Clostridium novyi-NT in cancer therapy

AbstractThe attenuated anaerobic bacterium Clostridium novyi-NT (C. novyi-NT) is known for its ability to precisely germinate in and eradicate treatment-resistant hypoxic tumors in various experimental animal models and spontaneously occurring canine sarcomas. In this article, we review the therapeutic and toxicologic aspects of C. novyi-NT therapy, key challenges and limitations, and promising strategies to optimize its performance via recombinant DNA technology and immunotherapeutic approaches, to establish C. novyi-NT as an essential tool in cancer therapy

Adaptive Robust Guidance Scheme Based on the Sliding Mode Control in an Aircraft Pursuit-Evasion Problem

In this chapter, a robust guidance scheme utilizing a line-of-sight (LOS) observation is presented. Initial relative speed and distance, and error boundaries of them are estimated in accordance with the interceptor-target relative motion kinematics. A robust guidance scheme based on the sliding mode control (SMC) is developed, which requires the boundaries of the target maneuver, and inevitably has jitter phenomenon. For solving above-mentioned problems, an estimation to the target acceleration’s boundary is developed for enhancing robustness of the guidance scheme and the Lyapunov stabilization is analyzed. The proposed robust guidance scheme’s brief characteristic is to reduce the effect of relative speed and distance, to reduce the effect of target maneuverability on the guidance precision, and to strengthen the influence of line-of-sight angular velocity. The proposed scheme’s performances are validated by the simulations of different target maneuvers under two worst-case conditions

A Max-relevance-min-divergence Criterion for Data Discretization with Applications on Naive Bayes

In many classification models, data is discretized to better estimate its distribution. Existing discretization methods often target at maximizing the discriminant power of discretized data, while overlooking the fact that the primary target of data discretization in classification is to improve the generalization performance. As a result, the data tend to be over-split into many small bins since the data without discretization retain the maximal discriminant information. Thus, we propose a Max-Dependency-Min-Divergence (MDmD) criterion that maximizes both the discriminant information and generalization ability of the discretized data. More specifically, the Max-Dependency criterion maximizes the statistical dependency between the discretized data and the classification variable while the Min-Divergence criterion explicitly minimizes the JS-divergence between the training data and the validation data for a given discretization scheme. The proposed MDmD criterion is technically appealing, but it is difficult to reliably estimate the high-order joint distributions of attributes and the classification variable. We hence further propose a more practical solution, Max-Relevance-Min-Divergence (MRmD) discretization scheme, where each attribute is discretized separately, by simultaneously maximizing the discriminant information and the generalization ability of the discretized data. The proposed MRmD is compared with the state-of-the-art discretization algorithms under the naive Bayes classification framework on 45 machine-learning benchmark datasets. It significantly outperforms all the compared methods on most of the datasets.Comment: Under major revision of Pattern Recognitio

Dynamics of delay induced composite multi-scroll attractor and its application in encryption

This work was supported in part by NSFC (60804040, 61172070), Key Program of Nature Science Foundation of Shaanxi Province (2016ZDJC-01), Innovative Research Team of Shaanxi Province(2013KCT-04), Fok Ying Tong Education Foundation Young Teacher Foundation(111065), Chao Bai was supported by Excellent Ph.D. research fund (310-252071603) at XAUT.Peer reviewedPostprin

Herbal carrier-based floating microparticles of diltiazem hydrochloride for improved cardiac activity

Purpose: To formulate and characterize a gastroretentive floating drug delivery system for diltiazem hydrochloride using psyllium husk and sodium alginate as natural herbal carriers to improve the therapeutic effect of the drug in cardiac patients.Methods: Floating microparticles containing diltiazem hydrochloride were prepared by the orifice ionic gelation technique. Various physicochemical properties of the floating microspheres were characterized, including drug content, particle size, surface morphology, in vitro drug release, and in vivo antihypertensive effect.Results: The diltiazem hydrochloride microparticles exhibited a high drug content ranging from 63.23 ± 1.14 to 85.56 % ± 1.14 %. The particle size was 891.40 ± 2.14, 928.40 ± 1.79, 900.65 ± 2.22, and 1345.40 ± 1.36 μm (p < 0.05 compared to blank microspheres for formulations FDD1, FDD2, FDD3, and FFD4), respectively. Scanning electron microscopy showed that all the formulations had a smooth spherical surface with little pores and few cracks. The maximum floatability value was 83.11 % ± 3.18 % for FDD1. All of the formulations showed good in vitro drug release profiles, with a maximum release of 87.4 % of the drug at the end of 12 hours. The in vivo antihypertensive effects of the microparticles in human subjects were significant (p < 0.05 compared to normal controls), with a reduction in diastolic blood pressure from 120 to 78 mmHg at the end of 4 hours compared to diltiazem sustained-release tablets.Conclusion: Psyllium husk and sodium alginate-based microspheres can be suitably prepared for the controlled delivery of diltiazem hydrochloride to cardiac patients. However, further study is required to develop the delivery system.Keywords: Diltiazem, Cardiac disease, Psyllium husk, Sodium alginate, Microsphere, Microparticle, Controlled drug release, Gastroretentive, Floating drug deliver

M2-like macrophages in the fibrotic liver protect mice against lethal insults through conferring apoptosis resistance to hepatocytes.

