Transgenic plants as protein factories

Transgenic plants are showing considerable potential for the economic production of proteins, with a few already being marketed. Recent clinical trials of pharmaceuticals produced from transgenic plants are encouraging, with plant glycans showing reassuringly poor immunogenicity. Our increasing understanding of protein targeting and accumulation should further improve the potential of this new technology.     

Progress in clinical trials for coronary arterial restenosis using beta radiation sources

Vascular brachytherapy has yet taken the leap into progression from emerging technology to standard of care dependent on the outcome of clinical trials. Data collected from early pilot trials and on-going clinical trials indicate that such a progression is achievable. Three-year follow-up data from patients treated with intracoronary radiation for the prevention of restenosis are now available. Data from larger trials are being assessed using angiographic and intravascular ultrasound analysis. The beta radiation studies are demonstrating different levels of efficacy, raising new issues regarding dosimetry and potential complications. Past trials have examined the use of vascular brachytherapy for recurrence prevention of restenosis in patients with in-stent restenosis. New data related to the use of liquid-filled balloon systems and radioactive stent are also being collected. This article updates the current status of clinical trials in vascular brachytherapy utilizing beta emitters, highlighting preliminary results and assessing their implications for the development of this field.     

Management of Incidental Findings in the Era of Next-generation Sequencing

Next-generation sequencing (NGS) technologies allow for the generation of whole exome or whole genome sequencing data, which can be used to identify novel genetic alterations associated with defined phenotypes or to expedite discovery of functional variants for improved patient care. Because this robust technology has the ability to identify all mutations within a genome, incidental findings (IF)- genetic alterations associated with conditions or diseases unrelated to the patient’s present condition for which current tests are being performed- may have important clinical ramifications. The current debate among genetic scientists and clinicians focuses on the following questions: 1) should any IF be disclosed to patients, and 2) which IF should be disclosed – actionable mutations, variants of unknown significance, or all IF? Policies for disclosure of IF are being developed for when and how to convey these findings and whether adults, minors, or individuals unable to provide consent have the right to refuse receipt of IF. In this review, we detail current NGS technology platforms, discuss pressing issues regarding disclosure of IF, and how IF are currently being handled in prenatal, pediatric, and adult patients.     

Tissue-type plasminogen activator: characteristics, applications and production technology

Plasminogen activators have immense clinical significance as thrombolytic agents for management of stroke and myocardial infarction. Tissue-type plasminogen activator (tPA) is generally preferred as being effective and safer than either urokinase or streptokinase type activators. Large-scale production of tPA became possible through groundbreaking developments in cell lines and bioprocess technology. Nevertheless, at thousands of dollars per treatment, tPA remains expensive. Enhancing cellular productivity and downstream product recovery through new approaches continue to be major challenges as discussed in this review. Recent clinical experience suggests the need for yet better fibrinolytic agents and attempts are underway to modify the tPA molecule to second generation products. Emerging trends in this field are outlined.     

Inducible RNAi system and its application in novel therapeutics

RNA interference (RNAi) was discovered as a cellular defense mechanism more than decade ago. It has been exploited as a powerful tool for genetic manipulation. Characterized with specifically silencing target gene expression, it has great potential application for disease treatment. Currently, there are human clinical trials in progress or planned. Despite the excitement regarding this prominent technology, there are many obstacles and concerns that prevent RNAi from being widely used in the therapeutic field. Among them, the non-spatial and non-temporal control is the most difficult challenge, as well as off-target effects and triggering type I immune responses. Inducible RNAi technology can effectively regulate target genes by inducer-mediated small hairpin RNA expression. Combination with inducible regulation systems this makes RNAi technology more sophisticated and may provide a wider application field. This review discusses approaches of inducible RNAi systems, the potential problem areas and solutions and their therapeutic applications. Given the limitations discussed herein being resolved, we believe that inducible RNAi will be a major therapeutic modality within the next several years.     

Applications of whole-cell matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry in systematic microbiology

In the last few years matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been increasingly studied and applied for the identification and typing of microorganisms. Very recently, MALDI-TOF MS has been introduced in clinical routine microbiological diagnostics with marked success, which is remarkable considering that not long ago the technology was generally seen as being far from practical application. The identification of microbial isolates by whole-cell mass spectrometry (WC-MS) is being recognized as one of the latest tools forging a revolution in microbial diagnostics, with the potential of bringing to an end many of the time-consuming and man-power-intensive identification procedures that have been used for decades. Apart from applications of WC-MS in clinical diagnostics, other fields of microbiology also have adopted the technology with success. In this article, an over-view of the principles of MALDI-TOF MS and WC-MS is presented, highlighting the characteristics of the technology that allow its utilization for systematic microbiology.     

New developments in microarray technology

Microarrays have emerged as indispensable research tools for gene expression profiling and mutation analysis. New classification of cancer subtypes, dissecting the yeast metabolism and large-scale genotyping of human single nucleotide polymorphisms are important results being obtained with this technique. Realizing the microsphere-based massively parallel signature sequencing technique as fluid microarrays, building new types of protein arrays and constructing miniaturized flow-through systems, which can potentially take this technology from the research bench into industrial, clinical and other routine applications, exemplify the intense developments that are now ongoing in this field.     

