Antiphospholipid syndrome (APS) is an acquired systemic autoimmune disorder characterized by a combination of clinical criteria, including vascular thrombosis or pregnancy morbidity and elevated antiphospholipid antibody titers. It is one of the causes of deep vein thrombosis and pulmonary embolism that can be critical due to the mortality risk. Overall recurrence of thromboembolism is very low with adequate anticoagulation prophylaxis. The most effective treatment to prevent recurrent thrombosis is long-term anticoagulation. We report on a 17-year-old male with APS, who manifested blue toe syndrome, deep vein thrombosis, pulmonary thromboembolism, and cerebral infarction despite adequate long-term anticoagulation therapy.
Antiphospholipid Syndrome; Venous Thrombosis; Pulmonary Embolism; Cerebrovascular Disorders; Blue Toe Syndrome
To evaluate clinicobiochemical factors predicting severe hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection.
859 treatment-naïve Korean patients with HCV who underwent liver biopsy. Severe fibrosis was defined as fibrosis stage ≥3 based on the METAVIR system.
Primary outcome measures
Clinicobiochemical factors predicting severe hepatic fibrosis.
The median serum alanine aminotransferase (ALT) level was 68 IU/L and body mass index (BMI) was 24.2 kg/m2. Severe fibrosis was observed in 326 (39.7%) of the 859 patients. The frequencies of severe fibrosis were 0%, 37.8%, 41.9% and 42% in patients with serum ALT concentrations (IU/L) of ≤20, 20–30, 30–40 and >40 (p<0.01), respectively, and 10.7%, 19.8%, 30.5%, 39.2% and 55.6% in patients <30, 30–40, 40–50, 50–60 and ≥60 years old, respectively (p<0.01). Categorised age in years (50–60 (OR 4.26, p=0.03) and ≥60 (OR 7.53, p<0.01) compared with <30), categorised ALT level in IU/L (20–30 (OR 16.76, p<0.01), 30–40 (OR 20.02, p<0.01) and >40 (OR 21.49, p<0.01) compared with ≤20) and BMI >27.5 kg/m2 (OR 1.65, p=0.03) were independently related to severe fibrosis in patients with chronic HCV. The severe fibrosis rate was 60.6% in patients aged ≥50 years with ALT >20 IU/L and BMI >27.5 kg/m2.
More advanced age (≥50 years), obesity and serum ALT>20 IU/L are associated with severe fibrosis in patients with chronic HCV. Anti-HCV therapy may be considered for these patients without histological confirmation, regardless of HCV genotype. A wait-and-see policy may be justified for patients with serum ALT ≤20 IU/L.
The aim of this research was to investigate the association between job loss and the development of stroke or cardiovascular disease among middle-aged to older individuals in Korea. We also examined how this relationship was modified by gender and the nature of the job loss.
This study used samples from the first- to fourth-wave datasets from the Korean Longitudinal Study of Aging (KLoSA), which were collected in 2006, 2008, 2010, and 2012. The study collected data from a total of 10,254 subjects aged ≥45 years at baseline. After applying exclusion criteria, the final sample size for analysis consisted of 4,000 individuals. Information about employment status, development of stroke or cardiovascular disease, and covariates (age, income level, and behavioral factors) was obtained. Cox proportional hazards models were used to evaluate the association between voluntary/involuntary job loss and the development of stroke or cardiovascular disease. We performed these analyses separately according to disease, gender, and the nature of the job loss.
Involuntary job loss significantly increased the risk of stroke or cardiovascular disease among males (adjusted hazard ratio [HR] = 3.560, 95% confidence interval [CI] = 2.055–6.168). Voluntary retirement also increased the risk of cardiovascular disease or stroke among males (adjusted HR = 2.879, 95% CI = 1.533–5.409). Job loss was more closely associated with stroke than with cardiovascular disease (stroke, adjusted HR = 6.208, 95% CI = 2.417–15.943; cardiovascular disease, adjusted HR = 2.768, 95% CI = 1.402–5.465).
Our findings suggest that both voluntary retirement and involuntary job loss increase the risk for stroke or cardiovascular disease in middle-aged to older individuals, especially males.
