autism spectrum disorders(ASD) is increasing. In order to get the benefits from EIBI, early identification of ASD is essential but a challenge for clinicians. Therefore, we designed this study to know what differs from other developmental disorders in terms of early developmental patterns and clinical and laboratory characteristics. METHODS: Among 518 children diagnosed developmental delay in Ilsan Hospital Developmental Disorder Clinic from April 2001 to January 2005, we analyzed 122 ASD patients as a study group, and 133 mentally retarded(MR) and 101 specific language impaired(SLI) patients as control groups. We used a questionnaire survey to assess past and family history. We performed various kinds of tools for the evaluation of the development, and cognitive and speech functions according to the patients' age. MRI, SPECT, EEG, genetic and metabolic studies were performed as optional tests. RESULTS: The mean age of ASD was 55.9+/-30.7 months and male was predominant in ASD(male:female ratio was 3.2:1). In early developmental history, motor functions are relatively well preserved in ASD(P<0.05). In speech and social milestones, single word speech was noticeably delayed in all the 3 groups. However, there was no appreciable difference in stranger anxiety among the 3 groups. In the developmental evaluation, speech and social functions were most significantly delayed in ASD(P<0.05). There was a significant motor delay in ASD and MR than SLI(P<0.05). In physical examination, a raised rate of macrocedphaly in ASD was not noted. Abnormal EEG findings were significantly noted in ASD and MR than in SLI and MRI abnormalities were least found in these groups. The etiologic diagnosis was much less identified in ASD than MR. CONCLUSION: In an early stage, absence of stranger anxiety was not statistically significant. However, this seems to be an important risk factor for predicting ASD. Motor functions were relatively well preserved in ASD in an early stage. In the developmental evaluation, social and language areas were the most significantly delayed domains in ASD and motor functions were most delayed in MR. Routine MRI studies are not indicated for identifying the etiology in ASD. It was harder to find out the etiology in ASD than MR.
Anxiety ; Autistic Disorder* ; Child ; Autism Spectrum Disorder* ; Diagnosis ; Electroencephalography ; Humans ; Magnetic Resonance Imaging ; Male ; Physical Examination ; Surveys and Questionnaires ; Risk Factors ; Tomography, Emission-Computed, Single-Photon

PURPOSE: It has been reported that the sodium/iodide symporter (NIS) gene is expressed in several breast cancer tissues, suggesting the possibility of radionuclide imaging and therapy. However, the regulatory mechanism of NIS gene expression in breast cancer is not yet understood. To assess the relationship between the hormonal status and the NIS expression in breast cancer tissue, we investigated the NIS expression and correlated it to the expression of the thyrotropin receptor (thyroid stimulating hormone receptor, TSH-R), the estrogen receptor (ER) and the progesterone receptor (PR) in human breast cancer tissues. MATERIALS AND METHODS: Breast cancer tissues were obtained from 44 patients. Pathological examination showed 2 cases of Grade I, 17 of Grade II, 22 of Grade III, and 3 of unknown grade. We measured the expression of NIS and TSH-R genes by using RT-PCR and we measured the status of ER and PR by using immunohisto-chemistry. RESULTS: The NIS gene was expressed in 15 (34%) of the 44 breast cancer tissues. The NIS gene was expressed in 32% of the cases with TSH-R gene expression. The NIS gene was expressed in 40% of the breast cancer tissues with a positive PR and in 31% with a negative PR (p>0.05). It was positive for PR in 18% of the cases and negative for PR in 39% of the cases (p>0.05). CONCLUSION: The NIS gene is expressed in approximately one-third of the human breast cancer tissues. Its expression was not related to the presence of the TSH-R gene or hormonal receptors, ER and PR.
Breast Neoplasms* ; Breast* ; Estrogens ; Gene Expression ; Humans* ; Ion Transport* ; Radionuclide Imaging ; Receptors, Estrogen ; Receptors, Progesterone ; Receptors, Thyrotropin