Supramolecular DNA nanogels through host-guest interaction for targeted drug delivery.

DNA hydrogels have been demonstrated with the advantages of good stability, easy modification, and extraordinary biocompatibility, which enables their great application prospects in biosensing, tissue engineering, and biomedicine. Based on the host-guest recognition properties of cucurbit[8]uril (CB[8]), we proposed a general method for constructing functional supramolecular DNA nanogels. Guest molecules have been conjugated into the DNA building units, which could be further crosslinked with CB[8] to construct supramolecular DNA nanogels. At the same time, the aptamer has also been modified into the hydrogel network to achieve cell targeting. These supramolecular DNA nanogels have been demonstrated with a controllable size and multiple stimuli responses, in addition to the excellent biocompatibility, stability and good targeting drug transport ability. Such a host-guest based strategy will provide a molecular library as a "toolbox" for the functionalization of DNA nanogels.

Elastic Strain Relaxation of Phase Boundary of α' Nanoscale Phase Mediated via the Point Defects Loop under Normal Strain.

Irradiation-induced point defects and applied stress affect the concentration distribution and morphology evolution of the nanophase in Fe-Cr based alloys; the aggregation of point defects and the nanoscale precipitates can intensify the hardness and embrittlement of the alloy. The influence of normal strain on the coevolution of point defects and the Cr-enriched α' nanophase are studied in Fe-35 at.% Cr alloy by utilizing the multi-phase-field simulation. The clustering of point defects and the splitting of nanoscale particles are clearly presented under normal strain. The defects loop formed at the α/α' phase interface relaxes the coherent strain between the α/α' phases, reducing the elongation of the Cr-enriched α' phase under the normal strains. Furthermore, the point defects enhance the concentration clustering of the α' phase, and this is more obvious under the compressive strain at high temperature. The larger normal strain can induce the splitting of an α' nanoparticle with the nonequilibrium concentration in the early precipitation stage. The clustering and migration of point defects provide the diffusion channels of Cr atoms to accelerate the phase separation. The interaction of point defect with the solution atom clusters under normal strain provides an atomic scale view on the microstructure evolution under external stress.

Dose-Response Association of Waist-to-Height Ratio Plus BMI and Risk of Depression: Evidence from the NHANES 05-16.

BACKGROUND: Obesity or underweight has been found to be associated with depression, but the relationship remains to be determined so that more precise prevention strategies can be implemented. Body mass index (BMI) and waist-height ratio (WHR) were used as indicators to study the dose-response relationship between depression and obesity or underweight. METHODS: We obtained basic information and disease-related data for 13,975 adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2016 dataset. The depressive status was determined based on the PHQ-9 scale (>4). Logistic regression was used to analyze the association and risk of BMI, WHTR and depressive status. Based on the results of logistic regression, the dose-response relationship between BMI, WHTR and depressive state was analyzed using restricted cubic splines (RCS). RESULTS: The adjusted model showed that compared with the fourth quartile (Q4) of BMI, the odds ratios (ORs) of depression for Q1, Q2 and Q3 were 0.63 (0.56-0.71), 0.61 (0.54-0.68) and 0.74 (0.66-0.82), and compared with the fourth quartile (Q4) of WHtR, the odds ratios (ORs) of depression for Q1, Q2 and Q3 were 0.55 (0.49-0.62), 0.57 (0.51-0.64) and 0.64 (0.57-0.71), respectively. The restricted cubic spline regression depicted a U-shaped dose-response relationship between continuous changes of obesity indicators and the risk of depression (P1, P2 < 0.001). When the participants' BMI reached approximately 25kg/m2 with the reference value of BMI was 18.5kg/m2, the risk of depression was minimized (OR=0.68, 95% Cl=0.56-0.83). When the WHtR reached approximately 0.52 with the reference value of WHtR was 0.40, the risk of depression was minimized (OR=0.69, 95% Cl=0.54-0.88). CONCLUSION: We found a significant U-shape correlation between BMI, WHtR and depression. People with slight overweight have the lowest risk of depression. However, according to the International Obesity standards, the population at these levels of weight may have an obesity-chronic disease risk, and this is not recommended.

Phase-field simulation of dose rate effect on the Cu precipitation with neutron irradiation.

