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Despite abundant evidence implicating receptor tyrosine kinases (RTK), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR-regulated pathway to targeted tyrosine kinase inhibitors, we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition. We found that tumors resistant to PDGFR inhibition required the expression and activation of the insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) for tumor cell proliferation and survival. Cotargeting IR/IGF1R and PDGFR decreased the emergence of resistant clones in vitro. Our findings characterize a novel model of glioma recurrence that implicates the IR/IGF1R signaling axis in mediating the development of resistance to PDGFR inhibition and provide evidence that IR/IGF1R signaling is important in the recurrence of the proneural subtype of glioma in which PDGF/PDGFR is most commonly expressed at a high level. Mol Cancer Ther; 16(4); 705–16. ©2017 AACR.

This paper studies the problem of global asymptotic stabilization for a class of upper-triangular systems with large delays in the state and input. Using the idea of feedback domination, we develop a Lyapunov-Krasovskii method for the design of time-invariant, memoryless linear state and output feedback controllers, achieving global asymptotic stabilization of the closed-loop systems under a linear growth condition. The resulting controllers are different from predictor-based or delay-dependent controllers in the sense that they are delay-free and easier to be implemented due to the nature of “memoryless” feedback. Two examples are presented to demonstrate the effectiveness of the proposed delay-free state and output feedback control strategies.

An otherwise healthy 24-year-old man presented with 1 week of fever, facial pain and swelling. He initially sought care at an outside hospital, where he was diagnosed with folliculitis and sent home with oral antibiotics. On arrival at our institution, CT neck was ordered, which demonstrated diffuse submental phlegmon, prompting incision and drainage. After initial improvement, the patient experienced high fevers and increased swelling just 12 hours later. The decision was made to take the patient for operative exploration, and wide debridement was performed due to suspicion for necrotising fasciitis intraoperatively that was ultimately confirmed on final pathology. Final speciation of intraoperative culture demonstrated a clindamycin-resistant and methicillin-resistant strain of Staphylococcus aureus. The patient was managed with intravenous antibiotics, additional debridement and careful wound care. Delayed partial closure of wound was eventually performed once patient showed marked and persistent clinical improvement. The patient was discharged on hospital day 12 with close follow-up.

(E)-Methyl-4-aryl-4-oxabut-2-enoate, designated YH-8, is a novel Serflhr protein kinase B (PknB) inhibitor, which is designed for the treatment of tuberculosis. The aim of this study was to investigate the pharmacokinetics, bioavailability, tissue distribution and excretion characteristics of YH-8 in rats and study its plasma protein binding in vitro. The pharmacokinetic properties were examined after intravenously injected YH-8 at 10 and 20 mg/kg and oral administrated YH-8 at 50, 100 and 200 mg/kg to rats. The concentrations of YH-8 in plasma were determined with LC-MS/MS, with a liquid-liquid extraction. The tissue distribution and urinary, fecal and -biliary excretion patterns of YH-8 were investigated following a single oral dosing of 100 mg/kg. The plasma protein binding rates of YH-8 were determined using ultra-filtration method. After intra- venous and oral administration, YH-8 showed dose-independent pharmacokinetic characteristics, with T(1/2) of approximately 5.5 h and 7.1 h, respectively. The oral absolute bioavailability of YH-8 was relatively low (about 12%). YH-8 was widely distributed in various tissues and showed substantial deposition in intestine, stomach, liver, lung and kidney. The drug was mainly eliminated via fecal excretion and its binding rate with plasma protein was concentration-dependent. In conclusion, this study as first provided the full pharmacokinetic characteristics of YH-8, which would be helpful for its further development and clinical application.

SUMMARY This paper considers the problem of output feedback stabilization for a class of stochastic feedforward nonlinear systems with input and state delay. Under a set of coordinate transformations, we first design a linear output feedback controller for a nominal system. Then, with the aid of feedback domination technique and an appropriate Lyapunov–Krasovskii functional, it is proved that the proposed linear output feedback controller can drive the closed-loop system globally asymptotically stable in probability. Copyright © 2015 John Wiley & Sons, Ltd.

