T cell immunoglobulin and mucin domain-3 (Tim-3) is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. Little is known, though, about the function of Tim-3/Gal-9 signaling in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) mediated by hepatic natural killer T (NKT) cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti IL-15R/IL-15 mAb, recombinant IL-15, α-galactosylceramide and multilamellar liposomes containing Cl2MDP. The expression of Tim-3 and various markers reflected cell proliferation, activation, cytokine production and apoptosis were analyzed. Liver histology, steatosis grade and hepatic triglyceride content were also evaluated. In the liver, Tim-3+ NKT cells are in an activated state and Gal-9 directly induces Tim-3+ NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3 expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cells funtion. In summary, the Tim-3/Gal-9 signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation induced apoptosis and secondary proliferation and thus contribute to the pathogenesis of NAFLD.
Increasing evidence suggests gut flora play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous studies show hepatic NKT cells play a significant role in the pathogenesis of NAFLD. In this study, we explore the mechanism by which modification of gut flora leads to the alteration of hepatic NKT cells and improvement of steatosis. Mice were fed HF to induce NAFLD. Some of them also received different dose of mixed strain probiotics (VSL#3); single strain probiotic (B. infantis) or antibiotics. Animal weight, glucose tolerance, liver steatosis and hepatic NKT cells were assessed. Lipid extracts from probiotics were tested their ability to activate NKT cells. Toll like receptor 4 knockout (TLR4 ko) mice were also evaluated for their responses to HF. High dose VSL#3 was much more effective than low dose VSL#3 and B. infantis for the improvement of hepatic NKT cell depletion and steatosis. The lipids extracted from VSL#3 stimulated NKT cells both in vivo and in vitro. In contrast, lipids from B. infantis decreased α-GalCer -mediated NKT cell activation in vitro, but were able to stimulate NKT cells. TLR4 ko mice have a similar effect towards HF-induced NKT cell depletion and obesity. These results suggest alterations in the gut flora have profound effects on hepatic NKT cells and steatosis, which are both strain specific and dose dependent, but not through TLR4 signaling. Furthermore, these data suggest probiotics may contain bacterial glycolipid antigens that directly modulate the effector functions of hepatic NKT cells.
Probiotics; Nonalcoholic fatty liver disease; NKT cells; Steatosis; IL-2
Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response.
The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in
vivo and in
vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells.
Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in
vitro and co-cultured with NKT cells.
High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in
vivo or in
vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis.
High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD.
The increasing prevalence of metabolic syndrome (MS) poses a serious public health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their inter-correlations: waist circumference, systolic and diastolic blood pressure, fasting plasma glucose, triglycerides, and high density lipoprotein cholesterol. We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% CI: 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL-C, and FPG. HDL-C was mainly influenced by common environmental factors (0.62, 95%CI: 0.58–0.62), while the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as inter-correlated traits, and to carefully consider environmental and genetic factors in studying MS etiology.
metabolic syndrome; twin study; heritability; Chinese
Vitamin nutritional status may influence some xenobiotic metabolism or vice versa.
This analysis examines the relationship between B-vitamin concentrations and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT) isomers and metabolites in healthy women. Serum pp′DDT, pp′DDE, pp′DDD, op′DDT, op′DDE, and serum folate, cysteine, and vitamins B6 and B12 were measured in 296 nonsmoking female textile workers (21–34 yr) in Anhui, China. Mean (SD) age and body mass index of this cohort were 24.9 (1.5) y and 19.7 (2.0) kg/m2, respectively.
Median pp′DDT, pp′DDE, pp′DDD, op′DDT, and op′DDE were 1.5, 29.2, 0.22, 0.17, and 0.09 ng/g, respectively. Median folate and cysteine were 9.2 and 200.0 nmol/L, respectively. Folate was significantly inversely associated with pp′DDT and pp′DDE: β (95% confidence interval [CI]) = −0.23 (−0.39, −0.07) and −0.20 (−0.36, −0.05), respectively, and it was marginally associated with pp′DDD. Cysteine was significantly inversely associated with pp′DDT, β (95% CI) = −0.69 (−1.00, −0.37); pp′DDE, β (95% CI) = −0.32 (−0.62, −0.02); pp′DDD, β (95% CI) = −0.31 (−0.59, −0.03); and op′DDT, β (95% CI) = −0.35 (−0.68, −0.02).
