The targeting of DNA methylation in cancer using DNA hypomethylating drugs has been well known to sensitize cancer cells to chemotherapy and immunotherapy by affecting multiple pathways. Herein, we investigated the combinational effects of DNA hypomethylating drugs and ionizing radiation (IR) in human sarcoma cell lines both in vitro and in vivo. Clonogenic assays were performed to determine the radiosensitizing properties of two DNA hypomethylating drugs on sarcoma cell lines we tested in this study with multiple doses of IR. We analyzed the effects of 5-aza-dC or SGI-110, as DNA hypomethylating drugs, in combination with IR in vitro on the proliferation, apoptosis, caspase-3/7 activity, migration/invasion, and Western blotting using apoptosis- or autophagy-related factors. To confirm the combined effect of DNA hypomethylating drugs and IR in our in vitro experiment, we generated the sarcoma cells in nude mouse xenograft models. Here, we found that the combination of DNA hypomethylating drugs and IR improved anticancer effects by inhibiting cell proliferation and by promoting synergistic cell death that is associated with both apoptosis and autophagy in vitro and in vivo. Our data demonstrated that the combination effects of DNA hypomethylating drugs with radiation exhibited greater cellular effects than the use of a single agent treatment, thus suggesting that the combination of DNA hypomethylating drugs and radiation may become a new radiotherapy to improve therapeutic efficacy for cancer treatment.

Background/Aims: Overwhelming evidence suggests that inflammatory bowel disease (IBD) is caused by a complicated interplay between the multiple genes and abnormal epigenetic regulation in response to environmental factors. It is becoming apparent that epigenetic factors are significantly associated with the development of the disease. DNA methylation remains the most studied epigenetic modification, and hypermethylation of gene promoters is associated with gene silencing. Methods: DNA methylation alterations may contribute to the many complex diseases development by regulating the interplay between external and internal environmental factors and gene transcriptional expression. In this study, we used 15 tumor suppressor genes (TSGs), originally identified in colon cancer, to detect promoter methylation in patients with Crohn’s disease (CD). Methylation specific polymerase chain reaction and bisulfite sequencing analyses were performed to assess methylation level of TSGs in CD patients. Results: We found 6 TSGs (sFRP1, sFRP2, sFRP5, TFPI2, Sox17, and GATA4) are robustly hypermethylated in CD patient samples. Bisulfite sequencing analysis confirmed the methylation levels of the sFRP1, sFRP2, sFRP5, TFPI2, Sox17, and GATA4 promoters in the representative CD patient samples. Conclusions In this study, the promoter hypermethylation of the TSGs observed indicates that CD exhibits specific DNA methylation signatures with potential clinical applications for the noninvasive diagnosis of IBD and the prognosis for patients with IBD.

OBJECTIVE: The present study investigated the clinical characteristics of Alzheimer's disease (AD) dementia with low brain amyloid-beta (Aβ-AD) burden comparing with AD dementia with high amyloid-beta burden (Aβ+AD). We also developed a prediction model for the amyloid positivity on ¹¹C-labelled Pittsburgh Compound B (PiB) positron emission tomography (PET) with distinct clinical variables in AD dementia patients. METHODS: Fifty-nine clinically defined AD dementia individuals, who participated in the Korean Brain Aging Study for Early diagnosis and prediction of AD (KBASE) study, were included. All the subjects received comprehensive clinical evaluations and PiB-PET. Based on cerebral PiB retention, all subjects were divided into Aβ+AD (n=47) and Aβ-AD (n=12) subgroups. To develop a prediction model for amyloid positivity, stepwise multiple logistic regression analysis was conducted. RESULTS: When compared to Aβ+AD, Aβ-AD showed older age, later age-at-onset, and lower education. In regard of risk factors for dementia, Aβ-AD had higher frequency of hypertension and diabetes mellitus as well as lower frequency of apolipoprotein E (APOE) ε4 allele. Although there was no between group difference in Clinical Dementia Rating (CDR) or CDR sum-of-boxes scores, mini-mental state examination and constructional recall scores were higher for Aβ-AD than Aβ+AD. The final amyloid positivity prediction model included APOE4 genotype, hypertension, and diabetes mellitus. CONCLUSION: The findings from this study indicated that clinically diagnosed AD dementia may have high possibility of not being pathological AD if they have older age and higher vascular risks, and did not have APOE4 genotype.
Age of Onset ; Aging ; Alleles ; Alzheimer Disease* ; Amyloid* ; Apolipoprotein E4 ; Apolipoproteins ; Brain ; Dementia* ; Diabetes Mellitus ; Early Diagnosis ; Education ; Genotype ; Humans ; Hypertension ; Logistic Models ; Positron-Emission Tomography ; Risk Factors

