Oral Porphyromonas gingivalis infection affects intestinal microbiota and promotes atherosclerosis.

AIM: The link between periodontitis and intestinal dysbiosis, two factors that contribute to atherosclerosis, has not been clearly defined. We investigated the integrative effects of oral infection with Porphyromonas gingivalis (PG), the major pathogen for periodontitis, on intestinal microbiota and atherosclerosis. MATERIALS AND METHODS: ApoE-/- mice were fed a normal chow diet (NC), a Western diet (WD) or a WD with oral PG infection (PG). The PG infection was investigated by placing a total of 109 CFUs of live PG into the oral cavity of each mouse using a feeding needle five times a week for 3 weeks. Atherosclerotic lesions of the aortae were measured, and blood lipoproteins and the expression of molecules related to lipid metabolism in the liver were analysed. We also performed 16S RNA sequencing and a microbiome analysis using faeces. RESULTS: En face bloc preparation of the aortae showed that the PG group had a 1.7-fold increase in atherosclerotic lesions compared with the WD group (p < .01). Serum analyses showed that oral PG infection induced a significant decrease in high-density lipoprotein (HDL) and triglyceride. Western blots of hepatic tissue lysates revealed that PG infection reduced the expression of scavenger receptor class B type 1 (SR-B1) in the liver by 50%. Faecal microbiota analysis revealed that species richness estimates (Chao1, ACE) decreased immediately after PG infection. PG infection also induced a significant decrease in Shannon diversity and an increase in Simpson's indices in the WD-fed mice. PG infection significantly increased the phyla Actinobacteria and Deferribacteres, along with the species Mucispirillum schaedleri and Lactobacillus gasseri, in the mice. The functional study showed that PG infection increased the expression of proteins that function in carbohydrate and glucose metabolism, including phosphotransferase system (PTS) proteins and the GntR family transcriptional regulator. CONCLUSIONS: Oral PG infection promotes atherosclerosis and induces significant metabolic changes, including reduced serum HDL and reduced hepatic SR-B1 and ABCA1 expression, as well as changes in intestinal microbiota. Our study suggests that intestinal dysbiosis accompanies periodontitis and could play a role in atherosclerosis.

Plasma Membrane Localization of CD36 Requires Vimentin Phosphorylation; A Mechanism by Which Macrophage Vimentin Promotes Atherosclerosis.

Vimentin is a type III intermediate filament protein expressed in cells of mesenchymal origin. Vimentin has been thought to function mainly as a structural protein and roles of vimentin in other cellular processes have not been extensively studied. Our current study aims to reveal functions of vimentin in macrophage foam cell formation, the critical stage of atherosclerosis. We demonstrated that vimentin null (Vim -/ - ) mouse peritoneal macrophages take up less oxidized LDL (oxLDL) than vimentin wild type (Vim +/+) macrophages. Despite less uptake of oxLDL in Vim -/ - macrophages, Vim +/+ and Vim -/ - macrophages did not show difference in expression of CD36 known to mediate oxLDL uptake. However, CD36 localized in plasma membrane was 50% less in Vim -/ - macrophages than in Vim +/+ macrophages. OxLDL/CD36 interaction induced protein kinase A (PKA)-mediated vimentin (Ser72) phosphorylation. Cd36 -/ - macrophages did not exhibit vimentin phosphorylation (Ser72) in response to oxLDL. Experiments using phospho-mimetic mutation of vimentin revealed that macrophages with aspartate-substituted vimentin (V72D) showed more oxLDL uptake and membrane CD36. LDL receptor null (Ldlr -/ - ) mice reconstituted with Vim -/ - bone marrow fed a western diet for 15 weeks showed 43% less atherosclerotic lesion formation than Ldlr -/ - mice with Vim +/+ bone marrow. In addition, Apoe -/ -Vim- / - (double null) mice fed a western diet for 15 weeks also showed 57% less atherosclerotic lesion formation than Apoe -/ - and Vim +/+mice. We concluded that oxLDL via CD36 induces PKA-mediated phosphorylation of vimentin (Ser72) and phosphorylated vimentin (Ser72) directs CD36 trafficking to plasma membrane in macrophages. This study reveals a function of vimentin in CD36 trafficking and macrophage foam cell formation and may guide to establish a new strategy for the treatment of atherosclerosis.