Exposure to perinatal anxiety affects disease susceptibility in offspring but studies on the association between perinatal anxiety and gene polymorphisms are lacking. This study aimed to elucidate the interaction between perinatal anxiety and polymorphisms in antioxidant defense and innate immunity genes on the development of respiratory tract infections (RTIs) during early infancy.
Trait anxiety levels in 440 women were assessed by the State-Trait Anxiety Inventory during late gestation. The occurrence of RTIs, including bronchiolitis, during the first year of life was assessed by parent-reported doctor diagnosis. Polymorphisms in glutathione S-transferase P-1 (GSTP1, rs1695) and CD14 (rs2569190) were genotyped using the TaqMan assay. Copy number variations of GSTT1 were measured by real-time polymerase chain reaction.
Exposure to high levels of perinatal anxiety increased the risk of bronchiolitis in the first year of life (adjusted odds ratio [aOR], 1.30; 95% confidence interval [CI]: 1.00–1.80), in particular among children with the AG + GG genotype of GSTP1 or the GSTT1 null genotype (aOR 3.36 and 2.79). In infants with the TC + CC genotype of CD14, high levels of perinatal anxiety were associated with an increased risk of upper RTI, lower RTI, and bronchiolitis (aOR 2.51, 4.60, and 4.31, respectively).
Perinatal maternal anxiety levels affect the occurrence of bronchiolitis in offspring. The effect of perinatal anxiety on the occurrence of bronchiolitis during infancy was influenced by genetic polymorphisms in antioxidant defense and innate immunity genes.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-154) contains supplementary material, which is available to authorized users.
Anxiety; Bronchiolitis; CD14; Perinatal; Glutathione S-transferase; Polymorphism; Respiratory tract infection
Cell migration is an important step in pulpal wound healing. Although components in the resin-based dental materials are known to have adverse effects on pulp wound healing including proliferation and mineralization, their effects on cell migration have been scarcely examined. Here, we investigated effects of 2-Hydroxyethyl methacrylate (HEMA) on migration of dental pulp stem cells (DPSC) in vitro.
Cell viability was assessed using MTT assay, and cell migration was evaluated using wound scratch assay and transwell migration assay at non-cytotoxic doses. Western blotting was used to examine pathways associated with migration such as focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and glycogen synthase kinase 3 (GSK3).
There were no drastic changes in the cell viability below 3mM HEMA. When DPSC were treated with HEMA at 0.5, 1.0, and 2.5mM, cell migration was diminished. HEMA-treated DPSC exhibited the loss of phosphorylated focal adhesion kinase (FAK) in a dose-dependent manner. The HEMA-mediated inhibition of cell migration was associated with phosphorylation of p38 but not GSK3, ERK or JNK pathways. When we inhibited the p38 signaling pathway using a p38 inhibitor, migration of DPSC was suppressed.
HEMA inhibits migration of dental pulp cells in vitro, suggesting that poor pulpal wound healing under resin-based dental materials may be due, in part, to inhibition of cell migration by HEMA.
HEMA; dental pulp stem cells; migration; pulpal wound healing; p38
Methyl jasmonate (MeJA) spray treatments were applied to the kale varieties ‘Dwarf Blue Curled Vates’ and ‘Red Winter’ in replicated field plantings in 2010 and 2011 to investigate alteration of glucosinolate (GS) composition in harvested leaf tissue. Aqueous solutions of 250 µM MeJA were sprayed to saturation on aerial plant tissues four days prior to harvest at commercial maturity. The MeJA treatment significantly increased gluconasturtiin (56%), glucobrassicin (98%), and neoglucobrassicin (150%) concentrations in the apical leaf tissue of these genotypes over two seasons. Induction of quinone reductase (QR) activity, a biomarker for anti-carcinogenesis, was significantly increased by the extracts from the leaf tissue of these two cultivars. Extracts of apical leaf tissues had greater MeJA mediated increases in phenolics, glucosinolate concentrations, GS hydrolysis products, and QR activity than extracts from basal leaf tissue samples. The concentration of the hydrolysis product of glucoraphanin, sulforphane was significantly increased in apical leaf tissue of the cultivar ‘Red Winter’ in both 2010 and 2011. There was interaction between exogenous MeJA treatment and environmental conditions to induce endogenous JA. Correlation analysis revealed that indole-3-carbanol (I3C) generated from the hydrolysis of glucobrassicin significantly correlated with QR activity (r = 0.800, P<0.001). Concentrations required to double the specific QR activity (CD values) of I3C was calculated at 230 µM, which is considerably weaker at induction than other isothiocyanates like sulforphane. To confirm relationships between GS hydrolysis products and QR activity, a range of concentrations of MeJA sprays were applied to kale leaf tissues of both cultivars in 2011. Correlation analysis of these results indicated that sulforaphane, NI3C, neoascorbigen, I3C, and diindolylmethane were all significantly correlated with QR activity. Thus, increased QR activity may be due to combined increases in phenolics (quercetin and kaempferol) and GS hydrolysis product concentrations rather than by individual products alone.