Radiation-enhanced precipitation (REP) of Cu in Fe-Cu alloys results in hardening and degradation of the mechanical properties. By combining the CALPHAD-based free energy for phase-field modeling, and radiation-enhanced diffusion (RED) with neutron irradiating energetic particle, the precipitation of Cu in binary Fe-Cu alloys is studied under different dose rates, concentrations, and temperatures. Rate theory (RT) provides the RED that serves as an input parameter for the phase-field simulation to capture the morphology of the precipitates. The REP results agree with the theoretical predictions: the increase in the dose rates increases the concentration of defects, and accelerates the kinetics of precipitation. The simulation predicts the stability of the precipitates even under high damage rates. The increase in radius is achieved for high damage rates. Precipitate dissolution is observed to be dependent on the combination of dose rate, concentration, and temperature. The work also outlines the limitations of the model and the potential future improvements.

Positive feedback of SuFu negating protein 1 on Hedgehog signaling promotes colorectal tumor growth.

Hedgehog (Hh) signaling plays a critical role in embryogenesis and tissue homeostasis, and its deregulation has been associated with tumor growth. The tumor suppressor SuFu inhibits Hh signaling by preventing the nuclear translocation of Gli and suppressing cell proliferation. Regulation of SuFu activity and stability is key to controlling Hh signaling. Here, we unveil SuFu Negating Protein 1 (SNEP1) as a novel Hh target, that enhances the ubiquitination and proteasomal degradation of SuFu and thus promotes Hh signaling. We further show that the E3 ubiquitin ligase LNX1 plays a critical role in the SNEP1-mediated degradation of SuFu. Accordingly, SNEP1 promotes colorectal cancer (CRC) cell proliferation and tumor growth. High levels of SNEP1 are detected in CRC tissues and are well correlated with poor prognosis in CRC patients. Moreover, SNEP1 overexpression reduces sensitivity to anti-Hh inhibitor in CRC cells. Altogether, our findings demonstrate that SNEP1 acts as a novel feedback regulator of Hh signaling by destabilizing SuFu and promoting tumor growth and anti-Hh resistance.

Phase-field crystal modeling of crystal growth patterns with competition of undercooling and atomic density.

Crystal growth with various patterns, hexagonal, circular, square, rectangular, star-like, and faceted, was investigated using the one-mode approximation of phase-field crystal (PFC) modeling. The simulations were carried out at different temperatures and average densities of the diverse patterns. The pattern selection of crystal growth is caused by the competition between undercooling temperature ε and average density ψ. When the undercooling temperature reaches ε = -0.75, the crystal evolves into a stable striped phase. Further increasing from ε = -0.75 to -0.25, a combination of a triangular-striped coexistence pattern, a triangular-liquid coexistence phase and a stable triangular pattern forms with average densities ψ = -0.130, -0.185 and -0.285, respectively. In particular, when the time, undercooling temperature and average density increase, the crystal grows to a secondary pattern. The introduction of noise terms breaks the symmetry in the growth morphology. For a hexagonal lattice, a large undercooling temperature ε leads to faster crystallization. Finally, a morphological phase diagram under the effect of ε and ψ with star-like dendrite and compact spherical shape (CSS) is constructed as a function of the phase-field crystal parameters.

The critical role of dysregulated Hh-FOXM1-TPX2 signaling in human hepatocellular carcinoma cell proliferation.

BACKGROUND: Aberrant activation of the Hedgehog (Hh) signaling pathway is frequently observed in hepatocellular carcinoma (HCC), nevertheless, the precise molecular mechanism remains unclear. Forkhead box M1 (FOXM1), a target of the Hh pathway, is a key oncofetal transcription factor and a master cell cycle regulator. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an oncogene critical for mitosis. However, how these molecular events affect HCC progression remains unclear. METHODS: Realtime PCR, immunohistochemistry, western blotting, and analyses of datasets TCGA and Gene Expression Omnibus (GEO) were conducted to assess the expression of TPX2 and FOXM1 at the mRNA and protein levels in HCC samples or HCC cells. Expression and knockdown of TPX2 and FOXM1 were performed to assess their role in regulating HCC cell proliferation in vitro and in vivo. Dual luciferase report assay and chromosome immunoprecipitation (ChIP) were investigated to seek the FOXM1 binding sites in the promoter of TPX2. RESULTS: Specific antagonists (cyclopamine and GANT61) of the Hh pathway down-regulated TPX2, whereas activation of Hh signaling stimulated TPX2 expression. Furthermore, TPX2 over-expression accelerated HCC cell proliferation when upstream events of Hh signaling were inhibited, and TPX2 knockdown significantly alleviated Sonic Hh ligand (Shh)-induced HCC cell proliferation. Reporter assays and ChIP showed that FOXM1 bound to the TPX2 promoter, confirming that TPX2 is a direct downstream target of FOXM1. Xenograft model further verified the cell function and expression regulation of TPX2 and FOXM1 in vivo. Furthermore, FOXM1 regulated TPX2 activity to drive HCC proliferation. Immunohistochemical (IHC) analysis indicated that FOXM1 and TPX2 were highly-expressed in HCC samples and cohort study revealed that FOXM1 and TPX2 may act as negative predictors for the prognosis of patients with HCC. CONCLUSIONS: TPX2 acts as a novel downstream target and effector of the Hh pathway, and Hh signaling contributes to HCC proliferation via regulating the FOXM1-TPX2 cascade, suggesting that this signaling axis may be a novel therapeutic target for HCC.

