Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings.

OBJECTIVE: To quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI). DESIGN, SETTING AND POPULATION: Population-based nationwide cohort study. METHODS: Using data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2 109 288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale. MAIN OUTCOME MEASURES: IRR of endometriosis among women with and without affected siblings. RESULTS: From 19 195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10 000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25-3.36), and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19-11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43-7.55), 3.47 (95% CI 2.82-4.26) and 3.09 (95% CI 2.68-3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant. CONCLUSION: Genetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene-environment interaction exists between family history and smoking or early menarche. TWEETABLE ABSTRACT: Significant gene-environment interaction exists between family history of endometriosis and smoking or early menarche.

Assessment of the efficacy of intra-articular platelet rich plasma treatment in an ACLT experimental model by dynamic contrast enhancement MRI of knee subchondral bone marrow and MRI T2∗ measurement of articular cartilage.

OBJECTIVE: The vascularization of subchondral bone plays a significant role in the progression of knee osteoarthritis (OA). Treatment with platelet-rich plasma (PRP) has positive effects on cartilage lesions. However, PRP's efficacy for subchondral bone marrow lesions and the relationship of these lesions to cartilage are still undiscovered. Therefore, our aims were first to longitudinally investigate the change in subchondral flow by dynamic contrast enhanced MRI and degeneration of cartilage by MRI T2∗ in an anterior cruciate transection rodent (ACLT) model, and second to examine changes in parameters after intra-articular PRP injection. DESIGN: A 32-week investigation in 18 rats allocated to sham-control, ACLT with normal saline injection (ACLT + NS), and ACLT with PRP injection groups ended with histological evaluation. Another rat was used as a donor of allogenic PRP. RESULTS: Compared to the sham-control group, the ACLT + NS group had higher subchondral blood volume A (0.051, 95% confidence interval: 0.009, 0.092) and lower venous washout kel (-0.030: -0.055, -0.005) from week 4; lower permeability kep from week 18 (-0.954: -1.339, -0.569); higher cartilage T2∗ values (1.803: 1.504, 2.102) reflecting collagen loss beginning at week 10. For the PRP treatment group, subchondral bone marrow A and cartilage T2∗ decreased from week 10. Histological results confirmed and were correlated with the MRI findings. CONCLUSION: Subchondral hyper-perfusion plays a vital role in the pathogenesis of OA and was associated with cartilage degeneration. The efficacy of PRP can be observed from reduced perfusion and MRI T2∗ values.

A simple and efficient method of generating HCMV pp65-specific T cells using overlapping peptides.

The methods for expansion of human cytomegalovirus (HCMV)-specific T lymphocytes are limited due to the complex culture process, long culture duration, and human leukocyte antigen (HLA) restriction. Here, we report that in vitro stimulation with pp65 kDa phosphoprotein (pp65)-derived overlapping synthetic peptides rapidly generates large numbers of HCMV-specific cytotoxic T lymphocytes from peripheral blood mononuclear cells (PBMCs) regardless of HLA type. Treatment of PBMCs from healthy volunteers expressing HLA-A*02:01 or HLA-A*24:02 with 138 pp65 overlapping peptides (OLP) resulted in an expansion of HCMV pp65 NLVPMVATV (NLV) pentamer-specific CD8+ T lymphocytes that expressed interferon (IFN)-γ, but the pp65 NLV peptide did not generate HCMV-specific CD8+ T lymphocytes in PBMCs obtained from an HLA-A*24:02 donor due to HLA restriction. The OLP-induced T lymphocytes specific for HCMV derived from PBMCs of HLA-A*02:01- and HLA-A*24:02-expressing donors showed effective cytolytic responses against target cells loaded with OLP or the NLV epitope, but pp65 NLV peptide-induced T lymphocytes did not. Phenotypic analyses demonstrated that OLP increased the frequency of CD3+ CD8+ cells, but not CD3+ CD4+, CD14+, or CD56+ cells, in donor PBMCs. Thus, this study provides evidence that in vitro stimulation with OLP efficiently generates sufficient numbers of HCMV pp65-specific cytotoxic T lymphocytes for adoptive cell therapy. Keywords: human cytomegalovirus; cytotoxic T lymphocyte; overlapping peptides; pp65; cytotoxicity.

