Background & Aims
Guanylin, an endogenous gastrointestinal peptide, causes the translocation of NaCl from interstitial fluid to the intestinal lumen. The aim of this study was to examine whether changes in dietary salt intake lead to compensatory changes in expression of the guanylin signaling pathway.
Rats received low-, normal-, or high-sodium diets for 1 week. Colonic guanylin expression was evaluated by Western and Northern blotting, rates of guanylin secretion by measuring biologically active guanylin released into the medium from colon explants, and expression of the guanylin receptor (C-type guanylate cyclase) by Northern blotting and bioassay.
By every criterion, the low-salt diet reduced expression of guanylin to 30%–40% of the level found in control animals. Guanylin receptor expression was also decreased, although less dramatically and with a lower statistical significance. For both guanylin and guanylin receptor, the high-salt diet had no significant effect on expression.
The data support the hypothesis that the guanylin pathway is down-regulated as an adaptive response to salt restriction.
The aim of the present work was to study the in vitro/in vivo characteristics of dutasteride loaded biodegradable microspheres designed for sustained release of dutasteride over four weeks. An O/W emulsion-solvent evaporation method was used to incorporate dutasteride, which is of interest in the treatment of benign prostatic hyperplasia (BPH), into poly(lactide-co-glycolide) (PLGA). A response surface method (RSM) with central composite design (CCD) was employed to optimize the formulation variables. A prolonged in vitro drug release profile was observed, with a complete release of the entrapped drug within 28 days. The pharmacokinetics study showed sustained plasma drug concentration-time profile of dutasteride loaded microspheres after subcutaneous injection into rats. The in vitro drug release in rats correlated well with the in vivo pharmacokinetics profile. The pharmacodynamics evaluated by determination of the BPH inhibition in the rat models also showed a prolonged pharmacological response. These results suggest the potential use of dutasteride loaded biodegradable microspheres for the management of BPH over long periods.
Large-volume paracentesis (LVP) can be time and labor intensive depending on the amount of ascites removed and the method of drainage. Wall suction has been adopted as the preferred method of drainage at many centers, though the safety and benefits of this technique have not been formally evaluated. The primary objective of this study was to define the cost and time savings of wall suction over the traditional glass vacuum bottle method for ascites drainage. The secondary objective was to compare the safety profile and patient satisfaction using these two techniques.
We conducted a randomized, controlled pilot study of the wall suction versus vacuum bottle methods for LVP in hospitalized patients. All LVPs were performed under ultrasound guidance by a single proceduralist. Patients with at least 4 liters removed received 25% intravenous albumin, 8 g/liter fluid removed. Demographic, clinical characteristics, and procedure details were recorded. Laboratory and hemodynamic data were recorded for 24 h prior to and 24–48 h post LVP. An electronic chart review was conducted to evaluate procedure-related complications. Data were compared using Fisher’s exact test, t test, or Mann–Whitney U test.
Thirty-four patients were randomized to wall suction at 200 mmHg (n = 17) or glass vacuum bottle drainage (n = 17). Wall suction was significantly faster and less costly than vacuum bottle drainage (7 versus 15 min, p = 0.002; $4.59 versus $12.73, p < 0.001). There were no differences in outcomes at 24 and 48 h post LVP, or at 60-day follow up.
Performing LVP using wall suction resulted in significantly shorter procedure time and supply cost savings. There were no differences in outcomes between the groups, suggesting equivalent safety, though larger studies powered to detect small differences are needed. Given its efficiency, convenience, and cost effectiveness, wall suction may be a superior method of ascites drainage for LVP.
ascites; cirrhosis; methods; paracentesis
The aim of the present study was to compare radiotherapy treatment plans for gastric cancer using intensity-modulated radiotherapy (IMRT) and single/double-arc volumetric modulated arc therapy (SA/DA-VMAT) delivery techniques. A total of 29 postoperative gastric cancer patients were enrolled in this study and each patient was scheduled 5-field IMRT (5F-IMRT), 7-field IMRT (7F-IMRT), SA-VMAT and DA-VMAT techniques. Dose-volume histogram statistics, conformal index (CI), homogeneity index (HI) and monitor units (MUs) were analyzed to compare treatment plans. The DA-VMAT plans exceeded the other three methods in terms of planning tumor volume dose and organs at risk in the kidneys, but not in the liver. DA-VMAT exhibited a better mean CI (0.87±0.03) and HI (0.10±0.01) than the other techniques. In addition, for the kidneys the dose sparing (V13, V18 and mean kidney dose) was improved by DA-VMAT plans. Similar results were observed for MUs. However, 5F-IMRT showed a marginal advantage in V30 and mean dose in normal liver when compared with DA-VMAT. The results of this study suggest that DA-VMAT provides improved tumor coverage when compared with 5F-IMRT, 7F-IMRT and SA-VMAT; however, DA-VMAT exhibits no advantage in liver protection when compared with 5F-IMRT. Further studies are required to establish differences in treatment outcomes among the four technologies.
gastric cancer; intensity-modulated radiotherapy; volumetric modulated arc therapy; dosimetric comparison
Effects of chronic cadmium exposure on liver disease and liver-related mortality are unknown. We evaluated the association of creatinine-corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population.
We analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988–1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study.
The cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83 μg/g for men and women, respectively (P<0.001). After multivariate adjustment for other factors including smoking, the odds ratios [95 % confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95 % CI, 1.64–3.00), 1.30 (95 % CI, 1.01–1.68) and 1.95 (95 % CI, 1.11–3.41) for men and 1.26 (95 % CI, 1.01–1.57), 1.11 (95 % CI, 0.88–1.41) and 1.34 (95 % CI, 0.72–2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95 % CI, 1.12–10.47) and 1.25 (95 % CI, 0.37–4.27).
Environmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality.
Liver; Cadmium; Steatosis; Survey; Mortality; NHANES
Hyperactive EGFR and mutant p53 are common genetic abnormalities driving the progression of non-small cell lung cancer (NSCLC), the leading cause of cancer deaths in the world. The Drosophila gene Dachshund (Dac) was originally cloned as an inhibitor of hyperactive EGFR alleles. Given the importance of EGFR signaling in lung cancer etiology, we examined the role of DACH1 expression in lung cancer development. DACH1 protein and mRNA expression was reduced in human NSCLC. Re-expression of DACH1 reduced NSCLC colony formation and tumor growth in vivo via p53. Endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar location, and shared occupancy of -15% of p53 bound genes in ChIP Seq. The C-terminus of DACH1 was necessary for direct p53 binding, contributing to the inhibition of colony formation and cell cycle arrest. Expression of the stem cell factor SOX2 was repressed by DACH1, and SOX2 expression was inversely correlated with DACH1 in NSCLC. We conclude that DACH1 binds p53 to inhibit NSCLC cellular growth.
Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates the pRB protein and promotes G1/S cell cycle progression and oncogenesis. Dicer is a central regulator of miRNA maturation, encoding an enzyme that cleaves double strand RNA or stem-loop-stem RNA into 20–25 nucleotide long small RNA, governing sequence specific gene silencing and heterochromatin methylation. The mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Here we show that cyclin D1−/− cells are defective in pre-miRNA processing which is restored by cyclin D1a rescue. Cyclin D1 induces Dicer expression in vitro and in vivo. Dicer is transcriptionally targeted by cyclin D1, via a cdk-independent mechanism. Cyclin D1 and Dicer expression significantly correlates in luminal A and basal-like subtypes of human breast cancer. Cyclin D1 and Dicer maintain heterochromatic histone modification (Tri-m-H3K9). Cyclin D1-mediated cellular proliferation and migration is Dicer-dependent. We conclude that cyclin D1 induction of Dicer coordinates microRNA biogenesis.
Background: Children are recognized as “therapeutic orphan” in many parts of the world, one expression of this is the lack of adequate pediatric labeling information. Some research studies have been done to investigate the pediatric labeling condition in the U.S. and other countries, but no national studies had been carried out in China. This survey was conducted aiming to inquire the current situation of pediatric labeling in China.
Methods: We investigated 6020 child-applied medicines from 15 representative Chinese hospitals, and analyzed the information according to the dosage forms, therapeutic category, and label information integrity.
Results: Among all these medicines, only 238 (3.95%) are pediatric products, the rest are adult formulations with an extended use in children. The major pediatric formulations were injection (45.95%), tablet (23.69%), and capsule (4.93%), respectively. Alimentary tract/metabolism medicine (24.70%) and infections medicines (20.60%) had the most species. In prescription drugs, only 210 of 5187 (4%) medicines had adequate pediatric labeling information. The main cause of this deficiency was lack of evidence derived from pediatric clinical trials.
Conclusion: The dilemma of “therapeutic orphan” requires significant attention. Inadequate labeling information and lack of pediatric clinical trials were two prominent issues in China. It calls for more efforts from pharmaceutical industries, regulatory agencies, and legislature in China to collaborate and find solution to improve the situation.
pediatric; label; information; integrity; China
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