Soluble cytokine receptors in biological therapy

Due to their fundamental involvement in the pathogenesis of many diseases, cytokines constitute key targets for biotherapeutic approaches. The discovery that soluble forms of cytokine receptors are involved in the endogenous regulation of cytokine activity has prompted substantial interest in their potential application as immunotherapeutic agents. As such, soluble cytokine receptors have many advantages, including specificity, low immunogenicity and high affinity. Potential disadvantages, such as low avidity and short in vivo half-lifes, have been addressed by the use of genetically-designed receptors, hybrid proteins or chemical modifications. The ability of many soluble cytokine receptors to inhibit the binding and biological activity of their ligands makes them very specific cytokine antagonists. Several pharmaceutical companies have generated a number of therapeutic agents based on soluble cytokine receptors and many of them are undergoing clinical trials. The most advanced in terms of clinical development is etanercept (Enbrel?, Immunex), a fusion protein between soluble TNF receptor Type II and the Fc region of human IgG1. This TNF-α antagonist was the first soluble cytokine receptor to receive approval for use in humans. In general, most agents based on soluble cytokine receptors have been safe, well-tolerated and have shown only minor side effects in the majority of patients. Soluble cytokine receptors constitute a new generation of therapeutic agents with tremendous potential for applications in a wide variety of human diseases. Two current areas of research are the identification of their most promising applications and characterisation of their long-term effects.     

Soluble cytokine receptors in biological therapy

Due to their fundamental involvement in the pathogenesis of many diseases, cytokines constitute key targets for biotherapeutic approaches. The discovery that soluble forms of cytokine receptors are involved in the endogenous regulation of cytokine activity has prompted substantial interest in their potential application as immunotherapeutic agents. As such, soluble cytokine receptors have many advantages, including specificity, low immunogenicity and high affinity. Potential disadvantages, such as low avidity and short in vivo half-lifes, have been addressed by the use of genetically-designed receptors, hybrid proteins or chemical modifications. The ability of many soluble cytokine receptors to inhibit the binding and biological activity of their ligands makes them very specific cytokine antagonists. Several pharmaceutical companies have generated a number of therapeutic agents based on soluble cytokine receptors and many of them are undergoing clinical trials. The most advanced in terms of clinical development is etanercept (Enbrel, Immunex), a fusion protein between soluble TNF receptor Type II and the Fc region of human IgG1. This TNF-alpha; antagonist was the first soluble cytokine receptor to receive approval for use in humans. In general, most agents based on soluble cytokine receptors have been safe, well-tolerated and have shown only minor side effects in the majority of patients. Soluble cytokine receptors constitute a new generation of therapeutic agents with tremendous potential for applications in a wide variety of human diseases. Two current areas of research are the identification of their most promising applications and characterisation of their long-term effects.     

Flow cytometry: basic concepts and clinical applications in immunodiagnostics.

OBJECTIVE: To review current and possible future clinical applications of flow cytometry in immunodiagnostic procedures. DATA SOURCES: Recent research and review articles and textbooks on laboratory diagnosis and flow cytometry. STUDY SELECTION: Not applicable. DATA EXTRACTION: Performed by the author. DATA SYNTHESIS: Flow cytometry is the measurement of cellular and fluorescent properties of stained cells in a fluid stream as they move past a set of fixed detectors. The instruments are capable of measuring these properties on thousands of cells in but a few seconds. Many specimen types can be analyzed on the flow cytometer. CONCLUSION: Flow cytometry is especially useful in monitoring immunodeficiencies, leukemias, and other malignancies, but it has other uses, as well. Improvements in instruments, reagents, and methods will cause an increase in the number of applications for flow cytometry. More laboratories will be able to purchase the equipment as it becomes less expensive. Flow cytometry provides the clinician valuable information in the diagnosis and treatment of disease.     

Soluble cytokine receptors are present in normal human urine

Affinity chromatography of crude human urinary proteins on either human rIL-6, human rIFN-gamma, or anti-IFN-gamma-R mAb yielded the two respective soluble receptors in significant quantities. A single sequence of 30 amino acid residues was obtained by NH2-terminal microsequencing of the protein peak purified in tandem by affinity chromatography on an IL-6 column and reversed-phase HPLC. This sequence was identical to the predicted NH2-terminal sequence of IL-6-R as previously reported. Analysis of the eluted proteins from both IFN-gamma and anti-IFN-gamma-R columns by inhibition of solid phase RIA, ELISA, SDS-PAGE, and Western blotting proved the existence of soluble IFN-gamma-R in normal urine. Our finding, together with the already known presence of urinary TNF binding proteins and a soluble IL-2-R both in plasma and in urine, indicates that release of soluble cytokine receptors into body fluids is a general phenomenon that occurs under normal physiological conditions.     