Lung function as a predictor of incident type 2 diabetes in community-dwelling adults: A longitudinal finding over 12 years from the Korean Genome and Epidemiology Study.

AIM: Reduced lung function is associated with type 2 diabetes (T2D), but there are limited data in East Asian populations on the relationship between them. For this reason, this study investigated the longitudinal relationship of lung function with incident T2D in Korean adults. METHODS: The study included 7583 non-diabetic adults aged 40-69 years from the Korean Genome and Epidemiology Study. Participants were divided into four groups according to gender-specific quartiles (Q1-Q4) of %PFVC and %PFEV1. Also, HRs with 95% CIs for incident T2D were prospectively analyzed as per American Diabetes Association criteria using multivariate Cox proportional-hazards regression models. RESULTS: During a 12-year follow-up, 1403 (18.5%) participants presented with newly developed T2D. HRs (95% CIs) of incident T2D in Q1 vs. Q4 (reference) of %PFVC were 1.67 (1.35-2.07) for men and 1.77 (1.39-2.24) for women and, of %PFEV1, 1.58 (1.28-1.95) for men and 1.61 (1.27-2.03) for women, after adjusting for age, waist circumference, smoking status, alcohol intake, regular exercise, education levels, monthly household income, family history of diabetes, HOMA-IR, triglycerides, HDL cholesterol and high-sensitivity C-reactive protein levels. CONCLUSION: Reduced lung function precedes and significantly predicts the future development of T2D independently of obesity, smoking and inflammation in community-dwelling middle-aged and elderly people.

Inhibitory effects of herbal decoction Ojeoksan on proliferation and migration in vascular smooth muscle cells.

The proliferation of vascular smooth muscle cells plays a crucial role in pathogenesis of cardiovascular disease. The principal objective of this study was to determine the effects of Ojeoksan (OJS) on human aortic smooth muscle cell (HASMC) proliferation induced by tumor necrosis factor α (TNF-aα). Thymidine incorporation after TNF-α treatment was increased and this effect was inhibited significantly by OJS treatment. HASMC proliferation and migration by kinetic live cell imaging were also reduced by treatment with OJS. TNF-α induced the expression of cyclins/cyclin-dependent kinases (CDKs) and reduced the expression of p21waf1/cip1/p27kip1. However, OJS also attenuated the expression of TNF-α-induced cell-cycle regulatory proteins. The results of Western blot analysis demonstrated that the TNF-α treated HASMC secreted gelatinases, probably including MMP-2/-9, which may be involved in the invasion and migration of HASMC. Additionally, OJS suppressed the mRNA expression levels of matrix metalloproteinase-2/-9 (MMP-2/-9) in a dose-dependent manner. OJS inhibited the production of TNF-α-induced hydrogen peroxide (H2O2) and the formation of DCF-sensitive intracellular reactive oxygen species (ROS). Further, OJS suppressed the nuclear translocation and phosphorylation of inhibitor of kappa B-α (IκB-α) of nuclear factor κB (NF-κB) under TNF-α conditions. Our results demonstrate that OJS exerts inhibitory effects on TNF-α-induced HASMC proliferation and migration, suggesting the involvement of the inhibition of both MMP-2 and MMP-9 expressions, and the downregulation of ROS/NF-κB signaling. Thus, herbal decoction OJS may be a possible therapeutic approach to the inhibition of cardiovascular disease including atherosclerosis.

The effect of low body mass index on the development of chronic obstructive pulmonary disease and mortality.

