Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Chemical index components and quality control of Traditional Chinese Medicine: "Never change a winning team"? -A case study of volatile oil from Bupleuri radix.

Chemical index components, especially those defined as quality control (QC) markers through spectrum-effect relationship approach, are commonly suggested and adopted as indicator for quality control of Traditional Chinese Medicines (TCMs). However, are chemical index components and quality control of TCMs "never change a winning team"? In this study, under the ponderation of the applicability of QC markers strategy, spectrum-effect relationship and OPLS-DA between GC×GC-MS fingerprint and inhibitory effect on the expression of extracellular secretory TNF-α of volatile oil from Bupleuri radix (BVO) was studied with the purpose of discovery of QC markers and establish a bioactive compounds-based QC method. 290 compounds of BVO were identified by GC×GC-MS. Besides, BVO had significant inhibitory effects on the expression of extracellular secretory TNF-α in a dose-dependent manner. The potency of different batches of BVOs could be distinguished with this bioassay-based method, which has been validated in terms of intermediate precision, repeatability, linearity, range and credibility tests. The QC markers of BVO were investigated by Spearman's correlation test and OPLS-DA. It is regrettable that there were no ideal QC markers of BVO could be found. In conclusion, quality control method relayed on chemical QC markers is not feasible for TCMs with complex composition but lack of ingredients that dominate in content, just like BVO. Alternatively, a bioassay-based method established in our study is suitable for quality control of BVO.

Protective Efficacy on Adult Ischemic Myocardium under Bypass: Del Nido vs. St. Thomas Blood Cardioplegia.

PURPOSE: To compare the myocardial protective efficacy of del Nido cardioplegia (DNC) with St. Thomas blood cardioplegia (SBC) in adult cardiac surgery. METHODS: From January to December 2021, all the patients who underwent elective cardiac operation were randomly divided into two cohorts based on the type of cardioplegia: DNC group and SBC group. Three categories of variables were compared: patient demographics, clinical variables, and laboratory variables. RESULTS: A total of 133 patients were enrolled in this study: DNC group, n = 65; and SBC group, n = 68. Except that the volume of cardioplegia administration were obvious less in the DNC group (P <0.01), no significant difference was found in the other postoperative clinical variables (P >0.05). No statistical significance was proved (P >0.05) in postoperative troponin I, creatine kinase, and B-type natriuretic peptide. The malondialdehyde concentration was higher in the SBC group, whether it is at 4 hours (P <0.05) or 24 hours (P >0.05) after operation. At the same two points in time, the change in superoxide dismutase activity was more significant in the SBC group (P <0.05). CONCLUSION: The DNC cardioplegia was safe and effective on adult myocardium protection. The potential antioxidant stress effect in DNC may provide a direction for further improvement on the formula of cardioplegic solution.

Galectin-9 expression predicts poor prognosis in hepatitis B virus-associated hepatocellular carcinoma.

OBJECTIVES: The aim of this study was to explore the expression of Galectin-9 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), evaluate its clinicopathological significance, and investigate whether Galecin-9 expression has prognostic value in HBV-associated HCC. METHODS: Immunohistochemistry staining was performed to examine the expression of Galectin-9 in paraffin-embedded tissues from 140 cases of HBV-associated HCC specimens. The association between Gal-9 expression, clinicopathological features and prognosis was analyzed by Kaplan-Meier method, log-rank test and Cox regression analysis. Dual immunofluorescence (IF) staining was performed to identify the cell types that have positive Gal-9 expression. RESULTS: Among the 140 cases of HBV-associated HCC, 39 (27.9%) cases showed high Gal-9 expression (score≥6), 21 (15%) cases showed moderate Gal-9 expression (6>score≥3), 33 (23.6%) cases showed weak Gal-9 expression (3>score>0), and 47 (33.6%) cases had no detectable Gal-9 expression (score=0). Positive Gal-9 expression (score>0) was associated with lymph node metastasis (P=0.029), Ki-67 proliferation index (P=0.009) and poor prognosis. Univariate and multivariate analyses showed that Gal-9 expression could be used as an independent prognostic marker for HBV-associated HCC. Dual IF staining indicated that Gal-9 was mainly expressed in CD68+CD163+ Kupffer cells (KCs) in HBV-associated HCC. CONCLUSIONS: Gal-9 was specifically expressed in certain HBV-associated HCC. Positive Gal-9 expression was significantly associated with poor prognosis, and Gal-9 could be used as a prognostic marker in HBV-associated HCC. Specific expression of Gal-9 on KCs indicated it may have immunosuppressive function in HBV-associated HCC.