Folate and cysteine are independently inversely associated with DDT isomers, adjusting for vitamins B6 and B12, age, and body mass index. These nutrients may play a role in DDT metabolism; however, it is also possible that DDT may exert a negative impact on folate and cysteine levels. Longitudinal studies are needed to ascertain the direction of this association.
DDT isomers/metabolites; folate; cysteine; vitamin B6; vitamin B12
This study investigated whether the association between passive smoking exposure and dysmenorrhea is modified by two susceptibility genes, CYP1A1MspI and CYP1A1HincII.
This report includes 1645 (1124 no dysmenorrhea, 521 dysmenorrhea) nonsmoking and nondrinking newly wed female workers at Anqing, China between June 1997 and June 2000. Multiple logistic regression models were used to estimate the associations of passive smoking exposure and genetic susceptibility with dysmenorrhea, adjusting for perceived stress.
When stratified by women genotype, the adjusted OR of dysmenorrhea was 1.6 (95%CI=1.3-2.1) for passive smoking group with Ile/Ile462 genotype, and 1.5 (95%CI=1.1-2.1) with C/C6235 genotype, compared to non passive smoking group, respectively. The data further showed that there was a significant combined effect between passive smoking and the CYP1A1 Msp1 C/C6235 and HincII Ile/Ile462 genotype (OR=2.6, 95%CI=1.3-5.2).
CYP1A1 MspI and HincII genotypes modified the association between passive smoking and dysmenorrhea.
Cytochrome P-450 CYP1A1; dysmenorrhea; polymorphism; genetic; tobacco smoke polution
Purpose: The aim of this study was to explore the risk factors, clinical symptoms, hematological parameters, causative pathogen and antibiotic susceptibility of neonatal sepsis in a Chinese NICU. Methods: A retrospective survey was conducted on 116 cases of neonatal sepsis in NICU at the Maternal and Child Care Hospital in Shenzhen, China from January 2009 to December 2012. Patients were divided into early-onset sepsis (EOS) and late-onset sepsis groups according to their positive blood culture occurrence time (in the first 7 days of life or later). Results: 116 cases of neonatal sepsis were divided into early-onset sepsis (EOS) group and late-onset sepsis (LOS) group. There was significant difference for risk factors like peripherally insertion central catheter (PICC) between two groups. The clinical symptoms or laboratory results such as chilly periphery, fever, jaundice, platelet and hemoglobin also had between-group differences. The most common responsible pathogenic bacteria species present in EOS group was Coagulase-negative Staphylococcus (CoNS). Among those CoNS Staphylococcus epidermidis provided 24.24%, and Staphylococcus haemolyticus contributed 13.63%. Both were sensitive to vancomycin, teicoplanin and linezolid. The most common responsible pathogenic bacteria species in LOS group was Staphylococcus epidermidis (16%). Antimicrobial susceptibility in EOS group is higher than in LOS group. Conclusion: PICC is a bigger risk factor for neonatal late-onset sepsis. Staphylococcus epidermidis was the leading pathogen present in neonatal sepsis in a tertiary maternal & child care hospital in southern China. Vancomycin, teicoplanin and linezolid may be the best choice to management of neonatal sepsis.
Early-onset sepsis; late-onset sepsis; antimicrobial susceptibility; NICU; China
There are limited data about the role of gender on the relationship between sleep duration and blood pressure (BP) from rural populations.
We conducted a cross-sectional rural population-based study. This report includes 1,033 men and 783 women aged 18–65 years from a cohort of twins enrolled in Anhui, China, between 2005 and 2008. Sleep duration was derived from typical bedtime, wake-up time, and sleep latency as reported on a standard sleep questionnaire. Primary outcomes included measured systolic blood pressure (SBP) and diastolic blood pressure (DBP). High blood pressure (HBP) was defined as SBP≥130 mmHg, DBP ≥85 mmHg, or physician diagnosed hypertension. Linear and logistic regression models were used to assess gender-specific associations between sleep duration and BP or HBP, respectively, with adjustment for known risk factors including adiposity and sleep-related disorder risk from the questionnaires. Generalized estimating equations were used to account for intra-twin pair correlations.