BACKGROUND: Sarcopenia may worsen disease progression and lead to poor outcomes in chronic obstructive pulmonary disease (COPD). OBJECTIVES: We aimed to determine the effect of BMI on the development of COPD and mortality. METHODS: We enrolled 437 584 participants registered in the physical health check-up cohort database of the Korean National Health Interview Survey from 2002 to 2003, and we defined COPD diagnosis based on the ICD-10 code and prescribed medication. BMI (kg m-2 ) classified them to five groups (low BMI < 18.5, normal BMI 18.5-23, overweight 23-25, obesity 25-30, severe obesity ≥30) at baseline. RESULTS: Participants in the low BMI group had a significantly higher rate of COPD development for 13 years (7.6%) than those in other groups (3.4-4.1%, P < 0.0001). Amongst never or light smokers, COPD development in the low BMI group (5.6-6.7%) was significantly higher than that in other groups (2.8-4.7%). Similarly, amongst participants with a smoking history of ≥30 years, COPD development in the low BMI group (20.1%) was higher than those in other groups (8.4-12.4%). On multivariable analysis, normal or higher than normal body weight was significantly protective against the development of COPD (hazard ratio [HR], 0.609-0.739,) compared to low BMI. COPD-free-survival (HR, 0.491-0.622) and overall survival (HR, 0.440-0.585) were also better in them compared to those with low BMI (all P < 0.0001). CONCLUSIONS: Low BMI is an important risk factor for COPD development and mortality. Maintaining adequate body weight may reduce the risk for COPD development and mortality.

Effects of α-lipoic acid on chronic cerebrovascular hypoperfusion in an animal model of vascular dementia.

OBJECTIVE: Given the aging population, the treatment of vascular dementia (VaD) is becoming increasingly important. The antioxidant α-lipoic acid (α-LA) protects against neurodegeneration in VaD, but the underlying mechanisms remain unclear. Hence, we aimed to identify the effects of α-LA on cognitive function following chronic cerebrovascular hypoperfusion in a VaD animal model. MATERIALS AND METHODS: Mice were categorized into the sham, bilateral common carotid artery stenosis (BCAS), or BCAS + α-LA group. The BCAS + α-LA group was intraperitoneally injected (100 mg/kg) once daily with α-LA for 4 weeks after BCAS surgery, while the BCAS and sham groups were injected with saline. After the last injection, we examined cognitive function and exploration behavior using the Morris water maze. Mice brains were then harvested for Western blot analyses. RESULTS: The BCAS group, but not the BCAS + α-LA group, showed cognitive dysfunction in the Morris water maze. Apoptosis pathways involving poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-3-phosphoinositide-dependent protein kinase-1, and phosphorylated-protein kinase B (p-AKT) were enhanced in the BCAS group than the α-LA group. The BCAS + α-LA group demonstrated less PARP cleavage and p-mTOR function than did the BCAS group. The activity of autophagy pathways involving LC3B was higher in the BCAS and BCAS + α-LA groups than the sham group, but there were no significant differences between the BCAS and BCAS + α-LA groups. CONCLUSIONS: In the BCAS rodent model, cognitive dysfunction and apoptosis mediated by the phosphatase and tensin homolog/AKT/mTOR pathway were observed in the hippocampus. However, acting on the mTOR pathway, α-LA improved cognitive function and led to hippocampal cell survival. Thus, α-LA may be useful for treating VaD.

Isolation of internal and external sphincter progenitor cells from the human anal sphincter with or without radiotherapy.

AIM: We aimed to isolate and propagate internal and external anal sphincter progenitor cells from the human anal sphincter, with or without radiotherapy, for tailored cell therapy of faecal incontinence. METHODS: Sphincter progenitor cells were isolated from normal internal and external anal sphincters collected from 10 patients with rectal cancer who had undergone abdominoperineal resection with (n = 6) or without (n = 4) preoperative chemoradiotherapy. The isolated cells and differentiated muscle fibres were identified using immunofluorescence assay, western blotting and reverse transcription polymerase chain reaction (RT-PCR). The proliferation of progenitor cells with and without radiotherapy was compared by quantitative 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The immunofluorescence assay before differentiation confirmed that the internal anal sphincter progenitor cells expressed CD34 and neural-glial antigen 2 (NG2), whereas the external anal sphincter progenitor cells expressed CD34 and PAX7. After differentiation, the internal anal sphincter progenitor cells expressed desmin, calponin and α-smooth muscle actin, whereas the external anal sphincter progenitor cells expressed desmin, myogenic factor 4 and myosin heavy chain. The differential expression profiles of both cell types were confirmed by western blotting and RT-PCR. MTT assays showed that the viability of internal and external anal sphincter progenitor cells was significantly lower in the radiotherapy group than that in the nonradiotherapy group. CONCLUSIONS: This study describes the differential harvest internal and external sphincter muscle progenitor cells from human anal sphincters. We confirm that radiotherapy decreases the viability of internal and external anal sphincter progenitor cells.