Bisphosphonates (BPs) are anti-resorptive agents commonly used to treat bone-related diseases; however, soft tissue-related side-effects are frequently reported in some BP users, such as oral or gastrointestinal (GI) ulcerations. BPs are stable analogs of pyrophosphate and have high affinity to hydroxyapatite, allowing them to bind to the bone surfaces and exert suppressive effects on osteoclast functions. However, the underlying mechanisms as to how bone-seeking BPs also exert cytotoxic effects on soft tissue remain unknown. In the present study, we investigated the localization of nitrogen-containing BPs (N-BPs) in hard and soft tissue using fluorescently-labeled N-BPs in vitro. We developed osteomucosal tissue constructs in vitro to recapitulate the hard and soft tissue of the oral cavity. A histological examination of the osteomucosal tissue constructs revealed a differentiated epithelium over the bone containing osteocytes and the periosteum, similar to that observed in the rat palatal tissues. Following treatment with the fluorescently-labeled bisphosphonate, AF647-ZOL, the osteomucosal constructs exhibited fluorescent signals, not only in the bone, but also in the epithelium. No fluorescent signals were observed from the control- or ZOL-treated constructs, as expected. Collectively, the data from the present study suggest that N-BPs localize to epithelial tissue and that such a localization and subsequent toxicity of N-BPs may be associated, at least in part, with soft tissue-related side-effects.
osteomucosal tissue constructs; soft tissue; hard tissue; bisphosphonates; osteonecrosis of the jaw; ulceration; toxicity
There are few available data regarding the association between the single nucleotide polymorphisms (SNPs) of the gene encoding interleukin 28B (IL28B) and a sustained virologic response (SVR) to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy in Korean chronic hepatitis C patients.
This was a retrospective cohort study of 156 patients with chronic hepatitis C virus (HCV) infection who received combination treatment of PEG-IFN plus RBV. Blood samples from these patients were analyzed to identify the IL28B SNPs at rs12979860, rs12980275, rs8099917, and rs8103142. Association analyses were performed to evaluate the relationships between each IL28B SNP and SVRs.
Seventy six patients with HCV genotype 1 and 80 with genotype non-1 were enrolled. The frequencies of rs12979860 CC and CT genotypes were 90.4% and 9.6%, respectively; those of rs12980275 AA and AG genotypes were 87.2% and 12.8%, respectively; those of rs8099917 TT and TG genotypes were 92.3% and 7.7%, respectively; and those of rs8103142 TT and CT genotypes were 90.4% and 9.6%, respectively. Among the patients with HCV genotype 1, the SVR rates were 69.7% and 80.0% for rs12979860 CC and CT, respectively (P=0.71). Among the HCV genotype non-1 patients, SVR rates were 88.0% and 100% for rs12979860 CC and CT (P=1.00), respectively.
Genotypes of the IL28B SNP that are known to be favorable were present in most of the Korean patients with chronic hepatitis C in this study. Moreover, the IL28B SNP did not influence the SVR rate in either the HCV genotype 1 or non-1 patients. Therefore, IL28B SNP analysis might be not useful for the initial assessment, prediction of treatment outcomes, or treatment decision-making of Korean chronic hepatitis C patients.
