As part of our search for new antifungal agents from natural resources, 22 C-27 steroidal saponins and 6 steroidal sapogenins isolated from several monocotyledonous plants were tested for their antifungal activity against the opportunistic pathogens Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus. The results showed that the antifungal activity of the steroidal saponins was associated with their aglycone moieties and the number and structure of monosaccharide units in their sugar chains. Within the 10 active saponins, four tigogenin saponins (compounds 1 to 4) with a sugar moiety of four or five monosaccharide units exhibited significant activity against C. neoformans and A. fumigatus, comparable to the positive control amphotericin B. The antifungal potency of these compounds was not associated with cytotoxicity to mammalian cells. This suggests that the C-27 steroidal saponins may be considered potential antifungal leads for further preclinical study.
A large amount of organophosphate pesticides (OPs) are used in agriculture in China every year, contributing to exposure of OPs through dietary consumption among the general population. However, the level of exposure to OPs in China is still uncertain.
To investigate the effect of the exposure to OPs on the neonatal neurodevelopment during pregnancy in Shenyang, China.
249 pregnant women enrolled in the Central Hospital Affiliated to Shenyang Medical College from February 2011 to August 2012. A cohort of the mothers and their neonates participated in the study and information on each subject was obtained by questionnaire. Dialkyl phosphate (DAP) metabolites were detected in the urine of mothers during pregnancy to evaluate the exposure level to OPs. Neonate neurobehavioral developmental levels were assessed according to the standards of the Neonatal Behavioral Neurological Assessment (NBNA). Multiple linear regressions were utilized to analyze the association between pregnancy exposure to OPs and neonatal neurobehavioral development.
The geometric means (GM) of urinary metabolites for dimethyl phosphate (DMP), dimethyl thiophosphate (DMTP), diethyl phosphate (DEP), and diethyl thiophosphate (DETP) in pregnant women were 18.03, 8.53, 7.14, and 5.64 µg/L, respectively. Results from multiple linear regressions showed that prenatal OP exposure was one of the most important factors affecting NBNA scores. Prenatal total DAP concentrations were inversely associated with scores on the NBNA scales.?Additionally, a 10-fold increase in DAP concentrations was associated with a decrease of 1.78 regarding the Summary NBNA (95% CI, −2.12 to −1.45). And there was an estimated 2.11-point difference in summary NBNA scores between neonates in the highest quintile of prenatal OP exposure and the lowest quintile group.
The high exposure of pregnant women to OPs in Shenyang, China was the predominant risk factor for neonatal neurobehavioral development.
Dynamic regulation of histone methylation represents a fundamental epigenetic mechanism underlying eukaryotic gene regulation, yet little is known about how the catalytic activities of histone demethylases are regulated. Here, we identify and characterize NPAC/GLYR1 as an LSD2/KDM1b-specific cofactor that stimulates H3K4me1 and H3K4me2 demethylation. We determine the crystal structures of LSD2 alone and LSD2 in complex with the NPAC linker region in the absence or presence of histone H3 peptide, at resolutions of 2.9, 2.0, and 2.25 Å, respectively. These crystal structures and further biochemical characterization define a dodecapeptide of NPAC (residues 214–225) as the minimal functional unit for its cofactor activity and provide structural determinants and a molecular mechanism underlying the intrinsic cofactor activity of NPAC in stimulating LSD2-catalyzed H3K4 demethylation. Thus, these findings establish a model for how a cofactor directly regulates histone demethylation and will have a significant impact on our understanding of catalytic-activity-based epigenetic regulation.
Severe spinal deformity is a complex morphological deformation that occurs and develops in three-dimensional space combined with abnormal development and morphology of anatomical structures, which presents great difficulties in the process of transpedicular screw placement. This study tried to explore the methods of transpedicular screw placement in surgical correction of severe spinal deformities.
Surgical corrections through posterior approach were performed in all the 76 cases (mean age 20.4 years). The averaging preoperative Cobb’s angle of scoliosis was 108.2° ± 33.6° (range 100°–170°). Among these patients, 34 cases were combined with kyphosis; the average Cobb’s angle of kyphosis was 77.3° (range 63°–160°). During operation, the screw tract was first established with the regular free-hand pedicle screw placement method. When this failed, in order to adjust the screw trajectory, a five-step remedial method was performed in the following order: (1) the“funnel” method; (2) exploring the pedicle exterior edge through the costotransverse joint; (3) exploring the superior and inferior edges of pedicle through the nerve root canal; (4) the vertebral plate fenestration; and (5) hemilaminectomy.
