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1.  Composition formulas of binary eutectics 
Scientific Reports  2015;5:17880.
The present paper addresses the long-standing composition puzzle of eutectic points by introducing a new structural tool for the description of short-range-order structural unit, the cluster-plus-glue-atom model. In this model, any structure is dissociated into a 1st-neighbor cluster and a few glue atoms between the clusters, expressed by a cluster formula [cluster]gluex. This model is applied here to establish the structural model for eutectic liquids, assuming that a eutectic liquid consist of two subunits issued from the relevant eutectic phases, each being expressed by the cluster formula for ideal metallic glasses, i.e., [cluster](glue atom)1 or 3. A structural unit is then composed of two clusters from the relevant eutectic phases plus 2, 4, or 6 glue atoms. Such a dual cluster formulism is well validated in all boron-containing (except those located by the extreme phase diagram ends) and in some commonly-encountered binary eutectics, within accuracies below 1 at.%. The dual cluster formulas vary extensively and are rarely identical even for eutectics of close compositions. They are generally formed with two distinctly different cluster types, with special cluster matching rules such as cuboctahedron plus capped trigonal prism and rhombidodecahedron plus octahedral antiprism.
doi:10.1038/srep17880
PMCID: PMC4677321  PMID: 26658618
2.  Investigating the Composition and Conductance Distributions on Highly GeSi Mixed Quantum Dots and Inside Oxidation Problem 
With the help of a nanoscale trench, the composition and conductance distributions of single GeSi quantum dots (QDs) are obtained by conductive atomic force microscopy combined with selective chemical etching. However, the obtained composition and current distributions are unwonted and inconsistent on the QDs grown at 680 °C. With a series of confirmatory experiments, it is suggested that a thick oxide layer is formed and remains on the QDs’ surface after etching. Though this selective chemical etching has already been widely applied to investigate the composition distribution of GeSi nanostructures, the oxidation problem has not been concerned yet. Our results indicate that the oxidation problem could not be ignored on highly GeSi mixed QDs. After removing the oxide layer, the composition and conductance distributions as well as their correlation are obtained. The results suggest that QDs’ current distribution is mainly determined by the topographic shape, while the absolute current values are influenced by the Ge/Si contents.
doi:10.1186/s11671-015-1185-8
PMCID: PMC4674456  PMID: 26650513
GeSi quantum dots; Conductive atomic force microscopy; Composition distribution; Conductance distribution; Selective chemical etching
3.  Long-term changes in dietary and food intake behaviour in the Diabetes Prevention Program Outcomes Study 
Aims
To 1) compare change in dietary intake, with an emphasis on food groups and food behaviors, over time across treatment arms in a diabetes prevention trial and 2) assess differences in dietary intake across demographic groups within treatment arms.
Methods
Data are from the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Participants were randomized to lifestyle (n = 1079), metformin (n = 1073), or placebo (n = 1082) for an average of 3 years when the initial results regarding the benefits of the lifestyle intervention were released and all participants were offered a modified lifestyle intervention. Dietary intake was assessed using a food frequency questionnaire at baseline and at 1, 5, 6, and 9 years post-randomization.
Results
Compared to the metformin and placebo arms, lifestyle participants maintained a lower total and saturated fat, and higher fiber intake up to 9 years post-randomization; and lower intakes of red meat and sweets were maintained up to 5 years. Younger participants had higher intakes of poultry and lower intakes of fruits compared to their older counterparts, particularly in the lifestyle arm. African Americans tended to have lower dairy and higher poultry intakes compared to Caucasians and Hispanics. In the lifestyle arm, men tended to have higher grain, fruit and fish intakes compared to women.
Conclusions
Changes in nutrient intake among lifestyle participants were maintained for up to 9 years. Younger participants reported more unhealthy diets over time and thus may benefit from additional support to achieve and maintain dietary goals.
doi:10.1111/dme.12500
PMCID: PMC4307949  PMID: 24824893
4.  Lipoprotein lipase variants interact with polyunsaturated fatty acids for obesity traits in women: Replication in two populations 
Background and aims
Lipoprotein lipase (LPL) is a candidate gene for obesity based on its role in triglyceride hydrolysis and the partitioning of fatty acids towards storage or oxidation. Whether dietary fatty acids modify LPL associated obesity risk is unknown.