An easy way to secure catheter in position during marsupialization procedure.

Marsupialization is the conservative treatment for cystic lesion in children. This technique requires maintaining the patency between the cyst and oral cavity to allow spontaneous healing of cystic lesion. There have been various fixation methods for securing the patency. However, the previous fixation methods have limitation of being invasive and inability to retain catheter firmly during the treatment. In this technical note, we adopted a novel and easy fixation method to obtain firm stability of catheter without damage to intraoral tissues during marsupialization technique.

Post-operative corticosteroid irrigation for chronic rhinosinusitis after endoscopic sinus surgery: A meta-analysis.

BACKGROUND: Recently, topical steroid therapy delivery using high-volume sinonasal irrigations has been used more frequently, following endoscopic sinus surgery (ESS), to improve drug delivery into the paranasal sinuses. OBJECTIVE: The goal of this study was to perform a systematic review with meta-analysis of the efficacy of steroid nasal irrigation on post-operative management of Chronic rhinosinusitis (CRS) following ESS. METHODS: Five databases (PubMed, SCOPUS, Embase, Web of Science, and the Cochrane database) from inception to March 2017 were independently reviewed by two researchers. Studies that scored CRS endoscopic findings and CRS-related quality of life (QOL) post-operatively before and after steroid nasal irrigation and that compared the effects of steroid nasal irrigation (treatment groups) with saline alone irrigation (control group) were included in the analysis. RESULTS: Twelve studies (n = 360) met inclusion criteria. Steroid nasal irrigation significantly reduced the endoscopic score compared with pre-treatment values and also improved QOL. Adverse effects following steroid nasal irrigation such as increased intraocular pressure (IOP) and hypothalamus-pituitary-adrenal (HPA) axis disturbance were not significant. However, compared with saline alone irrigation, the additional effects of steroid irrigation were not significant in the view of the endoscopic score and disease-specific QOL. CONCLUSION: Although steroid nasal irrigation would not induce adverse effects related to systemic steroid absorption, the beneficial effects of additional steroids in saline irrigation were ambiguous in regard to endoscopic score and CRS-related QOL improvement compared with saline alone irrigation. However, further clinical trials with robust research methodologies should be conducted to confirm the results of this study.

Reversibility of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication - a prospective study for up to 10 years.

BACKGROUND: Atrophic gastritis and intestinal metaplasia are premalignant conditions for gastric cancer. Their reversibility by Helicobacter pylori eradication remains controversial. AIM: To evaluate the reversibility of atrophic gastritis and intestinal metaplasia by H. pylori eradication with long-term follow-up. METHODS: 598 subjects were prospectively enrolled and followed for up to 10 years. They were categorised as H. pylori-negative (n = 65), H. pylori non-eradicated (n = 91), and H. pylori-eradicated (n = 442). Histological assessment was performed for antrum and corpus by Sydney classification. RESULTS: Histological follow-up was performed regularly at 1, 2, 3-4 and ≥5 years, with mean follow-up of 1.07 ± 0.21, 2.29 ± 0.83, 3.93 ± 1.02, and 6.45 ± 1.28 years, respectively. Atrophic gastritis in antrum and corpus gradually and significantly (both P < .05 for all timepoints) improved only in the H. pylori-eradicated group compared to that at baseline. Significant difference in atrophic gastritis between H. pylori-eradicated and H. pylori-negative groups disappeared from 1-year follow-up. Similarly, intestinal metaplasia in antrum and corpus improved significantly (both P < .05 for all timepoints) only in the H. pylori-eradicated group in comparison with that at baseline. Significant difference in intestinal metaplasia between H. pylori-eradicated and H. pylori-negative groups disappeared from ≥5 years of follow-up in the antrum and from 3 years of follow-up in the corpus. CONCLUSION: H. pylori eradication may be a preventative strategy for intestinal-type gastric cancer by regression of atrophic gastritis and intestinal metaplasia.

Role of thymoglobulin in matched sibling allogeneic hematopoietic stem cell transplantation with busulfan and fludarabine conditioning in myeloid malignanicies.

