MODEM is a comprehensive database of maize multidimensional omics data, including genomic, transcriptomic, metabolic and phenotypic information from the cellular to individual plant level. This initial release contains approximately 1.06 M high quality SNPs for 508 diverse inbred lines obtained by combining variations from RNA sequencing on whole kernels (15 days after pollination) of 368 lines and a 50 K array for all 508 individuals. As all of these data were derived from the same diverse panel of lines, the database also allows various types of genetic mapping (including characterization of phenotypic QTLs, pQTLs; expression QTLs, eQTLs and metabolic QTLs, mQTLs). MODEM is thus designed to promote a better understanding of maize genetic architecture and deep functional annotation of the complex maize genome (and potentially those of other crop plants) and to explore the genotype–phenotype relationships and regulation of maize kernel development at multiple scales, which is also comprehensive for developing novel methods. MODEM is additionally designed to link with other databases to make full use of current resources, and it provides visualization tools for easy browsing. All of the original data and the related mapping results are freely available for easy query and download. This platform also provides helpful tools for general analyses and will be continually updated with additional materials, features and public data related to maize genetics or regulation as they become available.
Database URL: (http://modem.hzau.edu.cn)
Background: Myocardial fibrosis (MF) is a risk factor for poor prognosis in dilated cardiomyopathy (DCM). Late gadolinium enhancement (LGE) of the myocardium on cardiac magnetic resonance (CMR) represents MF. We examined whether the LGE amount increases the incidence of adverse cardiovascular events in patients with stage C or D heart failure (HF).
Methods: Eighty-four consecutive patients with stage C or D HF, either ischemic or non-ischemic, were enrolled. Comprehensive clinical and CMR evaluations were performed. All patients were followed up for a composite endpoint of cardiovascular death, heart transplantation, and cardiac resynchronization therapy with defibrillator (CRT-D).
Results: LGE was present in 79.7% of the end-stage HF patients. LGE distribution patterns were mid-wall, epi-myocardial, endo-myocardial, and the morphological patterns were patchy, transmural, and diffuse. During the average follow-up of 544 days, 13 (15.5%) patients had endpoint events: 7 patients cardiac death, 2 patients heart transplantation, and 4 patients underwent CRT-D implantation. On univariate analysis, LGE quantification on cardiac magnetic resonance, blood urine nitrogen, QRS duration on electrocardiogram, left ventricular end-diastolic diameter (LVEDD), and left ventricular end-diastolic volume (LVEDV) on CMR had the strongest associations with the composite endpoint events. However, on multivariate analysis for both Model I (after adjusting for age, sex, and body mass index) and Model II (after adjusting for age, sex, BMI, renal function, QRS duration, and atrial fibrillation on electrocardiogram, the etiology of HF, LVEF, CMR-LVEDD, and CMR-LVEDV), LGE amount was a significant risk factor for composite endpoint events (Model I 6SD HR 1.037, 95%CI 1.005–1.071, p = 0.022; Model II 6SD HR 1.045, 95%CI 1.001–1.084, p = 0.022).
Conclusion: LGE amount from high-scale threshold on CMR increased the incidence of adverse cardiovascular events for patients in either stage C or D HF.
heart failure; magnetic resonance imaging; late gadolinium enhancement; prognosis; adverse cardiovascular events
Detection of an epidermal growth factor receptor (EGFR) mutation in circulating cell-free DNA (cfDNA) is a noninvasive method to collect genetic information to guide treatment of lung cancer with tyrosine-kinase inhibitors (TKIs). However, the association between cfDNA and detection of EGFR mutations in tumor tissue remains unclear. Here, a meta-analysis was performed to determine whether cfDNA could serve as a substitute for tissue specimens for the detection of EGFR mutations. The pooled sensitivity, specificity, and areas under the curve of cfDNA were 0.60, 0.94, and 0.9208 for the detection of EGFR mutations, 0.64, 0.99, and 0.9583 for detection of the exon 19 deletion, and 0.57, 0.99, and 0.9605 for the detection of the L858R mutation, respectively. Our results showed that cfDNA has a high degree of specificity to detect exon 19 deletions and L858R mutation. Due to its high specificity and noninvasive characteristics, cfDNA analysis presents a promising method to screen for mutations in NSCLC and predict patient response to EGFR-TKI treatment, dynamically assess treatment outcome, and facilitate early detection of resistance mutations.
circulating cell-free DNA; non-small cell lung cancer; sensitivity; specificity; epidermal growth factor receptor
Nasal NK/T-cell lymphoma is a rare type of lymphoma in Caucasian individuals, but is relatively common in Asian populations. Genetic variants in immune and inflammatory response genes may thus be associated with the risk of developing lymphoma. Here, we investigated the association between immuno-modulatory gene polymorphisms and risk for nasal NK/T-cell lymphoma in a Chinese population.