Due to the extreme inaccessibility of fetal human inner ear tissue, defining of the microRNAs (miRNAs) that regulate development of the inner ear has relied on animal tissue. In the present study, we performed the first miRNA sequencing of otic precursors in human specimens. Using HTG miRNA Whole Transcriptome assays, we examined miRNA expression in the cochleovestibular ganglion (CVG), neural crest (NC), and otic vesicle (OV) from paraffin embedded (FFPE) human specimens in the Carnegie developmental stages 13-15. We found that in human embryonic tissues, there are different patterns of miRNA expression in the CVG, NC and OV. In particular, members of the miR-183 family (miR-96, miR-182, and miR-183) are differentially expressed in the CVG compared to NC and OV at Carnegie developmental stage 13. We further identified transcription factors that are differentially targeted in the CVG compared to the other tissues from stages 13-15, and we performed gene set enrichment analyses to determine differentially regulated pathways that are relevant to CVG development in humans. These findings not only provide insight into the mechanisms governing the development of the human inner ear, but also identify potential signaling pathways for promoting regeneration of the spiral ganglion and other components of the inner ear.

This paper considers the problem of output feedback stabilization of a class of stochastic nonlinear systems with time-varying delay. With the aid of feedback domination technique and the Razumikhin-type theorem, an output feedback controller is designed to drive the closed-loop system globally asymptotically stable in mean square. The main contributions are two folds: 1) Remove the slowly varying assumption on time-varying delay, which is frequently used in dealing with system with time-varying delay. 2) Construct a quadratic Lyapunov function, and present an easy way to deal with Hessian term.

In the application scenario of smart city, there exist many portable mobile devices that communicate in Wi-Fi technique, so communication conflicts among them are unavoidable and lead to low network performance and high energy consumption. To address this problem, this paper studies the optimization method of spatial reuse based on dynamic control of transmit power. Considering the metric of spatial reuse factor, this paper explores how to select the proper transmission radius and power to decrease the adverse effects from the hidden terminals and the exposed terminals. By setting the frame control field in the MAC layer frame according to the received signal strength, the method can adaptively adjust the transmission power of the communication nodes pair to maintain the reception power in the appropriate range. Through the simulation experiment in NS-2, the feasibility and effect of the optimization method for spatial reuse and energy saving are verified.

In this paper, the problem of state feedback stabilization for stochastic feedforward nonlinear systems with input time-delay is considered for the first time. By introducing a variable transformation, skillfully combining the homogeneous domination method, and constructing an appropriate Lyapunov-Krasovskii functional, a state feedback controller is developed to guarantee the closed-loop system globally asymptotically stable in probability.

For a class of stochastic high-order nonlinear systems, by introducing the combined homogeneous domination and sign function design approach, this technical note solves the problem of output-feedback control under the weaker high-order and nonlinear growth conditions.

Maturation defects occurring in adult tissue progenitor cells have the potential to contribute to tumor development; however, there is little experimental evidence implicating this cellular mechanism in the pathogenesis of solid tumors. Inhibitor of DNA-binding 2 (Id2) is a transcription factor known to regulate the proliferation and differentiation of primitive stem and progenitor cells. Id2 is derepressed in adult tissue neural stem cells (NSC) lacking the tumor suppressor Tp53 and modulates their proliferation. Constitutive expression of Id2 in differentiating NSCs resulted in maturation-resistant oligodendroglial precursor cells (OPC), a cell population implicated in the initiation of glioma. Mechanistically, Id2 overexpression was associated with inhibition of the Notch effector Hey1, a bHLH transcription factor that we here characterize as a direct transcriptional repressor of the oligodendroglial lineage determinant Olig2. Orthotopic inoculation of NSCs with enhanced Id2 expression into brains of mice engineered to express platelet-derived growth factor in the central nervous system resulted in glioma. These data implicate a mechanism of altered NSC differentiation in glioma development and characterize a novel mouse model that reflects key characteristics of the recently described proneural subtype of glioblastoma multiforme. Such findings support the emerging concept that the cellular and molecular characteristics of tumor cells are linked to the transformation of distinct subsets of adult tissue progenitors. Cancer Res; 74(6); 1822–32. ©2014 AACR.