Methods and results
We examined five single nucleotide polymorphisms (SNPs) (rs320, rs2083637, rs17411031, rs13702, rs2197089) for potential interaction with dietary fatty acids for obesity traits in 1171 participants (333 men and 838 women, aged 45–75 y) of the Boston Puerto Rican Health Study (BPRHS). In women, SNP rs320 interacted with dietary polyunsaturated fatty acids (PUFA) for body mass index (BMI) (P = 0.002) and waist circumference (WC) (P = 0.001) respectively. Higher intake of PUFA was associated with lower BMI and WC in homozygotes of the major allele (TT) (P = 0.01 and 0.005) but not in minor allele carriers (TG and GG). These interactions were replicated in an independent population, African American women of the Atherosclerosis Risk in Communities (ARIC) study (n = 1334).
Conclusion
Dietary PUFA modulated the association of LPL rs320 with obesity traits in two independent populations. These interactions may be relevant to the dietary management of obesity, particularly in women.
doi:10.1016/j.numecd.2014.07.003
PMCID: PMC4356006  PMID: 25156894
Gene-diet interaction; Lipoprotein lipase; Polyunsaturated fatty acids; Obesity
5.  Properties of different selection signature statistics and a new strategy for combining them 
Heredity  2015;115(5):426-436.
Identifying signatures of recent or ongoing selection is of high relevance in livestock population genomics. From a statistical perspective, determining a proper testing procedure and combining various test statistics is challenging. On the basis of extensive simulations in this study, we discuss the statistical properties of eight different established selection signature statistics. In the considered scenario, we show that a reasonable power to detect selection signatures is achieved with high marker density (>1 SNP/kb) as obtained from sequencing, while rather small sample sizes (~15 diploid individuals) appear to be sufficient. Most selection signature statistics such as composite likelihood ratio and cross population extended haplotype homozogysity have the highest power when fixation of the selected allele is reached, while integrated haplotype score has the highest power when selection is ongoing. We suggest a novel strategy, called de-correlated composite of multiple signals (DCMS) to combine different statistics for detecting selection signatures while accounting for the correlation between the different selection signature statistics. When examined with simulated data, DCMS consistently has a higher power than most of the single statistics and shows a reliable positional resolution. We illustrate the new statistic to the established selective sweep around the lactase gene in human HapMap data providing further evidence of the reliability of this new statistic. Then, we apply it to scan selection signatures in two chicken samples with diverse skin color. Our analysis suggests that a set of well-known genes such as BCO2, MC1R, ASIP and TYR were involved in the divergent selection for this trait.
doi:10.1038/hdy.2015.42
PMCID: PMC4611237  PMID: 25990878
6.  Prognostic significance of Versican expression in gastric adenocarcinoma 
Oncogenesis  2015;4(11):e178-.
Gastric cancer (GC) is the leading malignancy in the digestive system. Versican is a ubiquitous component of the extracellular matrix and has a role in tumor progression. We aim to examine the expression of Versican in GC and the relationship between Versican levels and patient survival. We detected the mRNA expression of Versican in tumorous pairs and adjacent normal tissues (ANTs) of 78 GC patients by quantitative real-time polymerase chain reaction. The protein expression of Versican in 101 cases of matched GC and ANT, as well as in 27 intraepithelial neoplastic (IN) samples, was evaluated by immunohistochemistry. We analyzed the correlation between Versican levels and clinical outcomes. Finally, we performed CCK-8 cell counting assay and transwell assay in GC cell lines. Versican mRNA expression was significantly greater in tumor tissues (P<0.001) than in ANT. Versican was majorly expressed in the stroma surrounding tumor epithelium and minorly some areas of tumor epithelium. The Versican expression level was higher in GC than in ANT (P=0.004), but no significant difference was observed between ANT and IN (P=0.517). The Versican mRNA and protein levels were consistent in GC. High Versican mRNA and protein expression correlated with greater tumor invasion depth (P=0.030, P=0.027). Univariate and multivariate analysis revealed that patients with high Versican mRNA expression exhibited poor disease-specific survival (P<0.001). In vitro experiments showed that Versican overexpression promoted cell proliferation and invasion. Our data indicate that Versican may be a novel prognostic indicator in GC and may be a potential target for clinical diagnosis.