Chronic Hepatitis C; Interleukin 28B; Polymorphism, Single Nucleotide; Korean
Although cesarean delivery and prenatal exposure to antibiotics are likely to affect the gut microbiome in infancy, their effect on the development of atopic dermatitis (AD) in infancy is unclear. The influence of individual genotypes on these relationships is also unclear. To evaluate with a prospective birth cohort study whether cesarean section, prenatal exposure to antibiotics, and susceptible genotypes act additively to promote the development of AD in infancy.
The Cohort for Childhood of Asthma and Allergic Diseases (COCOA) was selected from the general Korean population. A pediatric allergist assessed 412 infants for the presence of AD at 1 year of age. Their cord blood DNA was subjected to interleukin (IL)-13 (rs20541) and cluster-of-differentiation (CD)14 (rs2569190) genotype analysis.
The combination of cesarean delivery and prenatal exposure to antibiotics associated significantly and positively with AD (adjusted odds ratio, 5.70; 95% CI, 1.19–27.3). The association between cesarean delivery and AD was significantly modified by parental history of allergic diseases or risk-associated IL-13 (rs20541) and CD14 (rs2569190) genotypes. There was a trend of interaction between IL-13 (rs20541) and delivery mode with respect to the subsequent risk of AD. (P for interaction = 0.039) Infants who were exposed prenatally to antibiotics and were born by cesarean delivery had a lower total microbiota diversity in stool samples at 6 months of age than the control group. As the number of these risk factors increased, the AD risk rose (trend p<0.05).
Cesarean delivery and prenatal antibiotic exposure may affect the gut microbiota, which may in turn influence the risk of AD in infants. These relationships may be shaped by the genetic predisposition.
Hepatocellular carcinoma (HCC) is classified as a poor prognostic tumor, and becomes frequently aggressive. MicroRNAs emerge as key contributors to tumor progression. This study investigated whether miR-148a dysregulation differentiates poor prognosis of HCC, exploring new targets of miR-148a. miR-148a dysregulation discriminated not only the overall survival and recurrence free survival rates of HCC, but the microvascular invasion. In the human HCC samples, ubiquitin specific protease 4 (USP4) and sphingosine 1-phosphate receptor 1 (S1P1) were up-regulated as the new targets of miR-148a. USP4 and S1P1 were up-regulated in mesenchymal-type liver-tumor cells with miR-148a dysregulation, facilitating migration and proliferation of tumor cells. The inverse relationship between miR-148a and the identified targets was verified in a tumor xenograft model. In the analysis of human samples, the expression of USP4, but not S1P1, correlated with the decrease of miR-148a. In a heterotropic patient-derived HCC xenograft model, USP4 was also overexpressed in G1 and G2 tumors when miR-148a was dysregulated, reflecting the closer link between miR-148a and USP4 for a shift in the expansion phase of tumorgraft. In conclusion, miR-148a dysregulation affects the poor prognosis of HCC. Of the identified targets of miR-148a, USP4 overexpression may contribute to HCC progression towards more aggressive feature.
hepatocellular carcinoma; USP4; S1P1; miR-148a; migration; growth
MicroRNAs (miRNAs) are epigenetic regulators of eukaryotic gene expression and play key roles in many cellular processes. However, the role of miRNAs for replicative senescence of normal human keratinocytes (NHKs) remains unknown. Thus, we examined the expression profiles of 847 miRNAs in exponentially replicating and senescent NHKs and identified 126 senescence-associated miRNAs (SA-miRs). Among SA-miRs, 117 miRNAs (93%) were upregulated and 9 miRNAs (7%) were downregulated in senescent NHKs compared to those of exponentially replicating cells. Among the above miRNAs, we selected two miRNAs, miR-137 and miR-668, for further investigation because they were consistently upregulated with replicative senescence of three independent NHK cultures. Ectopic overexpression of miR-137 or miR-668 induced senescence in rapidly proliferating NHKs; a notable increase in senescence-associated β-galactosidase activity, p16INK4A and p53 was observed, indicating that they are novel senescence-inducing miRNAs. In addition, these senescence-inducing miRNAs were gradually increased during organismal aging of normal human oral epithelia. We also detected downregulation of miR-137 and miR-668 in many tested human head and neck squamous cell carcinoma cell lines. Since senescence would be viewed as a potent tumor suppressive pathway, the newly identified senescence-inducing miRNAs deserve to be further investigated for their therapeutic application in cancer treatment.
senescence; microRNA; normal human keratinocytes
The role of prostaglandin E2 (PGE2) in the modulation of cell growth is well established in colorectal cancer. The aim of this study was to elucidate the significance of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) down-regulation on the prognosis of hepatocellular carcinoma (HCC) patients.