In this paper, a combined homogeneous domination and sign function design approach is presented to state feedback control for a class of stochastic high-order nonlinear systems with time-varying delay. The use of the combined approach relaxes the restriction on nonlinear functions and makes the closed-loop system globally asymptotically stable in probability.

The differences in glucose metabolism that distinguish most malignant and normal tissues have called attention to the importance of understanding the molecular mechanisms by which tumor energy metabolism is regulated. Receptor tyrosine kinase (RTK) pathways that are implicated in proliferation and transformation have been linked to several aspects of tumor glucose metabolism. However, the regulation of glycolysis has invariably been examined under conditions in which proliferation is concomitantly altered. To determine whether RTKs directly regulate glycolysis without prerequisite growth modulation, we first identified a specific RTK signaling pathway, platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) that regulates glycolysis in glioma-derived tumor stem-like cells from a novel mouse model. We determined that PDGF-regulated glycolysis occurs independent of PDGF-regulated proliferation but requires the activation of AKT, a known metabolic regulator in tumor. Our findings identifying a key characteristic of brain tumors, aerobic glycolysis, mediated by a pathway with multiple therapeutic targets suggests the possibility of inhibiting tumor energy metabolism while also treating with agents that target other pathways of pathologic significance. Cancer Res; 73(6); 1831–43. ©2013 AACR.

This technical note further investigates more general stochastic nonlinear systems with stochastic integral input-to-state stability (SiISS) inverse dynamics and focuses on solving the following problems: 1) a class of counterexamples which are different from that in are reconstructed to discuss the relationship between two small-gain type conditions on SiISS and 2) under the weaker conditions on nonlinearities, based on a reduced-order observer, small-gain type condition on SiISS and stochastic LaSalle theorem, an output feedback controller is constructed to guarantee the global asymptotical stability in probability of the closed-loop stochastic system.

TACC3, a member of the transforming acidic coiled-coil protein (TACC) family, is a multifunctional protein that is involved in various biological functions, including proliferation and differentiation of tumor cells, cancer progression and metastasis. The aims of the present study were to examine whether TACC3 expression is associated with the proliferation and migration of osteosarcoma (OS) cells and to investigate the potential underlying molecular mechanisms of TACC3 in OS. First, the levels of mRNA and protein expression in OS cell lines by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively were examined. Second, the effects of TACC3 knockdown and overexpression on the proliferative, migratory and invasive capacities of OS cells were investigated. Finally, western blot analysis was employed to detect the potential mechanism of TACC3 in osteosarcoma. TACC3 expression was significantly increased in osteosarcoma tissues and cell lines, compared to matched controls. The knockdown of TACC3 was able to significantly inhibit the proliferation, migration and invasion of osteosarcoma cells, whereas the overexpression of TACC3 was able to promote cell proliferation and migration. Mechanistically, TACC3 may promote the migration and invasion of osteosarcoma cells via through nuclear factor-κB signaling. These data suggest that TACC3 has an important part in the progression of osteosarcoma and may serve as a potential target for gene therapy.

To establish a multi-pretreatment method for the determination of aflatoxin B1, B2, G1, G2 in Chinese patent medicines, aflatoxins were analyzed by high performance liquid chromatography-fluorescence detector with post-column derivatization, after the multi-pretreatment of samples. The results showed that after the samples extracted with MeOH-H2O, dehydrated by anhydrous magnesium sulphate and sodium chloride, and finally purified by neutral alumina, the impurity interference of different sources in Chinese patent medicines matrix can be effectively removed, and the main peak can be nicely separated from the impurity peak. The detection limits were 0.25, 0.25, 0.50, 0.25 μg x L(-1) for AFB1, AFB2, AFG1, AFG2, respectively. The quantification limits were 1.00, 0.50, 1.00, 0.50 μg x L(-1), respectively. Aflatoxin B1, G1 showed a good linear relationship at a range of 1.0-50 μg x L(-1), aflatoxin B2, G2 at a range of 0.5-12.5 μg x L(-1) (R20.99). The average recovery was 80.40% - 108.6%. The present method is simple, reproducible with the reasonable recoveries and can be applied for the determination of aflatoxins in Chinese patent medicines.

