Preparation of an indicator film based on pectin, sodium alginate, and xanthan gum containing blueberry anthocyanin extract and its application in blueberry freshness monitoring.

An active pH-sensitive film based on pectin-sodium alginate-xanthan gum composite film (PAX) was prepared, containing blueberry anthocyanin extract (BAEs), to monitor the freshness of blueberries. The effects of different contents of BAEs on the microstructure and physical properties of intelligent polysaccharide films were comprehensively evaluated. It was found that 75-BAEs-PAX film had a solid response to pH value and showed different and easily distinguishable colors at different pH values. In addition, when the freshness of blueberries stored at different temperatures (-1 °C, 4 °C, 10 °C, 15 °C, 25 °C) was monitored, the color of 75-BAEs-PAX film changed from purple to light pink from neutral to acidic environment, which was consistent with the change of pH value of blueberries from fresh to spoilage. The Arrhenius equation verified that the difference between the activation energy of the indicator film and the blueberry quality was less than 25 kJ/mol. Therefore, the 75-BAEs-PAX film can be used as an indicator film for blueberries freshness monitoring. In this study, the freshness of blueberries was monitored by BAEs, and the purpose of using ontology to monitor ontology was achieved. The freshness of blueberries was visualized during storage and transportation, which could effectively reduce the waste of blueberries. In the future, the method of ontology monitoring ontology could be extended to other foods.

Gefitinib-Tamoxifen Hybrid Ligands as Potent Agents against Triple-Negative Breast Cancer.

Anticancer drug conjugates may benefit from simultaneous action at two targets potentially overcoming the drawbacks of current cancer treatment, such as insufficient efficacy, high toxicity, and development of resistance. Compared to a combination of two single-target drugs, they may offer an advantage of pharmacokinetic simplicity and fewer drug-drug interactions. Here, we report a series of compounds connecting tamoxifen or endoxifen with the EGFR-inhibitor gefitinib via a covalent linkage. These hybrid ligands retain both ER antagonist activity and EGFR inhibition. The most potent analogues exhibited single-digit nanomolar activities at both targets. The amide-linked endoxifen-gefitinib drug conjugates 17b and 17c demonstrated the most favorable anti-cancer profile in cellular viability assays on MCF7, MDA-MB-231, MDA-MB-468, and BT-549 breast cancer cells. Most importantly, in TNBC cells 17b and 17c displayed nanomolar IC50-values (380 nM - 970 nM) and were superior in their anti-cancer activity compared to their control compounds and combinations thereof.

Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor.

Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.

Evolution of Rayleigh-Taylor instability under interface discontinuous acceleration induced by radiation.

Rayleigh-Taylor instability (RTI) under radiation background is commonly found in both engineering applications and natural phenomena. In the optically thin and incompressible limit, the corresponding problem can be simplified as an interface discontinuous acceleration (IDA) RTI problem, but to date has only been studied in the linear stage. In this paper, the entire IDA-RTI evolution was studied numerically and theoretically, particularly for the stages beyond the linear stage. The results show that the IDA-RTI problem is equivalent to the classical RTI with the effective acceleration g_{eff}^{*} that is introduced in this work. Moreover, our studies further show that IDA-RTI can occur if and only if g_{eff}^{*}>0 (from heavy fluid to light fluid). This criterion means that IDA-RTI can occur when (i) heavy fluid supports (or accelerates) the light fluid or (ii) the two fluids have the same density, in contrast to the classical RTI problem. Moreover, the quasisteady bubble and spike velocities are theoretically predicted with quantitative accuracy, showing good agreement with the results of numerical simulations in a wide range of density ratios and acceleration configurations.

Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition.

BACKGROUND: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms. METHODS: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry. RESULTS: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial-mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment. CONCLUSION: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways. Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC.

Correction: Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor.

[This corrects the article DOI: 10.18632/oncotarget.5221.].

p62 in Liver Disease: Good Guy or Bad Guy?

The multidomain adaptor protein p62 has been suggested to exert pro-oncogenic functions in hepatocytes and other epithelial cells. In this issue of Cancer Cell, Duran et al. show that p62 acts as a non-cell-autonomous tumor suppressor in liver cancer by counteracting the activation of hepatic stellate cells.

Lattice Boltzmann method for convection-diffusion equations with general interfacial conditions.

In this work, we propose an interfacial scheme accompanying the lattice Boltzmann method for convection-diffusion equations with general interfacial conditions, including conjugate conditions with or without jumps in heat and mass transfer, continuity of macroscopic variables and normal fluxes in ion diffusion in porous media with different porosity, and the Kapitza resistance in heat transfer. The construction of this scheme is based on our boundary schemes [Huang and Yong, J. Comput. Phys. 300, 70 (2015)JCTPAH0021-999110.1016/j.jcp.2015.07.045] for Robin boundary conditions on straight or curved boundaries. It gives second-order accuracy for straight interfaces and first-order accuracy for curved ones. In addition, the new scheme inherits the advantage of the boundary schemes in which only the current lattice nodes are involved. Such an interfacial scheme is highly desirable for problems with complex geometries or in porous media. The interfacial scheme is numerically validated with several examples. The results show the utility of the constructed scheme and very well support our theoretical predications.

Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor.