The flow of cytometry into systems biology.

Biomedical research is evolving to address biological systems as molecular pathways integrated into complex networks. Tools for molecular and cell analysis are also evolving to address the new challenges and opportunities of this approach. Flow cytometry is a versatile analytical platform, capable of high speed quantitative measurements of cells and other particles. These capabilities are being exploited and extended in a range of new applications stemming from opportunities presented by the advances of genomics, proteomics and systems biology, which are in turn impacting clinical diagnosis, vaccine development and drug discovery. In this review, we highlight some of these advances and consider the future evolution of flow cytometry technology.     

大分子的吸入治疗

随着重组DNA技术和分子生物学的发展,以蛋白质和多肽为主的大分子成为一类新型药物,并越来越受到重视,新兴的基因治疗技术使得核酸大分子也有可能成为药物。目前,绝大部分大分子药物都是通过注射途径给药,病人在医院注射费用昂贵且不方便,因而许多注射替代给药途径成为研究热门,通过肺部吸入给药就是一种很有吸引力的非侵入性给药途径。本介绍了肺吸收大分子的可能机制和大分吸入治疗的临床与基础研究以及面临的问题。     

Flow cytometry in radiation research: past, present and future

Flow cytometry is an invaluable technique in research and clinical laboratories. The technique has been applied extensively to many areas of radiation research at both the experimental and clinical level. In the past few years, there has been a significant increase in the capabilities of modern flow cytometers to undertake multicolor analysis in a user-friendly manner. The developments in cytometric technology are being matched by the rapid development of new reagents, new fluorochromes and new platforms such as bead arrays. These developments are facilitating many new applications in both basic and clinical research that have relevance for many fields of biology, including radiation research. This review provides a historical overview of the application of flow cytometry to radiobiology and an update on how technology and reagents have changed and cites examples of new applications relevant to radiation researchers. In addition, some entirely new flow instrumentation is currently under development that has significant potential for applications in radiation research.     

Pharma-Planta: road testing the developing regulatory guidelines for plant-made pharmaceuticals

Significant advances over the last few years have seen plant-made pharmaceuticals (PMPs) move from the exploratory research phase towards clinical trials, with the first commercial products for human use expected to reach the market by 2009. Europe has yet to witness the commercial application of PMP technology, although at least one product has begun phase II clinical trials with others following close behind. These emerging products are set to challenge the complex and overlapping regulations that currently govern GM plants and ‘conventional’ pharmaceutical production. The areas of responsibility are being mapped out between the different EU regulatory agencies, with specific guidelines currently being drawn up for the regulation of PMPs. This article discusses issues surrounding the development of robust risk-assessment and risk-management practices based on health and environmental impact, while working with EU regulatory authorities to ensure appropriate regulatory oversight.     

Atemonate and Imuteran: novel Russian monoclonal antibody-based therapeutic agents

The N. Blokhin National Cancer Research Center is one of the few Russian scientific institutions in which hybridoma technology of monoclonal antibody (mAb) production has been successfully established. Using this technology, several dozens of mAbs to various antigens of human leukocytes have been elaborated. These mAbs are widely used for immune status evaluation and for differential diagnostics of leukemias. Two mAbs were used to develop therapeutic drugs. Imuteran is a pharmaceutical form of mAb ICO-25 against a mucin-like antigen of human milk fat globules and proposed for treatment of epithelial cell-originating cancers (breast, intestinal, ovarian, lung cancer, etc.). ThePhase II clinical study of this agent is now nearly completed, and preliminary results suggest Imuteran to be a promising anticancer agent with tumor-stabilizing activity, but patients should be carefully monitored for signs of allergic reactions. mAb ICO-90 against the CD3 antigen of human T lymphocytes was used to develop the therapeutic agent Atemonate proposed for treatment of acute transplant rejection. At present, the Phase II clinical study of this agent is over, and the results confirm the drug safety and efficacy for this indication. The drug is being registered at the Ministry of Healthcare and Social Development, and transfer to serial production is expected shortly.     

Tegresstrade mark Urethral Implant Phase III Clinical Experience and Product Uniqueness

Advances in materials technology, coupled with a heightened understanding of wound healing and tissue-materials interactions in the lower urinary tract, have led to the development of a variety of new urethral bulking agents that are expected to be available in the near future. Experience with such bulking agents continues to grow and study results are disseminated as more clinical trials are initiated and completed. The intention of this report is to review the characteristics and initial clinical results for one of these new agents: Tegresstrade mark Urethral Implant (C. R. Bard, Inc., Murray Hill, NJ). This material, with unique phase-change properties upon exposure to body temperature fluids, offers ease of injection and requires less volume for clinical effect than bovine collagen. Additionally, Tegress Urethral Implant performance in clinical trials has suggested improved durability and correspondingly higher continence and improvement rates versus bovine collagen. As these materials evolve, an understanding of preferential implant techniques is being gained also. Delivery method and implant site may prove to substantially alter the biologic activity of these compounds. As outlined in this review, experience with Tegress Implant resulted in changes in delivery technique that translated into improved materials and tissue interaction.     