This paper further discusses output-feedback regulation for more general nonlinear systems with integral input-to-state stability (iISS) inverse dynamics and unknown control direction. By using the adaptive backstepping method, an output feedback controller is given to drive the output to the origin while maintaining other closed-loop signals bounded.

An intumescent flame retardant (IFR), pentaerytheritol phosphate ester melamine salt (PPEM) was synthesized and chemically modified by magnesium oxide (MgO) or/and calcium oxide (CaO), respectively. The fire retardant efficiency of MgO and CaO as synergistic agents in polypropylene (PP) was evaluated by normal fire testing methods. The results showed that MgO and CaO exhibited a synergistic effect on fire retardancy of PP. The addition of 0.2% of MgO or CaO into PP/PPEM composite could decrease the self-extinguishing time and improve the limited oxygen index (LOI) obviously. The cone calorimeter (CONE) tests and the thermal analysis revealed that the introduction of MgO and CaO neutralized the acidity of PPEM, which leads to a thermal stabilization and a delay of the intumescent process of the system, and promote the formation of a high quality charred layer which can prevent PP from decomposing. Thus, a suitable amount of MgO and CaO acts as a synergistic agent in the flame-retarded PP/PPEM system. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

This paper further considers more general high-order stochastic nonlinear system driven by noise of unknown covariance and its adaptive state-feedback stabilization problem. A smooth state-feedback controller is designed to guarantee that the origin of the closed-loop system is globally stable in probability.

Glioblastoma is a highly malignant brain tumor that relentlessly defies therapy. Efforts over the past decade have begun to tease out the biochemical details that lead to its aggressive behavior and poor prognosis. There is hope that this new understanding will lead to improved treatment strategies for patients with glioblastoma, in the form of targeted, molecularly based therapies that are individualized to specific changes in individual tumors. However, these new therapies have the potential to fundamentally alter the biologic behavior of glioblastoma and, as a result, its imaging appearance. Knowledge about common genetic alterations and the resultant cellular and tissue changes (ie, induced angiogenesis and abnormal cell survival, proliferation, and invasion) in glioblastomas is important as a basis for understanding imaging findings before treatment. It is equally critical that radiologists understand which genetic pathway is targeted by each specific therapeutic agent or class of agents in order to accurately interpret changes in the imaging appearances of treated tumors.

An otherwise healthy 24-year-old man presented with 1 week of fever, facial pain and swelling. He initially sought care at an outside hospital, where he was diagnosed with folliculitis and sent home with oral antibiotics. On arrival at our institution, CT neck was ordered, which demonstrated diffuse submental phlegmon, prompting incision and drainage. After initial improvement, the patient experienced high fevers and increased swelling just 12 hours later. The decision was made to take the patient for operative exploration, and wide debridement was performed due to suspicion for necrotising fasciitis intraoperatively that was ultimately confirmed on final pathology. Final speciation of intraoperative culture demonstrated a clindamycin-resistant and methicillin-resistant strain of Staphylococcus aureus. The patient was managed with intravenous antibiotics, additional debridement and careful wound care. Delayed partial closure of wound was eventually performed once patient showed marked and persistent clinical improvement. The patient was discharged on hospital day 12 with close follow-up.