Compared with those sleeping 7 to less than 9 hours, women sleeping <7 hours had a higher risk of HBP (odds ratios [ORs] 3.0, 95% confidence interval [CI], 1.4–6.6); men sleeping ≥9 hours had a higher risk of HBP (ORs=1.5, 95%CI: 1.1–2.2).
Among rural Chinese adults, a gender-specific association of sleep duration with BP exists such that HBP is associated with short sleep duration in women and long sleep duration in men. Longitudinal studies are needed to further examine the temporal relationship and biological mechanisms underlying sleep duration and BP in this population. Our findings underscore the potential importance of appropriate sleep duration for optimal blood pressure.
sleep duration; high blood pressure; gender difference; rural Chinese
Reports of the association between the time interval from coronary angiography (CAG) to cardiac surgery and risk of postoperative acute kidney injury (AKI) are controversial. We attempted to examine this association by conducting a meta-analysis.
We searched the Pubmed, MEDLINE, EMBASE, Web of Science databases, and the Cochrane Library from January 1966 to March 2013. A meta-analysis of studies reporting data for 1-day and 3-day time intervals between CAG and cardiac surgery was conducted after evaluation of heterogeneity and publication bias. Study-specific estimates were combined with inverse variance-weighted averages of logarithmic odds ratios (ORs) in fixed-effects models.
From 8 studies involving 11542 persons, the pooled OR of AKI associated with an interval of 1 day or less between CAG and surgery was 1.21 (95% confidence interval (CI), 1.04 to 1.39) relative to an interval of more than 1 day. From 4 studies involving 5420 persons in the cardiopulmonary-bypass subgroup, the pooled OR of AKI associated with an interval of 3 days or less between CAG and surgery was 1.25 (95% CI, 1.07 to 1.43) relative to an interval of more than 3 days. The adjusted OR of the study in the cardiopulmonary bypass/ deep hypothermic circulatory arrest subgroup was 0.35 (95% CI, 0.17 to 0.73).
A time interval of 1 day or less between CAG and on-pump cardiac surgery was significantly associated with increased risk of AKI. A delay of on-pump cardiac surgery until 24 hours after CAG can potentially decrease postoperative AKI.
Acute kidney injury; Coronary angiography; Cardiac surgery
To evaluate associations between adiposity trajectories over time and insulin sensitivity and glucose deterioration in a Chinese twin cohort.
RESEARCH DESIGN AND METHODS
This study focused on 341 males and 292 females aged 20–50 years at baseline who had physical clinical examinations and oral glucose tolerance test at two time points with an average of 6 years apart. BMI, waist circumference, percent body fat (PBF), and percent trunk fat (PTF) trajectories were classified into five track groups based on age- and sex-specific tertiles at each visit. We calculated the odds of the insulin sensitivity index(0,120) [ISI(0,120)] or glycemic deterioration at follow-up among five defined trajectories (tertilebaseline → tertilefollow-up) using generalized estimate equation models. Additionally, we applied structural equation models to examine genetic and environmental influences on adiposity, adiposity change over time (ACO), ISI(0,120), and the interrelationships among them.
Participants with stable adiposity (BMI, waist circumference, PBF, and PTF) in the highest tertile or shifting to the highest tertile tended to have the lowest ISI(0,120) at follow-up or experience glycemic deterioration. Genetic factors exerted the major influence on adiposity, but environmental factors unique to each twin contributed more strongly to ISI and ACO. Correlations between adiposity/ACO and insulin sensitivity were mainly due to environmental influences.
When adiposity stays or becomes high, insulin sensitivity falls and risk of glycemic deterioration rises. Additionally, we found that genetic factors exerted the major influence on adiposity, while environmental factors played the principal role for ACO and insulin sensitivity.
A 36-year-old man complained of cough, expectoration and progressive anhelation for more than 3 months. Thoracic computed tomography (CT) showed miliary nodules diffusely distributed throughout both lungs. Acute miliary pulmonary tuberculosis (AMPT) was confirmed by sputum culture; meanwhile lung adenocarcinoma was found by sputum cytology. Subsequently, adenocarcinoma of colon was diagnosed according to PET/CT images and histopathology. Herein we report this case of coexistence of AMPT and metastatic lung adenocarcinoma, and suggest that diagnosis of pulmonary tuberculosis should be made cautiously for patients with diffusely military nodules, especially for those without symptoms alleviated after anti-tuberculous treatment.
