FADD (Fas-associated protein with death domain) is a classical adaptor protein in apoptosis. Increasing evidences have shown that FADD is also implicated in cell cycle progression, proliferation and tumorigenesis. The role of FADD in cancer remains largely unexplored. In this study, In Silico Analysis using Oncomine and Kaplan Meier plotter revealed that FADD is significantly up-regulated in breast cancer tissues and closely associated with a poor prognosis in patients with breast cancer. To better understanding the FADD functions in breast cancer, we performed proteomics analysis by LC-MS/MS detection and found that Rheb-mTORC1 pathway was dysregulated in MCF-7 cells when FADD knockdown. The mTORC1 pathway is a key regulator in many processes, including cell growth, metabolism and autophagy. Here, FADD interference down-regulated Rheb expression and repressed mTORC1 activity in breast cancer cell lines. The autophagy was induced by FADD deficiency in MCF7 or MDA-231 cells but rescued by recovering Rheb expression. Similarly, growth defect in FADD-knockdown cells was also restored by Rheb overexpression. These findings implied a novel role of FADD in tumor progression via Rheb-mTORC1 pathway in breast cancer.
FADD (Fas-associated protein with death domain) is a classical adaptor protein in apoptosis. Increasing evidences have shown that FADD is also implicated in cell cycle progression, proliferation and tumorigenesis. The role of FADD in cancer remains largely unexplored. In this study, In Silico Analysis using Oncomine and Kaplan Meier plotter revealed that FADD is significantly up-regulated in breast cancer tissues and closely associated with a poor prognosis in patients with breast cancer. To better understanding the FADD functions in breast cancer, we performed proteomics analysis by LC-MS/MS detection and found that Rheb-mTORC1 pathway was dysregulated in MCF-7 cells when FADD knockdown. The mTORC1 pathway is a key regulator in many processes, including cell growth, metabolism and autophagy. Here, FADD interference down-regulated Rheb expression and repressed mTORC1 activity in breast cancer cell lines. The autophagy was induced by FADD deficiency in MCF7 or MDA-231 cells but rescued by recovering Rheb expression. Similarly, growth defect in FADD-knockdown cells was also restored by Rheb overexpression. These findings implied a novel role of FADD in tumor progression via Rheb-mTORC1 pathway in breast cancer.
Entities:
Keywords:
FADD; Rheb; autophagy; breast cancer; tumorigenesis
Fas-associated protein with death domain (FADD) is the key adaptor protein transmitting apoptotic signals mediated by death receptors (DRs). It was originally identified in FAS-induced apoptosis [1-3]. Following DD interaction between FADD and FAS, the cytoplasmic procapase-8 binds to FADD through DED-DED interactions, and forms the death-inducing signaling complex (DISC). Besides being a main death adaptor molecule, FADD is also required for T cell proliferation. Several groups have demonstrated that FADD deficiency in peripheral T lymphocytes resulted in an inhibition of mitogen-induced T cell proliferation [4, 5]. FADD deficiency also leads to a dysregulation of the cell cycle machinery. Recently, emerging evidences have shown that FADD expression was associated with tumor development [6]. Amplification of the 11q13, a chromosomal region containing the gene encoding FADD, is frequently observed in many cancer cells. Overexpression of FADD might be as a biomarker in head and neck squamous cell carcinoma [7, 8]. FADD protein expression could contribute to disease progression in several malignancies, so the mechanism of FADD in tumorigenesis needs further investigated.At present, In Silico Analysis using Oncomine Database is a useful platform to gain the disease summary for FADD, and proteomics coupled with bioinformatics analysis provides a powerful tool for us to find the potential targets of FADD and its signaling pathway networks. In this study, we first reported that FADD expression was remarkably higher in breast cancer and applied LC-MS/MS detection plus bioinformatics analysis to reveal that Rheb-mTORC1 pathway was dysregulated in breast cancer cells because of FADD knockdown. mTOR is a serine/ threonine kinase and functions as a key modulator in cell proliferation, protein synthesis, aging and autophagy [9, 10]. The best-described target of mTORC1 is its downstream marker ribosomal S6 protein kinase 1 (p70s6k). p70s6k activation requires mTORC1-mediated phosphorylation [11]. The mTORC1 activity is tightly regulated by a wide range of environmental signals. One key upstream activator of mTORC1 is the small GTP-binding protein Rheb (Ras homolog enriched in brain), which is the most well-known regulator of mTORC1 to date. Rheb promotes mTORC1 activity and enhances p70s6k phosphorylation in a rapamycin-dependent manner [12-15]. Latest studies show that Rheb-mTORC1 signaling axis is hyper-activated in a variety of humancancers and closely related to tumorigenesis [16, 17].Therefore, we performed further cell biological examinations on FADD knockdown to address the Rheb-mTORC1 pathway. Our data showed that FADD interference decreased Rheb expression on the transcriptional level. To explore the effect of FADD on Rheb-mTORC1 signaling axis, we detected the p70s6k phosphorylation for mTOR activity. The decrease of p70s6k phosphorylation was observed in FADD knockdown cells, which was rescued by recovered Rheb expression. Inhibition of autophagy is one important function of mTORC1. Similarly, the induction of autophagy by FADD deficiency was also rescued by recovering Rheb expression. Moreover, Rheb overexpression could improve cell growth which was retarded for FADD knockdown. Collectively, these data suggest a novel role of FADD in breast tumorigenesis through promoting Rheb expression.
RESULTS
High expression of FADD in human breast cancer correlated with poor prognosis
Oncomine platform (http://www.oncomine.org) is a free online bioinformatic resource of cancer transcriptome data. To gain an overview of FADD expression in humancancers, we performed analysis of published patient data using Oncomine and found that FADD mRNA level is significantly up-regulated in humanbreast cancer (Figure 1A). In Curtis breast dataset with 2136 samples [18], FADD expression levels were upregulated in most of breast cancer tissues (n>1556, p=3.09E-13), compared with normal tissues (n=144) (Figure 1B). To confirm the oncomine data, we analyzed FADD expression in a breast tissue microarray (TMA) containing 30 cases of breast specimens by Immunohistochemical (IHC) staining (Figure 1C). High FADD expression was observed in 21 of 30 (70%) of tumor tissues compared with adjacent histologically normal tissues, suggesting elevated FADD expression might contribute to tumor development. Using Kaplan Meier plotter, another free online tool for meta-analysis based biomarker assessment [19], the result revealed that FADD-High expression in patients was correlated with a worse survival ratio compared with FADD-low counterparts (HR=1.6, logrank P=1e-15) (Figure 1D). Collectively, these findings indicate that up-regulated FADD predicts a poor prognosis in breast patients and is closely correlated with tumor progression in breast cancer.
Figure 1
Elevated FADD expression was correlated with human breast cancer progression
A. The gene summary for FADD in cancers was gained from OncomineTM Research Edition. B. Increased FADD mRNA expression was analyzed in Curtis Breast dataset with 2,136 samples. C. FADD expression was determined by immunohistochemical analysis on tissue microarray. Representative images (pathological grades: II and III) were shown: (a) adjacent histologically nontumor tissue, (b) breast tumor tissue. D. Cancer survival analysis of FADD expression was assessed on Kaplan-Meier plotter. Meta-analysis based on biomarker assessment shows that High FADD expression versus low expression has a poor survival in human breast cancer. P-value is calculated using log-rank test.
Elevated FADD expression was correlated with human breast cancer progression
A. The gene summary for FADD in cancers was gained from OncomineTM Research Edition. B. Increased FADD mRNA expression was analyzed in Curtis Breast dataset with 2,136 samples. C. FADD expression was determined by immunohistochemical analysis on tissue microarray. Representative images (pathological grades: II and III) were shown: (a) adjacent histologically nontumor tissue, (b) breast tumor tissue. D. Cancer survival analysis of FADD expression was assessed on Kaplan-Meier plotter. Meta-analysis based on biomarker assessment shows that High FADD expression versus low expression has a poor survival in humanbreast cancer. P-value is calculated using log-rank test.
LC-MS/MS based proteomics analysis in breast cancer cell
To find out the molecular pathways directly or indirectly controlled by FADD in tumorigenesis of breast cancer, high throughput proteomic approaches was performed in human breast cell line MCF-7 with FADD knockdown. The expression of FADD was confirmed by western blotting shown in Supplementary Figure S1A. About 500 differentially expressed proteins were identified. We used the GeneGO/MetaCore software to analyze the biological networks related to these proteins. GeneGo Map Folder analysis was applied to predict top ten pathways in the highest significance in Figure 2A. Pathway in apoptosis and survival ranked first, which was consistent with the main function of FADD as an apoptotic protein. Among them, three pathways were linked with Rheb-mTORC1 signaling axis (Figures 2B–2D). Further analysis on GeneGo process also showed that three of the top ten processes were linked to Rheb-mTORC1 signal axis (Supplementary Figure S1B). Since mTOR pathway is a key regulator of cell growth and proliferation, its deregulation might be an important clue for FADD function in breast cancer.
Figure 2
Enrichment analysis of differentially expressed proteins in MCF-7 cells with FADD knockdown
A. Top ten most significant pathways predicted by GeneGo pathway analysis. The results were ordered by -log10 of the p value of the hypergeometric distribution. B–D. Pathways related to Rheb-mTORC1 signaling axis within the top ten most significant pathways. Thermometers with blueorred next to symbols show proteins identified in LC-MS/MS detection: red color represents the proteins that increased in FADD knockdown MCF-7 cells compared to control group; blue color represents the decreased proteins.
Enrichment analysis of differentially expressed proteins in MCF-7 cells with FADD knockdown
A. Top ten most significant pathways predicted by GeneGo pathway analysis. The results were ordered by -log10 of the p value of the hypergeometric distribution. B–D. Pathways related to Rheb-mTORC1 signaling axis within the top ten most significant pathways. Thermometers with blueorred next to symbols show proteins identified in LC-MS/MS detection: red color represents the proteins that increased in FADD knockdown MCF-7 cells compared to control group; blue color represents the decreased proteins.
Rheb expression decreased by FADD knockdown
Proteomics analysis showed that the expressions of Rheb and mTOR were down-regulated in MCF-7 cells of FADD knockdown compared with control cells (Supplementary Table S1), which was confirmed by western blotting analysis (Figure 3A). There was about 60% reduction of Rheb protein in MCF-7 cells treated with FADD siRNAs. No significant difference on mTOR expression was observed (Supplementary Figure S2). Similar result was reconfirmed in another breast cancer cell line MDA-MB-231 (Figure 3B). With an increasing transfection of FADD siRNAs, the protein level of Rheb was decreased in a dose-dependent manner in both MCF-7 and MDA-MB-231 cells (Figure 3C and 3D). Notably, Rheb expression was also elevated in breast TMA as well as FADD (Supplementary Figure S3), and reported to be correlated with poor prognosis in patients with breast cancer [20]. The protein level of Rheb had a good consistency with FADD expression in breast cancers.
Figure 3
FADD interference downregulated Rheb expression
NC or FADD siRNA was transfected in MCF-7 A. or MDA-MB-231 B. cells for 48 h. Total cell lysates were detected by western blotting with antibodies as indicated. Band intensity was quantified by chemiAnalysi software. Data was represented as mean ± S.D. P values were calculated by Student's t-test (*p < 0.05; **p < 0.01) and the experiment was repeated at least three times. Different dose of FADD siRNA was transfected into MCF-7 cells C. and MDA-MB-231 cells D. The expression of FADD and Rheb was detected by western blot.
FADD interference downregulated Rheb expression
NC or FADD siRNA was transfected in MCF-7 A. or MDA-MB-231 B. cells for 48 h. Total cell lysates were detected by western blotting with antibodies as indicated. Band intensity was quantified by chemiAnalysi software. Data was represented as mean ± S.D. P values were calculated by Student's t-test (*p < 0.05; **p < 0.01) and the experiment was repeated at least three times. Different dose of FADD siRNA was transfected into MCF-7 cells C. and MDA-MB-231 cells D. The expression of FADD and Rheb was detected by western blot.
The effect of FADD on Rheb transcription
We next tested the effect of FADD on Rheb gene expression at the transcription level. After RNAi for FADD, Rheb mRNA was examined by qPCR assays in MCF-7 cells (Figure 4A) and MDA-MB-231 (Figure 4B). Consistent with the above data, Rheb mRNA was also decreased in a dose dependent manner when FADD became gradually reduced. The decrease of mRNA level is generally considered for two factors, mRNA stability and transcriptional activity. To examine the effect of FADD on the stability of Rheb mRNA, MCF-7 cells were transfected with FADD siRNA or control siRNA for 48 h and treated with actinomycin D (ActD) for indicated times, then harvested to quantify the Rheb mRNA by qPCR. As shown in Figure 4C, the degradation speed of Rheb mRNA showed no obvious differences in two groups. Then we constructed the promoter-luciferase reporter vector to analyze the transcriptional activity of Rheb. FADD interference inhibited the luciferase acitivity of Rheb promoter (Figure 4D), suggesting the effect of FADD on Rheb expression at its transcriptional level.
Figure 4
FADD interference decreased Rheb expression on the transcriptional level
FADD siRNA was transfected into MCF-7 A. and MDA-MB-231 B. cells for 48 h. FADD mRNA was measured by qRT-PCR normalized to β-actin. C. MCF-7 cells were transfected with 80 μM FADD siRNA/NC for 48 h and then treated with 5 μg/ml Act D for indicated time. Rheb mRNA were quantified by qRT-PCR. D. Luciferase activity of Rheb-promoter reporter was detected in MCF-7 cells transfected with FADD siRNA/NC. Each bar is the mean of at least 3 independent experiments. Data are representedas mean ± S.D. *p < 0.05; **p < 0.01;***p < 0.001.
