Nanoemulsions in Translational Research—Opportunities and Challenges in Targeted Cancer Therapy

Nanoemulsion dosage form serves as a vehicle for the delivery of active pharmaceutical ingredients and has attracted great attention in drug delivery and pharmacotherapy. In particular, nanoemulsions act as an excellent vehicle for poorly aqueous soluble drugs, which are otherwise difficult to formulate in conventional dosage forms. Nanoemulsions are submicron emulsions composed of generally regarded as safe grade excipients. Particle size at the nanoscale and larger surface area lead to some very interesting physical properties that can be exploited to overcome anatomical and physiological barriers associated in drug delivery to the complex diseases such as cancer. Along these lines, nanoemulsions have been engineered with specific attributes such as size, surface charge, prolonged blood circulation, target specific binding ability, and imaging capability. These attributes can be tuned to assist in delivering drug/imaging agents to the specific site of interest, based on active and passive targeting mechanisms. This review focuses on the current state of nanoemulsions in the translational research and its role in targeted cancer therapy. In addition, the production, physico-chemical characterization, and regulatory aspects of nanoemulsion are addressed.     

Injectable Lipid Emulsions—Advancements,Opportunities and Challenges

Injectable lipid emulsions, for decades, have been clinically used as an energy source for hospitalized patients by providing essential fatty acids and vitamins. Recent interest in utilizing lipid emulsions for delivering lipid soluble therapeutic agents, intravenously, has been continuously growing due to the biocompatible nature of the lipid-based delivery systems. Advancements in the area of novel lipids (olive oil and fish oil) have opened a new area for future clinical application of lipid-based injectable delivery systems that may provide a better safety profile over traditionally used long- and medium-chain triglycerides to critically ill patients. Formulation components and process parameters play critical role in the success of lipid injectable emulsions as drug delivery vehicles and hence need to be well integrated in the formulation development strategies. Physico-chemical properties of active therapeutic agents significantly impact pharmacokinetics and tissue disposition following intravenous administration of drug-containing lipid emulsion and hence need special attention while selecting such delivery vehicles. In summary, this review provides a broad overview of recent advancements in the field of novel lipids, opportunities for intravenous drug delivery, and challenges associated with injectable lipid emulsions.     

Nitrification and degradation of halogenated hydrocarbons—a tenuous balance for ammonia-oxidizing bacteria

The process of nitrification has the potential for the in situ bioremediation of halogenated compounds provided a number of challenges can be overcome. In nitrification, the microbial process where ammonia is oxidized to nitrate, ammonia-oxidizing bacteria (AOB) are key players and are capable of carrying out the biodegradation of recalcitrant halogenated compounds. Through industrial uses, halogenated compounds often find their way into wastewater, contaminating the environment and bodies of water that supply drinking water. In the reclamation of wastewater, halogenated compounds can be degraded by AOB but can also be detrimental to the process of nitrification. This minireview considers the ability of AOB to carry out cometabolism of halogenated compounds and the consequent inhibition of nitrification. Possible cometabolism monitoring methods that were derived from current information about AOB genomes are also discussed. AOB expression microarrays have detected mRNA of genes that are expressed at higher levels during stress and are deemed “sentinel” genes. Promoters of selected “sentinel” genes have been cloned and used to drive the expression of gene-reporter constructs. The latter are being tested as early warning biosensors of cometabolism-induced damage in Nitrosomonas europaea with promising results. These and other biosensors may help to preserve the tenuous balance that exists when nitrification occurs in waste streams containing alternative AOB substrates such as halogenated hydrocarbons.     

Regulation and expression of transgenes in fish—a review

Transgenic fish, owing to a number of advantages which they offer over other species, are proving to be valuable model systems for the study of gene regulation and developmental genetics in addition to being useful targets for the genetic manipulation of commercially important traits. Despite having begun only a decade ago, the production of transgenic fish has become commonplace in a number of laboratories world-wide and considerable progress has been made. In this review, we initially consider the various regulatory elements and coding genes which have been used in fish, and subsequently discuss and compare both the transient and long-term fate and expression patterns of injected DNA sequences in the context of the different factors which are likely to have an effect on the expression of transgenes.     

Challenges and Opportunities： the Expanded Government-led HIV/AIDS Programs in China

HIV/AIDS has posed an increasingly serious issue in China. In recent years,Chinese government has taken further intensified efforts to combat HIV/AIDS with high-level political commitment,supportive policy development,increased financial allocation,large-scale of government-led initiatives,expanded international cooperation and great involvement of non-governmental organizations. Meanwhile gaps and challenges coexist impacting the implementation and the results of national HIV/AIDS programs. Thus,further government efforts are needed to improve and tailor the actions to meet the requirement of HIV/AIDS control in China.     