Clinical Significance of the Fetuin-A-to-Adiponectin Ratio in Obese Children and Adolescents with Diabetes Mellitus.

Fetuin-A and adiponectin are inflammatory cytokines associated with obesity and insulin resistance. This study aimed to examine the fetuin-A-to-adiponectin ratio (FAR) in diabetic children and to determine the role of FAR. A total of 54 children and adolescents with diabetes mellitus (DM) and 44 controls aged 9-16 years were included in this study. Clinical characteristics, including plasma fetuin-A and adiponectin levels, were compared with respect to body mass index (BMI) and diabetes type. Of 98 children, 54.1% were obese, whereas 18.4% were obese and diabetic. FAR was higher in obese children with DM than in non-obese children and also in type 2 DM children than in type 1. FAR showed a stronger association with BMI than with fetuin-A and adiponectin individually, and its association was more prominent in diabetic children than in controls. BMI was a risk factor for increased FAR. Plasma fetuin-A was elevated in obese children, and its association with insulin resistance and ß cell function seemed more prominent in diabetic children after adjustment for adiponectin. Thus, FAR could be a useful surrogate for the early detection of childhood metabolic complications in diabetic children, particularly those who are obese.

Transient Hyperinsulinemic Hypoglycemia Linked to PAX6 Mutation.

Prolonged hyperinsulinemic hypoglycemia in infancy can result in developmental sequelae. A mutation in the paired box-6 gene (PAX6) has been reported to cause disorders in oculogenesis and neurogenesis. A limited number of cases of diabetes mellitus in adults with a PAX6 mutation suggest that the gene also plays a role in glucose homeostasis. The present case report describes a boy with a PAX6 mutation, born with anophthalmia, who underwent hypoglycemic seizures starting at 5 months old, and showed a prediabetic condition at 60 months. This patient provides novel evidence that connects PAX6 to glucose homeostasis and highlights that life-threatening hypoglycemia or early onset glucose intolerance may be encountered. The role of PAX6 in glucose metabolism and insulin regulation should be further investigated.

Vimentin Deficiency Prevents High-Fat Diet-Induced Obesity and Insulin Resistance in Mice.

BACKGROUND: Obesity and type 2 diabetes mellitus are world-wide health problems, and lack of understanding of their linking mechanism is one reason for limited treatment options. We determined if genetic deletion of vimentin, a type 3 intermediate filament, affects obesity and type 2 diabetes mellitus. METHODS: We fed vimentin-null (Vim-/-) mice and wild-type mice a high-fat diet (HFD) for 10 weeks and measured weight change, adiposity, blood lipids, and glucose. We performed intraperitoneal glucose tolerance tests and measured CD36, a major fatty acid translocase, and glucose transporter type 4 (GLUT4) in adipocytes from both groups of mice. RESULTS: Vim-/- mice fed an HFD showed less weight gain, less adiposity, improved glucose tolerance, and lower serum level of fasting glucose. However, serum triglyceride and non-esterified fatty acid levels were higher in Vim-/- mice than in wild-type mice. Vimentin-null adipocytes showed 41.1% less CD36 on plasma membranes, 27% less uptake of fatty acids, and 50.3% less GLUT4, suggesting defects in intracellular trafficking of these molecules. CONCLUSION: We concluded that vimentin deficiency prevents obesity and insulin resistance in mice fed an HFD and suggest vimentin as a central mediator linking obesity and type 2 diabetes mellitus.

Discriminatory performance of insulin-like growth factor 1 and insulin-like growth factor binding protein-3 by correlating values to chronological age, bone age, and pubertal status for diagnosis of isolated growth hormone deficiency.