Analysis of 12 single nucleotide polymorphisms (SNPs) in IL-10, TNF-α, lymphotoxin-α (LTA), and CTLA-4 genes was performed for 125 patients with NK/T-cell lymphoma and 300 healthy controls by PCR-ligase detection reactions.
The LTA +252 GA + AA genotypes were associated with increased risk for NK/T-cell lymphoma (OR = 2.96, 95 % CI = 1.42–6.19, P = 0.004 for GA + AA genotype). Haplotype C-G-G-A (TNF-α -857, -308, −238 and LTA +252) also conferred an increased risk (OR = 1.52, 95 % CI = 1.14–2.06, P = 0.005). Additionally, the LTA +252 GA + AA genotype was associated with an even higher risk in populations positive for Epstein–Barr virus (OR = 5.20, 95 % CI = 1.22–23.41, P = 0.03 for the GA + AA genotype).
Our data suggest that the LTA +252 A > G polymorphism is associated with the risk of developing NK/T-cell lymphoma, especially for Epstein–Barr virus-positive NK/T-cell lymphoma in the Chinese population.
NK/T-cell lymphoma; Single nucleotide polymorphisms (SNP); Lymphotoxin-α
Nasopharyngeal carcinoma (NPC) is a common malignant tumor in southern China and Southeast Asia, but its molecular mechanisms of pathogenesis are poorly understood. Our previous work has demonstrated that BCAT1 mRNA is over expressed in NPC and knocking down its expression in 5-8F NPC cell line can potently inhibit cell cycle progression and cell proliferation. However, the mechanism of BCAT1 up-regulation and its functional role in NPC development remain to be elucidated yet.
Immunohistochemistry (IHC) method was utilized to detect the expression of BCAT1 protein in NPC at different pathological stages. The roles of gene mutation, DNA amplification and transcription factor c-Myc in regulating BCAT1 expression were analyzed using PCR-sequencing, quantitative polymerase chain reaction (qPCR), IHC, ChIP and luciferase reporter system, respectively. The functions of BCAT1 in colony formation, cell migration and invasion properties were evaluated by RNA interference (RNAi).
The positive rates of BCAT1 protein expression in normal epithelia, low-to-moderate grade atypical hyperplasia tissues, high-grade atypical hyperplasia tissues and NPC tissues were 23.6% (17/72), 75% (18/24 ), 88.9% (8/9) and 88.8% (71/80), respectively. Only one SNP site in exon1 was detected, and 42.4% (12/28) of the NPC tissues displayed the amplification of microsatellite loci in BCAT1. C-Myc could directly bind to the c-Myc binding site in promoter region of BCAT1 and up-regulate its expression. The mRNA and protein of c-Myc and BCAT1 were co-expressed in 53.6% (15/28) and 59.1% (13/22) of NPC tissues, respectively, and BCAT1 mRNA expression was also down-regulated in c-Myc knockdown cell lines. In addition, BCAT1 knockdown cells demonstrated reduced proliferation and decreased cell migration and invasion abilities.
Our study indicates that gene amplification and c-Myc up-regulation are responsible for BCAT1 overexpression in primary NPC, and overexpression of BCAT1 induces cell proliferation, migration and invasion. The results suggest that BCAT1 may be a novel molecular target for the diagnosis and treatment of NPC.
Nasopharyngeal carcinoma; BCAT1; c-Myc; Proliferation; Migration; Invasion; Gene amplification; Gene regulation
The incidence of young coronary heart disease (CHD, ≤45 years) in China is increasing. Secondary prevention to counter this trend is an important contemporary public health issure.
A total of 5288 patients (≤45 years) diagnosed with CHD and hospitalized at the Chinese PLA General Hospital and Anzhen Hospital, both in Beijing, were enrolled after satisfying the inclusion criteria.
Young CHD patients increased in number from 2010 to 2014, especially men. Among the studied patients, there was no significant change over those years in blood pressure, but heart rate increased significantly (P < 0.05) and body mass index showed a rising trend (P > 0.05). The incidence of hypertension increased from 40.7 to 47.5%, diabetes from 20.3 to 26.1%, and hyperlipidemia from 27.3 to 35.7% (P < 0.05). However, the incidences of smoking and drinking both trended downward (P < 0.05). The levels of total cholesterol and triglycerides also showed a downward trend (P < 0.05), as did levels of low-density lipoprotein, but not to the point of statistical significance (P > 0.05). Mortality during hospitalization decreased significantly from 2010 to 2014 (P < 0.05), but there was no significant improvement in the incidences of cardiac death and major adverse cardiovascular events (MACE) after 1-year follow-up (P > 0.05).