The expression of 15-PGDH in HCC cell lines and resected HCC tissues was investigated, and the correlation between 15-PGDH expression and HCC cell-line proliferation and patient survival was explored.
The interleukin-1-β-induced suppression of 15-PGDH did not change the proliferation of PLC and Huh-7 cells in the MTS [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The induction of 15-PGDH by transfection in HepG2 cells without baseline 15-PGDH expression was suppressed at day 2 of proliferation compared with empty-vector transfection, but there was no difference at day 3. Among the 153 patients who received curative HCC resection between 2003 and 2004 at our institution, 15-PGDH expression was observed in resected HCC tissues in 56 (36.6%), but the 5-year survival rate did not differ from that of the remaining 97 non-15-PGDH-expressing patients (57.1% vs 59.8%; P=0.93). Among 50 patients who exhibited baseline 15-PGDH expression in adjacent nontumor liver tissues, 28 (56%) exhibited a reduction in 15-PGDH expression score in HCC tissues, and there was a trend toward fewer long-term survivors compared with the remaining 22 with the same or increment in their 15-PGDH expression score in HCC tissues.
The prognostic significance of 15-PGDH down-regulation in HCC was not established in this study. However, maintenance of 15-PGDH expression could be a potential therapeutic target for a subgroup of HCC patients with baseline 15-PGDH expression in adjacent nontumor liver tissue.
Hepatocellular carcinoma; 15-hydroxyprostaglandin dehydrogenase; Transfection; Immunohistochemistry; Survival analysis
Camphorquinone (CQ) is a photoinitiator that triggers polymerization of light-curing materials such as dental adhesives and composites. CQ does not become a part of the polymer network, suggesting that CQ can be leached out into surrounding environment including dental pulp and exert adversary effects on tissues. In order to understand the mechanisms of CQ-induced side effects, we investigated the effect of CQ on cell viability, cytokine secretion, and odontogenic differentiation of dental pulp stem cells in vitro.
Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after CQ exposure. Western blotting was performed for p16INK4A, p21WAF1, and p53. Secretory cytokines were evaluated using the membrane–enzyme-linked immunosorbent assay as well as conventional and quantitative reverse-transcription polymerase chain reaction. The effects of CQ on odontogenic differentiation were evaluated using alkaline phosphatase and alizarin red S staining methods.
CQ treatment suppressed the proliferation of DPSCs and induced the expression of p16INK4A, p21WAF1, and p53. Levels of proinflammatory cytokines (eg, interleukin 6, interleukin 8, and matrix metalloproteinase-3 [MMP3]) were increased by CQ treatment. CQ also inhibited odontogenic differentiation and mineralization capacities of DPSC and MC3T3-E1 cells.
Our study showed that CQ may trigger pulpal inflammation by inducing proinflammatory cytokine production from the pulpal cells and may impair odontogenic differentiation of dental pulp cells, resulting in pulpal irritation and inflammation.
Camphorquinone; dental pulp stem cells; inflammation; odontogenic differentiation; pulpal wound healing
Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment.
Materials and Methods
A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT.
The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients’ survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%).
SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.
Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women’s Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90–1.11) in whites, 0.95 (0.85–1.06) in blacks, 0.96 (0.79–1.17) in Hispanics, and 0.88 (0.70–1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women.