Among all 1,472 screws planned to be placed for the patients, 1,210 (82.2 %) were successfully placed after using the regular method, and 262 (17.8 %) failed in this stage. After applying the five-step remedial method, 256 of the failed 262 screws were successfully placed. Among them, 176 screws (68.8 %) were successfully placed after Step 1, 44 (17.2 %) after Step 2, 21 (8.2 %) after Step 3, 12 (4.7 %) after Step 4, and 3 (1.2 %) after Step 5. In only six, pedicles screws could not be placed eventually. No nerve or blood vessel damages occurred in all cases. All final screw positions were validated by CT.
The five-step remedial method proved to be an effective supplementary method for transpedicular screw placement to treat patients with severe spinal deformities. The key points include a detailed preoperative plan, a meticulous hand drilling sensation, and an experienced probing technique for screw tract.
Spinal deformity; Transpedicular fixation; Free-hand
Atherosclerosis is the underlying cause of cardiovascular disease, the leading cause of morbidity and mortality in all American populations including American Indians. Genetic factors play an important role in the etiology of atherosclerosis. While a single SNP may explain only a small portion of variability in disease, the joint effect of multiple variants in a pathway on disease susceptibility could be large.
Methods and Results
Using a gene-family analysis, we investigated the joint associations of 61 tag SNPs in seven nicotinic acetylcholine receptors (nAChRs) genes with subclinical atherosclerosis, as measured by carotid intima-media thickness (IMT) and plaque score, in 3,665 American Indians from 94 families recruited by the Strong Heart Family Study (SHFS). Although multiple SNPs showed marginal association with IMT and/or plaque score individually, only a few survived adjustments for multiple testing. However, simultaneously modeling of the joint effect of all 61 SNPs in seven nAChRs genes revealed significant association of the nAChR gene family with both IMT and plaque score, independent of known coronary risk factors.
Genetic variants in the nicotinic acetylcholine receptors gene family jointly contribute to subclinical atherosclerosis in American Indians participated in the SHFS. These variants may influence the susceptibility of atherosclerosis through pathways other than cigarette smoking per se.
American Indians atherosclerosis; epidemiology; genetic variation; pathway analysis; smoking
Objective: to evaluate the therapeutic effect of targeted endostatin-loaded microbubbles, combined with improved, focused, directional ultrasound radiation for inhibition of subcutaneous translocation in situ colon tumor angiogenesis in colon cancer.
Methods: 65 BALB/c nude mice with subcutaneous translocation in situ colon tumors were randomly divided into five groups. Group A was the control group, without any treatments. In Group B, the mouse was treated with ultrasonic radiation. In Group C, the mouse was treated with ultrasonic radiation combined with empty SonoVue microbubbles. In Group D, the mouse was treated with ultrasonic radiation combined with empty Targestar-SA microbubbles. In Group E, the mouse was treated with ultrasonic radiation combined with endostatin microbubbles. The tumor size was measured before and 1, 14, and 28 days after irradiation. The peak intensity (PI), regional blood volume (RBV) and regional blood flow (RBF) were recorded using contrast-enhanced ultrasound. The tumor tissue was removed for pathological examination; the tumor necrosis area and microvascular density (MVD) were evaluated by immunohistochemistry.
Results: Tumors in Groups C, D and E were significantly smaller than in Groups A and B at 28 days after irradiation, with Group E the smallest. PI, RBF and RBV of Groups C, D, and E were significantly decreased 28 days after radiation with Group E the lowest, and significantly lower than Groups A and B (all P < 0.05). The tumor tissue necrosis area of Group E was clearly greater while MVD was obviously lower than the other groups (all P < 0.01) at 28 days after treatment.
Conclusion: The targeted endostatin microbubbles, combined with focused, directional ultrasound radiation can damage tumor microvasculature of subcutaneous colon translocation in situ colon cancer, as well as inhibit the tumor angiogenesis.
colorectal cancer; tumor angiogenesis; ultrasonic cavitation; endostatin
The newly diagnosed rate of HCV infection is increasing in China. However, the risk factors have not been fully identified. Here, a survey was performed in Yanbian Prefecture, a high-endemic area in China.
We identified newly diagnosed HCV infection in 2007–2011, using the local National Disease Supervision Information Management System from the Chinese Center for Disease Control and Prevention. We determined the risk factors using a case-control survey by questionnaire.