The N-terminal domain of the non-receptor tyrosine kinase ABL confers protein instability and suppresses tumorigenesis.

Chromosome translocation can lead to chimeric proteins that may become oncogenic drivers. A classic example is the fusion of the BCR activator of RhoGEF and GTPase and the ABL proto-oncogene nonreceptor tyrosine kinase, a result of a chromosome abnormality (Philadelphia chromosome) that causes leukemia. To unravel the mechanism underlying BCR-ABL-mediated tumorigenesis, here we compared the stability of ABL and the BCR-ABL fusion. Using protein degradation, cell proliferation, 5-ethynyl-2-deoxyuridine, and apoptosis assays, along with xenograft tumor analysis, we found that the N-terminal segment of ABL, which is lost in the BCR-ABL fusion, confers degradation capacity that is promoted by SMAD-specific E3 ubiquitin protein ligase 1. We further demonstrate that the N-terminal deletion renders ABL more stable and stimulates cell growth and tumorigenesis. The findings of our study suggest that altered protein stability may contribute to chromosome translocation-induced cancer development.

Vacancy and interstitial atom evolution with the separation of the nanoscale phase in Fe-Cr alloys: phase-field simulations.

Point defects induced by irradiation affect the phase decomposition and morphology evolution of Fe-Cr alloys, which results in the increase of hardness and embrittlement. The coevolution of point defects and the Cr-enriched nanoscale α' phase was studied by using phase-field simulations, and the interactive influence of point defects and Cr-enriched nanoscale particles on the kinetics evolution was clarified. It is found that the clustering of vacancies and interstitial atoms is earlier than the separation of the α' phase, and the point defects migrate from the initial cluster position to the interface of the α/α' phases, and accumulate into a defect concentration loop around the α' phase with the growth of the α' phase. In addition, with the increase of the initial defect concentration, phase separation is accelerated via the vacancy diffusion mechanism, and also the separation of Cr-enriched particles promotes the clustering of point defects. Point defects show a significant influence on phase separation with elevated temperature.

Autophagy regulator Atg9 is degraded by the proteasome.

Autophagy is a highly conserved biological process essential to protein, cellular and organismal homeostasis. As autophagy plays a critical role in cellular responses to various external and internal stimuli, it is important to understand the mechanism underlying autophagy regulation. Here, we monitor the stability of 17 key autophagy factors in the yeast S. cerevisiae and show that Atg9 and Atg14 are degraded under normal growth conditions. Whereas Atg14 is regulated by both the proteasome and autophagy, Atg9 turnover is normally mediated by the proteasome but impeded upon starvation or rapamycin treatment. Interestingly, distinct segments of Atg9 confer instability, suggesting that multiple pathways are involved in Atg9 degradation. Our results provide the foundation to further elucidate the physiological significance of Atg9 turnover and also the interplay between two major proteolytic systems (i.e., autophagy and the proteasome).

FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression.

BACKGROUND: Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression. METHODS: Bioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth. RESULTS: FOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo. CONCLUSION: The FOXM1-KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment.

A 5-gene prognostic nomogram predicting survival probability of glioblastoma patients.

BACKGROUND: Glioblastoma (GBM) remains the most biologically aggressive subtype of gliomas with an average survival of 10 to 12 months. Considering that the overall survival (OS) of each GBM patient is a key factor in the treatment of individuals, it is meaningful to predict the survival probability for GBM patients newly diagnosed in clinical practice. MATERIAL AND METHODS: Using the TCGA dataset and two independent GEO datasets, we identified genes that are associated with the OS and differentially expressed between GBM tissues and the adjacent normal tissues. A robust likelihood-based survival modeling approach was applied to select the best genes for modeling. After the prognostic nomogram was generated, an independent dataset on different platform was used to evaluate its effectiveness. RESULTS: We identified 168 differentially expressed genes associated with the OS. Five of these genes were selected to generate a gene prognostic nomogram. The external validation demonstrated that 5-gene prognostic nomogram has the capability of predicting the OS of GBM patients. CONCLUSION: We developed a novel and convenient prognostic tool based on five genes that exhibited clinical value in predicting the survival probability for newly diagnosed GBM patients, and all of these five genes could represent potential target genes for the treatment of GBM. The development of this model will provide a good reference for cancer researchers.