Effect of pre-harvest methyl jasmonate (MeJA) and post-harvest 1-methylcyclopropene (1-MCP) treatments on broccoli floret glucosinolate (GS) concentrations and quinone reductase (QR, an in vitro anti-cancer biomarker) inducing activity were evaluated two days prior to harvest, at harvest and at 10, 20, and 30 days of post-harvest storage at 4 °C. MeJA treatments four days prior to harvest of broccoli heads was observed to significantly increase floret ethylene biosynthesis resulting in chlorophyll catabolism during post-harvest storage and reduced product quality. Post-harvest treatment with 1-methylcyclopropene (1-MCP), which competitively binds to protein ethylene receptors, maintained post-harvest floret chlorophyll concentrations and product visual quality in both control and MeJA-treated broccoli. Transcript abundance of BoPPH, a gene which is responsible for the synthesis of pheophytinase, the primary enzyme associated with chlorophyll catabolism in broccoli, was reduced by 1-MCP treatment and showed a significant, negative correlation with floret chlorophyll concentrations. The GS, glucobrassicin, neoglucobrassicin, and gluconasturtiin were significantly increased by MeJA treatments. The products of some of the GS from endogenous myrosinase hydrolysis [sulforaphane (SF), neoascorbigen (NeoASG), N-methoxyindole-3-carbinol (NI3C), and phenethyl isothiocyanate (PEITC)] were also quantified and found to be significantly correlated with QR. Sulforaphane, the isothiocyanate hydrolysis product of the GS glucoraphanin, was found to be the most potent QR induction agent. Increased sulforaphane formation from the hydrolysis of glucoraphanin was associated with up-regulated gene expression of myrosinase (BoMyo) and the myrosinase enzyme co-factor gene, epithiospecifier modifier1 (BoESM1). This study demonstrates the combined treatment of MeJA and 1-MCP increased QR activity without post-harvest quality loss.
Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes-1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.
TNFα; OSCC; cancer stem cells; Notch; Hes1
Mesenchymal stem cells (MSCs) are adult stem cells whose self-renewal, multipotency, and immunosuppressive functions have been investigated for therapeutic applications. Although initially isolated from systemic tissue sources, MSCs have also been isolated from dental and orofacial tissues yielding odontoblastic and cementoblastic differentiation capacities. These unique features facilitate their application for pulpal, periradicular, and mineralized dental tissue regeneration. MSCs have utilized for various systemic organ regenerative therapies, allowing rescue of tissue function in damaged or failing organs. MSCs also possess immunosuppressive functions that allow improved management and treatment of chronic inflammatory disorders. However, their propensity to undergo cellular senescence, as well as host-immune response mediated loss of potency of allogenicically transplanted MSCs, may limit their use in clinical setting. Here we review the regenerative and immunomodulatory functions of MSCs and their applications in dental, orofacial and systemic tissue regeneration and treatment of inflammatory disorders. We also address challenges to MSC-mediated therapeutics arising from tissue and MSC aging and host immune response against allogenic MSC transplantation, and discuss alternative sources of MSCs aimed at overcoming these limitations.
Mesenchymal Stem Cells; Tissue Engineering; Immunosuppression; Epithelial-Mesenchymal Transition; Pulp Capping; Pulp Revitalization
Although efavirenz (EFV) is efficacious as an anti-retroviral therapy when combined with other antiretroviral drugs, it may cause adverse clinical effects, including skin and mucosal eruptions, central nervous system complications, hepatotoxicity, renal failure and pulmonary complications. The present study investigated the phenotypic alterations caused by EFV in normal human keratinocytes (NHKs) and determined the cell death pathways leading to the lack of epithelial proliferation and regeneration. Replication kinetics, cellular morphology, and protein and mRNA levels of cell cycle regulatory genes and cell death markers were compared between the EFV-exposed cells and the untreated control. EFV treatment led to cell proliferation arrest and cell death of the NHKs by inducing autophagy mediated by proteasome-dependent degradation of p53. EFV also reduced the levels of mTOR and active ERK signaling in NHKs. Chemical inhibition of p53 degradation with a proteasome inhibitor led to reduced autophagic response of NHKs to EFV. In addition, EFV triggered terminal differentiation of NHKs by inducing the expression of involucrin, filaggrin, loricrin and genes involved in cornified envelope formation. Inhibition of autophagy in the EFV-treated NHKs with 3-methylalanine reduced the levels of involucrin and the extent of cell death. Our data indicate that EFV elicits cytotoxic effects on NHKs in part through induction of autophagy and aberrant differentiation of cells.