doi:10.1038/oncsis.2015.36
PMCID: PMC4670962  PMID: 26619403
7.  Effects of Post-harvest Storage Duration and Variety on Nutrient Digestibility and Energy Content Wheat in Finishing Pigs 
This study was conducted to investigate the effects of post-harvest storage duration and wheat variety on the digestibility and energy content of new season wheat fed to finishing pigs. Two wheat varieties (Shi and Zhong) were harvested in 2013 and stored in the warehouse of the Fengning Pig Experimental Base at China Agricultural University for 3, 6, 9, or 12 mo. For each storage period, 12 barrows were placed in metabolism crates and allotted to diets containing 1 of the 2 wheat varieties in a randomized complete block design. The experimental diets contained 97.34% wheat and 2.66% of a vitamin and trace mineral premix. With an extension of storage duration from 3 mo to 12 mo, the gross energy (GE) and crude protein (CP) of the wheat decreased by 2.0% and 12.01%, respectively, while the concentration of neutral detergent fiber (NDF), acid detergent fiber (ADF) and starch content increased by 30.26%, 19.08%, and 2.46%, respectively. Total non-starch polysaccharide, total arabinose, total xylose and total mannose contents decreased by 46.27%, 45.80%, 41.71%, and 75.66%, respectively. However, there were no significant differences in the chemical composition between the two wheat varieties with the exception of ADF which was approximately 13.37% lower in Shi. With an extension of storage duration from 3 mo to 12 mo, the digestible energy (DE), metabolizable energy (ME) content and the apparent total tract digestibility of GE, CP, dry matter, organic matter, ether extract, ADF and metabolizability of energy in wheat decreased linearly (p<0.01) by 5.74%, 7.60%, 3.75%, 3.88%, 3.50%, 2.47%, 26.22%, 27.62%, and 3.94%, respectively. But the digestibility of NDF changed quadratically (p<0.01). There was an interaction between wheat variety and storage time for CP digestibility (p<0.05), such that the CP digestibility of variety Zhong was stable during 9 mo of storage, while the CP digestibility of variety Shi decreased (p<0.05). In conclusion, the GE, DE, and ME of wheat was stable during the first 3 to 6 mo of post-harvest storage, and decreased during the following 6 to 12 mo of storage under the conditions of this study.
doi:10.5713/ajas.15.0019
PMCID: PMC4554857  PMID: 26323405
Digestibility; Digestible and Metabolizable Energy; Finishing Pigs; Post-harvest Storage; Wheat
8.  Demonstration of self-truncated ionization injection for GeV electron beams 
Scientific Reports  2015;5:14659.
Ionization-induced injection mechanism was introduced in 2010 to reduce the laser intensity threshold for controllable electron trapping in laser wakefield accelerators (LWFA). However, usually it generates electron beams with continuous energy spectra. Subsequently, a dual-stage target separating the injection and acceleration processes was regarded as essential to achieve narrow energy-spread electron beams by ionization injection. Recently, we numerically proposed a self-truncation scenario of the ionization injection process based upon overshooting of the laser-focusing in plasma which can reduce the electron injection length down to a few hundred micrometers, leading to accelerated beams with extremely low energy-spread in a single-stage. Here, using 100 TW-class laser pulses we report experimental observations of this injection scenario in centimeter-long plasma leading to the generation of narrow energy-spread GeV electron beams, demonstrating its robustness and scalability. Compared with the self-injection and dual-stage schemes, the self-truncated ionization injection generates higher-quality electron beams at lower intensities and densities, and is therefore promising for practical applications.
doi:10.1038/srep14659
PMCID: PMC4589762  PMID: 26423136
9.  Strategic aspects of higher education reform to cultivate specialists in diagnostic and biopharma industry as applicable to Predictive, Preventive and Personalized Medicine as the Medicine of the Future 
The EPMA Journal  2015;6(1):18.