In vivo T-cell depletion using anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis of GvHD. We investigated the influence of thymoglobulin dose (an ATG) on GvHD following matched sibling donor (MSD) HSCT with a busulfan and fludarabine preparative regimen. Medical records of 180 patients who received MSD HSCT with a conditioning regimen of busulfan, fludarabine, and ATG (BuFluATG) were reviewed retrospectively. The median age was 53 years (range 18-68). Initial diagnoses were acute myeloid leukemia (73.3%) and myelodysplastic syndrome (26.7%). Forty-four and 68 patients (24.4 and 37.7%) experienced acute and chronic GvHD of any grade, respectively. High-dose (⩾4.5 mg/kg) ATG was independently associated with decreased risk of acute GvHD (hazard ratio=0.36, 95% confidence interval (CI): 0.15-0.84, P=0.019) compared to low-dose ATG (<4.5 mg/kg). Although ATG dose was associated with the risk of acute GvHD, it was not associated with the risk of chronic GvHD in our study. A higher dose (⩾4.5 mg/kg) of ATG decreases the risk of acute GvHD but had no significant impact on disease-free survival in MSD HSCT patients conditioned with BuFluATG. The optimal dose of ATG should be further investigated in a large prospective study context.

Mantidis ootheca induces vascular relaxation through PI3K/AKT-mediated nitric oxide-cyclic GMP-protein kinase G signaling in endothelial cells.

Mantidis ootheca (Sang Piao Xiao) is well known mantis eggs in a foamy pouch. The purpose of the present study was to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of the aqueous extract of Mantidis ootheca (AMO) in rat aorta and vascular endothelial cells. AMO was examined for its vascular relaxant effect in isolated phenylephrine-precontracted rat thoracic aortic rings. The roles of the nitric oxide (NO) signaling in the AMO-induced effects were tested in human umbilical vein endothelial cells (HUVECs). HUVEC treated with AMO produced higher amount of NO compared to control. However, AMO-induced increases in NO production were blocked by pretreatment with NG-nitro-L-arginine methylester (L-NAME) or wortmannin. AMO increased in phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt in HUVECs, which were attenuated by a NOS and Akt inhibitors. In aortic ring, AMO-induced dose-dependent relaxation of phenylephrine-precontracted aorta was abolished by removal of functional endothelium. Pretreatment with L-NAME, 1H-[1,2,4]-oxadiazolo-[4,3-alpha]-quinoxalin-1-one (ODQ), and KT5823 inhibited the AMO-induced vasorelaxation. Similarly, wortmannin and LY-294002, an inhibitors of the phosphatidylinositol 3-kinase (PI3K), an upstream signaling molecule of eNOS, attenuated the AMO-induced vasorelaxation. Moreover, AMO-induced increases in cGMP production were blocked by pretreatment with L-NAME or ODQ. The vasorelaxant effect of AMO was attenuated by tetraethylammonium, 4-aminopyridine, and glibenclamide. We conclude that AMO relaxed vascular smooth muscle via endothelium-dependent activation of PI3K/Akt-mediated NO-cGMP-PKG signaling pathway and possible involvement of K+ channel.

Immunologic regulatory effects of human umbilical cord blood-derived mesenchymal stem cells in a murine ovalbumin asthma model.

BACKGROUND: Mesenchymal stem cells (MSCs) have multiple immunomodulatory properties and hold therapeutic potential for inflammatory diseases. However, the therapeutic and immunologic effects of human umbilical cord blood-derived MSCs (huMSCs) remain largely unexamined for asthma. OBJECTIVE: This study was to investigate the immunomodulatory properties of huMSCs in an ovalbumin (OVA)-induced murine asthma model. METHODS: Mice were injected intraperitoneally with OVA and an aluminium hydroxide adjuvant. huMSCs were administered via the tail vein (5×105 cells/100 uL) to female BALB/c mice prior to the initial OVA challenge. The effects of huMSCs were assessed by investigating airway hyperresponsiveness, histological changes, inflammatory cell numbers, serum allergen-specific antibodies, cytokine production in spleen, lung tissue, and bronchoalveolar lavage (BAL) fluid as well as expansion of regulatory T cells. RESULTS: Administration of huMSCs significantly reduced methacholine bronchial hyperresponsiveness and eosinophil counts in BAL cells. Similarly, there was a significant decrease in serum OVA-specific IgE and IgG1 levels along with Th2 cytokine production (IL-4, IL-5, and IL-13) in the lung and spleen tissues, whereas increased percentage of regulatory T cells was observed after treatment with huMSCs. CONCLUSIONS: Our results suggest that huMSC treatment reduces OVA-induced allergic inflammation, which could be mediated by regulatory T cells.