FADD interference decreased Rheb expression on the transcriptional level
FADD siRNA was transfected into MCF-7 A. and MDA-MB-231 B. cells for 48 h. FADD mRNA was measured by qRT-PCR normalized to β-actin. C. MCF-7 cells were transfected with 80 μM FADD siRNA/NC for 48 h and then treated with 5 μg/ml Act D for indicated time. Rheb mRNA were quantified by qRT-PCR. D. Luciferase activity of Rheb-promoter reporter was detected in MCF-7 cells transfected with FADD siRNA/NC. Each bar is the mean of at least 3 independent experiments. Data are representedas mean ± S.D. *p < 0.05; **p < 0.01;***p < 0.001.
mTORC1 activity regulated by FADD through Rheb
Based on GeneGo Map analysis, Rheb-mTORC1 signaling axis became unusual because of FADD knockdown. p70s6k is a well-defined downstream of mTORC1 and its phosphorylation is a reliable measurement for mTORC1 activity [11, 15, 21]. Compared with transfection with NC siRNA, the level of p70s6k phosphorylation decreased to 60% in MCF-7 cells transfected with FADD siRNA (Figure 5A) and 40% in MDA-MB-231 cells (Figure 5B), respectively. The mTORC1 activity is tightly regulated by a wide range of environmental signals, including serum. MCF-7 cells were transfected with FADD siRNA for 24 h and then starved with DMEM without serum for 24 h followed by 20% serum stimulation for 15 min [22]. The stimulation of serum effectively enhanced p70s6k phosphorylation in MCF-7 cells with control siRNA, and no much phosphorylation shown in cells with FADD siRNA (Figure 5C), indicating an impairment of mTORC1 activity in FADD deficiency. To examine whether the influence of FADD on the mTORC1 activity is mediated by Rheb, we recovered Rheb expression in FADD-knockdown-MCF-7 cells via transfecting Rheb expression vector. p70s6k phosphorylation was rescued from 68% to 80% by supplement of Rheb expression (Figure 5D), which was also observed in MDA-MB-231 cells (Figure 5E). These findings suggested that Rheb was necessary for FADD modulation on mTORC1 activity.
Figure 5
FADD regulated mTORC1 activity through Rheb
MCF-7 A. or MDA-MB-231 B. cells were transfected with FADD siRNA/NC for 48 h. The cell lysates was performed by western blot with indicated antibodies (n=4). C. MCF-7 cells were transfected with FADD siRNA/NC for 24 h and then starved for 24 h. Then cells were stimulated by 20% serum for 15 minutes (n=3). Cells were cotransfected with FADD siRNA/NC with pRK5-Flag-Rheb or control vector for 48 h. Western blot analysis in MCF-7 D. or MDA-MB-231 E. Band intensity was quantified by chemiAnalysi software. Data are represented as mean ± S.D. *p < 0.05; ***p < 0.001. Each bar is the mean of 3 independent experiments.
FADD regulated mTORC1 activity through Rheb
MCF-7 A. or MDA-MB-231 B. cells were transfected with FADD siRNA/NC for 48 h. The cell lysates was performed by western blot with indicated antibodies (n=4). C. MCF-7 cells were transfected with FADD siRNA/NC for 24 h and then starved for 24 h. Then cells were stimulated by 20% serum for 15 minutes (n=3). Cells were cotransfected with FADD siRNA/NC with pRK5-Flag-Rheb or control vector for 48 h. Western blot analysis in MCF-7 D. or MDA-MB-231 E. Band intensity was quantified by chemiAnalysi software. Data are represented as mean ± S.D. *p < 0.05; ***p < 0.001. Each bar is the mean of 3 independent experiments.
Autophagy induced by FADD silencing in human breast cancer cells
One important function of mTORC1 is the inhibition of autophagy [23-25]. Considering the impairment of mTORC1 activity in FADD deficiency cells might initiate autophagy, we next detected autophagy using LC3B as a marker. During autophagy, LC3B I will be modified with phosphatidylethanolamine (PE) and converted to LC3B II, and the ratio of LC3B II to LC3BI is widely used to measure cellular autophagic activity [26, 27]. LC3BI to LC3BII conversion was markedly increased in MCF-7 or MDA-MA-231 cells when FADD was knocked down (Figure 6A and 6B). Meanwhile, another autophagosomal marker p62 expression was observed in 40% to 60% reduction accompanied by FADD reduction, which is reported to degrade during autophagy. When autophagy was induced by starvation, stronger autophagy activity was also observed in cells of FADD knockdown (Supplementary Figure S4). For avoiding the artificial effect, we tried another interference technique Crispr/Cas9 to effectively downregulate FADD expression and obtained similar results (Supplementary Figure S5). Furthermore, GFP-LC3 was used to display the images of autophagy. The formation of GFP-LC3 labeled vacuoles increased significantly in MCF-7 cells with deficient FADD, and the quantitation of GFP-LC3-punctate cells were shown in Figure 6C. Furthermore, autophagy induced by FADD silencing was confirmed by the morphological change using transmission electron microscopy (TEM) analysis (Figure 6D). There were more double-membrane cytoplasmic vacuoles (arrowheads) in cells transfected FADD siRNA than control siRNA, indicating the stronger autophagic activity. Chloroquine (CQ) inhibits autophagy as it leads to inhibition of both fusion of autophagosome with lysosome and lysosomal protein degradation. CQ treatment resulted in the accumulation of LC3B and p62, but did not change the appearance of the more conversion of LC3B I to LC3B II and lower expression of p62 in FADD-knockdown cells. These data demonstrated that FADD interference promoted the occurrence of autophagy in the early stage.
Figure 6
FADD interference induces autophagy
MCF-7 A. or MDA-MB-231 B. cells were transfected with FADD siRNA/NC for 48 h. LC3B and p62 were detected by western blotting. Band intensity was quantified. Each bar is the mean of 4 independent experiments. C. MCF-7 cells were transfected with GFP-LC3 plasmid together with FADD siRNA/NC for 48 h. Formation of vacuoles containing GFP-LC3 (dots) was examined by fluorescence microscopy. Scale bar: 5 μm. D. MCF-7 cells were transfected with FADD siRNA/NC for 48 h and then conducted to transmission electron microscopy (TEM) analysis. Representative image of different experiment was shown. Scale bar: 1 μm. E. MCF-7 cells were transfected with FADD siRNA/NC for 24 h and then treated with 20 μM chloroquine (CQ) at indicated times. Cell lysates were detected by western blotting (n=3). Each bar is the mean of 3 independent experiments. Data are represented as mean ± S.D. *p < 0.05; **p < 0.01; ***p < 0.001.
FADD interference induces autophagy
MCF-7 A. or MDA-MB-231 B. cells were transfected with FADD siRNA/NC for 48 h. LC3B and p62 were detected by western blotting. Band intensity was quantified. Each bar is the mean of 4 independent experiments. C. MCF-7 cells were transfected with GFP-LC3 plasmid together with FADD siRNA/NC for 48 h. Formation of vacuoles containing GFP-LC3 (dots) was examined by fluorescence microscopy. Scale bar: 5 μm. D. MCF-7 cells were transfected with FADD siRNA/NC for 48 h and then conducted to transmission electron microscopy (TEM) analysis. Representative image of different experiment was shown. Scale bar: 1 μm. E. MCF-7 cells were transfected with FADD siRNA/NC for 24 h and then treated with 20 μM chloroquine (CQ) at indicated times. Cell lysates were detected by western blotting (n=3). Each bar is the mean of 3 independent experiments. Data are represented as mean ± S.D. *p < 0.05; **p < 0.01; ***p < 0.001.
The autophagy mediated by FADD via Rheb-mTOR pathway
To examine whether Rheb is necessary for FADD-mediated autophagy, Rheb expression vector was cotransfected with FADD siRNA or control siRNA, respectively. The ratio of LC3B II/LC3B I was declined and p62 expression was increased when Rheb overexpression in both MCF-7 cells (Figure 7A) and MDA-MB-231 cells (Figure 7B). By fluorescence image, we observed that both the number of dots inside cells and the percentage of cell with GFP-LC3 puncta-formation were decreased because of Rheb overexpression, especially in FADD knockdown cells (Figure 7C). Transmission electron microscopy analysis further revealed that the autophagosome formation mediated FADD interference was inhibited by Rheb overexpression (Figure 7D). These data provided evidences for the role of FADD in autophagy via Rheb-mTOR pathway.
Figure 7
Rheb overexpression rescued autophagy induced by FADD knockdown
MCF-7 A. or MDA-MB-231 B. cells were transfected with FADD siRNA/NC together with pRK5-Flag-Rheb or control plasmid for 48 h and then lysed for western blotting. Band intensity was quantified. Each bar is the mean of 3 independent experiments. C. MCF-7 cells were cotransfected GFP-LC3 with FADD siRNA/NC, pRK5-Flag-Rheb, control vector as indicated. Formation of vacuoles containing GFP-LC3 (dots) was examined by fluorescence microscopy. Scale bar: 5 μm. D. MCF-7 cells were transfected with FADD siRNA/NC together with pRK5-Flag-Rheb/control plasmid for 48 h and then subjected to transmission electron microscopy (TEM) analysis. The representative of three different experiments was shown. Scale bar: 1μm. Data are represented as mean ± S.D. *p < 0.05; ***p < 0.001.
Rheb overexpression rescued autophagy induced by FADD knockdown
MCF-7 A. or MDA-MB-231 B. cells were transfected with FADD siRNA/NC together with pRK5-Flag-Rheb or control plasmid for 48 h and then lysed for western blotting. Band intensity was quantified. Each bar is the mean of 3 independent experiments. C. MCF-7 cells were cotransfected GFP-LC3 with FADD siRNA/NC, pRK5-Flag-Rheb, control vector as indicated. Formation of vacuoles containing GFP-LC3 (dots) was examined by fluorescence microscopy. Scale bar: 5 μm. D. MCF-7 cells were transfected with FADD siRNA/NC together with pRK5-Flag-Rheb/control plasmid for 48 h and then subjected to transmission electron microscopy (TEM) analysis. The representative of three different experiments was shown. Scale bar: 1μm. Data are represented as mean ± S.D. *p < 0.05; ***p < 0.001.
The crosstalk of cell proliferation and autophagy linked by FADD
The mTOR pathway integrates signals from nutrients and growth factors to regulate many progresses, including autophagy and cell proliferation. It interested us to figure out the influence of FADD on these two progresses. Two siRNAs of ATG5 was designed for blocking autophagy at early stage. #2 ATG5 siRNA seemed a more effective candidate and was thus used in later experiments (Figure 8A). As expected, ATG5 interference reduced the autophagic activity (Figure 8B). Then we monitored cell growth using Real-Time Cell Analysis (RTCA), which is a novel approach to assess cellular proliferation. The slope processed by software represents the growth rate showed in Figure 8C. At 48 h after transfection, there was no significant difference on cell proliferation among four groups. Extended to 96 h post transfection, the growth of cells treated with FADD siRNA was obviously restrained. Meanwhile when cells treated with double siRNAs of FADD and ATG5, it showed partly restored in cell proliferation (Figure 8C). For continuous culture for 96 h without supplement of fresh culture medium, nutrient deficiency would induce autophagy. At this time, the defect on cell proliferation by FADD siRNA was partly rescued by addition of ATG5 siRNA, suggesting that autophagy induced by FADD deficiency might be one important reason for cell growth defect. We further examined whether Rheb overexpression would effectively recover the impairment of cell proliferation mediated by FADD deficiency. Consistent with the previous results, Rheb also improved cell proliferation of FADD-deficient cells (Figure 8D).
Figure 8
FADD enhances cell proliferation by repressing autophagy
A. ATG5 siRNAs/NC was transfected in MCF-7 cells for 48 h. ATG5 expression was detected. B. MCF-7 cells were transfected with ATG5 siRNA/NC together with FADD siRNA/NC for 48 h and detected by western blotting. C. MCF-7 cells were transfected with ATG5 siRNA/NC together with FADD siRNA/NC and then seeded to E-Plate on Real-Time Cell Analysis (RTCA). Each bar is the mean of 4 independent experiments. Data are representedas mean ± S.D.*p < 0.05. D. MCF-7 cells were transfected with FADD siRNA/NC together with pRK5-Flag-Rheb and then performed to RTCA analysis. Each bar is the mean of 4 independent experiments. Data are represented as mean ± S.D.*p < 0.05. E. Proposed model of FADD in autophagy.
FADD enhances cell proliferation by repressing autophagy
A. ATG5 siRNAs/NC was transfected in MCF-7 cells for 48 h. ATG5 expression was detected. B. MCF-7 cells were transfected with ATG5 siRNA/NC together with FADD siRNA/NC for 48 h and detected by western blotting. C. MCF-7 cells were transfected with ATG5 siRNA/NC together with FADD siRNA/NC and then seeded to E-Plate on Real-Time Cell Analysis (RTCA). Each bar is the mean of 4 independent experiments. Data are representedas mean ± S.D.*p < 0.05. D. MCF-7 cells were transfected with FADD siRNA/NC together with pRK5-Flag-Rheb and then performed to RTCA analysis. Each bar is the mean of 4 independent experiments. Data are represented as mean ± S.D.*p < 0.05. E. Proposed model of FADD in autophagy.