Predictive, Preventive and Personalized Medicine as the Medicine of the Future represents an innovative model for advanced healthcare and robust platform for relevant industrial branches for diagnostics and pharmaceutics. However, rapid market penetration of new medicines and technologies demands the implementation of reforms not only in the spheres of biopharmaceutical industries and healthcare, but also in education. Therefore, the problem of the fundamental, modern preparation of specialists in bioengineering and affiliated fields is becoming particularly urgent, and it requires significant revision of training programs of higher education practice into current medical universities. Modernization and integration of widely accepted medical and teaching standards require consolidation of both the natural sciences and medical sciences that may become the conceptual basis for a university medical education. The main goal of this training is not simply to achieve advanced training and expansion of technological skills, but to provide development of novel multifaceted approaches to build academic schools for future generations.
doi:10.1186/s13167-015-0040-4
PMCID: PMC4570293  PMID: 26379805
Predictive, Preventive and Personalized Medicine; Education; Companion diagnostics; Pharma industry; Innovation; Drug design; Targeting; Bioinformatics; Translational medicine; Integration of science and education
10.  Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program 
Aims
To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program.
Methods
A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes.
Results
The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA1c, estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56–1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%).
Conclusions
These data suggest that ‘diabetes autoimmunity’, as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes.
doi:10.1111/dme.12437
PMCID: PMC4138247  PMID: 24646311
11.  The novel protective role of P27 in MLN4924-treated gastric cancer cells 
Zhang, Q | Hou, D | Luo, Z | Chen, P | Lv, B | Wu, L | Ma, Y | Chu, Y | Liu, H | Liu, F | Yu, S | Zhang, J | Yang, D | Liu, J
Cell Death & Disease  2015;6(8):e1867-.
The tumor-suppressor gene cyclin-dependent kinase inhibitor 1B (P27) is downregulated in gastric cancer cells mainly through proteolytic degradation mediated by the SKP-Cullin1-F-Box (SCF) complex. But the correlation between its downregulation and gastric cancer prognosis still remains indefinite. MLN4924, an anti-tumor agent, which suppresses the SCF complex by inhibiting Cullin1 neddylation, emerges as a promising tool to elucidate its functions in gastric cancer cells. In this study, MLN4924 induced significant growth inhibition of gastric cancer cells in a dose-dependent manner, along with the simultaneous accumulation of P27 and cell cycle abnormalities such as G2/M arrest. Importantly, we found that P27 silencing in MLN4924-treated cells resulted in an enhancement of growth inhibition both in vitro and in vivo. Mechanism analysis revealed the antagonism effects of antioxidants to this excess apoptosis, suggesting reactive oxygen species (ROS) overproduction especially in the mitochondria was the principal cause of the augmentation. Moreover, the robust ROS attacked the mitochondria to initiate collapse of the mitochondrial membrane permeability and the exportation of apoptosis-inducing factor (AIF), IAP-binding mitochondrial protein (SMAC/DIABLO) and cytochrome c. Finally, we also found that P27 knockdown affected the expression profile of several critical BH3 family members to amplify the mitochondrial dysfunction and apoptosis. In summary, our findings unveiled a protective role of P27 by maintaining mitochondrial membrane permeability in MLN4924-treated gastric cancer cells, and therefore highlighted the potential combination of MLN4924 with P27 inhibition to improve its therapeutic efficacy.
doi:10.1038/cddis.2015.215
PMCID: PMC4558507  PMID: 26313918
12.  Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly 
Scientific Reports  2015;5:12023.
Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4th injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.
doi:10.1038/srep12023
PMCID: PMC4499798  PMID: 26166066
13.  Yeast CUP1 protects HeLa cells against copper-induced stress 
As an essential trace element, copper can be toxic in mammalian cells when present in excess. Metallothioneins (MTs) are small, cysteine-rich proteins that avidly bind copper and thus play an important role in detoxification. YeastCUP1 is a member of the MT gene family. The aim of this study was to determine whether yeast CUP1 could bind copper effectively and protect cells against copper stress. In this study,CUP1 expression was determined by quantitative real-time PCR, and copper content was detected by inductively coupled plasma mass spectrometry. Production of intracellular reactive oxygen species (ROS) was evaluated using the 2',7'-dichlorofluorescein-diacetate (DCFH-DA) assay. Cellular viability was detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the cell cycle distribution of CUP1 was analyzed by fluorescence-activated cell sorting. The data indicated that overexpression of yeast CUP1 in HeLa cells played a protective role against copper-induced stress, leading to increased cellular viability (P<0.05) and decreased ROS production (P<0.05). It was also observed that overexpression of yeast CUP1 reduced the percentage of G1 cells and increased the percentage of S cells, which suggested that it contributed to cell viability. We found that overexpression of yeast CUP1 protected HeLa cells against copper stress. These results offer useful data to elucidate the mechanism of the MT gene on copper metabolism in mammalian cells.