Over the 5 years studied, the overall incidence of cardiac death and MACE for young CHD patients (≤45 years) has shown little improvement. Secondary prevention of young CHD, and its risk factors, as well as appropriate courses of medical treatment must be further elucidated.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-016-0458-1) contains supplementary material, which is available to authorized users.
Young; Coronary heart disease; Risk factors; Prevention; Prognosis
To assess racial, sexual, and regional differences in cerebral hemodynamic response to high altitude (HA, 3658 m). We performed cross-sectional comparisons on total cerebral blood flow (TCBF = sum of bilateral internal carotid and vertebral arterial blood flows = QICA + QVA), total cerebrovascular resistance (TCVR), total cerebral oxygen delivery (TCOD) and QVA/TCBF (%), among six groups of young healthy subjects: Tibetans (2-year staying) and Han (Han Chinese) at sea level, Han (2-day, 1-year and 5-year) and Tibetans at HA. Bilateral ICA and VA diameters and flow velocities were derived from duplex ultrasonography; and simultaneous measurements of arterial pressure, oxygen saturation, and hemoglobin concentration were conducted. Neither acute (2-day) nor chronic (>1 year) responses showed sex differences in Han, except that women showed lower TCOD compared with men. Tibetans and Han exhibited different chronic responses (percentage alteration relative to the sea-level counterpart value) in TCBF (−17% vs. 0%), TCVR (22% vs. 12%), TCOD (0% vs. 10%) and QVA/TCBF (0% vs. 2.4%, absolute increase), with lower resting TCOD found in SL- and HA-Tibetans. Our findings indicate racial but not sex differences in cerebral hemodynamic adaptations to HA, with Tibetans (but not Han) demonstrating an altitude-related change of CBF distribution.
Quercitrin is a well-known flavonoid that is contained in Flos Albiziae, which has been used for the treatment of anxiety. The present study investigated the anxiolytic-like effects of quercitrin in experimental models of anxiety. Compared with the control group, repeated treatment with quercitrin (5.0 and 10.0 mg/kg/day, p.o.) for seven days significantly increased the percentage of entries into and time spent on the open arms of the elevated plus maze. In the light/dark box test, quercitrin exerted an anxiolytic-like effect at 5 and 10 mg/kg. In the marble-burying test, quercitrin (5.0 and 10.0 mg/kg) also exerted an anxiolytic-like effect. Furthermore, quercitrin did not affect spontaneous locomotor activity. The anxiolytic-like effects of quercitrin in the elevated plus maze and light/dark box test were blocked by the serotonin-1A (5-hydroxytryptamine-1A (5-HT1A)) receptor antagonist WAY-100635 (3.0 mg/kg, i.p.) but not by the γ-aminobutyric acid-A (GABAA) receptor antagonist flumazenil (0.5 mg/kg, i.p.). The levels of brain monoamines (5-HT and dopamine) and their metabolites (5-hydroxy-3-indoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid) were decreased after quercitrin treatment. These data suggest that the anxiolytic-like effects of quercitrin might be mediated by 5-HT1A receptors but not by benzodiazepine site of GABAA receptors. The results of the neurochemical studies suggest that these effects are mediated by modulation of the levels of monoamine neurotransmitters.
Single nucleotide polymorphisms (SNPs) in the interleukin-17 (IL-17) gene have been shown to be correlated with susceptibility to cancer. However, various studies report different results of this association. The aim of the present work was to clarify the effects of IL-17A G197A (rs2275913) and IL-17F T7488C (rs763780) polymorphisms on cancer risk. We performed systematic searches of the PubMed and CNKI databases to obtain relevant publications. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the association of rs2275913 and rs763780 polymorphisms with cancer risk. Data were extracted from the selected studies, and statistical analysis was conducted using the STATA software. Our results indicated that rs2275913 and rs763780 polymorphisms significantly increase cancer risk, especially in gastric cancers. Subgroup analysis suggested the existence of a significant correlation between rs763780 polymorphism and cancer susceptibility in Caucasian populations. This updated meta-analysis confirms that rs2275913 and rs763780 polymorphisms are highly associated with increased risk for multiple forms of cancer.