Acute miliary pulmonary tuberculosis (AMPT); lung adenocarcinoma; coexistence; diagnosis
Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.
p53; breast cancer; cell fate; stem cells; dach
The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was sufficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using floxed Notch (Notchfl/fl ) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.
cancer biology; oncogenes; signal transduction
T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti–IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl2MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3+ NKT cells are in an activated state, and Gal-9 directly induces Tim-3+ NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3–expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9–signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD.
In the clinical setting, drug resistance remains a significant obstacle for successful chemotherapy. Bcl-2/adenovirus EIB 19-kDa-interacting protein 3 (BNIP3) is a proapoptotic member of the Bcl-2 family. To address its potential as a therapeutic target for chemosensitisation, this study investigated the effect of BNIP3 expression on chemosensitivity and reversal of oxaliplatin (L-OHP) resistance in human colon cancer cell lines. A plasmid expressing the BNIP3 gene was transfected into human parental colon cancer cell lines (SW620 and colo320) and L-OHP-resistant colon cancer cell lines (SW620/L-OHP and colo320/L-OHP) using Lipofectamine™ 2000, and the transfection efficiency was determined using fluorescence optics. Western blot analysis identified that SW620/L-OHP and colo320/L-OHP cells expressed lower levels of BNIP3 protein compared with the SW620 and colo320 cells. Transfection with the recombinant BNIP3 plasmid revealed an increase in BNIP3 expression in tumour cells. Following transfection with pDsRed-BNIP3, the chemosensitivity of parental and L-OHP-resistant cell lines to L-OHP was increased (P<0.01), as detected by the Cell Counting Kit-8 (CCK8) assay. Hoechst 33342 staining and flow cytometry revealed that the effects on L-OHP-induced apoptosis were enhanced by the overexpression of BNIP3. Chemosensitisation in human colon cancer cells was observed following treatment with the recombinant BNIP3 plasmid in vitro. The results of this study suggest that BNIP3 is a potential therapeutic target for reversing the resistance of L-OHP-resistant colon cancer cells to L-OHP.
Bcl-2/adenovirus EIB 19-kDa-interacting protein 3; colon cancer; drug resistance; oxaliplatin; chemosensitisation
Avian H5N1 influenza viruses present a challenge in the laboratory environment, as they are difficult to collect from the air due to their small size and relatively low concentration. In an effort to generate effective methods of H5N1 air removal and ensure the safety of laboratory personnel, this study was designed to investigate the characteristics of aerosolized H5N1 produced by laboratory manipulations during research studies.
Normal laboratory procedures used to process the influenza virus were carried out independently and the amount of virus polluting the on-site atmosphere was measured. In particular, zootomy, grinding, centrifugation, pipetting, magnetic stirring, egg inoculation, and experimental zoogenetic infection were performed. In addition, common accidents associated with each process were simulated, including breaking glass containers, syringe injection of influenza virus solution, and rupturing of centrifuge tubes. A micro-cluster sampling ambient air pollution collection device was used to collect air samples. The collected viruses were tested for activity by measuring their ability to induce hemagglutination with chicken red blood cells and to propagate in chicken embryos after direct inoculation, the latter being detected by reverse-transcription PCR and HA test. The results showed that the air samples from the normal centrifugal group and the negative-control group were negative, while all other groups were positive for H5N1.
Our findings suggest that there are numerous sources of aerosols in laboratory operations involving H5N1. Thus, laboratory personnel should be aware of the exposure risk that accompanies routine procedures involved in H5N1 processing and take proactive measures to prevent accidental infection and decrease the risk of virus aerosol leakage beyond the laboratory.
H5N1; Aerosol; Laboratory-associated infections; Occupational and environmental safety
Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization.
To explore the association between sleep duration and sensitization to food and aeroallergens.
This study includes 1534 rural Chinese adolescent twins aged 12 to 21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to 9 food and 5 aeroallergens. Total sleep time was defined as the interval from bedtime to wake-up time minus sleep latency. Sensitization was defined as having at least one positive SPT.
Compared to individuals with the highest (3rd) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 (95% confidence interval(CI):1.3–2.7) and 1.4 (95%CI:1.0–1.9) for the 1st and 2nd tertiles (trend test Ptrend=3×10−4), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95%CI: 1.1–2.0) and 1.3 (95%CI:1.0–1.7) (Ptrend=8×10−3). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (1st tertile) (Ptrend=1×10−3).