Catestatin enhances ATP-induced activation of glial cells mediated by purinergic receptor P2X4.

The activation of glial cells and its possible mechanism play an extremely important role in understanding the pathophysiological process of some clinical diseases, and catestatin (CST) is involved in regulating this activation. In this project, we found that CST could enhance the activation of satellite glial cells (SGCs) and microglial cells and that the expression of P2X4 was increased; the co-expression of the P2X4 receptor with glial fibrillary acidic protein (GFAP) and the P2X4 receptor with CD11b was also increased significantly in glial cells of the ATP + CST group, and TNF-α and IL-1ß also showed a rising trend; the expression of phosphorylated ERK1/2 was also increased in the ATP + CST group. In summary, we conclude that CST could enhance ATP-induced activation of SGCs and microglial cells mediated by the P2X4 receptor and that the ERK1/2 signaling pathway may be involved in this activation process.

Sur-X, a novel peptide, kills colorectal cancer cells by targeting survivin-XIAP complex.

BACKGROUND: Survivin and XIAP are two important members of the inhibitor of apoptosis protein family and have been considered as potential targets for cancer treatment due to their overexpression in large variety of cancers including colorectal cancer. It has been reported that survivin and XIAP can synergistically inhibit apoptosis by forming survivin-XIAP complex. In this study, we aimed to design a peptide that targets the survivin-XIAP complex and elucidate its anticancer mechanisms in colorectal cancer cells. METHODS: We designed and synthetized Sur-X, the peptide targeting survivin-XIAP complex. The anticancer effects of Sur-X were evaluated both in vitro and in vivo. The underlying molecular mechanisms were also investigated. RESULTS: Sur-X exhibited potent inhibitory effects on four colorectal cancer cell lines HCT116, HCT15, RKO and HT29, but not on human peritoneal mesothelial cell line HMrSV5. Mechanistically, Sur-X induced Caspase 9-dependent intrinsic apoptosis in colorectal cancer cells by disrupting the survivin-XIAP complex and subsequently destabilizing survivin and XIAP. Interestingly, we found that Sur-X can also promote necroptosis. It was demonstrated that Sur-X destroyed the interaction between XIAP and TAB1 in the XIAP-TAB1-TAK1 complex, leading to the instability of TAK1, an endogenous necroptosis inhibitor. Subsequently, the accelerated degradation of TAK1 attenuated its inhibition on necroptosis in colorectal cancer cells. Moreover, knockdown of TAK1 restored the sensitivity of TAB1-overexpressing colorectal cancer cells to Sur-X-induced necroptosis. The in vivo pro-apoptotic effect of Sur-X was confirmed by the enhanced TUNEL staining and the decreased expression of survivin and XIAP in tumor tissues from xenograft mouse models. In addition, extensive necrosis and weaker MLKL expression in xenografts provided evidence for the in vivo pro-necroptotic effect of Sur-X. CONCLUSIONS: Peptide Sur-X exhibits strong pro-apoptotic and pro-necroptotic effects in colorectal cancer cells and has a high clinical translation potential in the treatment of colorectal cancer.

Quantitative Lysine Reactivity Profiling Reveals Conformational Inhibition Dynamics and Potency of Aurora A Kinase Inhibitors.

Small-molecule inhibitors of protein kinases attract widespread interest in the field of disease therapy because of their high specificity and ease of administration. However, dissecting the conformational inhibition dynamics of kinase inhibitors is still challenging. Here, simultaneously monitoring the conformational inhibition details and potency of Aurora A kinase inhibitors has been achieved by active isotope dimethyl labeling coupled with mass spectrometry-based quantitative lysine reactivity profiling. The conformational effects of inhibitors on lysine reactivity can be globally quantified to feasibly reveal the regions involved in the kinase dynamic inhibition. The half-maximum disturbance concentrations (DC50 values) of the conformation-specific lysine residues could directly represent the conformational selectivity and potency of kinase inhibitors. Further, K309 is discovered as a novel hotspot contributing to the inhibition of Aurora A kinase via the specific rotation of kinase activation loop. This quantitative lysine reactivity profiling strategy might greatly promote the development of targeted drugs.

Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands.