doi:10.1590/1414-431X20153848
PMCID: PMC4512100  PMID: 26083994
Yeast; Overexpression; Copper stress; Viability; ROS
14.  Thalamic metabolism and symptom onset in preclinical Huntington’s disease 
Brain : a journal of neurology  2007;130(0 11):2858-2867.
The neural basis for the transition from preclinical to symptomatic Huntington’s disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P<0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P<0.003) but declined at 44 months (P<0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P<0.01). Striatal metabolism was abnormally low at all time points (P<0.005). By contrast, thalamic metabolism was elevated at baseline (P<0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.
doi:10.1093/brain/awm217
PMCID: PMC4455546  PMID: 17893097
preclinical Huntington’s disease (p-HD); brain metabolism; positron emission tomography (PET)
15.  IGFBP-rP1 suppresses epithelial–mesenchymal transition and metastasis in colorectal cancer 
Zhu, S | Zhang, J | Xu, F | Xu, E | Ruan, W | Ma, Y | Huang, Q | Lai, M
Cell Death & Disease  2015;6(3):e1695-.
Epithelial–mesenchymal transition (EMT) was initially recognized during organogenesis and has recently been reported to be involved in promoting cancer invasion and metastasis. Cooperation of transforming growth factor-β (TGF-β) and other signaling pathways, such as Ras and Wnt, is essential to inducing EMT, but the molecular mechanisms remain to be fully determined. Here, we reported that insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1), a potential tumor suppressor, controls EMT in colorectal cancer progression. We revealed the inhibitory role of IGFBP-rP1 through analyses of clinical colorectal cancer samples and various EMT and metastasis models in vitro and in vivo. Moreover, we demonstrated that IGFBP-rP1 suppresses EMT and tumor metastasis by repressing TGF-β-mediated EMT through the Smad signaling cascade. These data establish that IGFBP-rP1 functions as a suppressor of EMT and metastasis in colorectal cancer.
doi:10.1038/cddis.2015.59
PMCID: PMC4385937  PMID: 25789970
16.  The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia 
Cell Death and Differentiation  2013;21(1):100-112.
Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia (AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34+ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy.
doi:10.1038/cdd.2013.133
PMCID: PMC3857615  PMID: 24076586
acute myeloid leukemia; cell proliferation and apoptosis; miR-29 family; diagnostic markers; therapeutic targets
17.  Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8 
Cell Death and Differentiation  2013;21(1):59-68.
The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a large-spectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.
doi:10.1038/cdd.2013.73
PMCID: PMC3857625  PMID: 23787997
α factor; autophagy; apoptosis; BAX; endoplasmic reticulum stress; PERK
18.  Molecular mechanisms of ATP secretion during immunogenic cell death 
Cell Death and Differentiation  2013;21(1):79-91.
The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase- and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.
doi:10.1038/cdd.2013.75
PMCID: PMC3857631  PMID: 23852373
apoptosis; Beclin 1; caspases; endoplasmic reticulum stress; quinacrine; U2OS cells
19.  Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom 
British Journal of Cancer  2013;109(4):888-890.
Background:
The prognosis for hepatocellular carcinoma (HCC) is dependent upon tumour stage, performance status (PS), severity of underlying liver disease, and the availability of appropriate therapies. The unavailability of sorafenib may have a significantly adverse effect on the prognosis of UK patients with advanced HCC. During the study period, access to sorafenib was at the discretion of local health funding bodies, a process that may delay or deny access to the drug and that remains in place for Wales, Scotland, and Northern Ireland. Here, we attempt to address the impact of this system on patients with advanced HCC in the United Kingdom.