This study was investigated to know whether pachymic acid (PA), one of the predominant triterpenoids in Poria cocos (Hoelen) has the sedative-hypnotic effects, and underlying mechanisms are mediated via gamma-aminobutyric acid (GABA)-ergic systems. Oral administration of PA markedly suppressed locomotion activity in mice. This compound also prolonged sleeping time, and reduced sleep latency showing synergic effects with muscimol (0.2 mg/kg) in shortening sleep onset and enhancing sleep time induced by pentobarbital, both at the hypnotic (40 mg/kg) and sub-hypnotic (28 mg/kg) doses. Additionally, PA elevated intracellular chloride levels in hypothalamic primary cultured neuronal cells of rats. Moreover, Western blotting quantitative results showed that PA increased the amount of protein level expression of GAD65/67 over a broader range of doses. PA increased alpha- and beta-subunits protein levels, but decreased gamma-subunit protein levels in GABA(A) receptors. The present experiment provides evidence for the hypnotic effects as PA enhanced pentobarbital-induced sleeping behaviors via GABA(A)-ergic mechanisms in rodents. Taken together, it is proposed that PA may be useful for the treatment of sleep disturbed subjects with insomnia.
Administration, Oral ; Animals ; Blotting, Western ; Cocos ; gamma-Aminobutyric Acid ; Hypnotics and Sedatives ; Locomotion ; Mice* ; Muscimol ; Neurons ; Pentobarbital ; Poria ; Rats ; Receptors, GABA-A ; Rodentia ; Sleep Initiation and Maintenance Disorders

OBJECTIVE: Adenomatoid tumors of female genital tracts are benign lesions derived from mesothelium, occurring most commonly during the reproductive years. The aim of this study was to evaluate the overall incidence of adenomatoid tumors in Korean women and to analyze the clinical characteristics. METHODS: One hundred and ninety five patients with adenomatoid tumors were found in a retrospective medical records review of pathologic reports for 44,984 benign uterine diseases at Cheil General Hospital, from January 1995 to April 2009. RESULTS: The overall incidence rate was 0.42% of all benign uterine disease. Among them, 149 patients received hysterectomy, and 46 patients received uterine conservative surgery. Main symptoms of the patients were pain (25.1%), bleeding (30.2%), and palpable mass (18.5%). Most common associated pathologies were leiomyoma (46.6%), adenomyosis (25.1%) and endometriosis (13.1%). Most of the diagnosis was made postoperatively. Among 46 patients with conservative treatment, 13 patients showed successful pregnancy outcome. No recurrence occurred during the follow up period. CONCLUSION: Adenomatoid tumors are associated with fibroids and tend to mimic them clinically, making pre-operative diagnosis difficult. The recurrence is rare even after conservative operation. Our data about this benign neoplasm may be helpful for counseling patients after operations.
Adenomatoid Tumor ; Adenomyosis ; Counseling ; Endometriosis ; Epithelium ; Female ; Follow-Up Studies ; Hemorrhage ; Hospitals, General ; Humans ; Hydrazines ; Hysterectomy ; Incidence ; Leiomyoma ; Medical Records ; Mesothelioma ; Pregnancy ; Pregnancy Outcome ; Recurrence ; Retrospective Studies ; Uterine Diseases

BACKGROUND: An inflammatory mechanism has been suggested to contribute to the progression of diabetic nephropathy. Although retinoid, a known anti-inflammatory agent, has been reported to be beneficial in some experimental renal diseases, it has not been shown whether it prevents disease progression in diabetic nephropathy. Therefore, we investigated whether all-trans retinoic acid inhibits inflammatory changes and improves renal function during the early stages of diabetic nephropathy in streptozotocin-induced diabetic rats. METHODS: We evaluated anti-inflammatory effect of retinoid on streptozotocin-induced diabetic nephropathy. Anti-inflammatory effect was determined by the expression of monocyte chemoattractant peptide-1 (MCP-1). RESULTS: Urinary protein excretion was significantly higher in diabetic rats at four weeks after the induction of diabetes mellitus compared with controls, and proteinuria in the group with retinoic acid treatment was decreased (1.25+/-0.69 vs. 0.78+/-0.72 mg/mg Cr, p=0.056). Urinary excretion of MCP-1 was rapidly increased at two days after induction of diabetes mellitus in diabetic rats, and further increased until four weeks of age compared with control rats. Retinoic acid treatment suppressed to 30% reduction of the urinary level of MCP-1 compared with vehicle treated diabetic rats (119.3+/-74.2 vs. 78.1+/-62.7 pg/mg Cr, p=0.078). Immunohistochemistry revealed a significant increase in staining for MCP-1 protein in the diabetic kidney, and retinoic acid treatment significantly suppressed intrarenal MCP-1 protein synthesis. CONCLUSION: Retinoic acid suppressed proteinuria and inflammatory changes in diabetic rats. These results suggest that retinoic acid may have an anti- inflammatory effect in diabetic nephropathy.
Animals ; Diabetes Mellitus ; Diabetic Nephropathies* ; Disease Progression ; Immunohistochemistry ; Inflammation ; Kidney ; Monocytes ; Proteinuria ; Rats ; Tretinoin