PURPOSE: The discriminatory performance of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) was investigated by correlating their values with chronological age (CA), bone age (BA), and pubertal status (PS) for diagnosis of isolated growth hormone deficiency (IGHD). METHODS: We evaluated IGF-1 and IGFBP-3 levels in 310 short-stature subjects subdivided into 2 groups: IGHD (n=31) and non-IGHD (n=279). IGF-1 and IGFBP-3 were assayed using immune-radiometric assay and transformed into standard deviation score (SDS) according to CA, BA, and PS. RESULTS: The highest sensitivity was found in IGF-1-SDS for CA and IGFBP-3-SDS for CA (22.6% and 30.0%, respectively). The highest specificity was found in IGF-1-SDS for PS and IGFBP-3-SDS for PS (98.2% and 94.4%, respectively). Groups with the highest positive predictive values were IGF-1-SDS for BA and IGFBP-3-SDS for BA (10.9% and 5.1%, respectively). Highest negative predictive values were seen in IGF-1-SDS for CA and IGFBP-3-SDS for CA (98.4% and 98.4%, respectively). CONCLUSION: IGF-1-SDS for CA, instead of IGF-1-SDS for BA or PS, could be used as a standard variable for IGHD screening. The sufficiently high specificity of IGF-1-SDS for PS suggests that this value is a useful tool for identification of IGHD.

Oxidized LDL induces vimentin secretion by macrophages and contributes to atherosclerotic inflammation.

Activated macrophages show increased expression of vimentin, an intermediate filament protein. Macrophages secrete vimentin into extracellular space; however, the functions of extracellular vimentin and the process of vimentin secretion are not clearly defined. We found that oxidized low-density lipoproteins (oxLDL) via CD36 induced vimentin secretion in macrophages. We also revealed that extracellular vimentin induced macrophages to release inflammatory cytokines and augmented oxLDL-induced release of TNF-α and IL-6. Extracellular vimentin activated NF-κB signaling via phosphorylation of focal adhesion kinase (p-FAK) and IκB kinase (p-IκK). Extracellular vimentin also amplified the oxLDL-induced p-IκK increase and IκB decrease. Vimentin-induced TNF-α release was not dependent on Dectin-1, which is known to bind vimentin. We measured serum vimentin concentrations and found that patients with atherosclerotic coronary artery disease had higher levels of serum vimentin than normal subjects. Circulating oxLDL and vimentin concentrations showed a high degree of correlation. In mouse experiments, vimentin concentration was higher in the sera of apoE null mice with western diet-induced atherosclerosis than in the sera of chow diet-fed apoE null mice without atherosclerosis. We concluded that vimentin is secreted by oxLDL/CD36 interaction in macrophages and extracellular vimentin promotes macrophage release of pro-inflammatory cytokines. This may contribute to atherosclerotic inflammation and based on our analysis of serum vimentin, we suggest serum vimentin as a predictive marker for atherosclerosis. KEY MESSAGES: OxLDL via CD36 induces secretion of vimentin, a cytoskeletal protein in macrophages. Extracellular vimentin induces macrophages to release proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-α) and this process is mediated by activation of focal adhesion kinase (FAK) and NF-ƙB signaling. Serum concentrations of vimentin in coronary artery disease patients are higher than that in control group. Vimentin concentration is strongly correlated with oxLDL concentration in serum.

Shockwaves Suppress Adipocyte Differentiation via Decrease in PPARγ.

Adipogenesis is a crucial cellular process that contributes to the expansion of adipose tissue in obesity. Shockwaves are mechanical stimuli that transmit signals to cause biological responses. The purpose of this study is to evaluate the effects of shockwaves on adipogenesis. We treated 3T3L-1 cells and human primary preadipocytes for differentiation with or without shockwaves. Western blots and quantitative real-time reverse transcriptase PCR (qRT-PCR) for adipocyte markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPα) were performed. Extracellular adenosine triphosphate (ATP) and intracellular cyclic adenosine monophosphate (cAMP) levels, which are known to affect adipocyte differentiation, were measured. Shockwave treatment decreased intracellular lipid droplet accumulation in primary human preadipocytes and 3T3-L1 cells after 11-12 days of differentiation. Levels of key adipogenic transcriptional factors PPARγ and/or C/EBPα were lower in shockwave-treated human primary preadipocytes and 3T3L-1 cells after 12-13 days of differentiation than in shockwave-untreated cells. Shockwave treatment induced release of extracellular ATP from preadipocytes and decreased intracellular cAMP levels. Shockwave-treated preadipocytes showed a higher level of ß-catenin and less PPARγ expression than shockwave-untreated cells. Supplementation with 8-bromo-cAMP analog after shockwave treatment rescued adipocyte differentiation by preventing the effect of shockwaves on ß-catenin, Wnt10b mRNA, and PPARγ expression. Low-energy shockwaves suppressed adipocyte differentiation by decreasing PPARγ. Our study suggests an insight into potential uses of shockwave-treatment for obesity.