efavirenz; autophagy; keratinocytes; differentiation; p53
Previous studies suggest that maternal characteristics may be associated with neonatal outcomes. However, the influence of maternal characteristics on birth weight (BW) has not been adequately determined in Korean populations. We investigated associations between maternal characteristics and BW in a sample of 813 Korean women living in the Seoul metropolitan area, Korea recruited using data from the prospective hospital-based COhort for Childhood Origin of Asthma and allergic diseases (COCOA) between 2007 and 2011. The mean maternal age at delivery was 32.3 ± 3.5 yr and prepregnancy maternal body mass index (BMI) was 20.7 ± 2.5 kg/m2. The mean BW of infant was 3,196 ± 406 g. The overall prevalence of a maternal history of allergic disease was 32.9% and the overall prevalence of allergic symptoms was 65.1%. In multivariate regression models, prepregnancy maternal BMI and gestational age at delivery were positively and a maternal history of allergic disease and nulliparity were negatively associated with BW (all P < 0.05). Presence of allergic symptoms in the mother was not associated with BW. In conclusion, prepregnancy maternal BMI, gestational age at delivery, a maternal history of allergic disease, and nulliparity may be associated with BW, respectively.
Cohort Studies; Birth Weight; Infant, Newborn; Mothers; Family Characteristic; Body Mass Index; Allergy and Immunology
Identifying the impact of a patient's ethnicity on treatment responses in clinical practice may assist in providing individualized treatment regimens for chronic hepatitis C (CHC). The effectiveness of standard peginterferon plus ribavirin therapy and the need for triple combination therapy with protease inhibitors in Koreans remain matters of debate. These issues were investigated in the present study.
The clinical data of 272 treatment-naïve Korean CHC patients who were treated in a community-based clinical trial (Clinical Trial group; n=51) and in clinical practice (Cohort group; n=221), were analyzed and compared. All were treated with standard protocols of peginterferon alfa-2a plus ribavirin therapy.
For patients with hepatitis C virus (HCV) genotype 1, the sustained virological response (SVR) rates in the Clinical Trial and Cohort groups were 81% (21/26) and 55% (58/106), respectively, by intention-to-treat (ITT) analysis (P=0.02), and 100% (13/13) and 80% (32/40), respectively, in treatment-adherent patients (P=0.18). For patients with HCV genotype 2, the SVR rates in these two groups were 96% (24/25) and 88% (101/115), respectively, by ITT analysis (P=0.31). Adherence and treatment duration were independent predictors of SVR for genotypes 1 and 2, respectively (P<0.01 for each). Korean patients with CHC achieved high SVR rates with peginterferon alfa-2a plus ribavirin in both the clinical trial and clinical practice settings.
Measures to raise adherence to standard therapy in clinical practice may improve the SVR rates in these patients as effectively as adding protease inhibitors, thus obviating the need for the latter.
Medication adherence; Hepatitis C; Peginterferon alfa-2a; Ribavirin
A retropharyngeal abscess is a rare disease entity in young infants but can develop after nasopharyngeal viral infection. Group B Streptococcus and Staphylococcus aureus are the most common pathogens in young infants, however, Mycobacterium tuberculosis is very rare. We report the case of retropharyngeal abscess and coinfection with S. aureus and M. tuberculosis in a very young infant presenting with respiratory symptoms due to upper airway obstruction. Usually tuberculous retropharyngeal abscesses are caused by the direct invasion of the bacteria from the spine via anterior longitudinal ligament of the spine. However, in this case, no associated spinal disease was observed.