Cell-based therapies are major focus of current research for treatment of liver diseases. In this study, mesenchymal stem cells were isolated from human umbilical cord Wharton's jelly (WJ-MSCs). Results confirmed that WJ-MSCs isolated in this study could express the typical MSC-specific markers and be induced to differentiate into adipocytes, osteoblasts, and chondrocytes. They could also be induced to differentiate into hepatocyte-like cells. Poly (3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx) is a new member of polyhydroxyalkanoate family and biodegradable polyester produced by bacteria. PHBVHHx scaffolds showed much higher cell attachment and viability than the other polymers tested. PHBVHHx scaffolds loaded with WJ-MSCs were transplanted into liver-injured mice. Liver morphology improved after 30 days of transplantation and looked similar to normal liver. Concentrations of serum alanine aminotransferase and total bilirubin were significantly lower, and albumin was significantly higher on days 14 and 30 in the WJ-MSCs+scaffold group than in the carbon tetrachloride (CCl4) group. Hematoxylin-eosin staining showed that liver had similar structure of normal liver lobules and similar size and shape of normal hepatic cells, and Masson staining demonstrated that liver had less blue staining for collagen after 30 days of transplantation. Real-time reverse transcription–polymerase chain reaction (RT-PCR) showed that the expression of the bile duct epithelial cell gene CK-19 in mouse liver is significantly lower on days 14 and 30 in the WJ-MSCs+scaffold group than in the CCl4 group. Real-time RT-PCR, immunocytochemistry, and periodic acid–Schiff staining showed that WJ-MSCs in scaffolds differentiated into hepatocyte-like cells on days 14 and 30 in the WJ-MSCs+scaffold group. Real-time RT-PCR also demonstrated that WJ-MSCs in scaffolds expressed endothelial cell genes Flk-1, vWF, and VE-cadherin on days 14 and 30 in the WJ-MSCs+scaffold group, indicating that WJ-MSCs also differentiated into endothelial-like cells. These results demonstrated that PHBVHHx scaffolds loaded with WJ-MSCs significantly promoted the recovery of injured liver and could be further studied for liver tissue engineering.
Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1–/– phenotype. Here we demonstrate that cells derived from Bmi1–/– mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1–/– mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.
To evaluate the diagnostic performance of quantitative analysis as an adjunctive diagnostic tool to contrast-enhanced ultrasound (US) for the differentiation of atypical benign focal liver lesions (FLLs) from malignancies in fatty liver. Twenty-seven benign FLLs and fifty-six malignant FLLs that appeared hyper-enhanced during the arterial phase with washout in the portal or late phase in fatty liver were analyzed. Chi-square tests and logistic regression were applied to identify the specific features. Three sets of criteria were assigned: 1) all FLLs subjected to routine contrast-enhanced US; 2) all FLLs subjected to quantification analysis and contrast-enhanced US; and 3) parts of FLLs that could not be diagnosed using contrast-enhanced US (n = 66, 75.9%) but instead were diagnosed using parametric features. The sensitivity, specificity, accuracy and area under the receiver operating characteristic curve (AUC) of the three sets of criteria were analyzed. The AUCs of the criterion set 2 were significantly higher than those of criterion set 1 (0.904 versus 0.792, P = 0.008). Criterion set 3 showed a relatively high sensitivity (90.2%) with a relatively high AUC (0.845). The quantification analysis offers improved diagnostic performance for the differential identification of atypical benign FLLs from malignancies in fatty liver.
Supplemental Digital Content is available in the text
Elevated blood pressure (BP) as a risk factor accounts for the biggest burden of disease worldwide and in China. This study aimed to estimate attributed mortality and life expectancy (LE) to elevated BP in Jiangxi province between 2007 and 2010.
BP and mortality data (2007 and 2010 inclusive) were obtained from the National Chronic Diseases and Risk Factors Surveillance Survey and Disease Surveillance Points system, respectively. Population-attributable fraction used in comparative risk assessment of the Global Burden of Disease study 2010 were followed to quantify the attributed mortality to elevated BP, subsequently life table methods were applied to estimate its effects on LE. Uncertainty analysis was conducted to get 95% uncertainty intervals (95% uncertainty interval [UI]) for each outcome.
There are 35,482 (95% UI: 31,389–39,928) and 47,842 (42,323–53,837) deaths in Jiangxi province were caused by elevated BP in 2007 and 2010, respectively. 2.24 (1.87–2.65) years of LE would be gained if all the attributed deaths were eliminated in 2007, and increased to 3.04 (2.52–3.48) in 2010. If the mean value of elevated BP in 2010 was decreased by 5 and 10 mm Hg, 5324 (4710–5991) and 11,422 (10,104–12,853) deaths would be avoided, with 0.41 (0.37–0.48) and 0.85 (0.71–1.09) years of LE gained, respectively.