Proteolysis targeting chimera (PROTAC) recruits an E3 ligase to a target protein to induce its ubiquitination and subsequent degradation. We reported success in the development of two PROTACs (C3 and C5) that potently and selectively induce the degradation of Mcl-1 and Bcl-2 (DC50 = 0.7 and 3.0 µM), respectively, by introducing the E3 ligase cereblon-binding ligand pomalidomide to Mcl-1/Bcl-2 dual inhibitors S1-6 and Nap-1 with micromolar-range affinity. C3-induced Mcl-1 ubiquitination translated into much more lethality in Mcl-1-dependent H23 cells than the most potent Mcl-1 occupancy-based inhibitor A-1210477 with nanomolar-range affinity. Moreover, structure-activity relationship analysis and molecular dynamic simulations discovered the structural basis for turning nonselective or promiscuous Bcl-2 family ligands into selective PROTACs. C3 and C5 exhibited reversible depletion in living cells, which provides a new potent toolkit for gain-of-function studies to probe the dynamic roles of Bcl-2 and Mcl-1 in apoptosis networks.

Systems analysis of phosphorylation-regulated Bcl-2 interactions establishes a model to reconcile the controversy over the significance of Bcl-2 phosphorylation.

BACKGROUND AND PURPOSE: The biological significance of the multi-site phosphorylation of Bcl-2 at its loop region (T69, S70 and S87) has remained controversial for decades. This is a major obstacle for understanding apoptosis and anti-tumour drug development. EXPERIMENTAL APPROACH: We established a mathematical model into which a phosphorylation and de-phosphorylation process of Bcl-2 was integrated. Paclitaxel-treated breast cancer cells were used as experimental models. Changes in the kinetics of binding with its critical partners, induced by phosphorylation of Bcl-2 were experimentally obtained by surface plasmon resonance, using a phosphorylation-mimicking mutant EEE-Bcl-2 (T69E, S70E and S87E). KEY RESULTS: Mathematical simulations combined with experimental validation showed that phosphorylation regulates Bcl-2 with different dynamics depending on the extent of Bcl-2 phosphorylation and the phosphorylated Bcl-2-induced changes in binding kinetics. In response to Bcl-2 homology 3 (BH3)-only protein Bmf stress, Bcl-2 phosphorylation switched from diminishing to enhancing the Bcl-2 anti-apoptotic ability with increased phosphorylation of Bcl-2, and the turning point was 50% Bcl-2 phosphorylation induced by 0.2 µM paclitaxel treatment. In contrast, Bcl-2 phosphorylation enhanced the anti-apoptotic ability of Bcl-2 towards other BH3-only proteins Bim, Bad and Puma, throughout the entire phosphorylation procedure. CONCLUSIONS AND IMPLICATIONS: The model could accurately predict the effects of anti-tumour drugs that involve the Bcl-2 family pathway, as shown with ABT-199 or etoposide.

Saikosaponin D from Radix Bupleuri suppresses triple-negative breast cancer cell growth by targeting ß-catenin signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive and poor prognosis breast cancers. Currently, chemotherapy with conventional cytotoxic agents is the only available option to treat TNBC. Hence, we identified new therapeutic agents against TNBC from traditional Chinese medicine Radix Bupleuri and unveiled the molecule mechanism of anti-TNBC effects. METHODS: Multi-component bioactivity and structure-guided methods were used to identify the most effective anti-TNBC compound Saikosaponin D (SSD) from Radix Bupleuri. Cell viability and apoptosis assays were employed to demonstrate the effect of SSD on the proliferation and apoptosis of TNBC cells. Dynamic mass redistribution assay, TopFlash assay, western blotting, and special agonist were applied to dissect the potential molecular mechanisms of SSD. RESULTS: We screened twenty fractions in Radix Bupleuri and identified SSD as the most effective component to inhibit the proliferation of TNBC cells. Investigating the interaction of SSD with the frequently overexpressed targets in TNBC led to the identification that it markedly suppressed Wnt/ß-catenin signaling, but did not act on epidermal growth factor receptor and neurotensin receptor-1. Moreover, we demonstrated that SSD significantly repressed ß-catenin and its downstream target genes, resulting in TNBC cell apoptosis. Specifically, docking of SSD to the crystal structure of ß-catenin suggested that SSD interacted with ß-catenin via hydrogen bonds and hydrophobic interaction. CONCLUSION: We identified the most effective component SSD from Radix Bupleuri in inhibiting the proliferation of TNBC cells by targeting ß-catenin signaling. Given the important role of Wnt/ß-catenin signaling in breast cancer, SSD may present an opportunity to discover new therapeutics for the treatment of TNBC.