Retropharyngeal abscess; Staphylococcus aureus; Mycobacterium tuberculosis
We previously reported that wild type (wt) hnRNP G exhibited tumor suppressive activity in human oral squamous cell carcinoma (HOSCC) cell lines lacking hnRNP G. Wt hnRNP G markedly inhibited the proliferation capacity, anchorage independency and in vivo tumorigencity of HOSCC cells and notably enhanced the DNA repair capabilities of these cells. In the present study, we studied the genetic and expression states of hnRNP G in normal, premalignant and malignant human oral tissues to further understand the relationship between the hnRNP G alterations and the development of human oral cancer. To correlate the cancer development and the level of hnRNP G expression, we performed an immunohistochemistry staining of hnRNP G in normal, premalignant and malignant human oral tissues. Moreover, we examined the entire coding regions of hnRNP G from selected samples to understand the cause of the alterations of the gene expression. The expression of hnRNP G was notably decreased or completely abolished in 80% of premalignant-dysplastic and malignant oral epithelial tissues, whereas 100% of normal and 90% of hyperplastic non-dysplastic epithelium showed high level of hnRNP G in the nucleus of the basal cell layers. Approximately 80% of HOSCC lacking the expression of hnRNP G showed genetic alteration in hnRNP G, i.e., point mutation and exonic deletion. This study suggest that genetic alterations and aberrant expression of hnRNP G occurring during oral carcinogenesis might be useful markers for the early detection of human oral cancer.
hnRNP G; oral cancer; immunohistochemistry; genetic alteration
Since the risk of developing allergic disease increases in individuals exposed to allergens previously, even during the neonatal period, the immunologic status of a fetus may be important in the subsequent development of allergy. We evaluated the fetal factors to predict atopic dermatitis (AD) at 12 months in 412 infants of a COhort for Childhood Origin of Asthma and Allergic Diseases (COCOA) in the general Korean population. Cord blood mononuclear cells (CBMCs) were stimulated with ovalbumin and phytohemagglutinin and cellular proliferative response and concentrations of interleukin-13 and interferon-γ, were measured. The risk of developing AD was greater in boys than girls (OR 1.97, 95% CI 1.26-3.09), infants delivered by cesarean section than vaginally (OR 1.93, 95% CI 1.14-3.26) and infants with than without parental history of AD (OR 2.34, 95% CI 1.29-4.24). The CBMC proliferative response to phytohemagglutinin stimulation was higher in infants with than without AD (P = 0.048), but no difference was observed in ovalbumin-stimulated cells (P = 0.771). Risk factors for the development of AD at 12 months include male gender, delivery by cesarean section and parental history of AD. Increased CBMC proliferative response to phytohemagglutinin stimulation may predict the development of AD at 12 months.
Atopic Dermatitis; Cohort; Cord Blood; Cellular Proliferative Response; Cytokine; Risk Factor
Little is known about the long-term outcome of chronic hepatitis B (CHB) patients who discontinued antiviral therapy. We intended to analyze the long-term outcome of CHB patients who discontinued lamivudine therapy and to evaluate predictors for post-treatment outcome.
From 2007 to 2008, 138 lamivudine off-treated CHB patients with alanine aminotransferase normalization were consecutively enrolled. Post-treatment virologic relapse, biochemical breakthrough, hepatitis flare, and retreatment results were retrospectively analyzed.
Among 138 patients, 102 were initially HBeAg-positive at the start of lamivudine treatment. Virologic relapse, biochemical breakthrough, and hepatitis flare were observed in 45.2, 52.9, and 12.7% of HBeAg-positive and 29.4, 30.6, and 8.3% of HBeAg-negative patients during the median follow-up of 28 and 30 months, respectively. The cumulative virologic relapse and biochemical breakthrough rates were significantly lower in patients with HBV DNA <50 copies/mL than 50-104 copies/mL at lamivudine cessation. Hepatitis flare was observed in 4.8 and 11.8% of HBeAg-positive and HBeAg-negative patients with HBV DNA <50copies/mL, respectively. Thirty-eight among 138 patients received retreatment and most of them achieved biochemical (37/38) and virologic response (35/38) within 1 year of retreatment. Undetectable serum HBV DNA (<50 copies/mL) and young age at lamivudine cessation were inversely associated with virologic relapse. Undetectable HBV DNA at cessation, female, and initial HBeAg-negative were inversely associated with biochemical breakthrough.
Post-treatment virologic relapse and biochemical breakthrough incidence were low in patients who achieved undetectable viral titer at lamivudine cessation. Retreatment after biochemical breakthrough or virologic relapse was safe and effective. Intermittent antiviral therapy might be cautiously considered in appropriately selected CHB patients.
Chronic hepatitis B; Lamivudine cessation; Virologic relapse; Biochemical breakthrough; Hepatitis flare