The deaths attributable to elevated BP in Jiangxi province has increased by 35% from 2007 to 2010, with 0.8 years of LE loss, suggesting the necessity to take actions to control BP in Chinese population.
Myocardial infarction (MI) is a major cause of death and disability worldwide. In the last decade, mesenchymal stem cells (MSCs) based cell therapy has emerged as a promising therapeutic strategy. Although great advance have been made using MSCs to treat MI, the low viability of transplanted MSCs severely limits the efficiency of MSCs therapy. Here, we show evidence that ex vivo pre-treatment with melatonin, an endogenous hormone with newly found anti-oxidative activity, could improve survival and function of adipose tissue derived MSCs (ADSCs) in vitro as well as in vivo. ADSCs with 5 μM melatonin pre-treatment for 24 hrs showed increased expression of the antioxidant enzyme catalase and Cu/Zn superoxide dismutase (SOD-1), as well as pro-angiogenic and mitogenic factors like insulin-like growth factor 1, basic fibroblast growth factor, hepatocyte growth factor (HGF), epidermal growth factor. Furthermore, melatonin pre-treatment protected MSCs from reactive oxygen species (ROS) induced apoptosis both directly by promoting anti-apoptosis kinases like p-Akt as well as blocking caspase cascade, and indirectly by restoring the ROS impaired cell adhesion. Using a rat model of MI, we found that melatonin pre-treatment enhanced the viability of engrafted ADSCs, and promoted their therapeutic potency. Hopefully, our results may shed light on the design of more effective therapeutic strategies treating MI by MSCs in clinic.
adipose tissue derived MSCs; melatonin; myocardial infarction; reactive oxygen species; rat model; apoptosis; viability; therapeutic strategy
Fibroblast activation protein (FAP) plays a vital role in tumor invasion and metastasis. Previous studies have reported its prognostic value in different tumors. However, the results of these reports remain controversial. In this study, a meta-analysis was performed to clarify this issue.
A search of the PubMed, Embase and CNKI databases was conducted to analyze relevant articles. The outcomes included the relations between FAP expression and histological differentiation, tumor invasion, lymph node metastasis, distant metastasis and overall survival (OS). Sensitivity analysis by FAP expression in different cells and tumor types were further subjected to sensitivity analyses as subgroups. Pooled odds ratios (ORs) and hazard ratios (HRs) were evaluated using the random-effects model.
The global analysis included 15 studies concerning various solid tumors. For global analysis, FAP overexpression in tumor tissue displayed significant associations with poor OS and tumor progression (OS: HR = 2.18, P = 0.004; tumor invasion: OR = 4.48, P = 0.007; and lymph node metastasis: OR = 3.80, P = 0.004). The subgroup analyses yielded two notable results. First, the relation between FAP overexpression and poor OS and tumor lymph node metastasis was closer in the patients with FAP expression in tumor cells. Second, the pooled analyses of colorectal cancers or pancreatic cancers all indicated that FAP overexpression was associated with a detrimental OS (HR: 1.72, P = 0.009; HR: 3.18, P = 0.005, respectively). The magnitude of this effect was not statistically significant compared with that in patients with non-colorectal cancers or non-pancreatic cancers. These analyses did not display a statistically significant correlation between FAP expression and histological differentiation and distant metastasis in all of the groups.
FAP expression is associated with worse prognosis in solid tumors, and this association is particularly pronounced if FAP overexpression is found in the tumor cells rather than the stroma.
Electrochemical nanosensors based on nanoporous gold leaf (NPGL) and molecularly imprinted polymer (MIP) are developed for pharmaceutical analysis by using metronidazole (MNZ) as a model analyte. NPGL, serving as the loading platform for MIP immobilization, possesses large accessible surface area with superb electric conductivity, while electrochemically synthesized MIP thin layer affords selectivity for specific recognition of MNZ molecules. For MNZ determination, the hybrid electrode shows two dynamic linear range of 5 × 10−11 to 1 × 10−9 mol L−1 and 1 × 10−9 to 1.4 × 10−6 mol L−1 with a remarkably low detection limit of 1.8 × 10−11 mol L−1 (S/N = 3). In addition, the sensor exhibits high binding affinity and selectivity towards MNZ with excellent reproducibility and stability. Finally, the reliability of MIP-NPGL for MNZ detection is proved in real fish tissue samples, demonstrating the potential for the proposed electrochemical sensors in monitoring drug and biological samples.