Discovery of novel antagonists on ß2-adrenoceptor from natural products using a label-free cell phenotypic assay.

Label-free cell phenotypic assays were performed to establish a ß2-adrenoceptor (ß2-AR) target model in A431 cells and a ß1-AR target model in transfected HEK293-ß1 cells, using known ß2-AR and ß1-AR agonists and antagonists. A list of natural compounds was screened on the target models, among which seven new compounds were found to be antagonistically active against ß2-AR. After receptor specificity evaluations on hydroxyl carboxylic acid receptor-2 (ΗΧΑ-2), histamine receptor (H1R), and ß1-adrenoceptor (ß1-AR), six out of the seven compounds, including nuciferine, epiberberine, harmaline, harmine, palmatine, and columbamine, exhibited specific antagonistic activity against ß2-AR. Epiberberine and palmatine showed the strongest antagonistic activities against ß2-AR with IC50 values of 2.3 ± 0.2 µM and 2.6 ± 0.3 µM, respectively. Docking palmatine to the crystal structure of human ß2-AR (PDB 5X7D) suggested that the ligand forms a hydrogen bond with N312 and hydrophobic interaction with several amino acid residues in the binding pocket, such as D113 and V114. The kinetic binding profile of palmatine was further investigated using co-stimulation assays. Results suggested that palmatine was a competitive antagonist for ß2-AR. The six novel ß2-AR antagonists provide a promising chemical starting point for identification and optimization of drugs used for treating hypertension, glaucoma, and infantile hemangiomas. This study also lays the foundation for the in-depth investigation of biochemical mechanisms and pharmacological properties of natural compounds.

Risk factors for poor outcome in posterior reversible encephalopathy syndrome: systematic review and meta-analysis.

BACKGROUND: The roles of clinical etiology and symptoms, imaging findings and biochemical parameters in predicting the prognosis of posterior reversible encephalopathy syndrome (PRES) have not been well-characterized. We perform a meta-analysis of all published studies to assess the value of various risk factors in predicting the prognosis of PRES. METHODS: Searches of the PubMed, EMBASE, Cochrane Library, and Web of Science databases were performed to identify the eligible studies. The odds ratios (ORs) with their corresponding 95% confidence interval (CI) for related risk factors were used to calculate the pooled estimates of the outcomes. RESULTS: Six studies with 448 cases were included in the meta-analysis. Hemorrhage was associated with high risk for poor outcome in patients with PRES. Toxemia of pregnancy (pre-eclampsia/eclampsia) was associated with improved outcome in PRES patients. Cytotoxic edema was noted to be related to poor outcome, but did not show statistical significance. The pooled OR for hemorrhage, pre-eclampsia/eclampsia, cytotoxic edema was 4.93 (95% CI: 3.94-6.17; P<0.00001), 0.24 (95% CI: 0.15-0.40; P<0.00001) and 2.59 (95% CI: 0.84-7.99; P=0.10), respectively. CONCLUSIONS: PRES patients with hemorrhage or cytotoxic edema are likely to have poor outcomes. Pre-eclampsia/eclampsia is associated with reduced risk of poor outcome in patients with PRES.

Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.

The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.

Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors.

Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (Ki = 0.48 µM by fluorescence polarization) over Bcl-2 (Ki = 3.6 µM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.

Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics.

No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, we extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.

Mechanism of Mcl-1 Conformational Regulation Upon Small Molecule Binding Revealed by Molecular Dynamic Simulation.

Inhibition of interactions between Mcl-1 and proapoptotic proteins is considered to be a therapeutic strategy to induce apoptosis in cancer cells. Here, we adopted molecular dynamics simulation with molecular mechanics-Poisson Boltzmann/surface area method (MM-PB/SA) to study the inhibition mechanism of three Mcl-1 inhibitors, compounds 1, 2 and 3. Analysis of energy components shows that the better binding free energy of compound 3 than compounds 1 and 2 is attributable to the van der Waals energy (ΔEvdw ) and non-polar solvation energy (ΔGnp ) upon binding. In addition to the excellent agreement with previous experimentally determined affinities, our simulation results further show a bend of helix 4 on Mcl-1 upon compound 3 binding, which is driven by hydrophobic interaction with residue Val(253) , leading to a narrowed BH3-binding groove to impede Puma(BH) (3) binding. The computational result is consistent with our competitive isothermal titration calorimetry (ITC) assays, which shows that the competitive ability of compound 3 toward Mcl-1/Puma(BH) (3) complex is improved beyond its direct binding affinity toward Mcl-1 itself, and compound 3 exhibits much more efficiency to compete with Puma(BH) (3) than compound 2. Our study provides a new strategy to improve inhibitory activity on Mcl-1 based on the conformational dynamic change.