DISCUSSION
Recently, amplification of FADD has been observed in many different types of cancer and links to cancer progression [28-31]. Here, we provided evidence that FADD overexpression correlated with poor outcome in humanbreast cancer for the first time. With the help of high-throughput proteomics and bioinformatics analysis, the Rheb-mTORC1 pathway was predicted to be dysregulated in humanbreast adenocarcinoma cell line MCF-7 when FADD was knockdown (Figure 2). Rheb has been regarded as a novel prognostic factor in humancancer for that it activates the key metabolic regulator mTORC1. Elevated Rheb expression has been reported in a wide variety of tumors and coupled with mTORC1 hyper-activation, including humanbreast cancers [34, 57, 58]. In our study, Rheb downreglation by FADD deficiency was validated in humanbreast cancer cell lines MCF-7 and MDA-MB-231 (Figure 3), as well as the impairment of mTORC1 activity (Figure 5). Like FADD, high Rheb expression is also correlated to poor prognosis in humanbreast cancer [20].FADD is much more than an instrument of death and implicated in embryonic development, cell proliferation, tumor progression, inflammation, necrosis, and autophagy. However, the most important function of FADD is a pro-apoptotic adaptor. We previously reported that FADD protein had the potential to highly oligomerize. FADD self-aggregated in vitro and transfected FADD in mammalian cells effectively induced apoptosis by forming death effector filaments independent of receptor cross-linking at the plasma membrane [40]. The apoptosis induced by FADD overexpression also appeared in breast cancer cells (shown in Supplementary Figure S6), so RNA interference of FADD as a reasonable and practical approach of studying the effect of FADD protein expression level was widely used in our studies. In order to consolidate this conclusion of Rheb expression regulated by FADD, the results were fully verified in FADD-knockout MEF cells shown in Supplementary Figure S7. FADD could up-regulate Rheb expression and activate mTORC1 activity.The mTORC1 activity is tightly related with cellular processes like autophagy and cell proliferation [32]. FADD interference induced autophagy by down-regulating Rheb-mTORC1 activity, which was restored by recovering Rheb expression. Similarly, the proliferative deficiency caused by FADD silencing was also rescued by Rheb overexpression. Our findings indicated that Rheb might play an important role in the function of FADD on tumorigenesis.Growing evidence has shed light on the role of autophagy in proliferation and tumorigenesis. ATG5−/−CD4+ and CD8+ T cells failed to undergo efficient proliferation after TCR stimulation [33]. However, unrestricted autophagy impairs cell proliferation [34, 35]. Mice with systemic deletion of ATG5 and liver-specific ATG7−/−mice were reported to develop benign liver adenomas, together with elevated cell proliferation [36]. Similarly, ATG5 interference inhibited autophagy and partly rescued the proliferative deficiency in FADD knockdown cells. This might be a possible way in the proliferative role of FADD via regulating autophagy.In conclusion, our study strengthened the role of FADD in human breast tumorigenesis. FADD upregulates Rheb expression and promotes mTORC1 activity. Activated mTORC1 augments cell proliferation via autophagy inhibition. This finding helps to enrich the multifunction of FADD, and more importantly, represent a promising target for breast cancer therapy.
MATERIALS AND METHODS
Plasmids and reagents
The encoding sequence of humanRheb was amplified from cDNA of MCF-7 cells and cloned into pRK5-Flag vector. The promoter sequence of humanRheb (−1064/+217) was amplified and cloned into pGL3 reporter vector. GFP-LC3 plasmid was purchased from Addgene (#24987). Actinomycin D (Act D, 01815), chloroquine (CQ, C6628) were purchased from Sigma. Hoechst 33342 (H3570) was from Invitrogen.
Cell culture
Breast adenocarcinoma cell lines MCF-7 and MDA-MB-231 were cultured in Dulbecco's modified Eagle's medium (Wisent, Canada) supplemented with 10% fetal bovine serum (Invitrogen, USA), 50 μg/ml streptomycin and 50 U/ml penicillin. Cells were kept at 37¼C in a humidified incubator with 5% CO2.
siRNAs and transfection
All synthetic siRNAs and the negative control (NC) were purchased from Shanghai GenePharma Co. Ltd. For transfection, cells were transiently transfected with siRNAs or plasmids using lipofectamine 2000 (Invitrogen, USA) according to the manufacturer's instructions. The sequences of siRNAs for target as follows: FADD: 5′-CACAGAGAAGGAGAACGCA-3′; ATG5-#1: 5′-GC AACUCUGGAUGGGAUUGTT-3′; ATG5-#2: 5′-GACG TTGGTAACTGACAAATT-3′.
Western blotting
Cells were lysed in ice-cold lysis buffer (20 mMTris-HCl (pH 7.5), 150 mM NaCl, 1%Triton-X 100, 1 mM EDTA and a protein inhibitor cocktail) for 30 min. The supernatant was boiled with Laemmli sample buffer for SDS-PAGE. Antibodies as follows: anti-Rheb and anti-FADD from Abcam, anti-LC3B, anti-SQSTM1/p62, anti-p70s6k, anti-phospho-p70s6k (Thr389) and anti-ATG5 from Cell Signaling Tech, and other antibodies: anti-α-Tubulin (Epitomics, 2871-1), anti-Flag (Sigma-Aldrich, F7425), anti-GAPDH (Santa Cruz Biotechnology, L-3113). Band intensity was quantified by ChemiAnalysi software (Bioshine, China).
Quantitative real-time PCR
Total RNA was extracted with TRIzol reagent (Invitrogen, USA) following the manufacturer's instructions. Quantitative real-time PCR was performed using reverse transcription kit (Takara, Japan) and SYBR Green PCR Master Mix (Roche, Germany). The primers as follows: Rheb, 5′-GCCGCCGATCACAGCAGCAGGAG-3′ and 5′-CCCACAGACCGGTAGCCCAGGAT-3′; FADD, 5′-GC CGCGCCTGGGGAAGAAGAC-3′ and 5′-GCAAAGCA GCGGCCCATCAGGA-3′; β-actin, 5′- CATCGAGCAC GGCATCGTCA-3′ and 5′-TAGCACAGCCTGGATAGC AAC-3′.
Luciferase reporter assay
MCF-7 cells were transfected with siRNA/NC firstly and then cotransfected with Rheb-promoter luciferase and control pRL reporter for 24 h. Luciferase activities were measured consecutively by using Dual-Luciferase assays (Promega, USA). All measurements were normalized for Renilla luciferase activity to correct the variations in transfection efficiencies.
LC-MS/MS analysis and bioinformatics analysis
The LC-MS/MS analysis was performed as previously described [37]. Protein samples were carried out using the bicinchoninic acid (BCA) method. Equal amount of protein (200 μg) was used for iTRAQ labeling according to the manufacturer's instructions. Raw MS/MS data were analyzed by the Agilent G2721AA Spectrum Mill MS Proteomics Workbench (Rev A.03.03.078) in the UniProtKB/SWISS Prot database for protein identification. The network building tool MetaCoreTM version 5.4 (GeneGo) was used to establish potential signaling network.
Tissue microarray analysis
Tissue microarray (TMA) of breast cancer was purchased from Shanghai Outdo Biotech Co. Ltd. Specimens included stage II or III invasive ductal cancer (n=30) and adjacent normal tissue (n=30). TMA immunohistochemical analysis was performed as previously described [38]. The quantitative analysis of FADD and Rheb staining was applied with Image-Pro Plus software.
Transmission electron microscopy assay
MCF-7 cells were cultured in 100 mm dishes and co-transfected with FADD siRNA or NC siRNA and Rheb expression vector. After 48 h, cells were harvested and washed with cold PBS once in a 1.5 ml microcentrifuge tube. Cells were fixed with 0.25% glutaraldehyde at 4°C overnight. Then samples were observed under transmission electron microscopy (Hitachi, Japan).
Real-time cell analysis (RTCA) of cell proliferation
The procedure was described previously [39]. Briefly, cells were digested and counted with Automated Cell Counter (Invitrogen, USA). 5,000 cells of each group were seeded to modified 16-well plates (E-plate, Roche, Germany) and monitored using the xCELLigence RTCA DP instrument (Roche, Germany). Data collecting and analysis was in accordance with the manufacturer's guidelines.
Statistical analysis
Data were presented as means–SD. Comparisons within groups were done with a t-test with repeated measures; p-values indicated in figures are <0.05 (*), <0.01(**), and <0.001 (***).
Authors: Zhi Hong Lu; Mark B Shvartsman; Andrew Y Lee; Jenny M Shao; Mollianne M Murray; Raleigh D Kladney; Dong Fan; Stan Krajewski; Gary G Chiang; Gordon B Mills; Jeffrey M Arbeit Journal: Cancer Res Date: 2010-04-13 Impact factor: 12.701
Authors: Vikram Chandra; Ingrid Fetter-Pruneda; Peter R Oxley; Amelia L Ritger; Sean K McKenzie; Romain Libbrecht; Daniel J C Kronauer Journal: Science Date: 2018-07-27 Impact factor: 47.728