Regulation of Root Growth by Plant Hormones—Roles for Auxin and Gibberellin

Plant hormones are important biotic factors to regulate root growth. Among the seven kinds of plant hormones, auxin and gibberellin (GA) are strong accelerators of shoot growth, but these are not always accelerators for root growth. The classical views of root-growth regulation by auxin and gibberellin are summarized and current theory of the regulation mechanism is described in this review. The concentration-dependent deceleration of root growth is a key to understanding the auxin action on roots, since the endogenous concentration of indole-3-acetic acid (IAA) is inversely proportional to the growth rate. As massive IAA is transported from shoots to roots by polar transport, the influx speed of IAA mainly controls IAA levels in root cells. The classical view of IAA transport in roots has been supported by recent discoveries of IAA-carrier proteins such as AUX1, PINs and MDRs. The role of plasma membrane-located H⁺-ATPase and its regulation by IAA has also been described for the acid growth phenomenon caused by the acidification of root cell walls.

Compared to auxins, GA functions in roots are less remarkable. Nevertheless, GA also plays an indispensable role in the normal development of roots, since artificial GA-depletion causes abnormal expansion and suppression of root elongation. The GA-requirement for normal root growth was unveiled by the use of chemical inhibitors and mutants of GA biosynthesis. GA function that keeps root morphology long and slender is ascribed to the arrangement of cortical microtubules, cellulose microfibrils and unknown additional factor(s). Cross talks among plant hormones were recently found in the signal transduction pathways mainly in aerial organs. GA and IAA de-repress gene expression by degrading the gene-repressing proteins via the ubiquitin-mediated proteasome system. Another interaction of IAA and GA in growth regulation is the enhancement of GA₁ level by IAA. Since the final biochemical steps of growth regulation take place in cell walls, possible cross talks are also conceivable in cell wall formation and modification.     

Tetracycline-inducible Expression Systems： New Strategies and Practices in the Transgenic Mouse Modeling

To accurately analyze the function of transgene(s)of interest in transgenic mice,and togenerate credible transgenic animal models for multifarious human diseases to precisely mimic human dis-ease states,it is critical to tightly regulate gene expression in the animals in a conditional manner.The abilityto turn gene expression on or off in the restricted cells or tissues at specific time permits unprecedentedflexibility in dissecting gene functions in health and disease.Pioneering studies in conditional transgene ex-pression have brought about the development of a wide variety of controlled gene expression systems,whichmeet this criterion.Among them,the tetracycline-controlled expression systems(e.g.Tet-off system andTet-on system)have been used extensively in vitro and in vivo.In recent years,some strategies derived fromtetracycline-inducible system alone,as well as the combined use of Tet-based systems and Cre/lox P switch-ing gene expression system,have been newly developed to allow more flexibility for exploring gene functionsin health and disease,and produce credible transgenic animal models for various human diseases.In thisreview these newly developed strategies are discussed.     

Evidences for Chlorogenic Acid — A Major Endogenous Polyphenol Involved in Regulation of Ripening and Senescence of Apple Fruit

To learn how the endogenous polyphenols may play a role in fruit ripening and senescence, apple pulp discs were used as a model to study the influences of chlorogenic acid (CHA, a major polyphenol in apple pulp) on fruit ripening and senescence. Apple (‘Golden Delicious’) pulp discs prepared from pre-climacteric fruit were treated with 50 mg L^-1 CHA and incubated in flasks with 10 mM MES buffer (pH 6.0, 11% sorbitol). Compared to the control samples, treatment with CHA significantly reduced ethylene production and respiration rate, and enhanced levels of firmness and soluble solids content of the pulp discs during incubation at 25°C. These results suggested that CHA could retard senescence of the apple pulp discs. Proteomics analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry (MALDI-TOF/TOF) revealed that the expressions of several key proteins correlated to fruit ripening and senescence were affected by the treatment with CHA. Further study showed that treating the pulp discs with CHA remarkably reduced levels of lipoxygenase, β-galactosidase, NADP-malic enzyme, and enzymatic activities of lipoxygenase and UDP-glucose pyrophosphorylase, all of which are known as promoters of fruit ripening and senescence. These results could provide new insights into the functions of endogenous phenolic compounds in fruit ripening and senescence.     