Pretransplant C-reactive protein as a prognostic marker in allogeneic stem cell transplantation: A PRISMA-compliant meta-analysis.

BACKGROUND: Numerous reports have explored the prognostic value of pretransplant serum C-reactive protein (CRP) in patients receiving allogeneic stem cell transplant (ASCT), but the results remain conflicting. Therefore, we performed a meta-analysis to comprehensively assess the prognostic value of pretransplant serum CRP in patients receiving ASCT. METHODS: We systematically searched eligible studies in PubMed, Embase, and Web of Science from 1999 to September 2018. The pooled hazard ratios (HRs) and their corresponding 95% CIs were used to synthetically assess the prognostic value of pre-ASCT CRP in terms of overall survival (OS), non-relapse mortality (NRM), and acute graft versus host disease (aGVHD). RESULTS: A total of 14 articles with 15 studies containing 3458 patients were included in this meta-analysis. The pooled results showed that high pre-ASCT CRP level was significantly related to worse OS (HR = 1.63; 95% CI: 1.34-1.98; P < .05), to an increased risk of NRM (HR = 2.06; 95% CI: 1.62-2.62; P < .05), and aGVHD (HR = 1.35; 95% CI: 1.07-1.71; P < .05). Additionally, sensitivity and subgroup analyses demonstrated that our pooled results were stable and reliable. CONCLUSIONS: High pre-ASCT serum CRP was significantly associated with worse OS, as well as higher risk of NRM and aGVHD. CRP may be a candidate factor of updating the existing risk scoring systems or establishing a novel risk scoring systems, which has the potential of guiding patient selection for ASCT and proceeding with risk-adapted therapeutic strategies. However, more high-quality clinical studies and basic research are required to further validate our findings in view of several limitations in our meta-analysis.

Morphology and Kinetics Evolution of Nanoscale Phase in Fe⁻Cr Alloys under External Strain.

Uniaxial strain was applied to aging Fe⁻Cr alloys to study the morphological orientation and kinetics of the nanoscale α' phase by utilizing phase-field simulation. The effects of applied uniaxial compressive and tensile strain on the two and three-dimensional morphology as well as on the separation kinetics of the α' phase are quantitatively clarified. Compared with the applied uniaxial tensile strain, the applied uniaxial compressive strain shows a greater effect on the rate of phase separation, lath shape morphology and an increased rate of growth and coarsening in the α' phase, the boundary of the α + α' phase region is widened influenced by the applied compressive strain, while the applied tensile strain results in an increase of particle number density and a decrease of particle radius. The peak value of particle size distribution of the α' phase increases with aging time, while an opposite trend is shown under the applied strain, and there is an obvious deviation from the theoretical distribution of Lifshitz⁻Slyozov⁻Wagner under compressive strain. The orientation morphology and kinetic change show the substantial effects of applied strain on the phase separation and supplies the method for the morphological control of nanoscale particles.

Effect of pre-transplantation serum ferritin on outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation: A meta-analysis.

BACKGROUND: Pre-transplantation serum ferritin (SF) has been considered to be a potential prognostic biomarker in patients undergoing allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), but this conclusion remains controversial. Thus, we performed a meta-analysis to investigate the prognostic significance of pre-transplantation SF in patients undergoing allogeneic HSCT. METHODS: We systematically searched PubMed, Embase, and Web of Science up to September 2017, and finally identified a total of 25 eligible studies with 4545 patients. RESULTS: The pooled results of our meta-analysis showed that high pre-transplantation SF was markedly related to worse overall survival (OS) [hazard ratio (HR) = 1.82; 95% confidence interval (95% CI): 1.47-2.26; P < .001], nonrelapse mortality (NRM) (HR = 2.28; 95% CI: 1.79-2.89; P < .001), and progression-free survival (PFS) (HR = 1.72; 95% CI: 1.27-2.33; P < .001). In addition, high pre-transplantation SF was closely associated with a lower incidence of chronic graft versus host disease (cGVHD) (OR = 0.74, 95% CI: 0.58-0.96; P < .05), and a higher incidence of blood stream infections (BSIs) (OR = 1.67, 95% CI: 0.93-3.01; P = .09). However, no significance relationship was found between elevated pre-transplantation SF and acute graft versus host disease (aGVHD) (OR = 1.08, 95% CI:.72-1.62; P = .70). CONCLUSION: In patients undergoing allogeneic HSCT for hematological malignancies, elevated pre-transplantation SF was significantly associated with worse OS and PFS, higher incidence of NRM and BSI, and lower incidence of cGVHD, but it had no effect on aGVHD. Considering the limitations in our meta-analysis, more prospective and homogeneous clinical studies are needed to further confirm our findings.