Bioengineering of the digestive tract: approaching the clinic

The field of regenerative medicine is developing technologies that, in the near future, will offer alternative approaches to either cure diseases affecting the gastrointestinal tract or slow their progression by leveraging the intrinsic ability of our tissues and organs to repair after damage. This article will succinctly illustrate the three technologies that are closer to clinical translation—namely, human intestinal organoids, sphincter bioengineering and decellularization, whereby the cellular compartment of a given segment of the digestive tract is removed to obtain a scaffold consisting of the extracellular matrix. The latter will be used as a template for the regeneration of a functional organ, whereby the newly generated cellular compartment will be obtained from the patient's own cells. Although clinical application of this technology is approaching, product development challenges are being tackled to warrant safety and efficacy.     

Cancer therapy by biological response modifiers

Biological response modifiers (BRMs) are agents or approaches which can modify the biological response of the host to tumors and thereby are expected to augment the resistance to development or progression of cancer. Recent advances in the technology of genetic engineering and monoclonal antibodies have led to rapid progress in this field. There is an increasing number of genetically engineered cytokines, which appear promising for cancer treatment and are becoming available for clinical trials. These include the interferons, leukin-2, tumor necrosis factor, and colony-stimulating factors. For development of optimal therapeutic protocols with these and a variety of immunomodulatory agents, it appears necessary to develop a detailed understanding of the possible mechanisms of their antitumor effects, and to determine the optimal dose and schedule for altering the antitumor effector mechanisms. BRMs would also be expected to be quite useful in the prevention of cancer. Indeed, in a variety of animal tumor model systems, potent protective effects can be demonstrated. However, the strategies for clinical application of such information have yet to be adequately worked out. One more immediate application of this approach is for the prevention of metastatic spread of tumor cells. BRMs, which stimulate natural killer cell activity, have been shown to strongly protect against dissemination of tumors, and clinical strategies for this important aspect of cancer treatment are being developed.     

悬浮芯片技术应用进展

悬浮芯片技术(SAT)是一种新型、高通量的生物芯片技术,它是将流式细胞术、激光技术及应用流体学等技术结合在一起,利用悬浮在液相中的分类荧光编码微球作为检测载体,具有高通量、速度快、灵敏度高、特异性强及检测范围广等特点.近几年来,悬浮芯片技术在免疫学、基因组学、蛋白质组学及临床诊断检测等方面应用较广泛.就其原理、技术特点...     

A facile and sensitive method of quantifying glutaminase binding to its inhibitor CB-839 in tissues

Many cancer types reprogram their metabolism to become addicted to glutamine. One of the critical enzymes in the utilization of glutamine in these cells is glutaminase. CB-839 (telaglenastat) is a drug that targets glutaminase that is currently being evaluated in many clinical trials for efficacy in various cancer types that are known to be driven by glutamine metabolism. Despite its use, there are limited assays available for testing the pharmacodynamic on-target effects of CB-839 on the limited, small-volume patient samples that are obtained in early-phase clinical trials. Thus, we developed an assay based on the cellular thermal shift assay technique using AlphaLISA technology to show that CB-839 specifically engages glutaminase in colon cancer cell lines in vitro and in minute quantities of mouse xenograft tumors. Notably, we show that this assay detects CB-839 binding to glutaminase in platelets of patients collected while receiving CB-839 on a clinical trial. This assay may be used to study the pharmacodynamic profile of CB-839 in very small tissue samples obtained from patients on a clinical trial and may be useful in future studies designed to screen other inhibitors of glutaminase.     

Physical interactions of static magnetic fields with living tissues

Clinical magnetic resonance imaging (MRI) was introduced in the early 1980s and has become a widely accepted and heavily utilized medical technology. This technique requires that the patients being studied be exposed to an intense magnetic field of a strength not previously encountered on a wide scale by humans. Nonetheless, the technique has proved to be very safe and the vast majority of the scans have been performed without any evidence of injury to the patient. In this article the history of proposed interactions of magnetic fields with human tissues is briefly reviewed and the predictions of electromagnetic theory on the nature and strength of these interactions are described. The physical basis of the relative weakness of these interactions is attributed to the very low magnetic susceptibility of human tissues and the lack of any substantial amount of ferromagnetic material normally occurring in these tissues. The presence of ferromagnetic foreign bodies within patients, or in the vicinity of the scanner, represents a very great hazard that must be scrupulously avoided. As technology and experience advance, ever stronger magnetic field strengths are being brought into service to improve the capabilities of this imaging technology and the benefits to patients. It is imperative that vigilance be maintained as these higher field strengths are introduced into clinical practice to assure that the high degree of patient safety that has been associated with MRI is maintained.