Authors: Daniel J Klionsky; Amal Kamal Abdel-Aziz; Sara Abdelfatah; Mahmoud Abdellatif; Asghar Abdoli; Steffen Abel; Hagai Abeliovich; Marie H Abildgaard; Yakubu Princely Abudu; Abraham Acevedo-Arozena; Iannis E Adamopoulos; Khosrow Adeli; Timon E Adolph; Annagrazia Adornetto; Elma Aflaki; Galila Agam; Anupam Agarwal; Bharat B Aggarwal; Maria Agnello; Patrizia Agostinis; Javed N Agrewala; Alexander Agrotis; Patricia V Aguilar; S Tariq Ahmad; Zubair M Ahmed; Ulises Ahumada-Castro; Sonja Aits; Shu Aizawa; Yunus Akkoc; Tonia Akoumianaki; Hafize Aysin Akpinar; Ahmed M Al-Abd; Lina Al-Akra; Abeer Al-Gharaibeh; Moulay A Alaoui-Jamali; Simon Alberti; Elísabet Alcocer-Gómez; Cristiano Alessandri; Muhammad Ali; M Abdul Alim Al-Bari; Saeb Aliwaini; Javad Alizadeh; Eugènia Almacellas; Alexandru Almasan; Alicia Alonso; Guillermo D Alonso; Nihal Altan-Bonnet; Dario C Altieri; Élida M C Álvarez; Sara Alves; Cristine Alves da Costa; Mazen M Alzaharna; Marialaura Amadio; Consuelo Amantini; Cristina Amaral; Susanna Ambrosio; Amal O Amer; Veena Ammanathan; Zhenyi An; Stig U Andersen; Shaida A Andrabi; Magaiver Andrade-Silva; Allen M Andres; Sabrina Angelini; David Ann; Uche C Anozie; Mohammad Y Ansari; Pedro Antas; Adam Antebi; Zuriñe Antón; Tahira Anwar; Lionel Apetoh; Nadezda Apostolova; Toshiyuki Araki; Yasuhiro Araki; Kohei Arasaki; Wagner L Araújo; Jun Araya; Catherine Arden; Maria-Angeles Arévalo; Sandro Arguelles; Esperanza Arias; Jyothi Arikkath; Hirokazu Arimoto; Aileen R Ariosa; Darius Armstrong-James; Laetitia Arnauné-Pelloquin; Angeles Aroca; Daniela S Arroyo; Ivica Arsov; Rubén Artero; Dalia Maria Lucia Asaro; Michael Aschner; Milad Ashrafizadeh; Osnat Ashur-Fabian; Atanas G Atanasov; Alicia K Au; Patrick Auberger; Holger W Auner; Laure Aurelian; Riccardo Autelli; Laura Avagliano; Yenniffer Ávalos; Sanja Aveic; Célia Alexandra Aveleira; Tamar Avin-Wittenberg; Yucel Aydin; Scott Ayton; Srinivas Ayyadevara; Maria Azzopardi; Misuzu Baba; Jonathan M Backer; Steven K Backues; Dong-Hun Bae; Ok-Nam Bae; Soo Han Bae; Eric H Baehrecke; Ahruem Baek; Seung-Hoon Baek; Sung Hee Baek; Giacinto Bagetta; Agnieszka Bagniewska-Zadworna; Hua Bai; Jie Bai; Xiyuan Bai; Yidong Bai; Nandadulal Bairagi; Shounak Baksi; Teresa Balbi; Cosima T Baldari; Walter Balduini; Andrea Ballabio; Maria Ballester; Salma Balazadeh; Rena Balzan; Rina Bandopadhyay; Sreeparna Banerjee; Sulagna Banerjee; Ágnes Bánréti; Yan Bao; Mauricio S Baptista; Alessandra Baracca; Cristiana Barbati; Ariadna Bargiela; Daniela Barilà; Peter G Barlow; Sami J Barmada; Esther Barreiro; George E Barreto; Jiri Bartek; Bonnie Bartel; Alberto Bartolome; Gaurav R Barve; Suresh H Basagoudanavar; Diane C Bassham; Robert C Bast; Alakananda Basu; Henri Batoko; Isabella Batten; Etienne E Baulieu; Bradley L Baumgarner; Jagadeesh Bayry; Rupert Beale; Isabelle Beau; Florian Beaumatin; Luiz R G Bechara; George R Beck; Michael F Beers; Jakob Begun; Christian Behrends; Georg M N Behrens; Roberto Bei; Eloy Bejarano; Shai Bel; Christian Behl; Amine Belaid; Naïma Belgareh-Touzé; Cristina Bellarosa; Francesca Belleudi; Melissa Belló Pérez; Raquel Bello-Morales; Jackeline Soares de Oliveira Beltran; Sebastián Beltran; Doris Mangiaracina Benbrook; Mykolas Bendorius; Bruno A Benitez; Irene Benito-Cuesta; Julien Bensalem; Martin W Berchtold; Sabina Berezowska; Daniele Bergamaschi; Matteo Bergami; Andreas Bergmann; Laura Berliocchi; Clarisse Berlioz-Torrent; Amélie Bernard; Lionel Berthoux; Cagri G Besirli; Sebastien Besteiro; Virginie M Betin; Rudi Beyaert; Jelena S Bezbradica; Kiran Bhaskar; Ingrid Bhatia-Kissova; Resham Bhattacharya; Sujoy Bhattacharya; Shalmoli Bhattacharyya; Md Shenuarin Bhuiyan; Sujit Kumar Bhutia; Lanrong Bi; Xiaolin Bi; Trevor J Biden; Krikor Bijian; Viktor A Billes; Nadine Binart; Claudia Bincoletto; Asa B Birgisdottir; Geir Bjorkoy; Gonzalo Blanco; Ana Blas-Garcia; Janusz Blasiak; Robert Blomgran; Klas Blomgren; Janice S Blum; Emilio Boada-Romero; Mirta Boban; Kathleen Boesze-Battaglia; Philippe Boeuf; Barry Boland; Pascale Bomont; Paolo Bonaldo; Srinivasa Reddy Bonam; Laura Bonfili; Juan S Bonifacino; Brian A Boone; Martin D Bootman; Matteo Bordi; Christoph Borner; Beat C Bornhauser; Gautam Borthakur; Jürgen Bosch; Santanu Bose; Luis M Botana; Juan Botas; Chantal M Boulanger; Michael E Boulton; Mathieu Bourdenx; Benjamin Bourgeois; Nollaig M Bourke; Guilhem Bousquet; Patricia Boya; Peter V Bozhkov; Luiz H M Bozi; Tolga O Bozkurt; Doug E Brackney; Christian H Brandts; Ralf J Braun; Gerhard H Braus; Roberto Bravo-Sagua; José M Bravo-San Pedro; Patrick Brest; Marie-Agnès Bringer; Alfredo Briones-Herrera; V Courtney Broaddus; Peter Brodersen; Jeffrey L Brodsky; Steven L Brody; Paola G Bronson; Jeff M Bronstein; Carolyn N Brown; Rhoderick E Brown; Patricia C Brum; John H Brumell; Nicola Brunetti-Pierri; Daniele Bruno; Robert J Bryson-Richardson; Cecilia Bucci; Carmen Buchrieser; Marta Bueno; Laura Elisa Buitrago-Molina; Simone Buraschi; Shilpa Buch; J Ross Buchan; Erin M Buckingham; Hikmet Budak; Mauricio Budini; Geert Bultynck; Florin Burada; Joseph R Burgoyne; M Isabel Burón; Victor Bustos; Sabrina Büttner; Elena Butturini; Aaron Byrd; Isabel Cabas; Sandra Cabrera-Benitez; Ken Cadwell; Jingjing Cai; Lu Cai; Qian Cai; Montserrat Cairó; Jose A Calbet; Guy A Caldwell; Kim A Caldwell; Jarrod A Call; Riccardo Calvani; Ana C Calvo; Miguel Calvo-Rubio Barrera; Niels Os Camara; Jacques H Camonis; Nadine Camougrand; Michelangelo Campanella; Edward M Campbell; François-Xavier Campbell-Valois; Silvia Campello; Ilaria Campesi; Juliane C Campos; Olivier Camuzard; Jorge Cancino; Danilo Candido de Almeida; Laura Canesi; Isabella Caniggia; Barbara Canonico; Carles Cantí; Bin Cao; Michele Caraglia; Beatriz Caramés; Evie H Carchman; Elena Cardenal-Muñoz; Cesar Cardenas; Luis Cardenas; Sandra M Cardoso; Jennifer S Carew; Georges F Carle; Gillian Carleton; Silvia Carloni; Didac Carmona-Gutierrez; Leticia A Carneiro; Oliana Carnevali; Julian M Carosi; Serena Carra; Alice Carrier; Lucie Carrier; Bernadette Carroll; A Brent Carter; Andreia Neves Carvalho; Magali Casanova; Caty Casas; Josefina Casas; Chiara Cassioli; Eliseo F Castillo; Karen Castillo; Sonia Castillo-Lluva; Francesca Castoldi; Marco Castori; Ariel F Castro; Margarida Castro-Caldas; Javier Castro-Hernandez; Susana Castro-Obregon; Sergio D Catz; Claudia Cavadas; Federica Cavaliere; Gabriella Cavallini; Maria Cavinato; Maria L Cayuela; Paula Cebollada Rica; Valentina Cecarini; Francesco Cecconi; Marzanna Cechowska-Pasko; Simone Cenci; Victòria Ceperuelo-Mallafré; João J Cerqueira; Janete M Cerutti; Davide Cervia; Vildan Bozok Cetintas; Silvia Cetrullo; Han-Jung Chae; Andrei S Chagin; Chee-Yin Chai; Gopal Chakrabarti; Oishee Chakrabarti; Tapas Chakraborty; Trinad Chakraborty; Mounia Chami; Georgios Chamilos; David W Chan; Edmond Y W Chan; Edward D Chan; H Y Edwin Chan; Helen H Chan; Hung Chan; Matthew T V Chan; Yau Sang Chan; Partha K Chandra; Chih-Peng Chang; Chunmei Chang; Hao-Chun Chang; Kai Chang; Jie Chao; Tracey Chapman; Nicolas Charlet-Berguerand; Samrat Chatterjee; Shail K Chaube; Anu Chaudhary; Santosh Chauhan; Edward Chaum; Frédéric Checler; Michael E Cheetham; Chang-Shi Chen; Guang-Chao Chen; Jian-Fu Chen; Liam L Chen; Leilei Chen; Lin Chen; Mingliang Chen; Mu-Kuan Chen; Ning Chen; Quan Chen; Ruey-Hwa Chen; Shi Chen; Wei Chen; Weiqiang Chen; Xin-Ming Chen; Xiong-Wen Chen; Xu Chen; Yan Chen; Ye-Guang Chen; Yingyu Chen; Yongqiang Chen; Yu-Jen Chen; Yue-Qin Chen; Zhefan Stephen Chen; Zhi Chen; Zhi-Hua Chen; Zhijian J Chen; Zhixiang Chen; Hanhua Cheng; Jun Cheng; Shi-Yuan Cheng; Wei Cheng; Xiaodong Cheng; Xiu-Tang Cheng; Yiyun Cheng; Zhiyong Cheng; Zhong Chen; Heesun Cheong; Jit Kong Cheong; Boris V Chernyak; Sara Cherry; Chi Fai Randy Cheung; Chun Hei Antonio Cheung; King-Ho Cheung; Eric Chevet; Richard J Chi; Alan Kwok Shing Chiang; Ferdinando Chiaradonna; Roberto Chiarelli; Mario Chiariello; Nathalia Chica; Susanna Chiocca; Mario Chiong; Shih-Hwa Chiou; Abhilash I Chiramel; Valerio Chiurchiù; Dong-Hyung Cho; Seong-Kyu Choe; Augustine M K Choi; Mary E Choi; Kamalika Roy Choudhury; Norman S Chow; Charleen T Chu; Jason P Chua; John Jia En Chua; Hyewon Chung; Kin Pan Chung; Seockhoon Chung; So-Hyang Chung; Yuen-Li Chung; Valentina Cianfanelli; Iwona A Ciechomska; Mariana Cifuentes; Laura Cinque; Sebahattin Cirak; Mara Cirone; Michael J Clague; Robert Clarke; Emilio Clementi; Eliana M Coccia; Patrice Codogno; Ehud Cohen; Mickael M Cohen; Tania Colasanti; Fiorella Colasuonno; Robert A Colbert; Anna Colell; Miodrag Čolić; Nuria S Coll; Mark O Collins; María I Colombo; Daniel A Colón-Ramos; Lydie Combaret; Sergio Comincini; Márcia R Cominetti; Antonella Consiglio; Andrea Conte; Fabrizio Conti; Viorica Raluca Contu; Mark R Cookson; Kevin M Coombs; Isabelle Coppens; Maria Tiziana Corasaniti; Dale P Corkery; Nils Cordes; Katia Cortese; Maria do Carmo Costa; Sarah Costantino; Paola Costelli; Ana Coto-Montes; Peter J Crack; Jose L Crespo; Alfredo Criollo; Valeria Crippa; Riccardo Cristofani; Tamas Csizmadia; Antonio Cuadrado; Bing Cui; Jun Cui; Yixian Cui; Yong Cui; Emmanuel Culetto; Andrea C Cumino; Andrey V Cybulsky; Mark J Czaja; Stanislaw J Czuczwar; Stefania D'Adamo; Marcello D'Amelio; Daniela D'Arcangelo; Andrew C D'Lugos; Gabriella D'Orazi; James A da Silva; Hormos Salimi Dafsari; Ruben K Dagda; Yasin Dagdas; Maria Daglia; Xiaoxia Dai; Yun Dai; Yuyuan Dai; Jessica Dal Col; Paul Dalhaimer; Luisa Dalla Valle; Tobias Dallenga; Guillaume Dalmasso; Markus Damme; Ilaria Dando; Nico P Dantuma; April L Darling; Hiranmoy Das; Srinivasan Dasarathy; Santosh K Dasari; Srikanta Dash; Oliver Daumke; Adrian N Dauphinee; Jeffrey S Davies; Valeria A Dávila; Roger J Davis; Tanja Davis; Sharadha Dayalan Naidu; Francesca De Amicis; Karolien De Bosscher; Francesca De Felice; Lucia De Franceschi; Chiara De Leonibus; Mayara G de Mattos Barbosa; Guido R Y De Meyer; Angelo De Milito; Cosimo De Nunzio; Clara De Palma; Mauro De Santi; Claudio De Virgilio; Daniela De Zio; Jayanta Debnath; Brian J DeBosch; Jean-Paul Decuypere; Mark A Deehan; Gianluca Deflorian; James DeGregori; Benjamin Dehay; Gabriel Del Rio; Joe R Delaney; Lea M D Delbridge; Elizabeth Delorme-Axford; M Victoria Delpino; Francesca Demarchi; Vilma Dembitz; Nicholas D Demers; Hongbin Deng; Zhiqiang Deng; Joern Dengjel; Paul Dent; Donna Denton; Melvin L DePamphilis; Channing J Der; Vojo