Yanbian Prefecture had a rapid increase in the yearly newly diagnosed rate of HCV infection from 32.6 to 72.1/100.000 from the year 2007 to 2011. People aged 50–64 years had a high HCV infection of 43.4%, but only 0.3% of cases were reported in those aged less than 20 years. Cosmetic treatment, family history, blood transfusion, and dental treatment were independent risk factors for HCV infection. Unexpectedly, cosmetic treatments [odd ratio (OR) = 5.15, 95% confidence interval (CI) = 2.31–11.48, P = 0.00] and family history (OR = 4.68, 95% CI = 2.67–8.75, P = 0.00) showed a higher risk than the conventional risk factors of blood transfusion (OR = 4.49, 95% CI = 1.95–10.37, P = 0.001) and dental treatment (OR = 2.98, 95% CI = 1.42–6.25, P = 0.00). To further analyze the intrafamilial transmission, we found that spouses of HCV patients had an increased risk for acquiring HCV (OR = 5.75, 95% CI: 1.94–17.07), without significant association between either HCV RNA viral load (P = 0.29) or genotype (P = 0.43).
HCV infection was increased in Yanbian Prefecture. Cosmetic treatment was a higher risk factor than medical procedure. HCV infection had a clear family clustering phenomenon, especially between spouses.
The search for strongly inversion asymmetric topological insulators is an active research field because these materials possess distinct properties compared with the inversion symmetric ones. In particular, it is desirable to realize a large Rashba spin-splitting (RSS) in such materials, which combined with the topological surface states (TSS) could lead to useful spintronics applications. In this report, based on first principles calculations, we predict that the heterostructure of BiTeI/Bi2Te3 is a strong topological insulator with a giant RSS. The coexistence of TSS and RSS in the current system is native and stable. More importantly, we find that both the invariants and the Rashba energy can be controlled by engineering the layer geometries of the heterostructure, and the Rashba energy can be made even larger than that of bulk BiTeI. Our work opens a new route for designing topological spintronics devices based on inversion asymmetric heterostructures.
Tibial defect is generally caused by high-energy injury, tumor, osteomyelitis, development deformity and bone non-union after internal fixation. This study was to determine stability of tibial defect reconstruction with fibular graft (FG) of different lengths by single free vascularized fibular graft (SFVFG) and double-barrel free vascularized fibular graft (DBFVFG). The left lower extremity of a male volunteer was scanned with computer tomography scanner. The contours of the tibia and fibula were extracted and the geometry of both bones rebuilt. From this intact model, the models of tibial defect reconstruction with fibular graft and external fixation were developed. Inter-fragmentary motion (IFM) and Von Mises stress on the fibular bone flap, and the locations of maximum Von Mises stress were introduced to quantify the biomechanical environment. Under the condition of the same graft length, the Von Mises stress value in DBFVFG group was 1.37 to 1.77 times higher than that in SFVFG group. When the length of graft was greater than 15 cm in the SFVFG group, the IFM exceeded 1 mm, but the IFM of the graft in the DBFVFG group was always less than 1 mm. The maximum Von Mises stress of models was frequently located at the second or third pin-bone interface. Thus, external fixation can provide a stable biomechanical environment for the reconstruction of tibial defect by both SFVFG and DBFVFG. The second or third pin-bone interface requires intensive care and that in the reconstruction of tibial defect by SFVFG, the graft length should not exceed 15 cm.
Tibial defect; external fixation; fibular graft; finite element
Monodispersed magnetite (Fe3O4) particles were synthesized using a high-temperature hydrolysis reaction with the assistance of ethylenediaminetetraacetic acid (EDTA) as capping ligands. These particles were composed of small primary nanocrystals and their sizes could be tuned from about 400 to about 800 nm by simply changing the EDTA or precursor concentration. Surface-tethered EDTA made the particles highly water-dispersible. The as-prepared magnetite particles also showed superparamagnetic behavior at room temperature, and their magnetic properties were size dependent. In addition, the particles had a strong response to external magnetic field due to their high magnetization saturation values. These properties were very important for some potential biomedical applications, such as magnetic separation and magnetic-targeted substrate delivery.
Magnetite; Magnetic properties; Nanocrystalline materials
The aim of this study was to compare the long-term survival outcome and late toxicity in patients with FIGO (International Federation of Gynecology and Obstetrics) stage IIB cervical carcinoma after two treatment modalities, ie, concurrent chemoradiotherapy followed by radical surgery and concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy.