Methods:
This is a retrospective study performed in the two largest specialist hepatobiliary oncology units in the United Kingdom. Funding applications were made to local funding bodies for patients with advanced HCC for whom sorafenib was considered appropriate (advanced HCC not suitable for loco-regional therapies, compensated chronic liver disease, PS 0–2).
Results:
A total of 133 applications were made, of which 57 (43%) were approved and 76 (57%) declined. Demographics and prognostic factors were balanced between the two groups. This cohort had a number of adverse prognostic features: patients were predominantly PS 1–2; the majority had multifocal disease with the largest lesion being >5 cm; and macroscopic vascular invasion, metastases, and AFP >1000 ng ml−1, were each present in one-third of cases. The median time from application to funding decision was 17 days (range 3–260 days). For the primary ‘intention-to-treat' analysis, median overall survival was 4.1 months when funding was declined, and 9.5 months when funding was approved (hazard ratio (HR) 0.48; 95% CI 0.3186–0.7267; P=0.0005).
Conclusion:
These data support the use of sorafenib for patients with advanced HCC as an effective intervention. In the United Kingdom, this applies to a relatively small group of patients, estimated to total ∼800 per year who, unfortunately, do not survive long enough to themselves lobby for the availability of this drug. These data provide a comparison of sorafenib with supportive care and demonstrate the potential detrimental impact on patient outcomes of rationing health-care resources on the basis of cost.
doi:10.1038/bjc.2013.410
PMCID: PMC3749577  PMID: 23880824
sorafenib; multikinase inhibitor; advanced hepatocellular cancer; primary care trusts; health-care rationing; supportive care
20.  Decreasing Excess Mortality of HIV-infected Patients Initiating Antiretroviral Therapy: Comparison with Mortality in General Population in China, 2003 – 2009 
Objective
To evaluate excess mortality across calendar time comparing HIV-infected patients receiving cART with the general Chinese population.
Methods
Patients receiving free cART through the National Free Antiretroviral Therapy Program (NFATP) between 1 January 2003 and 31 December 2009 were included. Observed mortality rates, excess mortality rates and standardized mortality ratios were calculated by calendar periods. Factors associated with excess mortality across calendar time were evaluated in multivariable Poisson regression models.
Results
Among 64,836 HIV-infected patients the observed and excess mortality rates in 2003/2004 were 9.5 deaths/100 person-years (95% confidence interval [95% CI]: 8.8, 10.2) and 9.1 (8.5, 9.8); in 2008/2009 these decreased to 5.6 (5.4, 5.8) and 5.2 (5.0, 5.4) respectively. The adjusted excess hazard ratio (eHR) for 2003/2004 in comparison to 2008/2009 was 1.27 (95% CI: 1.11, 1.45). Patients initiating cART at CD4 cell counts <50 cells/μL in comparison to ≥350 cells/μL had an adjusted eHR of 9.92 (95% CI: 8.59, 11.44). Patients starting cART at older ages also had greater excess mortality with an eHR of 1.63 (95% CI: 1.47, 1.82) comparing ages ≥ 45 to 18–29. Standardized mortality ratio results were consistent with those for excess mortality.
Conclusion
Substantial decreases in excess mortality were observed from 2003 to 2009 in China among HIV-infected patients receiving free cART. However, mortality among HIV-infected patients remained higher than the general Chinese population. As more efficacious first and second line cART regimens become increasingly available to Chinese HIV-infected patients, further reductions in overall and excess mortality are likely.
doi:10.1097/QAI.0b013e3182948d82
PMCID: PMC3752313  PMID: 23572014
HIV; Mortality; China; Antiretroviral Therapy
21.  Cav-1 deletion impaired hematopoietic stem cell function 
Bai, L | Shi, G | Zhang, L | Guan, F | Ma, Y | Li, Q | Cong, Y-S | Zhang, L
Cell Death & Disease  2014;5(3):e1140-.