Perfusion MR imaging: basic principles and clinical applications

Dynamic contrast-enhanced perfusion MR imaging provides hemodynamic information that complements traditional structural imaging and is increasingly used in clinical practice to diagnose, manage, and understand brain tumors. Relative cerebral blood volume maps derived from perfusion MR imaging data provide quantifiable estimates of regional blood volume that can be used to grade gliomas, differentiate different brain tumor types, and distinguish tumors from non-neoplastic lesions. There are a few minor limitations of the dynamic contrastenhanced perfusion MR imaging technique-susceptibility artifacts, relative rather than absolute quantification of cerebral blood volume, and the inaccurate estimation of cerebral blood volume in patients in whom the blood-brain barrier has been severely disrupted or destroyed. Despite the minor potential pitfalls of the technique, inclusion of perfusion MR imaging as part of a routine evaluation of brain tumors can lead to improved diagnostic accuracy, understanding of tumor pathophysiology, and detection and quantification of tumor angiogenesis. With further work, perfusion MR imaging could be used to assess existing and novel cancer therapies that target blood vessels.     

Ischemic preconditioning: from basic mechanisms to clinical applications

When the heart is subjected to a transient nonlethal period of ischemia, it quickly adapts itself to become resistant to infarction from a subsequent ischemic insult. This adaptation is called preconditioning. This cardioprotection has been shown to be mediated by stimulation of receptors linked to protein kinase C (PKC) (adenosine, bradykinin, opioids, etc.), and these receptors protect by activating PKC. PKC appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in the preconditioned heart. Recent studies imply that p38 mitogen-activated protein kinase carries the signal from PKC to the mitochondrial K(ATP) channels, causing them to open and thus protect the heart. The cardioprotection of preconditioning occurs in all species tested to date, and possibly also humans. It is expected that as the mechanism of preconditioning is more thoroughly understood, pharmacological preconditioning will become practical for clinical use.     

Differentiation therapy of human cancer: basic science and clinical applications

Current cancer therapies are highly toxic and often nonspecific. A potentially less toxic approach to treating this prevalent disease employs agents that modify cancer cell differentiation, termed ‘differentiation therapy.’ This approach is based on the tacit assumption that many neoplastic cell types exhibit reversible defects in differentiation, which upon appropriate treatment, results in tumor reprogramming and a concomitant loss in proliferative capacity and induction of terminal differentiation or apoptosis (programmed cell death). Laboratory studies that focus on elucidating mechanisms of action are demonstrating the effectiveness of ‘differentiation therapy,’ which is now beginning to show translational promise in the clinical setting.     

卵巢癌肿瘤标志物的临床应用及研究进展

卵巢癌是妇科常见的恶性肿瘤之一,其病死率位居妇科恶性肿瘤之首。肿瘤标志物对卵巢癌的早期诊断、疗效监测及预后评估具有重要意义。CA125、HE4是临床上应用最广泛的卵巢癌血清肿瘤标志物,但其存在一些不足之处,寻找更加敏感的肿瘤标志物具有重要的意义。近年来,随着二代测序技术的快速发展,循环肿瘤DNA、循环肿瘤细胞及mi RNA为卵巢癌肿瘤标志物的临床研究提供了新的思路。     

Sixteen-row multislice computed tomography: basic concepts, protocols, and enhanced clinical applications.

Since its introduction, spiral computed tomography (CT) technology underwent a continuous and fast technical and clinical development. In particular, spatial and temporal resolutions were constantly increased during the last decade. The main breakthrough for clinical application was the introduction of multislice technology, first with 2-row and 4-row equipment and more recently with 16-row scanners. A high-resolution sub-millimeter CT dataset can be acquired easily, although with an increased x-ray exposure for the patient. The high speed of the scan requires up-to-date and careful protocol optimization. Scanner technology and geometry affect image formation procedure and imaging protocols should be adapted accordingly. The technical foundations of spiral CT imaging and the main scan and reconstruction parameters are described in this article. Updated protocols and clinical examples of the latest applications are also discussed.     