Between November 2004 and November 2011, 240 patients with FIGO stage IIB cervical carcinoma were analyzed, comprising 119 patients treated with concurrent chemoradiotherapy followed by radical surgery (group 1) and 121 patients treated with concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy (group 2). Local control, overall survival, progression-free survival, and treatment-related complications were compared between the two groups.
The median follow-up duration was 36 months. Concurrent chemoradiotherapy followed by radical surgery showed a survival benefit when comparing group 1 and group 2 (3-year overall survival, 94.9% versus 84.6%, P=0.011; 3-year progression-free survival, 91.0% versus 81.8%, P=0.049, respectively). Three-year local pelvic control was 94.6% in group 1 and 93.3% in group 2 (P=0.325). Prognostic factors in group 1 were: age (≤35 years versus >35 years), 3-year progression-free survival (74.1% versus 90.9%, P=0.037); tumor diameter (≥6 cm versus <6 cm); and 3-year progression-free survival, (60.6% versus 92.9%, P=0.004). Prognostic factors in group 2 were: tumor diameter (≥4 cm versus <4 cm); 3-year overall survival (78.0% versus 94.8%, P=0.043); tumor diameter (≥6 cm versus <6 cm); 3-year progression-free survival (42.9% versus 84.2%, P=0.032); and 3-year overall survival (42.9% versus 87.1%, P=0.013). Further, 50 patients (42.02%) in group 1 and 46 patients (38.02%) in group 2 suffered from late complications. Analysis of the difference in composition of late complications showed that the rate of leg edema was higher in group 1 (35.29% versus 4.96%, P=0.000) while the rate of radiation enteritis was higher in group 2 (30.58% versus 5.04%, P=0.000).
In patients with FIGO stage IIB cervical carcinoma, concurrent chemoradiotherapy followed by radical surgery achieved higher overall survival and progression-free survival rates in comparison with radical radiotherapy associated with concurrent chemotherapy. Tumor diameter could be a common prognostic factor in these two groups of patients.
cervical carcinoma; preoperative concurrent chemoradiotherapy; radical radiotherapy; prognostic factors; late toxicity
Enterovirus 71 (EV71) is the major pathogen responsible for fatal hand, foot and mouth disease (HFMD). Our previous work reported on an EV71-infected rhesus monkey infant model that presented with histo-pathologic changes of the central nervous system (CNS) and lungs. This study is focused on the correlated modulation of gene expression in the peripheral blood mononuclear cells (PBMCs) from EV71-infected rhesus monkey infants. The expression of more than 500 functional genes associated with multiple pathways was modulated. The expression of genes associated with immune inflammatory responses was up-regulated during the period from days 4 to 10 post-infection. The expression of two genes (TAC1 and IL17A), which play major roles in inflammatory reactions, was remarkably up-regulated during the infection period. Furthermore, a higher expression level of the TAC1 gene was identified in the CNS compared to the lungs, but a high expression level of the IL-17A gene was observed in the lungs and not in the CNS. The results of this study suggest at least two facts about EV71 infection, which are that: the TAC1 gene that encodes substance P and neurokinin-A is present in both PBMCs and the hypothalamus; and the up-regulation of IL-17A is sustained in the peripheral blood.
Sophora japonica Linn (Chinese Scholar Tree) is a shrub species belonging to the subfamily Faboideae of the pea family Fabaceae. In this study, RNA sequencing of S. japonica transcriptome was performed to produce large expression datasets for functional genomic analysis. Approximate 86.1 million high-quality clean reads were generated and assembled de novo into 143010 unique transcripts and 57614 unigenes. The average length of unigenes was 901 bps with an N50 of 545 bps. Four public databases, including the NCBI nonredundant protein (NR), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Cluster of Orthologous Groups (COG), were used to annotate unigenes through NCBI BLAST procedure. A total of 27541 of 57614 unigenes (47.8%) were annotated for gene descriptions, conserved protein domains, or gene ontology. Moreover, an interaction network of unigenes in S. japonica was predicted based on known protein-protein interactions of putative orthologs of well-studied plant genomes. The transcriptome data of S. japonica reported here represents first genome-scale investigation of gene expressions in Faboideae plants. We expect that our study will provide a useful resource for further studies on gene expression, genomics, functional genomics, and protein-protein interaction in S. japonica.