A tightly controlled balance between hematopoietic stem and progenitor cell compartments is required to maintain normal blood cell homeostasis throughout life, and this balance is regulated by intrinsic and extrinsic cellular factors. Cav-1 is a 22-kDa protein that is located in plasma membrane invaginations and is implicated in regulating neural stem cell and embryonic stem cell proliferation. However, the role of Cav-1 in hematopoietic stem cell (HSC) function is largely unknown. In this study, we used Cav-1−/− mice to investigate the role of Cav-1 in HSCs function during aging. The results showed that Cav-1−/− mice displayed a decreased percentage of B cells and an increased percentage of M cells in the bone marrow and peripheral blood, and these changes were due to an increased number of HSCs. FACS analysis showed that the numbers of Lin−Sca1+c-kit+ cells (LSKs), long-term HSCs (LT-HSCs), short-term HSCs and multipotent progenitors were increased in Cav-1−/− mice compared with Cav-1+/+ mice, and this increase became more pronounced with aging. An in vitro clonogenic assay showed that LT-HSCs from Cav-1−/− mice had reduced ability to self-renew. Consistently, an in vivo competitive transplantation assay showed that Cav-1−/− mice failed to reconstitute hematopoiesis. Moreover, a Cav-1 deletion disrupted the quiescence of LSKs and promoted cell cycle progression through G2/M phase. In addition, we found that Cav-1 deletion impaired the ability of HSCs to differentiate into mature blood cells. Taken together, these data suggest that Cav-1-deficient cells impaired HSCs quiescence and induced environmental alterations, which limited HSCs self-renewal and function.
doi:10.1038/cddis.2014.105
PMCID: PMC3973224  PMID: 24675458
Cav-1; HSC; quiescence
22.  Magnetic Exchange Coupling and Anisotropy of 3d Transition Metal Nanowires on Graphyne 
Scientific Reports  2014;4:4014.
Applying two-dimensional monolayer materials in nanoelectronics and spintronics is hindered by a lack of ordered and separately distributed spin structures. We investigate the electronic and magnetic properties of one-dimensional zigzag and armchair 3d transition metal (TM) nanowires on graphyne (GY), using density functional theory plus Hubbard U (DFT + U). The 3d TM nanowires are formed on graphyne (GY) surfaces. TM atoms separately and regularly embed within GY, achieving long-range magnetic spin ordering. TM exchange coupling of the zigzag and armchair nanowires is mediated by sp-hybridized carbon, and results in long-range magnetic order and magnetic anisotropy. The magnetic coupling mechanism is explained by competition between through-bond and through-space interactions derived from superexchange. These results aid the realization of GY in spintronics.
doi:10.1038/srep04014
PMCID: PMC3918920  PMID: 24510164
23.  Tumor suppressor NDRG2 tips the balance of oncogenic TGF-β via EMT inhibition in colorectal cancer 
Shen, L | Qu, X | Ma, Y | Zheng, J | Chu, D | Liu, B | Li, X | Wang, M | Xu, C | Liu, N | Yao, L | Zhang, J
Oncogenesis  2014;3(2):e86-.
Transforming growth factor-beta (TGF-β), a pluripotent cytokine expressed in the colon, has a crucial but paradoxical role in colorectal cancer (CRC). TGF-β is a potent proliferation inhibitor of normal colon epithelial cells and acts as a tumor suppressor. However, TGF-β also promotes invasion and metastasis during late-stage CRC, thereby acting as an oncogene. Thus, understanding the factors behind the paradoxical roles of TGF-β and elucidating the mechanisms by which TGF-β-induced proliferation inhibition is impaired in CRC are necessary. Here, we found that the N-Myc tumor suppressor gene downstream-regulated gene NDRG2 (N-Myc downstream-regulated gene 2), which is a TGF-β-responsive gene, abrogated TGF-β-induced epithelial–mesenchymal transition (EMT) and further inhibited the invasion and migration of CRC cells. TGF-β positively induced NDRG2 expression through direct transactivation mediated by Sp1 and by abrogation of the repressive c-Myc/Miz-1 complex on NDRG2 promoter in normal epithelial cells. Aberrant hypermethylation of NDRG2, which could respond to TGF-β growth inhibition signaling, abrogated the inhibitory effect of NDRG2 in TGF-β-induced EMT in CRCs. Reduced NDRG2 expression was highly correlated with the invasion stage and metastasis of CRC. Our study establishes that NDRG2 is a new tumor suppressor gene that responds to TGF-β anti-proliferative signaling and tips the balance of oncogenic TGF-β during late-stage CRC.