Multifetal gestations are high-risk pregnancies involving higher perinatal morbidity and mortality, and are subject to unique complications including twin oligohydramnios-polyhydramnios sequence, twin-to-twin transfusion syndrome, acardiac twins, conjoined twins, co-twin demise, and heterotopic pregnancies. The purpose of this study is to describe the prenatal ultrasonographic and pathologic findings of these complications.

Congenital myotonic dystrophy is a severe and early-onset form of myotonic dystrophy (DM) with a prevalence of 2.5-5.5/100,000 live births. Expansion of the trinucleotide CTG repeat in the 3 untranslated region of the DM gene, which is located at a chromosome 19q13.3 is a common mutation in DM. Clinical features are generalized hypotonia (floppy infant), respiratory and feeding difficulty, and the neonatal mortality rate is approximately 40%. We experienced a case of recurrent congenital myotonic dystrophy, and report with a review of related literatures. Women with recurrent neonatal hypotonia or ultrasonographic evidence of hypotonia, including positional abnormalities of the extremities and idiopathic polyhydramnios, should be offered testing for the genetic studies for myotonic mutation, such as PCR (Polymerase chain reaction) analysis and Southern blot analysis.
Blotting, Southern ; Diagnosis* ; Extremities ; Female ; Humans ; Infant ; Infant Mortality ; Live Birth ; Muscle Hypotonia ; Myotonic Dystrophy* ; Polyhydramnios ; Polymerase Chain Reaction ; Prenatal Diagnosis ; Prevalence ; Untranslated Regions

Congenital myotonic dystrophy is a severe and early-onset form of myotonic dystrophy (DM) with a prevalence of 2.5-5.5/100,000 live births. Expansion of the trinucleotide CTG repeat in the 3 untranslated region of the DM gene, which is located at a chromosome 19q13.3 is a common mutation in DM. Clinical features are generalized hypotonia (floppy infant), respiratory and feeding difficulty, and the neonatal mortality rate is approximately 40%. We experienced a case of recurrent congenital myotonic dystrophy, and report with a review of related literatures. Women with recurrent neonatal hypotonia or ultrasonographic evidence of hypotonia, including positional abnormalities of the extremities and idiopathic polyhydramnios, should be offered testing for the genetic studies for myotonic mutation, such as PCR (Polymerase chain reaction) analysis and Southern blot analysis.
Blotting, Southern ; Diagnosis* ; Extremities ; Female ; Humans ; Infant ; Infant Mortality ; Live Birth ; Muscle Hypotonia ; Myotonic Dystrophy* ; Polyhydramnios ; Polymerase Chain Reaction ; Prenatal Diagnosis ; Prevalence ; Untranslated Regions

Mutation of the p53 gene is one of the most common genetic alterations in invasive breast carcinoma. However, it is unclear that the mutation usually occurs in noninvasive breast lesions. It might be expected that there is a correlation between histologic progression of breast lesions and proliferative rate. We investigated the expression of p53 protein and Ki-67 labelling index (LI) using immunohistochemistry in 16 ductal carcinoma in situ with microinvasion (DCIS-Mi), 56 DCIS, 15 atypical ductal hyperplasia (ADH), and 7 intraductal hyperplasia (IDH). Expression of p53 protein was detected in 33.9% of DCIS and 56.3% of DCIS-Mi and was confined exclusively in Van Nuys DCIS group 2 and 3. In ADH and IDH, no expression of p53 protein was found. There was no significant correlation between Van Nuys DCIS groups and Ki-67 LI. In conclusion, p53 mutation may be involved in the neoplastic progression from ADH to DCIS and is directly related to high nuclear grade and associated necrosis of DCIS.
Breast Neoplasms ; Breast* ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating* ; Genes, p53 ; Hyperplasia* ; Immunohistochemistry ; Necrosis