Smoking cessation and carotid atherosclerosis: The guangzhou biobank cohort studydCVD

Introduction Smoking has been shown to be associated with carotid atherosclerosis in cross-sectional and prospective studies in Western populations. However, few studies have examined the reversal of risk resulting from quitting smoking, and the results are conflicting. Methods 959 men aged 50e85 years were randomly selected from phase III (2006e2007) of the Guangzhou Biobank Cohort Study into this cross-sectional study. Common carotid artery intima-media thickness (CCAIMT) was measured by B-mode ultrasonography, and carotid artery plaques were identified. Major cardiovascular risk factors, including fasting triglyceride, low-density and high-density lipoprotein (LDL and HDL) cholesterol and glucose, and systolic and diastolic blood pressure, were assessed. Results CCA-IMT and the number of carotid plaque increased from never to former to current smokers (both p≤0.001). Among former smokers compared to current smokers, after adjustment for cigarette pack-years and other potential confounders, the adjusted ORs (95% CI) for quitting for 1-9, 10-19 and 20+ years were 0.77 (0.47 to 1.26), 0.45 (0.26 to 0.79) and 0.37 (0.17 to 0.77) for the presence of CCA atherosclerosis, and 0.69 (0.43 to 1.12), 0.47 (0.27 to 0.82) and 0.45 (0.23 to 0.96) for the presence of carotid plaques, respectively. Longer duration of quitting smoking was also significantly associated with decreasing risk of the severity of CCA atherosclerosis and carotid plaques (all p≤0.001). Conclusion Smoking cessation was beneficial in attenuating the risk of carotid atherosclerosis associated with cigarette smoking. The short duration of cessation in earlier studies is a likely explanation for the inconsistent results.published_or_final_versio

Albuminuria is a marker of increasing intracranial and extracranial vascular involvement in Type 2 diabetic Chinese patients

AIMS/HYPOTHESIS: Albuminuria has been reported to be a marker of cardiovascular risk factors and disease morbidity and mortality, but its relationship with intracerebral atherosclerotic disease is less clear. The aim of this study was to investigate the association between albuminuria and intracranial and extracranial vascular involvement in Chinese Type 2 diabetic patients. METHODS: The anthropometric and fasting biochemical measurements of 966 Type 2 diabetic patients with normoalbuminuria (55.6%), microalbuminuria (27.7%) or macroalbuminuria (16.7%) were compared. The prevalence of microvascular and macrovascular disease and middle cerebral artery (MCA) stenosis, measured by transcranial Doppler ultrasound, were also compared between the groups. RESULTS: Albuminuria was closely associated with a range of adverse parameters, including high BP, dyslipidaemia, smoking and adiposity (all p<0.01). The prevalence of microvascular disease (retinopathy p<0.001) and macrovascular disease (peripheral vascular disease p=0.012, myocardial infarction, p=0.004, MCA stenosis p<0.001) increased significantly with increasing levels of albuminuria. Albuminuria was also found to be an independent predictor of microvascular and macrovascular disease. CONCLUSIONS/INTERPRETATION: Albuminuria was an independent predictor of increasing levels of vascular risk factors and microvascular and macrovascular disease in this group of Type 2 diabetic patients, and a possible role for albuminuria as a marker of intracranial cerebrovascular disease should be further investigated.postprin

The association of pulmonary function with carotid atherosclerosis in older Chinese: Guangzhou Biobank Cohort Study-CVD Subcohort

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Machine Learning based Early Prediction of End-stage Renal Disease in Patients with Diabetic Kidney Disease using Clinical Trials Data