The Molecular Chaperone Heat Shock Protein 70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA Damage and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways.

Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC but also for the development of diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several cochaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, the HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated. Here, we show that genetic ablation of HSP70 markedly impairs HCC initiation and progression by distinct but overlapping pathways. This includes the potentiation of the carcinogen-induced DNA damage response, at the tumor initiation stage, to increase the p53-dependent surveillance response leading to the cell cycle exit or death of genomically damaged differentiated pericentral hepatocytes, and this may also prevent their conversion into more proliferating HCC progenitor cells. Subsequently, activation of a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) negative feedback pathway diminishes oncogenic signals, thereby attenuating premalignant cell transformation and tumor progression. Modulation of HSP70 function may be a strategy for interfering with oncogenic signals driving liver cell transformation and tumor progression, thus providing an opportunity for human cancer control.

The effect of overweight on the luteinizing hormone level after gonadorelin stimulation test in girls with idiopathic central precocious puberty.

PURPOSE: We investigated the effect of overweight on luteinizing hormone (LH) levels after a gonadorelin stimulation test in Korean girls with idiopathic central precocious puberty (CPP). METHODS: Medical records of 234 girls diagnosed with idiopathic CPP were reviewed retrospectively. CPP was diagnosed when the peak LH levels after gonadorelin stimulation was >5.0 U/L. The enrolled girls had a peak LH level >5.0 U/L after a gonadorelin stimulation test. Selected girls were classified as normoweight (body mass index [BMI] below the 85th percentile with respect to age) and overweight (BMI greater than the 85th percentile with respect to age). RESULTS: The peak LH (8.95±2.85 U/L vs. 11.97±8.42 U/L, P<0.01) and peak follicle-stimulating hormone (9.60±2.91 U/L vs. 11.17±7.77 U/L, P=0.04) after gonadorelin stimulation were lower in overweight girls with idiopathic CPP than in normoweight girls with idiopathic CPP. Being overweight was negatively associated with peak LH levels after gonadorelin stimulation test (odds ratio, 0.89; 95 % confidence interval, 0.81-0.98, P=0.02). CONCLUSION: In girls with idiopathic CPP, being overweight led to a lower LH peak after gonadorelin stimulation. Further research is needed to better understand the role of overweight on gonadotropin secretion in precocious puberty.

Relationships of physical fitness and obesity with metabolic risk factors in children and adolescents: Chungju city cohort study.

PURPOSE: The purpose of this study was to investigate the relationships of physical fitness and obesity with metabolic risk factors in children and adolescents. METHODS: This cohort study was conducted in Chungju city, South Korea. Total 843 subjects were enrolled, including 193 elementary school 4th grade male (E4M), 189 elementary school 4th grade female (E4F) and 461 male-middle school students (M1M). The subjects were also classified into 2 groups by body mass index; normal weight (NW) group and overweight included obesity (OW/OB) group. Physical fitness was measured by shuttle run (cardiorespiratory fitness, CRF), sit and reach (flexibility), handgrip strength (muscular strength) and stand long jump (agility). RESULTS: The prevalence of OW/OB was respectively 33.7% (65 of 193) among E4M, 28.6% (54 of 189) among E4F, and 28.0% (129 of 461) among M1M. Hematocrit, white blood cell, triglyceride, low-density lipoprotein, insulin, homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure were higher, while high-density lipoprotein were lower in the OW/OB group than in the NW group. The OW/OB group presented significantly lower CRF (P<0.01) and lower agility, but higher muscular strength compared with NW group. CRF was negatively correlated with obesity indices and metabolic risk factors. After adjustments for potential confounders, odds ratios for 4th-5th grade CRF of OW/OB compared NW in the E4M, E4F, M1M, were 7.38 (95 % CI, 3.24-16.83), 4.10 (95% CI, 1.83-9.18), 16.06 (95% CI, 8.23-31.00) (P<0.01). CONCLUSION: Our study has shown that CRF has negative correlation with OW/OB in children and adolescents of Chungju city. We suggest that improvement of CRF through regular physical activity would be an important method for reducing the metabolic risks of childhood obesity.