Deretic; Albert Descoteaux; Laura Devis; Sushil Devkota; Olivier Devuyst; Grant Dewson; Mahendiran Dharmasivam; Rohan Dhiman; Diego di Bernardo; Manlio Di Cristina; Fabio Di Domenico; Pietro Di Fazio; Alessio Di Fonzo; Giovanni Di Guardo; Gianni M Di Guglielmo; Luca Di Leo; Chiara Di Malta; Alessia Di Nardo; Martina Di Rienzo; Federica Di Sano; George Diallinas; Jiajie Diao; Guillermo Diaz-Araya; Inés Díaz-Laviada; Jared M Dickinson; Marc Diederich; Mélanie Dieudé; Ivan Dikic; Shiping Ding; Wen-Xing Ding; Luciana Dini; Jelena Dinić; Miroslav Dinic; Albena T Dinkova-Kostova; Marc S Dionne; Jörg H W Distler; Abhinav Diwan; Ian M C Dixon; Mojgan Djavaheri-Mergny; Ina Dobrinski; Oxana Dobrovinskaya; Radek Dobrowolski; Renwick C J Dobson; Jelena Đokić; Serap Dokmeci Emre; Massimo Donadelli; Bo Dong; Xiaonan Dong; Zhiwu Dong; Gerald W Dorn Ii; Volker Dotsch; Huan Dou; Juan Dou; Moataz Dowaidar; Sami Dridi; Liat Drucker; Ailian Du; Caigan Du; Guangwei Du; Hai-Ning Du; Li-Lin Du; André du Toit; Shao-Bin Duan; Xiaoqiong Duan; Sónia P Duarte; Anna Dubrovska; Elaine A Dunlop; Nicolas Dupont; Raúl V Durán; Bilikere S Dwarakanath; Sergey A Dyshlovoy; Darius Ebrahimi-Fakhari; Leopold Eckhart; Charles L Edelstein; Thomas Efferth; Eftekhar Eftekharpour; Ludwig Eichinger; Nabil Eid; Tobias Eisenberg; N Tony Eissa; Sanaa Eissa; Miriam Ejarque; Abdeljabar El Andaloussi; Nazira El-Hage; Shahenda El-Naggar; Anna Maria Eleuteri; Eman S El-Shafey; Mohamed Elgendy; Aristides G Eliopoulos; María M Elizalde; Philip M Elks; Hans-Peter Elsasser; Eslam S Elsherbiny; Brooke M Emerling; N C Tolga Emre; Christina H Eng; Nikolai Engedal; Anna-Mart Engelbrecht; Agnete S T Engelsen; Jorrit M Enserink; Ricardo Escalante; Audrey Esclatine; Mafalda Escobar-Henriques; Eeva-Liisa Eskelinen; Lucile Espert; Makandjou-Ola Eusebio; Gemma Fabrias; Cinzia Fabrizi; Antonio Facchiano; Francesco Facchiano; Bengt Fadeel; Claudio Fader; Alex C Faesen; W Douglas Fairlie; Alberto Falcó; Bjorn H Falkenburger; Daping Fan; Jie Fan; Yanbo Fan; Evandro F Fang; Yanshan Fang; Yognqi Fang; Manolis Fanto; Tamar Farfel-Becker; Mathias Faure; Gholamreza Fazeli; Anthony O Fedele; Arthur M Feldman; Du Feng; Jiachun Feng; Lifeng Feng; Yibin Feng; Yuchen Feng; Wei Feng; Thais Fenz Araujo; Thomas A Ferguson; Álvaro F Fernández; Jose C Fernandez-Checa; Sonia Fernández-Veledo; Alisdair R Fernie; Anthony W Ferrante; Alessandra Ferraresi; Merari F Ferrari; Julio C B Ferreira; Susan Ferro-Novick; Antonio Figueras; Riccardo Filadi; Nicoletta Filigheddu; Eduardo Filippi-Chiela; Giuseppe Filomeni; Gian Maria Fimia; Vittorio Fineschi; Francesca Finetti; Steven Finkbeiner; Edward A Fisher; Paul B Fisher; Flavio Flamigni; Steven J Fliesler; Trude H Flo; Ida Florance; Oliver Florey; Tullio Florio; Erika Fodor; Carlo Follo; Edward A Fon; Antonella Forlino; Francesco Fornai; Paola Fortini; Anna Fracassi; Alessandro Fraldi; Brunella Franco; Rodrigo Franco; Flavia Franconi; Lisa B Frankel; Scott L Friedman; Leopold F Fröhlich; Gema Frühbeck; Jose M Fuentes; Yukio Fujiki; Naonobu Fujita; Yuuki Fujiwara; Mitsunori Fukuda; Simone Fulda; Luc Furic; Norihiko Furuya; Carmela Fusco; Michaela U Gack; Lidia Gaffke; Sehamuddin Galadari; Alessia Galasso; Maria F Galindo; Sachith Gallolu Kankanamalage; Lorenzo Galluzzi; Vincent Galy; Noor Gammoh; Boyi Gan; Ian G Ganley; Feng Gao; Hui Gao; Minghui Gao; Ping Gao; Shou-Jiang Gao; Wentao Gao; Xiaobo Gao; Ana Garcera; Maria Noé Garcia; Verónica E Garcia; Francisco García-Del Portillo; Vega Garcia-Escudero; Aracely Garcia-Garcia; Marina Garcia-Macia; Diana García-Moreno; Carmen Garcia-Ruiz; Patricia García-Sanz; Abhishek D Garg; Ricardo Gargini; Tina Garofalo; Robert F Garry; Nils C Gassen; Damian Gatica; Liang Ge; Wanzhong Ge; Ruth Geiss-Friedlander; Cecilia Gelfi; Pascal Genschik; Ian E Gentle; Valeria Gerbino; Christoph Gerhardt; Kyla Germain; Marc Germain; David A Gewirtz; Elham Ghasemipour Afshar; Saeid Ghavami; Alessandra Ghigo; Manosij Ghosh; Georgios Giamas; Claudia Giampietri; Alexandra Giatromanolaki; Gary E Gibson; Spencer B Gibson; Vanessa Ginet; Edward Giniger; Carlotta Giorgi; Henrique Girao; Stephen E Girardin; Mridhula Giridharan; Sandy Giuliano; Cecilia Giulivi; Sylvie Giuriato; Julien Giustiniani; Alexander Gluschko; Veit Goder; Alexander Goginashvili; Jakub Golab; David C Goldstone; Anna Golebiewska; Luciana R Gomes; Rodrigo Gomez; Rubén Gómez-Sánchez; Maria Catalina Gomez-Puerto; Raquel Gomez-Sintes; Qingqiu Gong; Felix M Goni; Javier González-Gallego; Tomas Gonzalez-Hernandez; Rosa A Gonzalez-Polo; Jose A Gonzalez-Reyes; Patricia González-Rodríguez; Ing Swie Goping; Marina S Gorbatyuk; Nikolai V Gorbunov; Kıvanç Görgülü; Roxana M Gorojod; Sharon M Gorski; Sandro Goruppi; Cecilia Gotor; Roberta A Gottlieb; Illana Gozes; Devrim Gozuacik; Martin Graef; Markus H Gräler; Veronica Granatiero; Daniel Grasso; Joshua P Gray; Douglas R Green; Alexander Greenhough; Stephen L Gregory; Edward F Griffin; Mark W Grinstaff; Frederic Gros; Charles Grose; Angelina S Gross; Florian Gruber; Paolo Grumati; Tilman Grune; Xueyan Gu; Jun-Lin Guan; Carlos M Guardia; Kishore Guda; Flora Guerra; Consuelo Guerri; Prasun Guha; Carlos Guillén; Shashi Gujar; Anna Gukovskaya; Ilya Gukovsky; Jan Gunst; Andreas Günther; Anyonya R Guntur; Chuanyong Guo; Chun Guo; Hongqing Guo; Lian-Wang Guo; Ming Guo; Pawan Gupta; Shashi Kumar Gupta; Swapnil Gupta; Veer Bala Gupta; Vivek Gupta; Asa B Gustafsson; David D Gutterman; Ranjitha H B; Annakaisa Haapasalo; James E Haber; Aleksandra Hać; Shinji Hadano; Anders J Hafrén; Mansour Haidar; Belinda S Hall; Gunnel Halldén; Anne Hamacher-Brady; Andrea Hamann; Maho Hamasaki; Weidong Han; Malene Hansen; Phyllis I Hanson; Zijian Hao; Masaru Harada; Ljubica Harhaji-Trajkovic; Nirmala Hariharan; Nigil Haroon; James Harris; Takafumi Hasegawa; Noor Hasima Nagoor; Jeffrey A Haspel; Volker Haucke; Wayne D Hawkins; Bruce A Hay; Cole M Haynes; Soren B Hayrabedyan; Thomas S Hays; Congcong He; Qin He; Rong-Rong He; You-Wen He; Yu-Ying He; Yasser Heakal; Alexander M Heberle; J Fielding Hejtmancik; Gudmundur Vignir Helgason; Vanessa Henkel; Marc Herb; Alexander Hergovich; Anna Herman-Antosiewicz; Agustín Hernández; Carlos Hernandez; Sergio Hernandez-Diaz; Virginia Hernandez-Gea; Amaury Herpin; Judit Herreros; Javier H Hervás; Daniel Hesselson; Claudio Hetz; Volker T Heussler; Yujiro Higuchi; Sabine Hilfiker; Joseph A Hill; William S Hlavacek; Emmanuel A Ho; Idy H T Ho; Philip Wing-Lok Ho; Shu-Leong Ho; Wan Yun Ho; G Aaron Hobbs; Mark Hochstrasser; Peter H M Hoet; Daniel Hofius; Paul Hofman; Annika Höhn; Carina I Holmberg; Jose R Hombrebueno; Chang-Won Hong Yi-Ren Hong; Lora V Hooper; Thorsten Hoppe; Rastislav Horos; Yujin Hoshida; I-Lun Hsin; Hsin-Yun Hsu; Bing Hu; Dong Hu; Li-Fang Hu; Ming Chang Hu; Ronggui Hu; Wei Hu; Yu-Chen Hu; Zhuo-Wei Hu; Fang Hua; Jinlian Hua; Yingqi Hua; Chongmin Huan; Canhua Huang; Chuanshu Huang; Chuanxin Huang; Chunling Huang; Haishan Huang; Kun Huang; Michael L H Huang; Rui Huang; Shan Huang; Tianzhi Huang; Xing Huang; Yuxiang Jack Huang; Tobias B Huber; Virginie Hubert; Christian A Hubner; Stephanie M Hughes; William E Hughes; Magali Humbert; Gerhard Hummer; James H Hurley; Sabah Hussain; Salik Hussain; Patrick J Hussey; Martina Hutabarat; Hui-Yun Hwang; Seungmin Hwang; Antonio Ieni; Fumiyo Ikeda; Yusuke Imagawa; Yuzuru Imai; Carol Imbriano; Masaya Imoto; Denise M Inman; Ken Inoki; Juan Iovanna; Renato V Iozzo; Giuseppe Ippolito; Javier E Irazoqui; Pablo Iribarren; Mohd Ishaq; Makoto Ishikawa; Nestor Ishimwe; Ciro Isidoro; Nahed Ismail; Shohreh Issazadeh-Navikas; Eisuke Itakura; Daisuke Ito; Davor Ivankovic; Saška Ivanova; Anand Krishnan V Iyer; José M Izquierdo; Masanori Izumi; Marja Jäättelä; Majid Sakhi Jabir; William T Jackson; Nadia Jacobo-Herrera; Anne-Claire Jacomin; Elise Jacquin; Pooja Jadiya; Hartmut Jaeschke; Chinnaswamy Jagannath; Arjen J Jakobi; Johan Jakobsson; Bassam Janji; Pidder Jansen-Dürr; Patric J Jansson; Jonathan Jantsch; Sławomir Januszewski; Alagie Jassey; Steve Jean; Hélène Jeltsch-David; Pavla Jendelova; Andreas Jenny; Thomas E Jensen; Niels Jessen; Jenna L Jewell; Jing Ji; Lijun Jia; Rui Jia; Liwen Jiang; Qing Jiang; Richeng Jiang; Teng Jiang; Xuejun Jiang; Yu Jiang; Maria Jimenez-Sanchez; Eun-Jung Jin; Fengyan Jin; Hongchuan Jin; Li Jin; Luqi Jin; Meiyan Jin; Si Jin; Eun-Kyeong Jo; Carine Joffre; Terje Johansen; Gail V W Johnson; Simon A Johnston; Eija Jokitalo; Mohit Kumar Jolly; Leo A B Joosten; Joaquin Jordan; Bertrand Joseph; Dianwen Ju; Jeong-Sun Ju; Jingfang Ju; Esmeralda Juárez; Delphine Judith; Gábor Juhász; Youngsoo Jun; Chang Hwa Jung; Sung-Chul Jung; Yong Keun Jung; Heinz Jungbluth; Johannes Jungverdorben; Steffen Just; Kai Kaarniranta; Allen Kaasik; Tomohiro Kabuta; Daniel Kaganovich; Alon Kahana; Renate Kain; Shinjo Kajimura; Maria Kalamvoki; Manjula Kalia; Danuta S Kalinowski; Nina Kaludercic; Ioanna Kalvari; Joanna Kaminska; Vitaliy O Kaminskyy; Hiromitsu Kanamori; Keizo Kanasaki; Chanhee Kang; Rui Kang; Sang Sun Kang; Senthilvelrajan Kaniyappan; Tomotake Kanki; Thirumala-Devi Kanneganti; Anumantha G Kanthasamy; Arthi Kanthasamy; Marc Kantorow; Orsolya Kapuy; Michalis V Karamouzis; Md Razaul Karim; Parimal Karmakar; Rajesh G Katare; Masaru Kato; Stefan H E Kaufmann; Anu Kauppinen; Gur P Kaushal; Susmita Kaushik; Kiyoshi Kawasaki; Kemal Kazan; Po-Yuan Ke; Damien J Keating; Ursula Keber; John H Kehrl; Kate E Keller; Christian W Keller; Jongsook Kim Kemper; Candia M Kenific; Oliver Kepp; Stephanie Kermorgant; Andreas