Nonviral approaches for targeted delivery of plasmid DNA and oligonucleotide

Successful gene therapy depends on the development of efficient delivery systems. Although pDNA and ODN are novel candidates for nonviral gene therapy, their clinical applications are generally limited owing to their rapid degradation by nucleases in serum and rapid clearance. A great deal of effort had been devoted to developing gene delivery systems, including physical methods and carrier-mediated methods. Both methods could improve transfection efficacy and achieve high gene expression in vitro and in vivo. As for carrier-mediated delivery in vivo, since gene expression depends on the particle size, charge ratio, and interaction with blood components, these factors must be optimized. Furthermore, a lack of cell-selectivity limits the wide application to gene therapy; therefore, the use of ligand-modified carriers is a promising strategy to achieve well-controlled gene expression in target cells. In this review, we will focus on the in vivo targeted delivery of pDNA and ODN using nonviral carriers.     

Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

Introduction: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options.

Areas covered: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers.

Expert opinion: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

INTRODUCTION: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options. AREAS COVERED: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers. EXPERT OPINION: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists

The majority of clinical trials of N-methyl d-aspartate antagonists have been conducted in the fields of stroke, traumatic brain injury (TBI) and dementia. Stroke and TBI trials have involved more than 9000 patients, but have yielded no therapeutically useful agents, with the possible exception of magnesium for treatment of subarachnoid haemorrhage. Several of the synthetic N-methyl D-aspartate antagonist development programmes have been abandoned owing to concerns about drug toxicity, particularly in stroke. Systematic reviews in stroke and TBI have shown that definitive conclusions cannot be drawn for most agents owing to early termination of trials. In dementia, memantine has shown some benefit in moderate-to-severe Alzheimer's disease, with no clear benefit to date for milder stages of Alzheimer's disease or for vascular dementia. Other therapeutic areas of promise remain inadequately explored at present.     

Guidelines on good clinical laboratory practice: bridging operations between research and clinical research laboratories

A set of Good Clinical Laboratory Practice (GCLP) standards that embraces both the research and clinical aspects of GLP were developed utilizing a variety of collected regulatory and guidance material. We describe eleven core elements that constitute the GCLP standards with the objective of filling a gap for laboratory guidance, based on IND sponsor requirements, for conducting laboratory testing using specimens from human clinical trials. These GCLP standards provide guidance on implementing GLP requirements that are critical for laboratory operations, such as performance of protocol-mandated safety assays, peripheral blood mononuclear cell processing and immunological or endpoint assays from biological interventions on IND-registered clinical trials. The expectation is that compliance with the GCLP standards, monitored annually by external audits, will allow research and development laboratories to maintain data integrity and to provide immunogenicity, safety, and product efficacy data that is repeatable, reliable, auditable and that can be easily reconstructed in a research setting.     

Therapeutic targeting of microenvironmental interactions in leukemia: Mechanisms and approaches

In hematological malignancies, there are dynamic interactions between leukemic cells and cells of the bone marrow microenvironment. Specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. This review focuses on molecular and cellular biology of the normal hematopoietic stem cell and the leukemia stem cell niche, and of the molecular pathways critical for microenvironment/leukemia interactions. The key emerging therapeutic targets include chemokine receptors (CXCR4), adhesion molecules (VLA4 and CD44), and hypoxia-related proteins HIF-1α and VEGF. Finally, the genetic and epigenetic abnormalities of leukemia-associated stroma will be discussed. This complex interplay provides a rationale for appropriately tailored molecular therapies targeting not only leukemic cells but also their microenvironment to ensure improved outcomes in leukemia.     

贝伐单抗治疗结直肠癌的研究进展

结直肠癌是消化系统常见的恶性肿瘤之一,严重威胁着人类的健康。肿瘤血管在肿瘤组织的发生、发展和转移过程中发挥着重要作用。目前,针对肿瘤血管的靶向治疗成为各种肿瘤治疗的策略之一。贝伐单抗是血管内皮生长因子的单克隆抗体,是抑制血管生长的重要单克隆抗体药物。本研究分析了贝伐单抗在结直肠癌靶向治疗中的可行性和安全性,旨在为临床治疗结直肠癌提供参考。     

Fractional technology: a review and clinical approaches

All of the FT devices that I have available to me work very well. Some may not be "true" FT devices and may be creating "holes" in the skin, but clinically the results seen with these devices have brought us pretty close to achieving the gold standard of ablative resurfacing. In the future, we may find FT will resurface the market of ablative resurfacing.     

临床试验中中心效应的评价及处理方法

探讨多中心临床试验中，中心效应的评价与处理方法，采用Breslow-Day检验对有效率的中心间差异进行评价，采用CMH方法对组间有效率及疗效等级进行分析，采用logistic回归方法对中心效应及有效率或疗效等级同时进行评价。结果提示，Breslow-Day检验只能对有效率的中心间差异进行评价。而不能对疗效等级的中心差异进行评价，CMH方法不能同时考虑其它协变量的影响。