Genes of different pathways regulate spermatogenesis, and the complexity of the spermatogenic process indicates that polymorphisms or mutations in these genes could cause male infertility. Published data on the association between the GSTM1 and GSTT1 polymorphism and male infertility risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed.
A total of 11 studies regarding GSTM1 and 9 studies regarding GSTT1 between 1999 and 2012 were identified through researching MEDLINE, EMBASE and the Chinese Biomedical Database. It was performed to obtain summary estimated odd ratios and 95 % confidence intervals of GSTM1 and GSTT1 for male infertility, with attention to study quality and publication bias.
Overall, a significant association was seen between GSTM1 (OR = 1.20, 95 % CI = 1.02–1.40, Pheterogeneity = 0.000, P = 0.027) genotypes and male infertility. Significant associations were also observed in subgroups of Caucasian populations (OR = 1.65, 95 %CI = 1.16–2.34, Pheterogeneity = 0.006, P = 0.005), but were not observed in Asian populations (OR = 1.09, 95 % CI = 0.72–1.65, Pheterogeneity = 0.054, P = 0.697) when stratified by ethnicity. While there was no significant association was seen between GSTT1 (OR = 1.00, 95 % CI = 0.74–1.35, Pheterogeneity = 0.000, P = 0.980) null genotypes and male infertility. Simultaneously, significant associations were not observed in subgroups of Caucasian populations (OR = 0.94, 95 %CI = 0.44–2.00, Pheterogeneity = 0.000, P = 0.867) and Asian populations (OR = 0.93, 95 % CI = 0.46–1.87, Pheterogeneity = 0.002, P = 0.838) when stratified by ethnicity.
Our results suggest the GSTM1 null genotype contributes to male infertility susceptibility, while GSTT1 gene polymorphisms are not associated with male infertility in our study.
Glutathione S-transferases M1; Glutathione S-transferases T1; Polymorphism; Male infertility; Meta-analysis; Molecular epidemiology
Design and synthesis of efficient drug delivery systems are of vital importance for medicine and healthcare. Materials innovation and nanotechnology have synergistically fueled the advancement of drug delivery. Innovation in material chemistry allows the generation of biodegradable, biocompatible, environment-responsive, and targeted delivery systems. Nanotechnology enables control over size, shape and multi-functionality of particulate drug delivery systems. In this review, we focus on the materials innovation and processing of drug delivery systems and how these advances have shaped the past and may influence the future of drug delivery.
Commercialized drug delivery system; nanoparticle; polyplex; natural polymers; polymer-drug conjugate; combinatorial chemistry; microfluidics; particle replication in non-wetting template; step-flash imprint lithography
The aim of this paper was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of nemonoxacin, a novel nonfluorinated quinolone, against Streptococcus pneumoniae
in vitro. A modified infection model was used to simulate the pharmacokinetics of nemonoxacin following scaling of single oral doses and multiple oral dosing. Four S. pneumoniae strains with different penicillin sensitivities were selected, and the drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid maximum-effect (Emax) model was used to analyze the relationship between PK/PD parameters and drug effect. Analysis indicated that the killing pattern of nemonoxacin shows a dualism which is mainly concentration dependent when the MIC is low and that the better PK/PD index should be the area under the concentration-time curve for the free, unbound fraction of the drug divided by the MIC (fAUC0–24/MIC), which means that giving the total daily amount of drug as one dose is appropriate under those conditions. When the MIC is high, the time (T) dependency is important and the valid PK/PD index should be the cumulative percentage of a 24-h period in which the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f%T>MIC), which means that to split the maximum daily dose into several separate doses will benefit the eradication of the bacteria. To obtain a 3-log10-unit decrease, the target values of fAUC0–24/MIC and f%T>MIC are 47.05 and 53.4%, respectively.
Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or stresses but can regrow under appropriate conditions. Persisters underlie persistent and latent infections and post-treatment relapse, posing significant challenges for the treatment of many bacterial infections. The current definition of persisters has drawbacks, and a Yin–Yang model is proposed to describe the heterogeneous nature of persisters that have to be defined in highly specific conditions. Despite their discovery more than 70 years ago, the mechanisms of persisters are poorly understood. Recent studies have identified a number of genes and pathways that shed light on the mechanisms of persister formation or survival. These include toxin–antitoxin modules, stringent response, DNA repair or protection, phosphate metabolism, alternative energy production, efflux, anti-oxidative defense and macromolecule degradation. More sensitive single-cell techniques are required for a better understanding of persister mechanisms. Studies of bacterial persisters have parallels in other microbes (fungi, parasites, viruses) and cancer stem cells in terms of mechanisms and treatment approaches. New drugs and vaccines targeting persisters are critical for improved treatment of persistent infections and perhaps cancers. Novel treatment strategies for persisters and persistent infections are discussed.
mechanisms; persistence; persisters; treatment strategies
Here, we report the complete genome sequences of two tembusu virus strains, ZC-1 and LQ-1, isolated from ducks and geese, respectively, in 2012. Phylogenetic analysis showed that the nucleotide and amino acid sequences of the two strains are closely related to those of the TMUV isolates around Shandong province. The full-length genome sequences of two waterfowl-origin TMUVs provided herein will help to understand the molecular epidemiology of tembusu virus in China, which deserves further investigation.
We report the complete genome sequence of Exiguobacterium sp. strain MH3, isolated from the rhizosphere of duckweed. The genome assembly is 3.16 Mb, with a G+C content of 47.24%, and it may provide useful information about plant-microbe interactions and the genetic basis for the tolerance of the strain to various environmental stresses.
Extracellular adenosine triphosphate (eATP) transduces purinergic signal and plays an important regulatory role in many biological processes, including tumor cell growth and cell death. A large amount of eATP exists in the fast-growing tumor center and inflammatory tumor microenvironment. Tumor cells could acquire anoikis resistance and anchorage independence in tumor microenvironment and further cause metastatic lesion. Whether such a high amount of eATP has any effect on the anchored and non-anchored tumor cells in tumor microenvironment has not been elucidated and is investigated in this study. Our data showed that autophagy helped hepatoma cells to maintain survival under the treatment of no more than 1 mM of eATP. Only when eATP concentration reached a relatively high level (2.5 mM), cell organelle could not be further maintained by autophagy, and apoptosis and cell death occurred. In hepatoma cells under treatment of 2.5 mM of eATP, an AMP-activated protein kinase (AMPK) pathway was dramatically activated while mTOR signaling pathway was suppressed in coordination with apoptosis. Further investigation showed that the AMPK/mTOR axis played a key role in tipping the balance between autophagy-mediated cell survival and apoptosis-induced cell death under the treatment of eATP. This work provides evidence to explain how hepatoma cells escape from eATP-induced cytotoxicity as well as offers an important clue to consider effective manipulation of cancer.
Apoptosis; Autophagy; Anoikis; Extracellular ATP; AMPK; mTOR
Single nucleotide polymorphisms (SNPs) may affect the development of diseases. The -2518A/G polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimation of the relationship between the -2518A/G polymorphism and cancer risk.
We performed a meta-analysis, including 4,162 cases and 5,173 controls, to evaluate the strength of the association between the −2518A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Overall, the results indicated that the −2518A/G polymorphism was not statistically associated with cancer risk. However, sub-group analysis revealed that individuals with GG genotypes showed an increased risk of cancer in digestive system compared with carriers of the A allele (GG vs. AA: OR = 1.43, 95%CI = 1.05–1.96, Pheterogeneity = 0.08; GG vs. AG/AA: OR = 1.29, 95%CI = 1.02–1.64, Pheterogeneity = 0.14). In addition, the increased risk of GG genotype was also observed in Caucasians (GG vs. AG/AA: OR = 1.81, 95%CI = 1.10–2.96, Pheterogeneity = 0.02).
This meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. Large-scale and well-designed case-control studies are needed to validate the findings.
Wnt and Notch signaling pathways both play essential roles and interact closely in development and carcinogenesis, but their interaction in non-small-cell lung cancer (NSCLC) is poorly unknown. Here we investigated the effects of CHIR99021, a Wnt signaling agonist, or Notch3-shRNA, or the combined application of CHIR99021 and Notch3-shRNA on cell proliferation and apoptosis, as well as the expressions of Notch3, its downstream genes, cyclinA and caspase-3. Our results showed that CHIR99021 up-regulated the expression of Notch3 protein and HES1 and HEYL mRNA. CHIR99021 promoted cell proliferation and the expression of cyclinA, which were inhibited by Notch3-shRNA in these three cell lines. Moreover, Notch3-shRNA significantly attenuated the positive effects of CHIR99021 on cell proliferation and cyclinA in H460 and H157. As for apoptosis, Notch3-shRNA induced cell apoptosis and increased the expression of caspase-3, whereas CHIR99021 showed the different effects in these three cell lines. The inhibitory effect of CHIR99021 on apoptosis was significantly weakened by Notch3-shRNA only in H460. Overall, although the effects of CHIR99021 and the combined application of CHIR99021 and Notch3-shRNA on the cell proliferation and apoptosis aren’t completely similar in the three cell lines, our findings still indicate that Notch3 signaling can be activated by canonical Wnt signaling and a functional link between Wnt and Notch signaling pathways exists in NSCLC, at least, which partially is associated with their regulations on the expressions of cyclinA and caspase-3.