Comprehensive analysis of cytokine gene polymorphisms defines the association of IL-12 gene with ophthalmopthy in Korean children with autoimmune thyroid disease.

In early onset autoimmune thyroid disease (AITD) showing a strong genetic tendency, cytokines have been suggested to play a critical role in the development of AITD. To directly compare the influences of several cytokine gene polymorphisms, 25 single nucleotide polymorphisms (SNPs) in 17 cytokine genes were analyzed on 104 Korean children with AITD [Hashimoto's disease (HD) = 44, Graves' disease (GD) = 60 (thyroid-associated ophthalmopathy (TAO) = 29, non-TAO = 31)] and 192 controls. Compared with healthy controls, any significant association with polymorphisms of cytokine genes was not found in HD and GD. Among GD patients, non-TAO group only showed significant associations with IL-12 C allele (rs3212227: A > C) (76.6% vs. 51.6%, OR = 0.3 [0.15-0.71], Pc = 0.007). Particularly, the frequency of IL-12C allele was significantly lower in the non-TAO group than in the TAO group (82.8% vs. 51.6%, Pc = 0.018). Our comprehensive analysis of cytokine gene polymorphisms suggests that IL-12 gene may play impact on specific pathogenesis of ophthalmopathy in Korean children with AITD.

Corticotropin-Releasing Hormone (CRH) Promotes Macrophage Foam Cell Formation via Reduced Expression of ATP Binding Cassette Transporter-1 (ABCA1).

Atherosclerosis, the major pathology of cardiovascular disease, is caused by multiple factors involving psychological stress. Corticotropin-releasing hormone (CRH), which is released by neurosecretory cells in the hypothalamus, peripheral nerve terminals and epithelial cells, regulates various stress-related responses. Our current study aimed to verify the role of CRH in macrophage foam cell formation, the initial critical stage of atherosclerosis. Our quantitative real-time reverse transcriptase PCR (qRT-PCR), semi-quantitative reverse transcriptase PCR, and Western blot results indicate that CRH down-regulates ATP-binding cassette transporter-1 (ABCA1) and liver X receptor (LXR)-α, a transcription factor for ABCA1, in murine peritoneal macrophages and human monocyte-derived macrophages. Oil-red O (ORO) staining and intracellular cholesterol measurement of macrophages treated with or without oxidized LDL (oxLDL) and with or without CRH (10 nM) in the presence of apolipoprotein A1 (apoA1) revealed that CRH treatment promotes macrophage foam cell formation. The boron-dipyrromethene (BODIPY)-conjugated cholesterol efflux assay showed that CRH treatment reduces macrophage cholesterol efflux. Western blot analysis showed that CRH-induced down-regulation of ABCA1 is dependent on phosphorylation of Akt (Ser473) induced by interaction between CRH and CRH receptor 1(CRHR1). We conclude that activation of this pathway by CRH accelerates macrophage foam cell formation and may promote stress-related atherosclerosis.

Cerebral salt-wasting syndrome after hematopoietic stem cell transplantation in adolescents: 3 case reports.

Cerebral salt-wasting syndrome (CSWS) is a rare disease characterized by a extracellular volume depletion and hyponatremia induced by marked natriuresis. It is mainly reported in patients who experience a central nervous system insult, such as cerebral hemorrhage or encephalitis. The syndrome of inappropriate antidiuretic hormone secretion is a main cause of severe hyponatremia after hematopoietic stem cell transplantation, whereas CSWS is rarely reported. We report 3 patients with childhood acute leukemia who developed CSWS with central nervous system complication after hematopoietic stem cell transplantation. The diagnosis of CSW was made on the basis of severe hyponatremia accompanied by increased urine output with clinical signs of dehydration. All patients showed elevated natriuretic peptide and normal antidiuretic hormone. Aggressive water and sodium replacement treatment was instituted in all 3 patients and 2 of them were effectively recovered, the other one was required to add fludrocortisone administration.

Cushing syndrome secondary to CRH-producing Wilms tumor in a 6 year old.