Conclusions and Clinical Relevance
In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increased risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth.
sleep duration; skin prick test; allergen; sensitization; adolescent
Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1–/– mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1–rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland–targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.
Aim of the study
The current study aimed to evaluate the clinical efficacy and adverse effects of small doses of propranolol intervention therapy for infants with infantile facial hemangioma in the proliferation stage.
Material and methods
A total of 22 patients including 9 males and 13 females with an average age of 5.5 months were enrolled. These patients were diagnosed with facial hemangioma. During the first week of hospitalization, the patients were requested to take propranolol according to their weight (1.0 mg/kg to 1.5 mg/kg once daily). After hospital discharge, the patients were requested to take propranolol consistently and were reassessed every two weeks. We closely observed the process, recorded information about the size, color, and texture of the hemangioma, coped with the adverse effect during the treatment, and evaluated the clinical efficacy of propranolol.
The color of the hemangioma faded 24 h after taking propranolol. After 3 months to 9 months of observation, we obtained the following clinical efficacies: level I, 0; level II, 2; level III, 13; and level IV, 7. The effective rate was 100%. The heart rate of 22 patients became slower than before treatment, 2 patients had slight diarrhea that disappeared after treatment, and there was no serious adverse effect during the entire process.
With the advantages of minor side effects, convenience, safety, and evident efficacy, the administration of small doses of propranolol is a good method for treating hemangioma in infants.
infants; propranolol; hemangioma
Cyclin D1 overexpression is a common feature of many human malignancies. Genomic deletion analysis has demonstrated a key role for cyclin D1 in cellular proliferation, angiogenesis and cellular migration. To investigate the mechanisms contributing to cyclin D1 functions, we purified cyclin D1a-associated complexes by affinity chromatography and identified the PACSIN 2 (protein kinase C and casein kinase substrate in neurons 2) protein by mass spectrometry. The PACSIN 2, but not the related PACSIN 1 and 3, directly bound wild-type cyclin D1 (cyclin D1a) at the carboxyl terminus and failed to bind cyclin D1b, the alternative splicing variant of cyclin D1. PACSIN 2 knockdown induced cellular migration and reduced cell spreading in LNCaP cells expressing cyclin D1a. In cyclin D1−/− mouse embryonic fibroblasts (MEFs), cyclin D1a, but not cyclin D1b, reduced the cell spreading to a polarized morphology. siPACSIN 2 had no effect on cellular migration of cyclin D1−/− MEFs. Cyclin D1a restored the migratory ability of cyclin D1−/− MEFs, which was further enhanced by knocking down PACSIN 2 with siRNA. The cyclin D1-associated protein, PACSIN 2, regulates cell spreading and migration, which are dependent on cyclin D1 expression.
PACSIN 2; cyclin D1; polymorphism; cellular migration; cell spreading; cancer
We examined the tracking of blood glucose, the development of prediabetes, and estimated their genetic contributions in a prospective, healthy, rural Chinese twin cohort. This report includes 1,766 subjects (998 males, 768 females) aged 6–21 years at baseline who completed a 6-year follow-up study. Oral glucose tolerance test was performed for all subjects at both baseline and follow-up. We found that subjects with low fasting plasma glucose (FPG) or 2 h post-load glucose (PG) levels at baseline tended to remain at the low level at follow-up. Subjects in the top tertile of baseline plasma glucose tended to have a higher risk of developing prediabetes at follow-up compared to the low tertile: in males, 37.6% vs. 27.6% for FPG and 37.2% vs. 25.7% for 2hPG, respectively; in females, 31.0% vs. 15.4% for FPG and 28.9% vs. 15.1% for 2 h PG, respectively. Genetic factors explained 43% and 41% of the variance of FPG, and 72% and 47% for impaired fasting glucose for males and females, respectively; environmental factors substantially contribute to 2hPG status and impaired glucose tolerance. In conclusion, in this cohort of healthy rural Chinese children and adolescents, we demonstrated that both FPG and 2hPG tracked well and was a strong predictor of prediabetes. The high proportion of children with top tertile of blood glucose progressed to prediabetes, and the incidence of prediabetes has a male predominance. Genetic factors play more important role in fasting than postload status, most of which was explained by unique environmental factors.