To determine whether single nucleotide polymorphism (SNP) rs641153 is associated with the risk of age-related macular degeneration (AMD), we performed a systematic meta-analysis of 15 eligible studies. SNP in the complement factor B (CFB) gene is considered to have significant association with AMD susceptibility, but there is great discrepancy in these results.
The eligible studies were identified by searching the databases of PubMed, EMBASE, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. All data were analyzed using Stata software.
The association between rs641153 and AMD risk was statistically significant under the homozygous model (AA vs GG:OR=0.26, 95%CI=0.15-0.45, Ph=0.973, I2=0.0%, fixed effects), dominant model (AA+GA vs GG:OR=0.49, 95%CI=0.40-0.59, Ph=0.004, I2=56.4%, random effects) and recessive model (AA vs GA+GG:OR=0.30, 95%CI=0.17-0.51, Ph=0.983, I2=0.0%, fixed effects). The same results were also observed in the stratified analyses by ethnicity, source of control and sample size.
Our meta-analysis suggests that rs641153 in the CFB gene may play a protective role in AMD susceptibility, the late AMD in particular, both in Caucasians and in Asians.
complement factor B; rs641153; age-related macular degeneration; meta-analysis
Microbiota have recently been shown to be associated with many disease conditions. However, the microbiota associated with tuberculosis (TB) infection, recurrence and treatment outcome have not been systematically characterized. Here, we used high throughput 16S RNA sequencing to analyze the sputum microbiota associated with Mycobacterium tuberculosis infection and also to identify the microorganisms associated with different outcomes of TB treatment. We recruited 25 new TB patients, 30 recurrent TB patients and 20 TB patients with treatment failure, as well as 20 healthy controls. Streptococcus, Gramulicatella and Pseudomonas were more abundant in TB patients while Prevotella, Leptotrichia, Treponema, Catonella and Coprococcus were less abundant in TB patients than in the healthy controls. We found reduced frequency and abundance of some genera such as Bulleidia and Atopobium in recurrent TB patients compared with those in new TB patients. In addition, the ratio of Pseudomonas / Mycobacterium in recurrent TB was higher than that in new TB while the ratio of Treponema / Mycobacterium in recurrent TB was lower than that in new TB, indicating that disruption of these bacteria may be a risk factor of TB recurrence. Furthermore, Pseudomonas was more abundant and more frequently present in treatment failure patients than in cured new patients, and the ratio of Pseudomonas / Mycobacterium in treatment failure was higher than that in new TB. Our data suggest that the presence of certain bacteria and the disorder of lung microbiota may be associated with not only onset of TB but also its recurrence and treatment failure. These findings indicate that lung microbiota may play a role in pathogenesis and treatment outcome of TB and may need to be taken into consideration for improved treatment and control of TB in the future.
An attractive option for tissue engineering is to use of multicellular spheroids as microtissues, particularly with stem cell spheroids. Conventional approaches of fabricating spheroids suffer from low throughput and polydispersity in size, and fail to supplement cues from extracellular matrix (ECM) for enhanced differentiation. In this study, we report the application of microfluidics-generated water-in-oil-in-water (w/o/w) double-emulsion (DE) droplets as pico-liter sized bioreactor for rapid cell assembly and well-controlled microenvironment for spheroid culture. Cells aggregated to form size-controllable (30–80 μm) spheroids in DE droplets within 150 min and could be retrieved via a droplet-releasing agent. Moreover, precursor hydrogel solution can be adopted as the inner phase to produce spheroid-encapsulated microgels after spheroid formation. As an example, the encapsulation of human mesenchymal stem cells (hMSC) spheroids in alginate and alginate-arginine-glycine-aspartic acid (-RGD) microgel was demonstrated, with enhanced osteogenic differentiation further exhibited in the latter case.