AimTo predict end‐stage renal disease (ESRD) in patients with type 2 diabetes by using machine‐learning models with multiple baseline demographic and clinical characteristics.Materials and methodsIn total, 11 789 patients with type 2 diabetes and nephropathy from three clinical trials, RENAAL (n = 1513), IDNT (n = 1715) and ALTITUDE (n = 8561), were used in this study. Eighteen baseline demographic and clinical characteristics were used as predictors to train machine‐learning models to predict ESRD (doubling of serum creatinine and/or ESRD). We used the area under the receiver operator curve (AUC) to assess the prediction performance of models and compared this with traditional Cox proportional hazard regression and kidney failure risk equation models.ResultsThe feed forward neural network model predicted ESRD with an AUC of 0.82 (0.76‐0.87), 0.81 (0.75‐0.86) and 0.84 (0.79‐0.90) in the RENAAL, IDNT and ALTITUDE trials, respectively. The feed forward neural network model selected urinary albumin to creatinine ratio, serum albumin, uric acid and serum creatinine as important predictors and obtained a state‐of‐the‐art performance for predicting long‐term ESRD.ConclusionsDespite large inter‐patient variability, non‐linear machine‐learning models can be used to predict long‐term ESRD in patients with type 2 diabetes and nephropathy using baseline demographic and clinical characteristics. The proposed method has the potential to create accurate and multiple outcome prediction automated models to identify high‐risk patients who could benefit from therapy in clinical practice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163629/2/dom14178.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163629/1/dom14178_am.pd

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Apoptosis Governs the Elimination of Schistosoma japonicum from the Non-Permissive Host Microtus fortis

The reed vole, Microtus fortis, is the only known mammalian host in which schistosomes of Schistosoma japonicum are unable to mature and cause significant pathogenesis. However, little is known about how Schistosoma japonicum maturation (and, therefore, the development of schistosomiasis) is prevented in M. fortis. In the present study, the ultrastructure of 10 days post infection schistosomula from BALB/c mice and M. fortis were first compared using scanning electron microscopy and transmission electron microscopy. Electron microscopic investigations showed growth retardation and ultrastructural differences in the tegument and sub-tegumental tissues as well as in the parenchymal cells of schistosomula from M. fortis compared with those in BALB/c mice. Then, microarray analysis revealed significant differential expression between the schistosomula from the two rodents, with 3,293 down-regulated (by ≥2-fold) and 71 up-regulated (≥2 fold) genes in schistosomula from the former. The up-regulated genes included a proliferation-related gene encoding granulin (Grn) and tropomyosin. Genes that were down-regulated in schistosomula from M. fortis included apoptosis-inhibited genes encoding a baculoviral IAP repeat-containing protein (SjIAP) and cytokine-induced apoptosis inhibitor (SjCIAP), genes encoding molecules involved in insulin metabolism, long-chain fatty acid metabolism, signal transduction, the transforming growth factor (TGF) pathway, the Wnt pathway and in development. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and PI/Annexin V-FITC assays, caspase 3/7 activity analysis, and flow cytometry revealed that the percentages of early apoptotic and late apoptotic and/or necrotic cells, as well as the level of caspase activity, in schistosomula from M. fortis were all significantly higher than in those from BALB/c mice

Transcriptional Changes in Schistosoma mansoni during Early Schistosomula Development and in the Presence of Erythrocytes

Schistosome blood flukes cause more mortality and morbidity than any other human worm infection, but current control methods primarily rely on a single drug. There is a desperate need for new approaches to control this parasite, including vaccines. People become infected when the free-swimming larva, the cercaria, enters through the skin and becomes the schistosomulum. Schistosomula are susceptible to immune responses during their first few days in the host before they become adult parasites. We characterised the genes that these newly transformed parasites switch on when they enter the host to identify molecules that are critical for survival in the human host. Some of these highly up-regulated genes can be targeted for future development of new vaccines and drugs

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Transgenic tobacco plants constitutively expressing Arabidopsis NPR1 show enhanced resistance to root-knot nematode, Meloidogyne incognita

In Arabidopsis, non-expressor of pathogenesis related genes-1, NPR1 has been shown to be a positive regulator of the salicylic acid controlled systemic acquired resistance pathway and modulates the cross talk between SA and JA signaling. Transgenic plants expressing AtNPR1 constitutively exhibited resistance against pathogens as well as herbivory. In the present study, tobacco transgenic plants expressing AtNPR1 were studied further for their response to infection by the sedentary endoparasitic root knot nematode, Meloidogyne incognita. Transgenic plants showed enhanced resistance against the root-knot nematode infection. Prominent differences in the shoot and root weights of wild type and transgenic plants were observed post-inoculation with M. incognita. This was associated with a decrease in the number of root galls and egg masses in transgenic plants compared to WT. The transgenic plants also showed constitutive and induced expression of some PR protein genes, when challenged with M. incognita