[Alteration of IFN-γ, IL-4, IL-17 and TGF-ß levels in Serum of Patients with Chronic Lymphocytic Leukemia Treated with FCR].

OBJECTIVE: To investigate the alteration and clinical significance of IFN-γ, IL-4, IL-17 and TGF-ß levels in serum of patients with chronic lymphocytic leukemia treated with FCR. METHODS: Forty-seven CLL patients treated with FCR regimen were enrolled in CLL group, meanwhile 30 healthy persons were selected in control group. The serum levels of IFN-γ, IL-4, IL-17 and TGF-ß were detected by ELISA in CLL group before and after treatment and in control group, then the differences of IFN-γ, IL-4, IL-17 and TGF-ß levels as well as IFN-γ/IL-4 ratio and TGF-ß/IL-17 ratio were compared between 2 groups. RESULTS: Before treatment with PCR regimen, the IL-4, IL-17 and TGF-ß levels as well as TGF-ß/IL-17 in CLL group were higher than those in control group (P<0.05), while the IFN-γ level and IFN-γ/IL-4 ratio in CLL group were lower than those in control group (P<0.05); after treatment with PCR regimen, the IL-4, IL-17 and TGF-ß levels as well as TGF-ß/IL-17 ratio all significantly decreased (P<0.05), while IFN-γ level and IFN-γ/IL-4 ratio significantly increased (P<0.05) as compared with those before treatment, moreover, the IL-4 and IL-17 levels as well as TGF-ß/ IL-17 and IFN-γ /IL-4 ratio were no significantly different from those in control group (P>0.05), only the IFN-γ and TGF-ß levels were significantly diffrent from control group (P<0.05). The analysis of Binet staging (stage A, B, C) showed that along with pregression of Binet stages, the TGF-γ/IL-17 levels as well as the IFN-γ/IL-4 ratio in CLL group negatively correlated with Binet staging (r=-0.53), while the TGF-ß/IL-17 ratio positively correlated with Binet staging (r=0.46). The analysis of grouping accoraing to therapentic efficacy fonnd that the IL-4 and IL-17 levels and IFN-γ/IL-4 and TGF-ß/IL-17 ratios in CR and PR groups were significantly different before and after treatment (P<0.05), while those in SD and PD groups did not showed statistical difference before and after treatment (P>0.05). CONCLUSION: Along with the progression of disease, the IFN-γ/ IL-4 ratio gradually decreases, and the TGF-ß / L-17 ratio gradually increases. The treatment with FCR regimen can overcome this tread, therefore dynamically monitoring the chages of IFN-γ/ IL-4 and TGF-ß / L-17 ratios may contribute to guide the clinical treatment.

Aldehyde dehydrogenase 1A1 stabilizes transcription factor Gli2 and enhances the activity of Hedgehog signaling in hepatocellular cancer.

The Gli transcription factors are primary transcriptional regulators that mediate the activation of Hedgehog (Hh) signaling. Recent studies have revealed that Gli proteins are also regulated transcriptionally and post-translationally through noncanonical mechanisms, independent of Hh signaling. However, the precise mechanisms involved in the regulation of Gli proteins remain unclear. Using a differential mass-spectrometry approach, we found that aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with transcription factor Gli2. Overexpression of ALDH1A1 increased Gli2 protein levels; in contrast, ALDH1A1 depletion facilitated Gli2 degradation. In addition, Gli2 mRNA expression was not affected by ectopic expression of ALDH1A1, indicating the role of ALDH1A1 in the stabilization of Gli2. Further investigation showed that ALDH1A1 prolonged the stability of Gli2 protein in a catalytic-independent manner. Finally, we showed that overexpression of ALDH1A1 activated the Hh signaling pathway and promoted cell growth, migration and invasion in hepatocellular cancer cells. Together, these results illustrate regulatory roles of ALDH1A1 in the activation of the Hh signaling pathway and highlight a novel mechanism for the aberrant activation of the Hh signaling pathway in hepatocellular cancer cells.