Identifying fibromyalgia subgroups using cluster analysis: Relationships with clinical variables.

BACKGROUND: Patients with fibromyalgia (FM) exhibit significant clinical heterogeneity, in terms of physical, social and psychological functions, as well as therapeutic responses. Here, we examined FM patients in terms of pain, physical, social and psychological variables to identify clinical subgroups that may be predictive of treatment patterns. METHODS: A total of 313 FM patients were interviewed using a structured questionnaire that included sociodemographic data, current or past FM symptoms and current use of relevant medications. A K-means cluster analysis was conducted using variables reflecting tender points, the Fibromyalgia Impact Questionnaire, Beck Depression Inventory, State-Trait Anxiety Inventor and Social Support Scale. RESULTS: Four distinct clusters were identified in these patients. Group 1 was characterized by high pain levels, severe physical and mental impairment and low social support. Group 2 had moderate pain and physical impairment, mild mental impairment and moderate social support. Group 3 had moderate pain, low physical and moderate mental impairment and low social support. Group 4 had low pain levels, nearly normal physical and mental function and high social support. Group 1 was more often a current or past smoker, more likely to have a variety of symptoms, including swelling, cognitive dysfunction, dizziness, syncope, oesophageal dysmotility, dyspepsia, irritable bladder, vulvodynia and restless leg syndrome. CONCLUSIONS: We identified four subgroups of FM patients based on pain, physical, social and psychological function. These subgroups had different clinical symptoms and medication profiles, suggesting that FM may be better managed using a more comprehensive assessment of an individual patient's symptoms. SIGNIFICANCE: FM patients can be clustered into four distinct subgroups based on clinically measurable variables - pain, physical involvement, psychological function and social support. These subgroups had different clinical symptoms and medication profiles.

Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) and Microsatellite Instability in Patients with Colorectal Cancer and Its Clinical Features.

PURPOSE: Recently, a different type of microsatellite instability (MSI) instability designated 'elevated microsatellite alterations at selected tetranucleotide repeats' (EMAST) has been reported in several neoplasms, but its clinical implications remain unclear. We aimed to determine the relationships among EMAST, MSI and clinicopathologic characteristics, including oncologic outcomes, in colorectal cancer (CRC). MATERIALS AND METHODS: We evaluated 100 sporadic CRC cases subjected to surgery using five markers (MYCL1, D9S242, D20S85, D8S321, and D20S82) for EMAST and the Bethesda panel for MSI status. Immunohistochemical detection of hMSH3, c-erbB2, EGFR and thymidylate synthase was performed. Clinical characteristics and prognostic relevance were assessed. RESULTS: We identified 22 EMAST-positive tumors (22.0%) and 32 MSI-high (MSI-H) tumors (32.0%). EMAST was more frequent in colon cancer than rectal cancer (p=0.033), and associated with MSI-H phenotype (p<0.001), low expression of hMSH3 (p=0.004), and overexpression of thymidylate synthase (p=0.006). Among the 38 MSI-L tumors, only one (4.5%) showed EMAST. Long-term oncologic results in terms of overall and disease-free survival were similar between EMAST and non-EMAST tumors. CONCLUSION: EMAST is more closely related to MSI-H than MSI-L or MSS status. The clinical and molecular characteristics of EMAST were distinct in terms of tumor location, thymidylate synthase expression, MSI status and hMSH3 expression. Our preliminary findings support the utility of EMAST as a new potential classifier in CRC.

Association between catechol-O-methyl transferase gene polymorphisms and fibromyalgia in a Korean population: A case-control study.