HER2, a well established oncogenic member of EGFR family, is among the most intensely investigated kinase drug targets. In contrast to hotspot mutations of EGFR, few mutations of HER2 locate in activation loop within kinase domain. We previously reported the molecular mechanism underlying hyper kinase activity of HER2H878Y, a mutation located in activation loop. However, its tumorigenicity in vivo and relevant therapeutics remain to be determined. Here, we report for the first time that HER2H878Y was tumorigenic in vivo in lung adenocarcinoma transgenic mouse model. Induced expression of HER2H878Y in lung epithelial compartments resulted in formation of poorly differentiated lung adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. Strikingly, we found that these tumors depended on continuous expression of HER2H878Y for maintenance. Typical HER2 downstream signaling mediators, including PLCγ1, STAT5 and AKT, were hyperactivated in HER2H878Y driven lung tumors. More importantly, administration of HKI-272, a tyrosine kinase inhibitor (TKI), efficiently shrank HER2H878Y driven tumors in transgenic mouse model. Moreover, we found that combinational treatment with HKI272 and mTOR inhibitor, Rapamycin, showed a superior cytotoxicity to H878Y mutant transformed cells and enhanced activity to elicit apoptosis and inhibit growth in situ in tumorous area. Our work therefore showed that HER2H878Y mutant was a reasonable drug target. Hence, our work supported the assessment of HKI-272/rapamycin treatment in clinical trials.

Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity.

Amplification, overexpression, and somatic mutation of the HER2 gene have been reported to play a critical role in tumorigenesis of various cancers. The HER2 H878Y mutation was recently reported in 11% of hepatocellular carcinoma (HCC) patients. However, its functional impact on the HER2 protein and its role in tumorigenesis has not been determined. Here, we show that HER2 H878Y is a gain-of-function mutation. Y878 represents a phosphorylation site, and phospho-Y878 interacts with R898 residue to stabilize the active conformation of HER2, thereby enhancing its kinase activity. H878Y mutant is transforming and the transformed cells are sensitive to HER2 kinase inhibitors. Thus, our study reveals the following novel mechanism underlying the tumorigenic function of the HER2 H878Y mutation: the introduction of a tyrosine residue into the kinase activation loop via mutagenesis modulates the conformation of the kinase, thereby enhancing its activity.

Regulation of splicing enhancer activities by RNA secondary structures.

In this report, we studied the effect of RNA structures on the activity of exonic splicing enhancers on the SMN1 minigene model by engineering known ESEs into different positions of stable hairpins. We found that as short as 7-bp stem is sufficient to abolish the enhancer activity. When placing ESEs in the loop region, AG-rich ESEs are fully active, but a UCG-rich ESE is not because of additional structural constraints. ESEs placed adjacent to the 3' end of the hairpin structure display high enhancer activity, regardless of their sequence identities. These rules explain the suppression of multiple ESEs by point mutations that result in a stable RNA structure, and provide an additional mechanism for the C6T mutation in SMN2.

Effects of insulin resistance and insulin secretion on the efficacy of interventions to retard development of type 2 diabetes mellitus: the DA Qing IGT and Diabetes Study.

OBJECTIVE: To investigate the effects of insulin resistance (IR) and insulin secretion (IS) on the development of diabetes mellitus in individuals with impaired glucose tolerance (IGT) who underwent lifestyle interventions. METHODS: 284 out of 577 individuals with IGT identified by population-based screening in Da Qing, China, who were randomized to undergo diet change and/or increased physical activity had baseline fasting and 2 h post-load insulin determinations. They were followed for 6 years for the development of diabetes. IR and IS were assessed using calculated indices based on fasting plasma insulin and glucose. The interactions of IR, IS, obesity and plasma glucose and the effects of the lifestyle interventions were evaluated using Cox Proportional Hazards analysis. RESULTS: Both IR and IS were significantly associated with the development of diabetes. Lifestyle interventions were more effective in those with lower IT and higher IS at baseline. Diet plus exercise interventions resulted in significantly lower incidence of diabetes, even after controlling for IR, IS, BMI and 2hrPG. CONCLUSION: Both IR and beta-cell function were predictors of diabetes in Chinese with IGT. Lifestyle intervention reduced the incidence of DM and these interventions were more effective in those with less IR.

[Compensated hyperinsulinemia based on selective insulin resistance predicts elevation of blood pressure in non-diabetic adults].

OBJECTIVES: To investigate if hyperinsulinemia or insulin resistance could predict the elevation of blood pressure in non-diabetic adults. METHODS: One hundred and seventy non-diabetic adults (NGT 107, IGT 63) were included based on the screen by OGTT in 1986. Height, weight, blood pressure were measured. Plasma glucose and insulin concentration at 0.60 and 120 min during OGTT were determined at baseline. All the subjects were followed for six years with blood pressure and plasma glucose examined at the end of the study. Subjects worsening to diabetes were excluded. Insulin area under-curve (INSAUC) and insulin sensitivity index [IAI = (1/FINS x FPG)] were calculated. Stepwise regression analysis was performed to evaluate the effects of INSAUC and insulin sensitivity to the elevation of blood pressure. RESULTS: Both SBP and DBP levels at the end of the study were increased with increased INSAUC baseline. The SBP were (119.5 +/- 2.3), (122.1 +/- 2.5), (129.4 +/- 2.4) and (128.3 +/- 2.6) mmHg, and the DBP were (78.6 +/- 1.6), (79.7 +/- 1.7), (85.2 +/- 1.4) and (84.0 +/- 1.0) mmHg from the lowest to the highest quartiles of INSAUC respectively. Pearson correlation analysis showed Age, SBP, DBP, BMI, FINS, INS1h, INSAUC at baseline were positively correlated to blood pressure levels at the end of the study. After the adjustment of Age, sex, BMI, smoking, PG2 h and blood pressure at baseline, the INSAUC was significantly correlated to blood pressure six years later, while the insulin sensitivity index was not. CONCLUSION: The compensated hyperinsulinemia based on selective insulin resistance rather than insulin resistance to glucose per se could predict the elevation of blood pressure in nondiabetic adults.