Pubertal insulin resistance (IR) is well recognized but little data is available for glucose and insulin pattern from a large, unselected lean population. This report describes the age- and gender-specific distributions of glucose tolerance and IR in a rural Chinese twin population. This report includes 4,488 subjects aged 6 to 24 years. The primary variables of interest are fasting plasma glucose (FPG), 2h post-load plasma glucose (2h PG), fasting serum insulin (FSI), 2h post-load insulin (2h PI) and the homeostatic model assessment for IR (HOMA-IR) index. Age- and gender-specific patterns for the primary variables are described using smoothing plot, arithmetic or geometric mean, and percentiles. There is an increase in FPG, 2h PG and IR during puberty (10–19years) and return to pre-puberty level by the age of 20 years. IR peaks around age of 14 years in girls, and 16 years in boys. 2h PG and 2h PI are higher in girls than in boys from early puberty, and the gender differences are more pronounced afterward. Moreover, the prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) increase after puberty, and higher in girls than in boys. In this community based, non-obese rural Chinese twin population, we observed gender-specific remarkable pubertal surge of IR and modest increase in plasma glucose as well as increasing prevalence of IFG and IGT with age. Notably, females had higher 2h PG and higher prevalence of IFG and IGT. Our study underscored that adolescence (even more so in females) is a critical period for developing IR and pre-diabetes.
adolescents; glucose tolerance; insulin resistance; Chinese
To investigate the gene delivery efficiency of string-like PEG-b-PPA/DNA micellar nanoparticles in the liver after intravenous injection and intrabiliary infusion.
PEG-b-PPA/DNA micellar nanoparticles were prepared in aqueous solution through spontaneous self-assembly between plasmid DNA and PEG10K-b-PPA4K or PEG10K-b-PP13K polymer. The stability of these micellar nanoparticles in different physiological media was evaluated by monitoring the particle size change of micellar nanoparticles with dynamic light scattering (DLS). The transfection efficiency of string-like PEG-b-PPA/DNA micellar nanoparticles in the liver was examined and compared with that of PPA/DNA nanoparticles after intravenous and intrabiliary infusion.
These PEG-b-PPA/DNA micellar nanoparticles exhibited unique string-like morphology under TEM. The stability of these string-like nanoparticles in salt-, serum- or bile- containing media was significantly improved compared with PPA/DNA nanoparticles. More importantly, these PEG-b-PPA/DNA nanoparticles mediated 10-fold higher transfection efficiency than PPA/DNA nanoparticles in rat liver when delivered via intrabiliary infusion. In addition, histopathological data revealed that the PEG-b-PPA/DNA nanoparticles induced minimal level of liver toxicity or damage.
These string-like PEG-b-PPA/DNA micelles can mediate efficient transgene expression in the liver after bile duct infusion, and they have great potential to be used as effective gene carriers for liver-targeted gene delivery.
block copolymer; DNA micellar nanoparticles; liver-targeted gene delivery; morphology; string-like
Regulatory T cells (Tregs) and natural killer T (NKT) cells are two distinct lymphocyte subsets that independently regulate hepatic adaptive and innate immunity, respectively. In the current study, we examine the interaction between Tregs and NKT cells to understand the mechanisms of cross immune regulation by these cells.
The frequency and function of Tregs were evaluated in wild type and NKT cell deficient (CD1dko) mice. In vitro lymphocyte proliferation and apoptosis assays were performed with NKT cells co-cultured with Tregs. The ability of Tregs to inhibit NKT cells in vivo was examined by adoptive transfer of Tregs in a model of NKT cell mediated hepatitis.
CD1dko mice have a significant reduction in hepatic Tregs. Although, the Tregs from CD1dko mice remain functional and can suppress conventional T cells, their ability to suppress activation induced NKT cell proliferation and to promote NKT cell apoptosis is greatly diminished. These effects are CD1d dependent and require cell to cell contact. Adoptive transfer of Tregs inhibits NKT cell-mediated liver injury.
NKT cells promote Tregs, and Tregs inhibit NKT cells in a CD1d dependent manner requiring cell to cell contact. These cross-talk immune regulations provide a linkage between innate and adaptive immunity.