CD40 -1C>T polymorphism and the risk of lung cancer in a Chinese population.

BACKGROUND: The co-stimulatory molecule CD40 plays an important role in anti-tumor responses by promoting cytotoxic T lymphocyte (CTL) activity and differentiation of helper T cells. Growing evidence suggests that single nucleotide polymorphisms (SNPs) in CD40 are associated with the susceptibility to cancer. This study investigated the association between the CD40 -1C/T SNP (rs1883832) and lung cancer in a Chinese population. METHODS: We conducted a hospital-based case-control study including 105 lung cancer patients and 109 healthy control subjects. The -1C/T SNP in CD40 was genotyped by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and its association with lung cancer susceptibility was evaluated. RESULTS: The distribution of the genotypes of CD40-1C/T was significantly different between lung cancer patients and controls. The frequency of the TT genotype (adjusted P = 0.017; overall risk [OR] = 2.94; 95% confidence interval [CI] = 1.21-7.13) and TT/CT genotype (adjusted P = 0.020; OR = 1.95; 95% CI = 1.11-3.43) were significantly higher in lung cancer patients than that in controls. When the cases were categorized by tumor histology, the TT genotype was associated with a significantly increased risk of squamous cell carcinoma (adjusted OR = 6.53; 95% CI = 1.97-21.61; P = 0.002). CONCLUSION: Our findings suggest that the CD40 -1C/T SNP (rs1883832) is correlated with the susceptibility to lung cancer in Chinese, and the TT genotype may further increase the risk of lung cancer.

Epidemiological studies of esophageal cancer in the era of genome-wide association studies.

Esophageal cancer (EC) caused about 395000 deaths in 2010. China has the most cases of EC and EC is the fourth leading cause of cancer death in China. Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type (90%-95%), while the incidence of esophageal adenocarcinoma (EAC) remains extremely low in China. Traditional epidemiological studies have revealed that environmental carcinogens are risk factors for EC. Molecular epidemiological studies revealed that susceptibility to EC is influenced by both environmental and genetic risk factors. Of all the risk factors for EC, some are associated with the risk of ESCC and others with the risk of EAC. However, the details and mechanisms of risk factors involved in the process for EC are unclear. The advanced methods and techniques used in human genome studies bring a great opportunity for researchers to explore and identify the details of those risk factors or susceptibility genes involved in the process of EC. Human genome epidemiology is a new branch of epidemiology, which leads the epidemiology study from the molecular epidemiology era to the era of genome wide association studies (GWAS). Here we review the epidemiological studies of EC (especially ESCC) in the era of GWAS, and provide an overview of the general risk factors and those genomic variants (genes, SNPs, miRNAs, proteins) involved in the process of ESCC.

Improvement of the cytocompatibility of electrospun poly[(R)-3-hydroxybutyrate-co-(R)-3-hydroxyvalerate] mats by Ecoflex.

Poly[(R)-3-hydroxybutyrate-co-(R)-3-hydroxyvalerate] (PHBV) is a nature-derived polyester with potential application in tissue engineering scaffolds. However, PHBV is associated with disadvantages including high brittleness, slow degradation, high hydrophobicity, and unsatisfactory biocompatibility. In this study, we sought to improve the properties of PHBV by blending it with Ecoflex, a synthetic biopolyester with a high flexibility, fast degradation, and comparatively higher hydrophilicity. PHBV was codissolved with Ecoflex in dichloromethane at different mass ratios (PHBV/Ecoflex: 100/0, 70/30, 50/50, and 30/70) and electrospun into mats. Compared with the pure PHBV mat, the Ecoflex-containing mats showed decreased contact angles with phosphate-buffered saline (PBS), accelerated weight loss in PBS, and increased strain at break with increasing Ecoflex mass ratios. In vitro cell culture also showed significantly improved adhesion and proliferation of human bone marrow stroma cells with the introduction of Ecoflex. Blending PHBV with Ecoflex is a simple and effective method to improve the chemical, mechanical, and biological properties of PHBV simultaneously and thereby to expedite its application in tissue engineering. To our knowledge, this is the first report showing the biocompatibility of Ecoflex-containing materials with human cells.