Kern; Robin Ketteler; Tom G Keulers; Boris Khalfin; Hany Khalil; Bilon Khambu; Shahid Y Khan; Vinoth Kumar Megraj Khandelwal; Rekha Khandia; Widuri Kho; Noopur V Khobrekar; Sataree Khuansuwan; Mukhran Khundadze; Samuel A Killackey; Dasol Kim; Deok Ryong Kim; Do-Hyung Kim; Dong-Eun Kim; Eun Young Kim; Eun-Kyoung Kim; Hak-Rim Kim; Hee-Sik Kim; Jeong Hun Kim; Jin Kyung Kim; Jin-Hoi Kim; Joungmok Kim; Ju Hwan Kim; Keun Il Kim; Peter K Kim; Seong-Jun Kim; Scot R Kimball; Adi Kimchi; Alec C Kimmelman; Tomonori Kimura; Matthew A King; Kerri J Kinghorn; Conan G Kinsey; Vladimir Kirkin; Lorrie A Kirshenbaum; Sergey L Kiselev; Shuji Kishi; Katsuhiko Kitamoto; Yasushi Kitaoka; Kaio Kitazato; Richard N Kitsis; Josef T Kittler; Ole Kjaerulff; Peter S Klein; Thomas Klopstock; Jochen Klucken; Helene Knævelsrud; Roland L Knorr; Ben C B Ko; Fred Ko; Jiunn-Liang Ko; Hotaka Kobayashi; Satoru Kobayashi; Ina Koch; Jan C Koch; Ulrich Koenig; Donat Kögel; Young Ho Koh; Masato Koike; Sepp D Kohlwein; Nur M Kocaturk; Masaaki Komatsu; Jeannette König; Toru Kono; Benjamin T Kopp; Tamas Korcsmaros; Gözde Korkmaz; Viktor I Korolchuk; Mónica Suárez Korsnes; Ali Koskela; Janaiah Kota; Yaichiro Kotake; Monica L Kotler; Yanjun Kou; Michael I Koukourakis; Evangelos Koustas; Attila L Kovacs; Tibor Kovács; Daisuke Koya; Tomohiro Kozako; Claudine Kraft; Dimitri Krainc; Helmut Krämer; Anna D Krasnodembskaya; Carole Kretz-Remy; Guido Kroemer; Nicholas T Ktistakis; Kazuyuki Kuchitsu; Sabine Kuenen; Lars Kuerschner; Thomas Kukar; Ajay Kumar; Ashok Kumar; Deepak Kumar; Dhiraj Kumar; Sharad Kumar; Shinji Kume; Caroline Kumsta; Chanakya N Kundu; Mondira Kundu; Ajaikumar B Kunnumakkara; Lukasz Kurgan; Tatiana G Kutateladze; Ozlem Kutlu; SeongAe Kwak; Ho Jeong Kwon; Taeg Kyu Kwon; Yong Tae Kwon; Irene Kyrmizi; Albert La Spada; Patrick Labonté; Sylvain Ladoire; Ilaria Laface; Frank Lafont; Diane C Lagace; Vikramjit Lahiri; Zhibing Lai; Angela S Laird; Aparna Lakkaraju; Trond Lamark; Sheng-Hui Lan; Ane Landajuela; Darius J R Lane; Jon D Lane; Charles H Lang; Carsten Lange; Ülo Langel; Rupert Langer; Pierre Lapaquette; Jocelyn Laporte; Nicholas F LaRusso; Isabel Lastres-Becker; Wilson Chun Yu Lau; Gordon W Laurie; Sergio Lavandero; Betty Yuen Kwan Law; Helen Ka-Wai Law; Rob Layfield; Weidong Le; Herve Le Stunff; Alexandre Y Leary; Jean-Jacques Lebrun; Lionel Y W Leck; Jean-Philippe Leduc-Gaudet; Changwook Lee; Chung-Pei Lee; Da-Hye Lee; Edward B Lee; Erinna F Lee; Gyun Min Lee; He-Jin Lee; Heung Kyu Lee; Jae Man Lee; Jason S Lee; Jin-A Lee; Joo-Yong Lee; Jun Hee Lee; Michael Lee; Min Goo Lee; Min Jae Lee; Myung-Shik Lee; Sang Yoon Lee; Seung-Jae Lee; Stella Y Lee; Sung Bae Lee; Won Hee Lee; Ying-Ray Lee; Yong-Ho Lee; Youngil Lee; Christophe Lefebvre; Renaud Legouis; Yu L Lei; Yuchen Lei; Sergey Leikin; Gerd Leitinger; Leticia Lemus; Shuilong Leng; Olivia Lenoir; Guido Lenz; Heinz Josef Lenz; Paola Lenzi; Yolanda León; Andréia M Leopoldino; Christoph Leschczyk; Stina Leskelä; Elisabeth Letellier; Chi-Ting Leung; Po Sing Leung; Jeremy S Leventhal; Beth Levine; Patrick A Lewis; Klaus Ley; Bin Li; Da-Qiang Li; Jianming Li; Jing Li; Jiong Li; Ke Li; Liwu Li; Mei Li; Min Li; Min Li; Ming Li; Mingchuan Li; Pin-Lan Li; Ming-Qing Li; Qing Li; Sheng Li; Tiangang Li; Wei Li; Wenming Li; Xue Li; Yi-Ping Li; Yuan Li; Zhiqiang Li; Zhiyong Li; Zhiyuan Li; Jiqin Lian; Chengyu Liang; Qiangrong Liang; Weicheng Liang; Yongheng Liang; YongTian Liang; Guanghong Liao; Lujian Liao; Mingzhi Liao; Yung-Feng Liao; Mariangela Librizzi; Pearl P Y Lie; Mary A Lilly; Hyunjung J Lim; Thania R R Lima; Federica Limana; Chao Lin; Chih-Wen Lin; Dar-Shong Lin; Fu-Cheng Lin; Jiandie D Lin; Kurt M Lin; Kwang-Huei Lin; Liang-Tzung Lin; Pei-Hui Lin; Qiong Lin; Shaofeng Lin; Su-Ju Lin; Wenyu Lin; Xueying Lin; Yao-Xin Lin; Yee-Shin Lin; Rafael Linden; Paula Lindner; Shuo-Chien Ling; Paul Lingor; Amelia K Linnemann; Yih-Cherng Liou; Marta M Lipinski; Saška Lipovšek; Vitor A Lira; Natalia Lisiak; Paloma B Liton; Chao Liu; Ching-Hsuan Liu; Chun-Feng Liu; Cui Hua Liu; Fang Liu; Hao Liu; Hsiao-Sheng Liu; Hua-Feng Liu; Huifang Liu; Jia Liu; Jing Liu; Julia Liu; Leyuan Liu; Longhua Liu; Meilian Liu; Qin Liu; Wei Liu; Wende Liu; Xiao-Hong Liu; Xiaodong Liu; Xingguo Liu; Xu Liu; Xuedong Liu; Yanfen Liu; Yang Liu; Yang Liu; Yueyang Liu; Yule Liu; J Andrew Livingston; Gerard Lizard; Jose M Lizcano; Senka Ljubojevic-Holzer; Matilde E LLeonart; David Llobet-Navàs; Alicia Llorente; Chih Hung Lo; Damián Lobato-Márquez; Qi Long; Yun Chau Long; Ben Loos; Julia A Loos; Manuela G López; Guillermo López-Doménech; José Antonio López-Guerrero; Ana T López-Jiménez; Óscar López-Pérez; Israel López-Valero; Magdalena J Lorenowicz; Mar Lorente; Peter Lorincz; Laura Lossi; Sophie Lotersztajn; Penny E Lovat; Jonathan F Lovell; Alenka Lovy; Péter Lőw; Guang Lu; Haocheng Lu; Jia-Hong Lu; Jin-Jian Lu; Mengji Lu; Shuyan Lu; Alessandro Luciani; John M Lucocq; Paula Ludovico; Micah A Luftig; Morten Luhr; Diego Luis-Ravelo; Julian J Lum; Liany Luna-Dulcey; Anders H Lund; Viktor K Lund; Jan D Lünemann; Patrick Lüningschrör; Honglin Luo; Rongcan Luo; Shouqing Luo; Zhi Luo; Claudio Luparello; Bernhard Lüscher; Luan Luu; Alex Lyakhovich; Konstantin G Lyamzaev; Alf Håkon Lystad; Lyubomyr Lytvynchuk; Alvin C Ma; Changle Ma; Mengxiao Ma; Ning-Fang Ma; Quan-Hong Ma; Xinliang Ma; Yueyun Ma; Zhenyi Ma; Ormond A MacDougald; Fernando Macian; Gustavo C MacIntosh; Jeffrey P MacKeigan; Kay F Macleod; Sandra Maday; Frank Madeo; Muniswamy Madesh; Tobias Madl; Julio Madrigal-Matute; Akiko Maeda; Yasuhiro Maejima; Marta Magarinos; Poornima Mahavadi; Emiliano Maiani; Kenneth Maiese; Panchanan Maiti; Maria Chiara Maiuri; Barbara Majello; Michael B Major; Elena Makareeva; Fayaz Malik; Karthik Mallilankaraman; Walter Malorni; Alina Maloyan; Najiba Mammadova; Gene Chi Wai Man; Federico Manai; Joseph D Mancias; Eva-Maria Mandelkow; Michael A Mandell; Angelo A Manfredi; Masoud H Manjili; Ravi Manjithaya; Patricio Manque; Bella B Manshian; Raquel Manzano; Claudia Manzoni; Kai Mao; Cinzia Marchese; Sandrine Marchetti; Anna Maria Marconi; Fabrizio Marcucci; Stefania Mardente; Olga A Mareninova; Marta Margeta; Muriel Mari; Sara Marinelli; Oliviero Marinelli; Guillermo Mariño; Sofia Mariotto; Richard S Marshall; Mark R Marten; Sascha Martens; Alexandre P J Martin; Katie R Martin; Sara Martin; Shaun Martin; Adrián Martín-Segura; Miguel A Martín-Acebes; Inmaculada Martin-Burriel; Marcos Martin-Rincon; Paloma Martin-Sanz; José A Martina; Wim Martinet; Aitor Martinez; Ana Martinez; Jennifer Martinez; Moises Martinez Velazquez; Nuria Martinez-Lopez; Marta Martinez-Vicente; Daniel O Martins; Joilson O Martins; Waleska K Martins; Tania Martins-Marques; Emanuele Marzetti; Shashank Masaldan; Celine Masclaux-Daubresse; Douglas G Mashek; Valentina Massa; Lourdes Massieu; Glenn R Masson; Laura Masuelli; Anatoliy I Masyuk; Tetyana V Masyuk; Paola Matarrese; Ander Matheu; Satoaki Matoba; Sachiko Matsuzaki; Pamela Mattar; Alessandro Matte; Domenico Mattoscio; José L Mauriz; Mario Mauthe; Caroline Mauvezin; Emanual Maverakis; Paola Maycotte; Johanna Mayer; Gianluigi Mazzoccoli; Cristina Mazzoni; Joseph R Mazzulli; Nami McCarty; Christine McDonald; Mitchell R McGill; Sharon L McKenna; BethAnn McLaughlin; Fionn McLoughlin; Mark A McNiven; Thomas G McWilliams; Fatima Mechta-Grigoriou; Tania Catarina Medeiros; Diego L Medina; Lynn A Megeney; Klara Megyeri; Maryam Mehrpour; Jawahar L Mehta; Alfred J Meijer; Annemarie H Meijer; Jakob Mejlvang; Alicia Meléndez; Annette Melk; Gonen Memisoglu; Alexandrina F Mendes; Delong Meng; Fei Meng; Tian Meng; Rubem Menna-Barreto; Manoj B Menon; Carol Mercer; Anne E Mercier; Jean-Louis Mergny; Adalberto Merighi; Seth D Merkley; Giuseppe Merla; Volker Meske; Ana Cecilia Mestre; Shree Padma Metur; Christian Meyer; Hemmo Meyer; Wenyi Mi; Jeanne Mialet-Perez; Junying Miao; Lucia Micale; Yasuo Miki; Enrico Milan; Małgorzata Milczarek; Dana L Miller; Samuel I Miller; Silke Miller; Steven W Millward; Ira Milosevic; Elena A Minina; Hamed Mirzaei; Hamid Reza Mirzaei; Mehdi Mirzaei; Amit Mishra; Nandita Mishra; Paras Kumar Mishra; Maja Misirkic Marjanovic; Roberta Misasi; Amit Misra; Gabriella Misso; Claire Mitchell; Geraldine Mitou; Tetsuji Miura; Shigeki Miyamoto; Makoto Miyazaki; Mitsunori Miyazaki; Taiga Miyazaki; Keisuke Miyazawa; Noboru Mizushima; Trine H Mogensen; Baharia Mograbi; Reza Mohammadinejad; Yasir Mohamud; Abhishek Mohanty; Sipra Mohapatra; Torsten Möhlmann; Asif Mohmmed; Anna Moles; Kelle H Moley; Maurizio Molinari; Vincenzo Mollace; Andreas Buch Møller; Bertrand Mollereau; Faustino Mollinedo; Costanza Montagna; Mervyn J Monteiro; Andrea Montella; L Ruth Montes; Barbara Montico; Vinod K Mony; Giacomo Monzio Compagnoni; Michael N Moore; Mohammad A Moosavi; Ana L Mora; Marina Mora; David Morales-Alamo; Rosario Moratalla; Paula I Moreira; Elena Morelli; Sandra Moreno; Daniel Moreno-Blas; Viviana Moresi; Benjamin Morga; Alwena H Morgan; Fabrice Morin; Hideaki Morishita; Orson L Moritz; Mariko Moriyama; Yuji Moriyasu; Manuela Morleo; Eugenia Morselli; Jose F Moruno-Manchon; Jorge Moscat; Serge Mostowy; Elisa Motori; Andrea Felinto Moura; Naima Moustaid-Moussa; Maria Mrakovcic; Gabriel Muciño-Hernández; Anupam Mukherjee; Subhadip Mukhopadhyay; Jean M Mulcahy Levy; Victoriano Mulero; Sylviane Muller; Christian Münch; Ashok Munjal; Pura Munoz-Canoves; Teresa Muñoz-Galdeano; Christian Münz; Tomokazu Murakawa; Claudia Muratori; Brona M Murphy; J Patrick Murphy; Aditya Murthy; Timo