Inhibitor of DNA binding 4 (ID4) is a helix-loop-helix protein that heterodimerizes with basic helix-loop-helix transcription factors inhibiting their function. ID4 expression is important for adipogenic differentiation of the 3T3-L1 cell line, and inhibition of ID4 is associated with a concomitant decrease in CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma mRNA and protein expression. Mice with a homozygous deletion of Id4 (Id4(-/-)) have reduced body fat and gain much less weight compared with wild-type littermates when placed on diets with high fat content. Mouse embryonic fibroblasts (MEFs) isolated from Id4(-/-) mice have reduced adipogenic potential when compared with wild-type MEFs. In agreement with changes in morphological differentiation, the levels of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma were also reduced in MEFs from Id4(-/-) mice. Our results demonstrate the importance of ID4 in adipocyte differentiation and the implications of this regulation for adipose tissue formation.

To establish an EDTA complexation extraction pretreatment combining with GFAAS method for the determination of residual aluminium ion in Huoxiang zhengqi pellets without digestive treatment, systematical investigation was made on sample preparation, and EDTA was used for the complexation extraction of residual aluminium ion in samples. The pH, concentration and volume of extraction solution, the temperature and time of microwave extraction, and graphite furnace temperature program were investigated. The results were compared with the microwave digestion. It was showed that, 0.1 g of sample weight was added in 20 mL 0.05 mol x L(-1) EDTA solution (pH 3.5), followed by heating at 150 degrees C for 10 min in the microwave extraction device. The determination of GFAAS was performed at optimized detection wavelength (257.4 nm) as well as graphite furnace temperature program, the detection limits and quantification limits were 2.37 μg x L(-1) and 7.89 μg x L(-1), respectively. The precision (RSD) was less than 2.3%. The average recovery was 96.9% -101%. The present method is easy, rapid and accurate for the determination of residual aluminium ion in Huoxiang zhengqi pellets.

Several lines of evidence show that the nephrotoxic effect of melamine (MEL) in animals is consistent with combined ingestion of MEL and cyanuric acid (CYA). The aim of the present study was to compare the toxicokinetics of MEL in the presence and absence of CYA, and to elucidate the correlation between toxicity and kinetic properties of MEL. Sprague-Dawley rats were administered a single oral dose of MEL (100 mg kg(-1) ) with or without CYA (100 mg kg(-1) ). Plasma and tissue samples were analyzed by liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay. Significant changes in toxicokinetic parameters of MEL such as lower maximum concentration (7.4 ± 3.5 vs 78.0 ± 11.0 µg ml(-1) ) and area under curve (94.9 ± 53.5 vs 295.1 ± 93.7 µg h ml(-1) ), higher plasma elimination half-life (7.0 ± 3.3 vs 2.5 ± 0.3 h) and volume of distribution (11 505.5 ± 5030.3 vs 1312.7 ± 337.7 ml kg(-1) ), as well as significantly higher concentration of MEL in rat kidney (2.96-274.15 vs 1 µg g(-1) ) were detected in the CYA co-administration group when compared with MEL alone group (P 0.05). The differences in kinetic parameters between the two groups meant that CYA co-administration could lower absorption, slow excretion and induce tissue accumulation of MEL, which correlated well with the generation and development of renal toxicity. In conclusion, co-administration with CYA leads to the alteration of the kinetic characteristics of MEL, which provides an additional explanation for renal toxicity.

The E2f7 and E2f8 family members are thought to function as transcriptional repressors important for the control of cell proliferation. Here, we have analyzed the consequences of inactivating E2f7 and E2f8 in mice and show that their individual loss had no significant effect on development. Their combined ablation, however, resulted in massive apoptosis and dilation of blood vessels, culminating in lethality by embryonic day E11.5. A deficiency in E2f7 and E2f8 led to an increase in E2f1 and p53, as well as in many stress-related genes. Homo- and heterodimers of E2F7 and E2F8 were found on target promoters, including E2f1. Importantly, loss of either E2f1 or p53 suppressed the massive apoptosis in double-mutant embryos. These results identify E2F7 and E2F8 as a unique repressive arm of the E2F transcriptional network that is critical for embryonic development and control of the E2F1-p53 apoptotic axis.