Acute injury in the setting of liver fibrosis is an interesting and still unsettled issue. Most recently, several prominent studies have indicated the favourable effects of liver fibrosis against acute insults. Nevertheless, the underlying mechanisms governing this hepatoprotection remain obscure. In the present study, we hypothesized that macrophages and their M1/M2 activation critically involve in the hepatoprotection conferred by liver fibrosis. Our findings demonstrated that liver fibrosis manifested a beneficial role for host survival and apoptosis resistance. Hepatoprotection in the fibrotic liver was tightly related to innate immune tolerance. Macrophages undertook crucial but divergent roles in homeostasis and fibrosis: depleting macrophages in control mice protected from acute insult; conversely, depleting macrophages in fibrotic liver weakened the hepatoprotection and gave rise to exacerbated liver injury upon insult. The contradictory effects of macrophages can be ascribed, to a great extent, to the heterogeneity in macrophage activation. Macrophages in fibrotic mice exhibited M2-preponderant activation, which was not the case in acutely injured liver. Adoptive transfer of M2-like macrophages conferred control mice conspicuous protection against insult. In vitro, M2-polarized macrophages protected hepatocytes against apoptosis. Together, M2-like macrophages in fibrotic liver exert the protective effects against lethal insults through conferring apoptosis resistance to hepatocytes

Preparation and analysis of a new bioorganic metallic material

Biofouling on metal surfaces is one of the main reasons for increased ship drag. Many methods have already been used to reduce or remove it with moderate success. In this study, a synthetic peptide has been utilized to react with 304 stainless steel aiming to generate a bioorganic stainless steel using a facile technique. After the reaction, white matter was found on the surface of the treated stainless steel via SEM, whilst the nontreated stainless steel had none. Elemental analysis confirmed that excessive N existed on the surface of the treated samples using an integrated SEM-EDS instrument, implying the presence of peptides binding on the surface of the bioorganic stainless steel. The FTIR spectra showed amide A and II peaks on the surface of the bioorganic stainless steel suggesting that either the peptides grafted onto the steel surface or the polypeptide composition accumulated on the steel samples. XPS analysis of the treated steel demonstrated that there was nitrogen bonding on the surface and it was a chemical bond via a previously unreported chemical interaction. The treated steel has a markedly increased contact angle (water contact angle of 65.7 ± 4.7° for nontreated steel in comparison to treated, 96.4 ± 2.1°), which supported the observation of the wettability change of the surface, i.e. the decrease of the surface energy value after peptide treatment. The changes of the surface parameters (such as, Sa, Sq, Ssk and Sku) of the treated steel by surface analysis were observed

Proteomics profiling asthma induced-lysine acetylation

Asthma is a chronic inflammatory disease that has been extensively studied for many years. However, finding a complete cure remains a significant challenge. Protein acetylation, especially histone acetylation, plays a significant role in the anti-asthma process. Histone deacetylation inhibitors (HDACi) have been shown to have a curative effect on asthma in clinical practice. An asthmatic mouse model was created by ovalbumin induction. Proteome and acetylproteome analysis were performed on lung tissues. HDACi were tested in the asthmatic mice. A total of 5346 proteins and 581 acetylation sites were identified, among which 154 proteins and 68 acetylation peptides were significantly altered by asthma. Many activated and deactivated processes, pathways, and protein groups were identified through bioinformatics analysis. Sequence motif preference analysis gave rise to a novel Kac-related core histone region, -KAXXK-, which was postulated as a key regulatory unit of histone acetylation. Asthma involves a variety of proteome dynamics and is controlled by protein lysine acetylation through the core motif -KAXXK-. These findings provide novel avenues to target and treat asthma

Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors

Neurofibromatosis type 1, including the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), is featured by the loss of functional neurofibromin 1 (NF1) protein resulting from genetic alterations. A major function of NF1 is suppressing Ras activities, which is conveyed by an intrinsic GTPase-activating protein-related domain (GRD). In this study, we explored the feasibility of restoring Ras GTPase via exogenous expression of various GRD constructs, via gene delivery using a panel of adeno-associated virus (AAV) vectors in MPNST and human Schwann cells (HSCs). We demonstrated that several AAV serotypes achieved favorable transduction efficacies in those cells and a membrane-targeting GRD fused with an H-Ras C-terminal motif (C10) dramatically inhibited the Ras pathway and MPNST cells in a NF1-specific manner. Our results opened up a venue of gene replacement therapy in NF1-related tumors

NIPA Defines an SCF-Type Mammalian E3 Ligase that Regulates Mitotic Entry

SummaryThe regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-box subunit of the SCF specifically recruiting a given substrate to the SCF core. Here we identify NIPA (nuclear interaction partner of ALK) as a human F-box-containing protein that defines an SCF-type E3 ligase (SCFNIPA) controlling mitotic entry. Assembly of this SCF complex is regulated by cell-cycle-dependent phosphorylation of NIPA, which restricts substrate ubiquitination activity to interphase. We show nuclear cyclin B1 to be a substrate of SCFNIPA. Inactivation of NIPA by RNAi results in nuclear accumulation of cyclin B1 in interphase, activation of cyclin B1-Cdk1 kinase activity, and premature mitotic entry. Thus, SCFNIPA-based ubiquitination may regulate S-phase completion and mitotic entry in the mammalian cell cycle