T Myöhänen; Indira U Mysorekar; Jennifer Mytych; Seyed Mohammad Nabavi; Massimo Nabissi; Péter Nagy; Jihoon Nah; Aimable Nahimana; Ichiro Nakagawa; Ken Nakamura; Hitoshi Nakatogawa; Shyam S Nandi; Meera Nanjundan; Monica Nanni; Gennaro Napolitano; Roberta Nardacci; Masashi Narita; Melissa Nassif; Ilana Nathan; Manabu Natsumeda; Ryno J Naude; Christin Naumann; Olaia Naveiras; Fatemeh Navid; Steffan T Nawrocki; Taras Y Nazarko; Francesca Nazio; Florentina Negoita; Thomas Neill; Amanda L Neisch; Luca M Neri; Mihai G Netea; Patrick Neubert; Thomas P Neufeld; Dietbert Neumann; Albert Neutzner; Phillip T Newton; Paul A Ney; Ioannis P Nezis; Charlene C W Ng; Tzi Bun Ng; Hang T T Nguyen; Long T Nguyen; Hong-Min Ni; Clíona Ní Cheallaigh; Zhenhong Ni; M Celeste Nicolao; Francesco Nicoli; Manuel Nieto-Diaz; Per Nilsson; Shunbin Ning; Rituraj Niranjan; Hiroshi Nishimune; Mireia Niso-Santano; Ralph A Nixon; Annalisa Nobili; Clevio Nobrega; Takeshi Noda; Uxía Nogueira-Recalde; Trevor M Nolan; Ivan Nombela; Ivana Novak; Beatriz Novoa; Takashi Nozawa; Nobuyuki Nukina; Carmen Nussbaum-Krammer; Jesper Nylandsted; Tracey R O'Donovan; Seónadh M O'Leary; Eyleen J O'Rourke; Mary P O'Sullivan; Timothy E O'Sullivan; Salvatore Oddo; Ina Oehme; Michinaga Ogawa; Eric Ogier-Denis; Margret H Ogmundsdottir; Besim Ogretmen; Goo Taeg Oh; Seon-Hee Oh; Young J Oh; Takashi Ohama; Yohei Ohashi; Masaki Ohmuraya; Vasileios Oikonomou; Rani Ojha; Koji Okamoto; Hitoshi Okazawa; Masahide Oku; Sara Oliván; Jorge M A Oliveira; Michael Ollmann; James A Olzmann; Shakib Omari; M Bishr Omary; Gizem Önal; Martin Ondrej; Sang-Bing Ong; Sang-Ging Ong; Anna Onnis; Juan A Orellana; Sara Orellana-Muñoz; Maria Del Mar Ortega-Villaizan; Xilma R Ortiz-Gonzalez; Elena Ortona; Heinz D Osiewacz; Abdel-Hamid K Osman; Rosario Osta; Marisa S Otegui; Kinya Otsu; Christiane Ott; Luisa Ottobrini; Jing-Hsiung James Ou; Tiago F Outeiro; Inger Oynebraten; Melek Ozturk; Gilles Pagès; Susanta Pahari; Marta Pajares; Utpal B Pajvani; Rituraj Pal; Simona Paladino; Nicolas Pallet; Michela Palmieri; Giuseppe Palmisano; Camilla Palumbo; Francesco Pampaloni; Lifeng Pan; Qingjun Pan; Wenliang Pan; Xin Pan; Ganna Panasyuk; Rahul Pandey; Udai B Pandey; Vrajesh Pandya; Francesco Paneni; Shirley Y Pang; Elisa Panzarini; Daniela L Papademetrio; Elena Papaleo; Daniel Papinski; Diana Papp; Eun Chan Park; Hwan Tae Park; Ji-Man Park; Jong-In Park; Joon Tae Park; Junsoo Park; Sang Chul Park; Sang-Youel Park; Abraham H Parola; Jan B Parys; Adrien Pasquier; Benoit Pasquier; João F Passos; Nunzia Pastore; Hemal H Patel; Daniel Patschan; Sophie Pattingre; Gustavo Pedraza-Alva; Jose Pedraza-Chaverri; Zully Pedrozo; Gang Pei; Jianming Pei; Hadas Peled-Zehavi; Joaquín M Pellegrini; Joffrey Pelletier; Miguel A Peñalva; Di Peng; Ying Peng; Fabio Penna; Maria Pennuto; Francesca Pentimalli; Cláudia Mf Pereira; Gustavo J S Pereira; Lilian C Pereira; Luis Pereira de Almeida; Nirma D Perera; Ángel Pérez-Lara; Ana B Perez-Oliva; María Esther Pérez-Pérez; Palsamy Periyasamy; Andras Perl; Cristiana Perrotta; Ida Perrotta; Richard G Pestell; Morten Petersen; Irina Petrache; Goran Petrovski; Thorsten Pfirrmann; Astrid S Pfister; Jennifer A Philips; Huifeng Pi; Anna Picca; Alicia M Pickrell; Sandy Picot; Giovanna M Pierantoni; Marina Pierdominici; Philippe Pierre; Valérie Pierrefite-Carle; Karolina Pierzynowska; Federico Pietrocola; Miroslawa Pietruczuk; Claudio Pignata; Felipe X Pimentel-Muiños; Mario Pinar; Roberta O Pinheiro; Ronit Pinkas-Kramarski; Paolo Pinton; Karolina Pircs; Sujan Piya; Paola Pizzo; Theo S Plantinga; Harald W Platta; Ainhoa Plaza-Zabala; Markus Plomann; Egor Y Plotnikov; Helene Plun-Favreau; Ryszard Pluta; Roger Pocock; Stefanie Pöggeler; Christian Pohl; Marc Poirot; Angelo Poletti; Marisa Ponpuak; Hana Popelka; Blagovesta Popova; Helena Porta; Soledad Porte Alcon; Eliana Portilla-Fernandez; Martin Post; Malia B Potts; Joanna Poulton; Ted Powers; Veena Prahlad; Tomasz K Prajsnar; Domenico Praticò; Rosaria Prencipe; Muriel Priault; Tassula Proikas-Cezanne; Vasilis J Promponas; Christopher G Proud; Rosa Puertollano; Luigi Puglielli; Thomas Pulinilkunnil; Deepika Puri; Rajat Puri; Julien Puyal; Xiaopeng Qi; Yongmei Qi; Wenbin Qian; Lei Qiang; Yu Qiu; Joe Quadrilatero; Jorge Quarleri; Nina Raben; Hannah Rabinowich; Debora Ragona; Michael J Ragusa; Nader Rahimi; Marveh Rahmati; Valeria Raia; Nuno Raimundo; Namakkal-Soorappan Rajasekaran; Sriganesh Ramachandra Rao; Abdelhaq Rami; Ignacio Ramírez-Pardo; David B Ramsden; Felix Randow; Pundi N Rangarajan; Danilo Ranieri; Hai Rao; Lang Rao; Rekha Rao; Sumit Rathore; J Arjuna Ratnayaka; Edward A Ratovitski; Palaniyandi Ravanan; Gloria Ravegnini; Swapan K Ray; Babak Razani; Vito Rebecca; Fulvio Reggiori; Anne Régnier-Vigouroux; Andreas S Reichert; David Reigada; Jan H Reiling; Theo Rein; Siegfried Reipert; Rokeya Sultana Rekha; Hongmei Ren; Jun Ren; Weichao Ren; Tristan Renault; Giorgia Renga; Karen Reue; Kim Rewitz; Bruna Ribeiro de Andrade Ramos; S Amer Riazuddin; Teresa M Ribeiro-Rodrigues; Jean-Ehrland Ricci; Romeo Ricci; Victoria Riccio; Des R Richardson; Yasuko Rikihisa; Makarand V Risbud; Ruth M Risueño; Konstantinos Ritis; Salvatore Rizza; Rosario Rizzuto; Helen C Roberts; Luke D Roberts; Katherine J Robinson; Maria Carmela Roccheri; Stephane Rocchi; George G Rodney; Tiago Rodrigues; Vagner Ramon Rodrigues Silva; Amaia Rodriguez; Ruth Rodriguez-Barrueco; Nieves Rodriguez-Henche; Humberto Rodriguez-Rocha; Jeroen Roelofs; Robert S Rogers; Vladimir V Rogov; Ana I Rojo; Krzysztof Rolka; Vanina Romanello; Luigina Romani; Alessandra Romano; Patricia S Romano; David Romeo-Guitart; Luis C Romero; Montserrat Romero; Joseph C Roney; Christopher Rongo; Sante Roperto; Mathias T Rosenfeldt; Philip Rosenstiel; Anne G Rosenwald; Kevin A Roth; Lynn Roth; Steven Roth; Kasper M A Rouschop; Benoit D Roussel; Sophie Roux; Patrizia Rovere-Querini; Ajit Roy; Aurore Rozieres; Diego Ruano; David C Rubinsztein; Maria P Rubtsova; Klaus Ruckdeschel; Christoph Ruckenstuhl; Emil Rudolf; Rüdiger Rudolf; Alessandra Ruggieri; Avnika Ashok Ruparelia; Paola Rusmini; Ryan R Russell; Gian Luigi Russo; Maria Russo; Rossella Russo; Oxana O Ryabaya; Kevin M Ryan; Kwon-Yul Ryu; Maria Sabater-Arcis; Ulka Sachdev; Michael Sacher; Carsten Sachse; Abhishek Sadhu; Junichi Sadoshima; Nathaniel Safren; Paul Saftig; Antonia P Sagona; Gaurav Sahay; Amirhossein Sahebkar; Mustafa Sahin; Ozgur Sahin; Sumit Sahni; Nayuta Saito; Shigeru Saito; Tsunenori Saito; Ryohei Sakai; Yasuyoshi Sakai; Jun-Ichi Sakamaki; Kalle Saksela; Gloria Salazar; Anna Salazar-Degracia; Ghasem H Salekdeh; Ashok K Saluja; Belém Sampaio-Marques; Maria Cecilia Sanchez; Jose A Sanchez-Alcazar; Victoria Sanchez-Vera; Vanessa Sancho-Shimizu; J Thomas Sanderson; Marco Sandri; Stefano Santaguida; Laura Santambrogio; Magda M Santana; Giorgio Santoni; Alberto Sanz; Pascual Sanz; Shweta Saran; Marco Sardiello; Timothy J Sargeant; Apurva Sarin; Chinmoy Sarkar; Sovan Sarkar; Maria-Rosa Sarrias; Surajit Sarkar; Dipanka Tanu Sarmah; Jaakko Sarparanta; Aishwarya Sathyanarayan; Ranganayaki Sathyanarayanan; K Matthew Scaglione; Francesca Scatozza; Liliana Schaefer; Zachary T Schafer; Ulrich E Schaible; Anthony H V Schapira; Michael Scharl; Hermann M Schatzl; Catherine H Schein; Wiep Scheper; David Scheuring; Maria Vittoria Schiaffino; Monica Schiappacassi; Rainer Schindl; Uwe Schlattner; Oliver Schmidt; Roland Schmitt; Stephen D Schmidt; Ingo Schmitz; Eran Schmukler; Anja Schneider; Bianca E Schneider; Romana Schober; Alejandra C Schoijet; Micah B Schott; Michael Schramm; Bernd Schröder; Kai Schuh; Christoph Schüller; Ryan J Schulze; Lea Schürmanns; Jens C Schwamborn; Melanie Schwarten; Filippo Scialo; Sebastiano Sciarretta; Melanie J Scott; Kathleen W Scotto; A Ivana Scovassi; Andrea Scrima; Aurora Scrivo; David Sebastian; Salwa Sebti; Simon Sedej; Laura Segatori; Nava Segev; Per O Seglen; Iban Seiliez; Ekihiro Seki; Scott B Selleck; Frank W Sellke; Joshua T Selsby; Michael Sendtner; Serif Senturk; Elena Seranova; Consolato Sergi; Ruth Serra-Moreno; Hiromi Sesaki; Carmine Settembre; Subba Rao Gangi Setty; Gianluca Sgarbi; Ou Sha; John J Shacka; Javeed A Shah; Dantong Shang; Changshun Shao; Feng Shao; Soroush Sharbati; Lisa M Sharkey; Dipali Sharma; Gaurav Sharma; Kulbhushan Sharma; Pawan Sharma; Surendra Sharma; Han-Ming Shen; Hongtao Shen; Jiangang Shen; Ming Shen; Weili Shen; Zheni Shen; Rui Sheng; Zhi Sheng; Zu-Hang Sheng; Jianjian Shi; Xiaobing Shi; Ying-Hong Shi; Kahori Shiba-Fukushima; Jeng-Jer Shieh; Yohta Shimada; Shigeomi Shimizu; Makoto Shimozawa; Takahiro Shintani; Christopher J Shoemaker; Shahla Shojaei; Ikuo Shoji; Bhupendra V Shravage; Viji Shridhar; Chih-Wen Shu; Hong-Bing Shu; Ke Shui; Arvind K Shukla; Timothy E Shutt; Valentina Sica; Aleem Siddiqui; Amanda Sierra; Virginia Sierra-Torre; Santiago Signorelli; Payel Sil; Bruno J de Andrade Silva; Johnatas D Silva; Eduardo Silva-Pavez; Sandrine Silvente-Poirot; Rachel E Simmonds; Anna Katharina Simon; Hans-Uwe Simon; Matias Simons; Anurag Singh; Lalit P Singh; Rajat Singh; Shivendra V Singh; Shrawan K Singh; Sudha B Singh; Sunaina Singh; Surinder Pal Singh; Debasish Sinha; Rohit Anthony Sinha; Sangita Sinha; Agnieszka Sirko; Kapil Sirohi; Efthimios L Sivridis; Panagiotis Skendros; Aleksandra Skirycz; Iva Slaninová; Soraya S Smaili; Andrei Smertenko; Matthew D Smith; Stefaan J Soenen; Eun Jung Sohn; Sophia P M Sok; Giancarlo Solaini; Thierry Soldati; Scott A Soleimanpour; Rosa M Soler; Alexei