doi:10.1038/oncsis.2013.48
PMCID: PMC3940918  PMID: 24492480
colorectal cancer; TGF-β; NDRG2; EMT; methylation
24.  Stress-induced RNASET2 overexpression mediates melanocyte apoptosis via the TRAF2 pathway in vitro 
Wang, Q | Jiang, M | Wu, J | Ma, Y | Li, T | Chen, Q | Zhang, X | Xiang, L
Cell Death & Disease  2014;5(1):e1022-.
The recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene; however, the functional roles of RNASET2 in vitiligo pathogenesis or in melanocyte apoptosis have yet to be determined. The current study was designed to investigate the vitiligo-related expression pattern of RNASET2 and its molecular function involving apoptosis-related signaling proteins and pathways. The results showed overexpression of RNASET2 in epidermis specimens from 40 vitiligo patients compared with that from matched healthy controls. In addition, in vitro analyses indicated that overexpression of RNASET2 was inducible in cultured primary human melanocytes and keratinocytes by stress conditions, that is, exposure to UV irradiation, hydrogen peroxide, and inflammatory factors, respectively, and led to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)–caspases pathway through the physical interaction of RNASET2 with TRAF2. Thus, RNASET2 may contribute to vitiligo pathogenesis by inhibiting TRAF2 expression and, as such, RNASET2 may represent a potential therapeutic target of vitiligo.
doi:10.1038/cddis.2013.539
PMCID: PMC4040706  PMID: 24457966
stress; RNASET2; melanocyte; apoptosis; TRAF2
25.  Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs 
Background
Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) benefit Non-small cell lung cancer (NSCLC) patients, and an EGFR-TKIi erlotinib, is approved for patients with recurrent NSCLC. However, resistance to erlotinib is a major clinical problem. Earlier we have demonstrated the role of Hedgehog (Hh) signaling in Epithelial-to-Mesenchymal transition (EMT) of NSCLC cells, leading to increased proliferation and invasion. Here, we investigated the role of Hh signaling in erlotinib resistance of TGF-β1-induced NSCLC cells that are reminiscent of EMT cells.
Methods
Hh signaling was inhibited by specific siRNA and by GDC-0449, a small molecule antagonist of G protein coupled receptor smoothened in the Hh pathway. Not all NSCLC patients are likely to benefit from EGFR-TKIs and, therefore, cisplatin was used to further demonstrate a role of inhibition of Hh signaling in sensitization of resistant EMT cells. Specific pre- and anti-miRNA preparations were used to study the mechanistic involvement of miRNAs in drug resistance mechanism.
Results
siRNA-mediated inhibition as well as pharmacological inhibition of Hh signaling abrogated resistance of NSCLC cells to erlotinib and cisplatin. It also resulted in re-sensitization of TGF-β1-induced A549 (A549M) cells as well the mesenchymal phenotypic H1299 cells to erlotinib and cisplatin treatment with concomitant up-regulation of cancer stem cell (CSC) markers (Sox2, Nanog and EpCAM) and down-regulation of miR-200 and let-7 family miRNAs. Ectopic up-regulation of miRNAs, especially miR-200b and let-7c, significantly diminished the erlotinib resistance of A549M cells. Inhibition of Hh signaling by GDC-0449 in EMT cells resulted in the attenuation of CSC markers and up-regulation of miR-200b and let-7c, leading to sensitization of EMT cells to drug treatment, thus, confirming a connection between Hh signaling, miRNAs and drug resistance.
Conclusions
We demonstrate that Hh pathway, through EMT-induction, leads to reduced sensitivity to EGFR-TKIs in NSCLCs. Therefore, targeting Hh pathway may lead to the reversal of EMT phenotype and improve the therapeutic efficacy of EGFR-TKIs in NSCLC patients.
doi:10.1186/1756-8722-6-77
PMCID: PMC3852827  PMID: 24199791
NSCLC; Erlotinib resistance; Hh signaling; miRNAs; EMT; GDC-0449

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