BACKGROUND: Although polymorphisms of the catechol-O-methyl transferase (COMT) gene have been implicated in altered pain sensitivity, results concerning the association between COMT gene polymorphisms and fibromyalgia (FM) are equivocal. We assessed the associations between COMT single-nucleotide polymorphisms (SNP) and FM risk and symptom severity. METHODS: In total, 409 FM patients and 423 controls were enrolled. Alleles and genotypes at five positions [rs6269 (A>G), rs4633 (C>T), rs4818 (C>G), rs4680 (C>G) and rs165599 (A>G)] in the COMT gene were genotyped from peripheral blood DNA. RESULTS: Alleles and genotypes of the rs4818 COMT gene polymorphism were significantly associated with increased susceptibility to FM. The rs4818 GG genotype was more strongly associated with FM compared to the CC genotype (OR = 1.680, 95% CI: 1.057, 2.672, p = 0.027). Although allele and genotype frequencies did not differ among groups, the rs4633 CT genotype was not associated with the presence of FM following adjustment for age and sex (OR = 0.745; 95% CI: 0.558, 0.995; p = 0.046). However, no association was observed between clinical measures and individual COMT SNPs. In haplotype analysis, there was a significant association between ACG haplotype and FM susceptibility sex (OR = 2.960, 95% CI: 1.447, 6.056, p = 0.003) and the number of tender points (p = 0.046). CONCLUSIONS: This large-scale study suggests that polymorphisms of the COMT gene may be associated with FM risk and pain sensitivity in Korean FM patients. However, our results differed to those of previous studies, suggesting ethnic variation in COMT gene polymorphisms in FM. WHAT DOES THIS STUDY ADD: By contrast to Caucasian and Latin-American populations, the COMT gene polymorphisms are associated with FM risk and pain sensitivity in Korean FM patients, suggesting ethnic variation in COMT gene polymorphisms.

The Introduction of Human Heme Oxygenase-1 and Soluble Tumor Necrosis Factor-α Receptor Type I With Human IgG1 Fc in Porcine Islets Prolongs Islet Xenograft Survival in Humanized Mice.

Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase-1 (HO-1) or soluble tumor necrosis factor-α receptor type I with human IgG1 Fc (sTNF-αR-Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO-1, sTNF-αR-Fc, sTNF-αR-Fc/HO-1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood-derived CD34(+) stem cells into NOD-scid-IL-2Rγ(null) mice. Both HO-1 and sTNF-αR-Fc reduced islet apoptosis under in vitro hypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig-to-humanized mice transplantation. The sTNF-αR-Fc/HO-1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor-α and IL-6 in treatment groups; however, frequency of pig-specific interferon-γ-producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO-1 or sTNF-αR-Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO-1 or sTNF-αR-Fc transgenic pigs have potential for islet xenotransplantation.

Disulfanyl peptide decreases melanin synthesis via receptor-mediated ERK activation and the subsequent downregulation of MITF and tyrosinase.

OBJECTIVE: Bioactive peptides are commonly used in cosmeceutical purpose. This study was performed to search for an effective and short hypopigmenting peptide using normal human melanocytes as a screening model. A peptide that exhibits multitarget activities will be a promising peptide. METHODS: Depigmenting effects were tested in normal human melanocytes. One peptide was selected, and signalling mechanism was investigated by Western blotting and immunofluorescent microscopic examination. RESULTS: A novel hypopigmenting peptide (dSHP) has been found to inhibit the production of melanin. This peptide significantly decreases tyrosinase activity but was not effective in a direct in vitro assay. It also induces the prolonged activation of ERK, and subsequently downregulates the levels of MITF. PD98059 abolished the dSHP-induced downregulation of MITF. These findings indicate that the dSHP-induced activation of ERK contributes to a reduced melanin synthesis via the downregulation of MITF. Fluorescent microscopic studies were consistent with such findings. Pertussis toxin reverses the downregulation of MITF, which means that the receptor-mediated ERK activation is involved. Moreover, it was also found that downregulation of MITF was clearly inhibited by lysosomal inhibitor (chloroquine). CONCLUSION: Novel tetrapeptide dSHP reduces the melanin synthesis by a receptor-mediated pathway. Furthermore, dSHP works by ERK activation and key transcription factor MITF degradation. Thus, it may be a good candidate as an effective hypopigmenting cosmetic agent.