CD34 cell separation: from basic research to clinical applications

Summary Advances in the immunological identification of primitive haematopoietic cells have led to the development of various techniques for their characterisation and purification. The expression of the CD34 antigen by the stem cell compartment has been exploited for these purposes. Separation systems capable of isolating CD34+ cells on a large scale are finding use in the clinic. Areas of interest overlap for both researchers and clinicians, and efforts to mobilise, characterise, purify and transplant these cells continue. Different CD34 purification systems are reviewed, focusing on their possible applications in different research fields. Clinical results of CD34+ selection and the possible future applications of this technology in the clinic are also reported.     

Human mesenchymal stem cells: from basic biology to clinical applications

Mesenchymal stem cells (MSC) are a group of clonogenic cells present among the bone marrow stroma and capable of multilineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. Due to their ease of isolation and their differentiation potential, MSC are being introduced into clinical medicine in variety of applications and through different ways of administration. Here, we discuss approaches for isolation, characterization and directing differentiation of human mesenchymal stem cells (hMSC). An update of the current clinical use of the cells is also provided.     

Clinical applications of flow cytometry in hematology and immunology.

OBJECTIVE: To review the major applications of flow cytometry in the diagnosis of hematologic and immunologic disease. DATA SOURCES: Professional literature and authors' experience. DATA SYNTHESIS: Flow cytometry is evolving as a major diagnostic tool for evaluating hematologic disease, monitoring HIV infection and assessing peripheral blood and bone marrow for CD34 positive stem cells in marrow transplantation. This review highlights the opportunities and pitfalls of this area of diagnostic laboratory medicine. CONCLUSION: The applications of flow cytometers in diagnostic hematology and immunology are expanding, providing new opportunities for enhanced precision in diagnosis. As in any relatively new field much work remains in order to optimize accuracy and efficiency while minimizing cost.     

Surfactant: clinical applications.

Pulmonary surfactant is an important chemical component of the lung. It decreases surface tension in the alveolar cells to help stabilize the alveoli, and it may help prevent pulmonary edema. Currently, naturally and synthetically derived surfactants are being used to treat neonatal respiratory distress syndrome, a leading cause of death in premature infants. Surfactant is recommended for prophylactic therapy in infants weighing less than 1,350 g (3 lb) and in infants weighing more than 1,350 g who show signs of pulmonary immaturity and for rescue therapy in infants with respiratory distress syndrome. Surfactant is administered by endotracheal tube, and the recommended dose is 5 mg per kg. Three doses, given 12 hours apart, is the recommended regimen for prophylactic therapy. Rescue therapy consists of one dose of surfactant given at the onset of respiratory distress and another dose given 12 hours later.     

Proteomics: clinical applications.

The word proteomics was coined in 1997 to describe the changes in all proteins expressed by a genome. Several sophisticated techniques including two-dimensional electrophoresis, imaging, mass spectrometry, and bioinformatics are used in proteomics to identify, quantify, and characterize proteins. Clinical proteomics is the application ofproteomics techniques to the medical field. The main aim of this methodology is to identify proteins involved in pathological processes and to understand how illness can lead to altered protein expression. Clinical proteomics offers the opportunity and the potential to develop new diagnostic and prognostic tests, to identify new therapeutic targets, and eventually to allow the design of individualized patient treatment. Here we present an overview of proteomics applications to the study of disease and its potential to improve diagnosis and prognosis.     

超声造影的基础研究与临床应用(述评)

超声造影是当前超声医学的热门研究课题,超声造影剂与造影技术发展迅速,超声造影的基础研究与临床应用日见深入.目前,超声造影在我国尚未广泛开展,但我们的一些超声造影的基础及临床应用研究水平已与国际接轨,本期专题发表了多篇超声造影的动物实验及临床研究论文,旨在促进超声造影知识的普及和研究工作的进一步深入.     

Soluble receptors of TNF-alpha with molecular mass 55 kDa in rheumatoid arthritis: clinical role

To evaluate clinical implications of the serum level of soluable receptors of tumor necrosis factor alpha (TNFa) with molecular mass 55 kDa (rTNF-55R) in rheumatoid arthritis, serum levels of rTNF-55R and rTNF-75R were measured with the use of radioimmunoassay in 76 RA patients, 38 donors and in 25 RA patients, 10 donors, respectively. RESULTS: Elevated serum level of rTNF-55R was recorded in 55.3% RA patients. This level correlated with basic clinical and laboratory parameters of RA, the disease activity, values of DAS indices. It is concluded that a serum level of rTNF-55R adequately reflects clinico-laboratory activity of RA and its measurement can be used for assessment of RA activity and treatment efficiency.