POISON CONTROL—Operation of an Information Center in a Rural and Agricultural Community

The Fresno Community Hospital Poison Control Center has been in operation for about three years, under the sole directorship of the pathologist. All expenses are paid by the hospital. It has served a definite need in the community. As an agricultural and more or less rural community, it shows more poison cases having to do with plants, insecticides, kerosene and fertilizers than do urban communities.     

Medical Product Development, Innovation, and Life-Cycle Regulation: The Challenges for Biostatistics

The article provides a perspective on the challenges for biostatistics as well as on contributions that biostatisticians are making and can make to medical product development and regulation and what the future might be in these areas. The current environment in the United States for pharmaceutical development and regulation is discussed along with the expectations that the public has for how medical products should contribute to public heath. The globalization of research and the use of study designs that incorporate multi-regional populations present new challenges for design and inference. The emerging interest in and development of the science of safety assessment and quantitative approaches to risk evaluation is considered. Guidance development, especially in the area of clinical trials design, continues to be one of the needs that FDA is asked to meet. Guidance development is proceeding for non-inferiority study designs, adaptive designs, multiple endpoints in clinical trials, and missing outcome data in clinical trials. Biostatisticians will be asked and challenged to take on leadership roles in new areas such as personalized medicine, biomarker and genomics, development of new tools for visual display of clinical data, quality assurance and monitoring in clinical trials.     

Immunoglobulin-M purification — Challenges and perspectives

Extensive research in the past two decades has led to the realization of Immunoglobulin-M (IgM) as a potential therapeutic and diagnostic agent. In order to fully exploit the potential of IgM, large quantities, in a highly pure and active form, must be available at low cost for performing clinical trials, characterization studies and quantitative-structure activity analyses. The complex physico–chemical properties, in particular its large size and labile nature renders downstream purification of IgM difficult. This review discusses the limitations and challenges associated with the current IgM purification strategies and proposes future directions for research. The uniqueness of affinity chromatography, specifically biomimetic affinity chromatography for protein purification is highlighted and its potential for IgM purification is discussed.     

The Origin of Patterning Systems in Bilateria——Insights from the Hox and ParaHox Genes in Acoelomorpha

Hox and ParaHox genes constitute two families of developmental regulators that pattern the Anterior-Posterior body axis in all bilaterians.The members of these two groups of genes are usually arranged in genomic clusters and work in a coordinated fashion,both in space and in time. While the mechanistic aspects of their action are relatively well known,it is still unclear how these systems evolved. For instance,we still need a proper model of how the Hox and ParaHox clusters were assembled over time.This problem is due to the shortage of information on gene complements for many taxa (mainly basal metazoans) and the lack of a consensus phylogenetic model of animal relationships to which we can relate our new findings.Recently, several studies have shown that the Acoelomorpha most probably represent the first offshoot of the Bilateria. This finding has prompted us,and others, to study the Hox and ParaHox complements in these animals,as well as their activity during development.In this review,we analyze how the current knowledge of Hox and ParaHox genes in the Acoelomorpha is shaping our view of bilaterian evolution.     

Regulation of mucin secretion and inflammation in asthma: a role for MARCKS protein?

BACKGROUND: A major characteristic of asthmatic airways is an increase in mucin (the glycoprotein component of mucus) producing and secreting cells, which leads to increased mucin release that further clogs constricted airways and contributes markedly to airway obstruction and, in the most severe cases, to status asthmaticus. Asthmatic airways show both a hyperplasia and metaplasia of goblet cells, mucin-producing cells in the epithelium; hyperplasia refers to enhanced numbers of goblet cells in larger airways, while metaplasia refers to the appearance of these cells in smaller airways where they normally are not seen. With the number of mucin-producing and secreting cells increased, there is a coincident hypersecretion of mucin which characterizes asthma. On a cellular level, a major regulator of airway mucin secretion in both in vitro and in vivo studies has been shown to be MARCKS (myristoylated alanine-rich C kinase substrate) protein, a ubiquitous substrate of protein kinase C (PKC). GENERAL SIGNIFICANCE: In this review, properties of MARCKS and how the protein may regulate mucin secretion at a cellular level will be discussed. In addition, the roles of MARCKS in airway inflammation related to both influx of inflammatory cells into the lung and release of granules containing inflammatory mediators by these cells will be explored. This article is part of a Special Issue entitled: Biochemistry of Asthma.