Physical inactivity remains an under-researched field in terms of studying burden of disease at provincial level, and no studies have examined the effects of inactivity on life expectancy (LE) in China. The purpose of this study was to estimate mortality risk and LE effects associated with insufficient levels of physical activity in Jiangxi province.
Prevalence of risk factors and mortality counts were extracted from Chronic Diseases and Risk Factors Surveillance Survey (CDRFSS) and Disease Surveillance Points system (DSP), respectively. Insufficient physical activity (IPA) was defined as less than 150 minutes of moderate-intensity physical activity or 60 minutes of vigorous-intensity physical activity per week, accumulated across work, home, transport and discretionary domains. Population-attributable fractions (PAF) were used to calculate the mortality attributable to risk factors, and life table methods were used to estimate the LE gains and LE shifts. Monte Carlo simulation techniques were used for uncertainty analysis. Overall, 5 885 (95% uncertainly interval (UI), 5 047–6 506) and 8 578 (95% UI, 8 227–9 789) deaths in Jiangxi province were attributable to IPA in 2007 and 2010, respectively. The LE gains for elimination of attributable deaths were 0.68 (95% UI, 0.61–076) in 2007, and increased to 0.91 (95% UI, 0.81–1.10) in 2010. If the prevalence of IPA in 2010 had been decreased by 50% or 30%, 3 678 (95% UI, 3 220–4 229) or 2 090 (95% UI, 1 771–2 533) deaths would be avoided, and 0.40 (95% UI, 0.34–0.53) or 0.23 (95% UI, 0.16–0.31) years of LE gained, respectively.
Adults in Jiangxi province of China have a high and increasing prevalence of IPA. Due to the deaths and potential LE gains associated with IPA, there is an urgent need to promote physical activity, one of the most modifiable risk factors, within China's health care reform agenda.
The primary aim of this research was to investigate the association between uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms and the toxicities of irinotecan-based regimens in Chinese patients with metastatic colorectal cancer.
The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The adverse reactions and tumor response were evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0, and Response Evaluation Criteria In Solid Tumors, Version 1.0, criteria, respectively. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia was analyzed. The influences of UGT1A1*6/*28 polymorphisms on response rate and progression-free survival were also analyzed. Survival analysis was performed by the Kaplan–Meier method, and we used the log-rank test to analyze the effect of genotypes on progression-free survival, the logistic regression model for multivariate analysis, and the Cox regression model for multivariate survival analysis.
A total of 167 patients with metastatic colorectal cancer who were treated with irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. The rate of UGT1A1*28 homozygous wild-type TA6/6, heterozygous mutant-type TA6/7, and homozygous mutant-type TA7/7 was 65.3% (109/167), 32.3% (54/167), and 2.4% (4/167), respectively; the incidence of UGT1A1*6 wild-type G/G was 67.1% (112/167), heterozygous mutant-type G/A accounted for 28.7% (48/167), and seven cases were homozygous mutant-type A/A (4.2%; 7/167). The incidence of grade 3 or 4 delayed diarrhea in patients carrying UGT1A1*6 (G/A and A/A) was higher than that in the wild-type (G/G) (P=0.021). The rate was significantly lower in patients with the UGT1A1*28 TA6/6 wide-type genotype than those with TA6/7 and TA7/7 mutant-type genotypes (P=0.027). However, neither UGT1A1*6 (P=0.34) nor UGT1A1*28 (P=0.232) variants were significantly associated with severe neutropenia. Our study found no significant differences of severe neutropenia in patients with different numbers of mutational alleles (P=0.354), but patients with two alleles or single allele variants had more chances to develop severe diarrhea than patients with wild-type (P=0.027). No significant differences of either response rate or progression-free survival were found among different genotypes (P>0.05).
For irinotecan-based regimens in metastatic colorectal cancer, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for irinotecan-associated severe delayed diarrhea, whereas no association between UGT1A1 gene polymorphisms and severe neutropenia was observed. We also found that neither clinical response nor prognosis were significantly associated with UGT1A1 gene polymorphisms.
uridine diphosphate glucuronosyltransferase 1A1; gene polymorphism; metastatic colorectal cancer; irinotecan
AIM: To investigate the effects of dihydromyricetin (DHM) on the migration and invasion of human hepatic cancer cells.
