Synthesis and evaluation of folate-based chlorambucil delivery systems for tumor-targeted chemotherapy

The development of tumor-targeting drug delivery systems, able to selectively transport cytotoxic agents into the tumor site by exploiting subtle morphological and physiological differences between healthy and malignant cells, currently stands as one of the most attractive anticancer strategies used to overcome the selectivity problems of conventional chemotherapy. Owing to frequent overexpression of folate receptors (FRs) on the surface of malignant cells, conjugation of cytotoxic agents to folic acid (FA) via suitable linkers have demonstrated to enhance selective drug delivery to the tumor site. Herein, the chemical synthesis and biological evaluation of two novel folate-conjugates bearing the anticancer agent chlorambucil (CLB) tethered to either an aminoether (4,7,10-trioxa-1,13-tridecanediamine) or a pseudo-β-dipeptide (β-Ala-ED-β-Ala) linker is reported. The two drug delivery systems have been prepared in high overall yields (54% and 34%) through straightforward and versatile synthetic routes. Evaluation of cell specificity was examined using three leukemic cell lines, undifferentiated U937 (not overexpressing FRs, FR(-)), TPA-differentiated U937 (overexpressing FRs, FR(+)), and TK6 (FR(+)) cells. Both conjugates exhibited high specificity only to FR(+) cells (particularly TK6), demonstrating comparable antitumor activity to CLB in its free form. These data confirm the reliability of folate-based drug delivery systems for targeted antitumor therapy; likewise, they lay the foundations for the development of other folate-conjugates with antitumor potential.     

Sequencing antibody repertoires: The next generation

Genomic studies have been revolutionized by the use of next generation sequencing (NGS), which delivers huge amounts of sequence information in a short span of time. The number of applications for NGS is rapidly expanding and significantly transforming many areas of life sciences. The field of antibody research and discovery is no exception. Several recent studies have harnessed the power of NGS for analyzing natural or synthetic immunoglobulin repertoires with unprecedented resolution and exploring alternative paths for antibody discovery. Thus, appreciating and then exploiting these advances is essential for staying at the edge of antibody innovation.Key words: next generation sequencing, phage display, hybridoma, antibody discovery, in vitro selection, immunization     

MicroRNA history: discovery, recent applications, and next frontiers

Since 1993, when the first small non-coding RNA was identified, our knowledge about microRNAs has grown exponentially. In this review, we focus on the main progress in this field and discuss the most important findings under a historical perspective. In addition, we examine microRNAs as markers of disease diagnosis and prognosis, and as new therapeutic targets.     

Regulation of p53: The next generation

The p53 protein is one of the most important tumor suppressor proteins. The most prevailing property of this tumor suppressor protein is its activation in response to DNA damage which counteracts the propagation of genetic alterations to daughter cells under conditions that provoke mutagenesis. In response to DNA damage and some other kinds of cellular stress the turnover of p53 is reduced or completely switched-off, which leads to a strong increase in the amount of the p53 protein and subsequently to the implementation of cell cycle arrest and apoptosis. Although post-translational modifications of p53 certainly contribute to the activation of p53 under physiologic conditions, an increase in the amount of the protein e.g. after overexpression, is sufficient for p53's deadly activities. This makes this tumor suppressor protein an interesting target for cancer therapy. This article summarizes the most important principles for the regulation of p53, with a particular focus on recent findings. Furthermore, open questions and possible future directions shall be discussed.     

The next generation of bacteriophage therapy

Bacteriophage therapy for bacterial infections is a concept with an extensive but controversial history. There has been a recent resurgence of interest into bacteriophages owing to the increasing incidence of antibiotic resistance and virulent bacterial pathogens. Despite these efforts, bacteriophage therapy remains an underutilized option in Western medicine due to challenges such as regulation, limited host range, bacterial resistance to phages, manufacturing, side effects of bacterial lysis, and delivery. Recent advances in biotechnology, bacterial diagnostics, macromolecule delivery, and synthetic biology may help to overcome these technical hurdles. These research efforts must be coupled with practical and rigorous approaches at academic, commercial, and regulatory levels in order to successfully advance bacteriophage therapy into clinical settings.     

The next generation of Optical Plankton Counter: the Laser-OPC

Optical Plankton Counters (OPCs) have been in operation for     

Hallmarks of cancer: the next generation

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.     

The next generation of exoskeletons: lighter, cheaper devices are in the works

Many researchers and engineers are busy in their laboratories working on devices that will bring mobility to people who have lost function in the lower body due to an accident, stroke, multiple sclerosis, or other disorders. "Several pretty sophisticated exoskeletons are already on the market now, and they are all similar to each other in terms of technologies, but we're not ready to replace the wheelchair yet," said exoskeleton developer Homayoon Kaz Kazerooni, Ph.D., professor of mechanical engineering at the University of California (UC) at Berkeley. "Eventually, we will have devices that are used by individuals on a daily basis to replace wheelchairs but not with the existing technology. We're at the beginning of a much bigger era in exoskeletons."     

Prebiotics and synbiotics: towards the next generation

Recent research in the area of prebiotic oligosaccharides and synbiotic combinations with probiotics is leading towards a more targeted development of functional food ingredients. Improved molecular techniques for analysis of the gut microflora, new manufacturing biotechnologies, and increased understanding of the metabolism of oligosaccharides by probiotics are facilitating development. Such developments are leading us to the time when we will be able to rationally develop prebiotics and synbiotics for specific functional properties and health outcomes.     

Flow cytometric chromosome sorting in plants: The next generation

Genome analysis in many plant species is hampered by large genome size and by sequence redundancy due to the presence of repetitive DNA and polyploidy. One solution is to reduce the sample complexity by dissecting the genomes to single chromosomes. This can be realized by flow cytometric sorting, which enables purification of chromosomes in large numbers. Coupling the chromosome sorting technology with next generation sequencing provides a targeted and cost effective way to tackle complex genomes. The methods outlined in this article describe a procedure for preparation of chromosomal DNA suitable for next-generation sequencing.     

The next frontier of systems biology: higher-order and interspecies interactions

Systems approaches are not so different in essence from classical genetic and biochemical approaches, and in the future may become adopted so widely that the term 'systems biology' itself will become obsolete.     

The next generation of microarray research: applications in evolutionary and ecological genomics

Microarray technology is one of the key developments in recent years that has propelled biological research into the post-genomic era. With the ability to assay thousands to millions of features at the same time, microarray technology has fundamentally changed how biological questions are addressed, from examining one or a few genes to a collection of genes or the whole genome. This technology has much to offer in the study of genome evolution. After a brief introduction on the technology itself, we then focus on the use of microarrays to examine genome dynamics, to uncover novel functional elements in genomes, to unravel the evolution of regulatory networks, to identify genes important for behavioral and phenotypic plasticity, and to determine microbial community diversity in environmental samples. Although there are still practical issues in using microarrays, they will be alleviated by rapid advances in array technology and analysis methods, the availability of many genome sequences of closely related species and flexibility in array design. It is anticipated that the application of microarray technology will continue to better our understanding of evolution and ecology through the examination of individuals, populations, closely related species or whole microbial communities.