Abstract Cushing syndrome is caused by prolonged exposure to elevated serum cortisol. It is uncommon in children, and etiology includes pituitary adenoma, adrenal tumor, and exogenous glucocorticoid administration. Rarely, it is paraneoplastic in origin. We present a case of paraneoplastic Cushing syndrome due to Wilms tumor that secreted corticotropin-releasing hormone (CRH). A 6-year-old male presented with polyphagia and weight gain. He showed Cushingoid appearance, hypertension, and palpable left flank mass. Serum cortisol and adrenocorticotropic hormone (ACTH) levels were elevated. Computed tomography showed a neoplasm originating from the left kidney. Pathologic diagnosis of Wilms tumor was made upon nephroureterectomy. Immunohistochemical staining was positive for CRH and negative for ACTH. All features of Cushing syndrome disappeared after surgery. This represents a rare case of Cushing syndrome secondary to Wilms tumor in which CRH production has been demonstrated.

Serum ferritin level is higher in male adolescents with obesity: results from the Korean National Health and Nutrition Examination Survey 2010.

PURPOSE: Previous reports show an association between high serum ferritin levels and metabolic syndrome (MS) in adults. In adolescents, little information is available with obesity and serum ferritin levels. METHODS: This is a cross-sectional study. Data were obtained from the 5th Korean National Health and Nutrition Examination Survey (K-NHANES) conducted during 2010 by the Korean Ministry of Health and Welfare. A total of 849 subjects aged 10-18 years participated in the 2010 survey. A body mass index (BMI) ≥95th percentile for age and sex or a BMI ≥25 was used to diagnose as obesity. RESULTS: The weighted prevalence of obesity was 13.4% (62/462) in male and 8.5% (33/387) in female. We observed significantly higher serum ferritin in male than in female (mean±standard error [SE], 50.5±2.3 µU/L vs. 30.6±1.3 µU/L; P<0.0001). In male, serum ferritin is positively correlated with age (P<0.0001). White blood cell (WBC) count, serum fasting blood sugar, triglyceride (TG), total cholesterol, low-density lipoprotein, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), systolic and diastolic blood pressure, and ferritin levels were higher and high-density lipoprotein (HDL) were lower in the obesity than in the normal group. In female adolescents, WBC count, TG, insulin, and HOMA-IR were higher and HDL were lower in the obesity than in the normal group. In male, serum ferritin levels showed positive association with obesity (ß=21.196, P=0.016). CONCLUSION: Serum ferritin levels appear to be associated with obesity in Korean male adolescents.

Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo.

Studies suggest that Hsf4 expression correlates with its role in cell growth and differentiation. However, the role of Hsf4 in tumorigenesis in vivo remains unexplored. In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice. Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes. Using mouse embryo fibroblasts deficient in the hsf4 gene, we have found that these cells exhibit reduced proliferation that is associated with induction of senescence and senescence-associated ß-galactosidase (SA-ß-gal). Cellular senescence in hsf4-deficient cells is associated with the increased expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins. Consistent with the cellular senescence observed in vitro, specific normal tissues of hsf4(-/-) mice and tumors that arose in mice deficient in both hsf4 and p53 genes exhibit increased SA-ß-gal activity and elevated levels of p27 compared with wild-type mice. These results suggest that hsf4 deletion-induced senescence is also present in vivo. Our results therefore indicate that Hsf4 is involved in modulation of cellular senescence, which can be exploited during cancer therapy.

Primary ovarian dysfunction after hematopoietic stem cell transplantation during childhood: busulfan-based conditioning is a major concern.

We evaluated the incidence of patient/treatment factors associated with primary ovarian failure (POF) after hematopoietic stem cell transplantation (HSCT) during childhood. Fifty girls over 12 years of age (15.0 +/- 2.2) who were referred to the pediatric endocrinology clinic between March 2002 and March 2010 after HSCT at the Catholic HSCT center were enrolled in the study. In total, 36 (72%) out of 50 patients developed POF. Twenty-three patients were diagnosed and treated as chronic graft-versus-host disease. As preparative regimens for HSCT, 23 patients received total body irradiation (TBI)-based regimen, 19 received busulfan (BU)-based regimen, 4 received both BU- and TBI-based, and 4 received reduced intensity conditioning regimen. In a univariate logistic regression analysis, the BU-based regimen (p = 0.028) showed a strong relationship with POF. The incidence of POF according to the route of BU administration, between orally and intravenously, were not different (p = 0.435). These results emphasize the importance of monitoring these patients at regular intervals and the need to develop complementary HSCT protocols for preventing POF in children.