METHODS: The hepatoma cell lines SK-Hep-1 and MHCC97L were used in this study. The cells were cultured in RPIM-1640 medium supplemented with 10% fetal bovine serum at 37 °C in a humidified 5% CO2 incubator. DHM was dissolved in dimethyl sulfoxide and diluted to various concentrations in medium before applying to cells. MTT assays were performed to measure the viability of the cells after DHM treatment. Wound healing and Boyden transwell assays were used to assess cancer cell motility. The invasive capacity of cancer cells was measured using Matrigel-coated transwell chambers. Matrix metalloproteinase (MMP)-2/9 activity was examined by fluorescence analysis. Western blot was carried out to analyze the expression of MMP-2, MMP-9, p-38, JNK, ERK1/2 and PKC-δ proteins. All data were analyzed by Student’s t tests in GraphPad prism 5.0 software and are presented as mean ± SD.
RESULTS: DHM was found to strongly inhibit the migration of the hepatoma cell lines SK-Hep-1 (without DHM, 24 h: 120 ± 8 μmol/L vs 100 μmol/L DHM, 24 h: 65 ± 10 μmol/L, P < 0.001) and MHCC97L (without DHM, 24 h: 126 ± 7 μmol/L vs 100 μmol/L DHM, 24 h: 74 ± 6 μmol/L, P < 0.001). The invasive capacity of the cells was reduced by DHM treatment (SK-Hep-1 cells without DHM, 24 h: 67 ± 4 μmol/L vs 100 μmol/L DHM, 24 h: 9 ± 3 μmol/L, P < 0.001; MHCC97L cells without DHM, 24 h: 117 ± 8 μmol/L vs 100 μmol/L DHM, 24 h: 45 ± 2 μmol/L, P < 0.001). MMP2/9 activity was also inhibited by DHM exposure (SK-Hep-1 cells without DHM, 24 h: 600 ± 26 μmol/L vs 100 μmol/L DHM, 24 h: 100 ± 6 μmol/L, P < 0.001; MHCC97L cells without DHM, 24 h: 504 ± 32 μmol/L vs 100 μmol/L DHM 24 h: 156 ± 10 μmol/L, P < 0.001). Western blot analysis showed that DHM decreased the expression level of MMP-9 but had little effect on MMP-2. Further investigation indicated that DHM markedly reduced the phosphorylation levels of p38, ERK1/2 and JNK in a concentration-dependent manner but had no impact on the total protein levels. In addition, PKC-δ protein, a key protein in the regulation of MMP family protein expression, was up-regulated with DHM treatment.
CONCLUSION: These findings demonstrate that DHM inhibits the migration and invasion of hepatoma cells and may serve as a potential candidate agent for the prevention of HCC metastasis.
Dihydromyricetin; Migration; Invasion; Hepatic cancer; Matrix metalloproteinase-9
The purpose of this research was to investigate the relationship between epidermal growth factor receptor (EGFR) mutations and the response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).
A total of 266 patients with stage IIIB or IV NSCLC who received platinum-based doublet therapies as first-line chemotherapy were investigated retrospectively, and their clinical data were assessed according to EGFR mutation.
EGFR mutations were identified in 45.5% of patients. There was no significant difference in response rate between EGFR mutation carriers and EGFR wild-type carriers (P=0.484). Among the patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type, however, those with EGFR mutations responded better to treatment than EGFR wild-type patients (46.2% versus 20.8%, P=0.043). The disease control rate associated with pemetrexed-based treatments was higher than for vinorelbine-based therapies in EGFR mutation patients (P=0.001). EGFR mutation was found in patients with longer progression-free survival and median survival time, and improved 1-year and 2-year overall survival when compared with EGFR wild-type patients (6.1 versus 5.0 months, P=0.004; 18.9 versus 13.8 months, P=0.001; 81.0% versus 63.4%, P=0.002; and 33.9% versus 22.8% P=0.044, respectively). Patients with the EGFR exon 19 mutation had longer progression-free survival than those with EGFR exon 21 mutation (P=0.007). Multivariate analysis showed that the response to first-line chemotherapy and the presence of EGFR mutations were independent prognostic factors in patients with advanced NSCLC.
Our data showed that the presence of EGFR mutations meant longer survival times for patients with advanced NSCLC who received platinum-based doublet first-line chemotherapy, especially in those with the exon 19 deletion mutation. Among KRAS wild-type patients, those with EGFR mutation responded better to first-line chemotherapy than EGFR wild-type patients.
non-small cell lung cancer; chemotherapeutic agents; epidermal growth factor receptor mutation; targeted therapy; prognosis
The human epidermal growth factor receptor 2 (HER2) represents one of the most studied tumor-associated antigens (TAAs) for cancer immunotherapy. The monoclonal antibody (mAb) trastuzumab has improved the outcomes of patients with HER2+ breast cancer. However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed.