Solovchenko; Jason A Somarelli; Avinash Sonawane; Fuyong Song; Hyun Kyu Song; Ju-Xian Song; Kunhua Song; Zhiyin Song; Leandro R Soria; Maurizio Sorice; Alexander A Soukas; Sandra-Fausia Soukup; Diana Sousa; Nadia Sousa; Paul A Spagnuolo; Stephen A Spector; M M Srinivas Bharath; Daret St Clair; Venturina Stagni; Leopoldo Staiano; Clint A Stalnecker; Metodi V Stankov; Peter B Stathopulos; Katja Stefan; Sven Marcel Stefan; Leonidas Stefanis; Joan S Steffan; Alexander Steinkasserer; Harald Stenmark; Jared Sterneckert; Craig Stevens; Veronika Stoka; Stephan Storch; Björn Stork; Flavie Strappazzon; Anne Marie Strohecker; Dwayne G Stupack; Huanxing Su; Ling-Yan Su; Longxiang Su; Ana M Suarez-Fontes; Carlos S Subauste; Selvakumar Subbian; Paula V Subirada; Ganapasam Sudhandiran; Carolyn M Sue; Xinbing Sui; Corey Summers; Guangchao Sun; Jun Sun; Kang Sun; Meng-Xiang Sun; Qiming Sun; Yi Sun; Zhongjie Sun; Karen K S Sunahara; Eva Sundberg; Katalin Susztak; Peter Sutovsky; Hidekazu Suzuki; Gary Sweeney; J David Symons; Stephen Cho Wing Sze; Nathaniel J Szewczyk; Anna Tabęcka-Łonczynska; Claudio Tabolacci; Frank Tacke; Heinrich Taegtmeyer; Marco Tafani; Mitsuo Tagaya; Haoran Tai; Stephen W G Tait; Yoshinori Takahashi; Szabolcs Takats; Priti Talwar; Chit Tam; Shing Yau Tam; Davide Tampellini; Atsushi Tamura; Chong Teik Tan; Eng-King Tan; Ya-Qin Tan; Masaki Tanaka; Motomasa Tanaka; Daolin Tang; Jingfeng Tang; Tie-Shan Tang; Isei Tanida; Zhipeng Tao; Mohammed Taouis; Lars Tatenhorst; Nektarios Tavernarakis; Allen Taylor; Gregory A Taylor; Joan M Taylor; Elena Tchetina; Andrew R Tee; Irmgard Tegeder; David Teis; Natercia Teixeira; Fatima Teixeira-Clerc; Kumsal A Tekirdag; Tewin Tencomnao; Sandra Tenreiro; Alexei V Tepikin; Pilar S Testillano; Gianluca Tettamanti; Pierre-Louis Tharaux; Kathrin Thedieck; Arvind A Thekkinghat; Stefano Thellung; Josephine W Thinwa; V P Thirumalaikumar; Sufi Mary Thomas; Paul G Thomes; Andrew Thorburn; Lipi Thukral; Thomas Thum; Michael Thumm; Ling Tian; Ales Tichy; Andreas Till; Vincent Timmerman; Vladimir I Titorenko; Sokol V Todi; Krassimira Todorova; Janne M Toivonen; Luana Tomaipitinca; Dhanendra Tomar; Cristina Tomas-Zapico; Sergej Tomić; Benjamin Chun-Kit Tong; Chao Tong; Xin Tong; Sharon A Tooze; Maria L Torgersen; Satoru Torii; Liliana Torres-López; Alicia Torriglia; Christina G Towers; Roberto Towns; Shinya Toyokuni; Vladimir Trajkovic; Donatella Tramontano; Quynh-Giao Tran; Leonardo H Travassos; Charles B Trelford; Shirley Tremel; Ioannis P Trougakos; Betty P Tsao; Mario P Tschan; Hung-Fat Tse; Tak Fu Tse; Hitoshi Tsugawa; Andrey S Tsvetkov; David A Tumbarello; Yasin Tumtas; María J Tuñón; Sandra Turcotte; Boris Turk; Vito Turk; Bradley J Turner; Richard I Tuxworth; Jessica K Tyler; Elena V Tyutereva; Yasuo Uchiyama; Aslihan Ugun-Klusek; Holm H Uhlig; Marzena Ułamek-Kozioł; Ilya V Ulasov; Midori Umekawa; Christian Ungermann; Rei Unno; Sylvie Urbe; Elisabet Uribe-Carretero; Suayib Üstün; Vladimir N Uversky; Thomas Vaccari; Maria I Vaccaro; Björn F Vahsen; Helin Vakifahmetoglu-Norberg; Rut Valdor; Maria J Valente; Ayelén Valko; Richard B Vallee; Angela M Valverde; Greet Van den Berghe; Stijn van der Veen; Luc Van Kaer; Jorg van Loosdregt; Sjoerd J L van Wijk; Wim Vandenberghe; Ilse Vanhorebeek; Marcos A Vannier-Santos; Nicola Vannini; M Cristina Vanrell; Chiara Vantaggiato; Gabriele Varano; Isabel Varela-Nieto; Máté Varga; M Helena Vasconcelos; Somya Vats; Demetrios G Vavvas; Ignacio Vega-Naredo; Silvia Vega-Rubin-de-Celis; Guillermo Velasco; Ariadna P Velázquez; Tibor Vellai; Edo Vellenga; Francesca Velotti; Mireille Verdier; Panayotis Verginis; Isabelle Vergne; Paul Verkade; Manish Verma; Patrik Verstreken; Tim Vervliet; Jörg Vervoorts; Alexandre T Vessoni; Victor M Victor; Michel Vidal; Chiara Vidoni; Otilia V Vieira; Richard D Vierstra; Sonia Viganó; Helena Vihinen; Vinoy Vijayan; Miquel Vila; Marçal Vilar; José M Villalba; Antonio Villalobo; Beatriz Villarejo-Zori; Francesc Villarroya; Joan Villarroya; Olivier Vincent; Cecile Vindis; Christophe Viret; Maria Teresa Viscomi; Dora Visnjic; Ilio Vitale; David J Vocadlo; Olga V Voitsekhovskaja; Cinzia Volonté; Mattia Volta; Marta Vomero; Clarissa Von Haefen; Marc A Vooijs; Wolfgang Voos; Ljubica Vucicevic; Richard Wade-Martins; Satoshi Waguri; Kenrick A Waite; Shuji Wakatsuki; David W Walker; Mark J Walker; Simon A Walker; Jochen Walter; Francisco G Wandosell; Bo Wang; Chao-Yung Wang; Chen Wang; Chenran Wang; Chenwei Wang; Cun-Yu Wang; Dong Wang; Fangyang Wang; Feng Wang; Fengming Wang; Guansong Wang; Han Wang; Hao Wang; Hexiang Wang; Hong-Gang Wang; Jianrong Wang; Jigang Wang; Jiou Wang; Jundong Wang; Kui Wang; Lianrong Wang; Liming Wang; Maggie Haitian Wang; Meiqing Wang; Nanbu Wang; Pengwei Wang; Peipei Wang; Ping Wang; Ping Wang; Qing Jun Wang; Qing Wang; Qing Kenneth Wang; Qiong A Wang; Wen-Tao Wang; Wuyang Wang; Xinnan Wang; Xuejun Wang; Yan Wang; Yanchang Wang; Yanzhuang Wang; Yen-Yun Wang; Yihua Wang; Yipeng Wang; Yu Wang; Yuqi Wang; Zhe Wang; Zhenyu Wang; Zhouguang Wang; Gary Warnes; Verena Warnsmann; Hirotaka Watada; Eizo Watanabe; Maxinne Watchon; Anna Wawrzyńska; Timothy E Weaver; Grzegorz Wegrzyn; Ann M Wehman; Huafeng Wei; Lei Wei; Taotao Wei; Yongjie Wei; Oliver H Weiergräber; Conrad C Weihl; Günther Weindl; Ralf Weiskirchen; Alan Wells; Runxia H Wen; Xin Wen; Antonia Werner; Beatrice Weykopf; Sally P Wheatley; J Lindsay Whitton; Alexander J Whitworth; Katarzyna Wiktorska; Manon E Wildenberg; Tom Wileman; Simon Wilkinson; Dieter Willbold; Brett Williams; Robin S B Williams; Roger L Williams; Peter R Williamson; Richard A Wilson; Beate Winner; Nathaniel J Winsor; Steven S Witkin; Harald Wodrich; Ute Woehlbier; Thomas Wollert; Esther Wong; Jack Ho Wong; Richard W Wong; Vincent Kam Wai Wong; W Wei-Lynn Wong; An-Guo Wu; Chengbiao Wu; Jian Wu; Junfang Wu; Kenneth K Wu; Min Wu; Shan-Ying Wu; Shengzhou Wu; Shu-Yan Wu; Shufang Wu; William K K Wu; Xiaohong Wu; Xiaoqing Wu; Yao-Wen Wu; Yihua Wu; Ramnik J Xavier; Hongguang Xia; Lixin Xia; Zhengyuan Xia; Ge Xiang; Jin Xiang; Mingliang Xiang; Wei Xiang; Bin Xiao; Guozhi Xiao; Hengyi Xiao; Hong-Tao Xiao; Jian Xiao; Lan Xiao; Shi Xiao; Yin Xiao; Baoming Xie; Chuan-Ming Xie; Min Xie; Yuxiang Xie; Zhiping Xie; Zhonglin Xie; Maria Xilouri; Congfeng Xu; En Xu; Haoxing Xu; Jing Xu; JinRong Xu; Liang Xu; Wen Wen Xu; Xiulong Xu; Yu Xue; Sokhna M S Yakhine-Diop; Masamitsu Yamaguchi; Osamu Yamaguchi; Ai Yamamoto; Shunhei Yamashina; Shengmin Yan; Shian-Jang Yan; Zhen Yan; Yasuo Yanagi; Chuanbin Yang; Dun-Sheng Yang; Huan Yang; Huang-Tian Yang; Hui Yang; Jin-Ming Yang; Jing Yang; Jingyu Yang; Ling Yang; Liu Yang; Ming Yang; Pei-Ming Yang; Qian Yang; Seungwon Yang; Shu Yang; Shun-Fa Yang; Wannian Yang; Wei Yuan Yang; Xiaoyong Yang; Xuesong Yang; Yi Yang; Ying Yang; Honghong Yao; Shenggen Yao; Xiaoqiang Yao; Yong-Gang Yao; Yong-Ming Yao; Takahiro Yasui; Meysam Yazdankhah; Paul M Yen; Cong Yi; Xiao-Ming Yin; Yanhai Yin; Zhangyuan Yin; Ziyi Yin; Meidan Ying; Zheng Ying; Calvin K Yip; Stephanie Pei Tung Yiu; Young H Yoo; Kiyotsugu Yoshida; Saori R Yoshii; Tamotsu Yoshimori; Bahman Yousefi; Boxuan Yu; Haiyang Yu; Jun Yu; Jun Yu; Li Yu; Ming-Lung Yu; Seong-Woon Yu; Victor C Yu; W Haung Yu; Zhengping Yu; Zhou Yu; Junying Yuan; Ling-Qing Yuan; Shilin Yuan; Shyng-Shiou F Yuan; Yanggang Yuan; Zengqiang Yuan; Jianbo Yue; Zhenyu Yue; Jeanho Yun; Raymond L Yung; David N Zacks; Gabriele Zaffagnini; Vanessa O Zambelli; Isabella Zanella; Qun S Zang; Sara Zanivan; Silvia Zappavigna; Pilar Zaragoza; Konstantinos S Zarbalis; Amir Zarebkohan; Amira Zarrouk; Scott O Zeitlin; Jialiu Zeng; Ju-Deng Zeng; Eva Žerovnik; Lixuan Zhan; Bin Zhang; Donna D Zhang; Hanlin Zhang; Hong Zhang; Hong Zhang; Honghe Zhang; Huafeng Zhang; Huaye Zhang; Hui Zhang; Hui-Ling Zhang; Jianbin Zhang; Jianhua Zhang; Jing-Pu Zhang; Kalin Y B Zhang; Leshuai W Zhang; Lin Zhang; Lisheng Zhang; Lu Zhang; Luoying Zhang; Menghuan Zhang; Peng Zhang; Sheng Zhang; Wei Zhang; Xiangnan Zhang; Xiao-Wei Zhang; Xiaolei Zhang; Xiaoyan Zhang; Xin Zhang; Xinxin Zhang; Xu Dong Zhang; Yang Zhang; Yanjin Zhang; Yi Zhang; Ying-Dong Zhang; Yingmei Zhang; Yuan-Yuan Zhang; Yuchen Zhang; Zhe Zhang; Zhengguang Zhang; Zhibing Zhang; Zhihai Zhang; Zhiyong Zhang; Zili Zhang; Haobin Zhao; Lei Zhao; Shuang Zhao; Tongbiao Zhao; Xiao-Fan Zhao; Ying Zhao; Yongchao Zhao; Yongliang Zhao; Yuting Zhao; Guoping Zheng; Kai Zheng; Ling Zheng; Shizhong Zheng; Xi-Long Zheng; Yi Zheng; Zu-Guo Zheng; Boris Zhivotovsky; Qing Zhong; Ao Zhou; Ben Zhou; Cefan Zhou; Gang Zhou; Hao Zhou; Hong Zhou; Hongbo Zhou; Jie Zhou; Jing Zhou; Jing Zhou; Jiyong Zhou; Kailiang Zhou; Rongjia Zhou; Xu-Jie Zhou; Yanshuang Zhou; Yinghong Zhou; Yubin Zhou; Zheng-Yu Zhou; Zhou Zhou; Binglin Zhu; Changlian Zhu; Guo-Qing Zhu; Haining Zhu; Hongxin Zhu; Hua Zhu; Wei-Guo Zhu; Yanping Zhu; Yushan Zhu; Haixia Zhuang; Xiaohong Zhuang; Katarzyna Zientara-Rytter; Christine M Zimmermann; Elena Ziviani; Teresa Zoladek; Wei-Xing Zong; Dmitry B Zorov; Antonio Zorzano; Weiping Zou; Zhen Zou; Zhengzhi Zou; Steven Zuryn; Werner Zwerschke; Beate Brand-Saberi; X Charlie Dong; Chandra Shekar Kenchappa; Zuguo Li; Yong Lin; Shigeru Oshima; Yueguang Rong; Judith C Sluimer; Christina L Stallings; Chun-Kit Tong Journal: Autophagy Date: 2021-02-08 Impact factor: 13.391
Authors: José L Marín-Rubio; Laura Vela-Martín; José Fernández-Piqueras; María Villa-Morales Journal: Cancers (Basel) Date: 2019-09-29 Impact factor: 6.639
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8