HER2-specific T cells were generated by the transfer of genes that encode chimeric antigen receptor (CAR). Using a multistep overlap extension PCR method, we constructed a novel, humanized HER2 CAR-containing, chA21 single-chain variable fragment (scFv) region of antigen-specific mAb and T-cell intracellular signaling chains made up of CD28 and CD3ζ. An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells. Furthermore, SKBR3 tumor–bearing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice were treated with HER2 CAR T cells to evaluate antitumor activity. Human CD3+ T cell accumulation in tumor xenograft was detected by immunohistochemistry.
chA21-28z CAR was successfully constructed, and both CD4+ and CD8+ T cells were transduced. The expanded HER2 CAR T cells expressed a central memory phenotype and specifically reacted against HER2+ tumor cell lines. Furthermore, the SKBR3 tumor xenograft model revealed that HER2 CAR T cells significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed robust accumulation of human CD3+ T cells in regressing SKBR3 lesions.
The results of this study show that novel chA21 scFv-based, HER2-specific CAR T cells not only recognized and killed HER2+ breast and ovarian cancer cells ex vivo but also induced regression of experimental breast cancer in vivo. Our data support further exploration of the HER2 CAR T-cell therapy for HER2-expressing cancers.
Investigations of Mycobacterium tuberculosis genetic diversity in China have indicated a significant regional distribution. The aim of this study was to characterize the genotypes of clinical M. tuberculosis isolates obtained from Gansu, which has a special geographic location in China.
A total of 467 clinical M. tuberculosis strains isolated in Gansu Province were genotyped by 15-locus mycobacterial interspersed repetitive units–variable number tandem repeats (MIRU-VNTR) and spoligotyping. The results showed that 445 isolates belonged to six known spoligotype lineages, whereas 22 isolates were unknown. The Beijing genotype was the most prevalent (87.58%, n = 409), while the shared type 1 was the dominant genotype (80.94%, n = 378). The second most common lineage was the T lineage, with 25 isolates (5.35%), followed by the H lineage with 5 isolates (1.07%), the MANU family (0.64%, 3 isolates), the U family (0.43%, 2 isolates) and the CAS lineage with 1 isolate (0.21%). By using the VNTR15China method, we observed 15 groups and 228 genotypes among the 467 isolates. We found no association between the five larger groups (including the Beijing genotype) and sex, age, or treatment status, and there was no noticeable difference in the group analysis in different areas. In the present study, seven of the 15 MIRU-VNTR loci were highly or moderately discriminative according to their Hunter-Gaston discriminatory index.
The Beijing genotype is the predominant genotype in Gansu province. We confirm that VNTR15China is suitable for typing Beijing strains in China and that it has a better discriminatory power than spoligotyping. Therefore, the use of both methods is the most suitable for genotyping analysis of M. tuberculosis.
Chronic obstructive pulmonary disease (COPD) is a common disease that severely threatens human health. Acute exacerbation of COPD (AECOPD) is a major cause of disease progression and death, and causes huge medical expenditures. This consensus statement represents a description of clinical features of AECOPD in the People’s Republic of China and a set of recommendations. It is intended to provide clinical guidelines for community physicians, pulmonologists and other health care providers for the prevention, diagnosis, and treatment of AECOPD.
COPD; AECOPD; recommendations; guidelines
To provide prognosis of an 18 patient cohort who were confirmed to have H7N9 lung infection in Shanghai.
Patients' history, clinical manifestation, laboratory test, treatment strategy and mortality were followed and recorded for data analysis.
A total of 18 patients had been admitted into Shanghai Public Health Clinical Center from April 8th to July 29, 2013. 22.2% of the patients were found to have live poultry contact history and 80% were aged male patients with multiple co-morbidities including diabetes, hypertension and/or chronic obstructive pulmonary disease (COPD). This group of patients was admitted to the clinical center around 10 days after disease onset. According to laboratory examinations, increased C reactive protein (CRP), Procalcitonin (PCT), Plasma thromboplastin antecedent (PTA) and virus positive time (days) were indicative of patients' mortality. After multivariate analysis, only CRP level showed significant prediction of mortality (P = 0.013) while results of prothrombin time (PT) analysis almost reached statistical significance (P = 0.056).
H7N9 infection induced pneumonia of different severity ranging from mild to severe pneumonia or acute lung injury/acute respiratory distress syndrome to multiple organ failure. Certain laboratory parameters such as plasma CRP, PCT, PTA and virus positive days predicted mortality of H7N9 infection and plasma CRP is an independent predictor of mortality in these patients.