Gout: Current Insights and Future Perspectives

Gout is a relatively common inflammatory arthritis that is typically known to occur in middle-aged men. The prevalence of gout appears to be shifting, however, and is increasing in the elderly population. Gout is characterized by severely intense pain and can greatly impact patient quality of life. The study of gout and associated conditions appears to have received research attention in the past, however there is a resurgence in gout interest due to the abundance of novel evidence surrounding its diagnosis, pathophysiology, and treatment. In this review we describe a general overview of gout including its assessment/diagnosis, clinical presentations, predisposing factors, pathophysiology, abortive and prophylactic therapy to control gouty inflammation, and the potential future direction of gout treatment.

Perspective

Gout is an underappreciated and extremely painful condition. Over the last 2 years new thought on pathophysiology of gout taking into account the inflammasome and new therapeutic agents have changed management strategies.     

酪氨酸激酶抑制剂逆转K562/A02细胞多药耐药的研究

本研究旨在比较酪氨酸激酶抑制剂伊马替尼(Imatinib)、尼洛替尼(Nilotinib)对K562/A02细胞多药耐药的逆转作用。用RT-PCR法检测各组mdr-1mRNA、bcr-abl mRNA表达;用Western blot法检测各组P-gp、P210蛋白表达;用流式细胞术检测各组细胞内柔红霉素(DNR)的蓄积。结果表明:0.0625μmol/L伊马替尼、5nmol/L尼洛替尼对K562/A02细胞无明显细胞毒性,伊马替尼和尼洛替尼上述剂量单独作用48小时均下调mdr-1mRNA、bcr-abl mRNA、P-gp、P210蛋白的表达,且尼洛替尼较伊马替尼作用更强。荧光强度检测显示,K562/A02细胞经伊马替尼、尼洛替尼单独处理48小时后,其细胞内DNR浓度分别为K562细胞中的7.85%、12.02%。结论:酪氨酸激酶抑制剂具有很好的逆转细胞耐药作用,且尼洛替尼较伊马替尼逆转作用更强。     

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

The Aurora kinase family is comprised of three serine/threonine kinases, Aurora‐A, Aurora‐B, and Aurora‐C. Among these, Aurora‐A and Aurora‐B play central roles in mitosis, whereas Aurora‐C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora‐A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora‐A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora‐A kinase inhibition.     

COX‐1 Inhibitors: Beyond Structure Toward Therapy

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX‐1 and COX‐2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX‐1 are mainly in cancer and inflammation. Five classes of COX‐1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX‐1 active site was achieved through X‐ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX‐1 inhibitors to be tested into those disease models in which COX‐1 is involved. Particularly, COX‐1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX‐1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX‐1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.     

Advancement of Sialyltransferase Inhibitors: Therapeutic Challenges and Opportunities

Hypersialylation of tumor cell surface proteins along with a marked upregulation of sialyltransferase (ST) activity is a well‐established hallmark of cancer. Due to the critical role of STs in tumor growth and progression, ST inhibition has emerged as a potential new antimetastatic strategy for a range of cancers including pancreatic and ovarian. Human STs are divided into subtypes based on their linkage and acceptor molecule, with each subtype controlling the synthesis of specific sialylated structures with unique biological roles. This has important implications for inhibitor development, as STs also play significant roles in immune responses, inflammation, viral infection, and neurological disorders. Thus, the current goal in order to advance to the clinic is the development of subtype selective, cell‐permeable and synthetically accessible, small‐molecule ST inhibitors. Herein is a comprehensive review of the latest developments in ST inhibitors from design, Nature, and high‐throughput screening, addressing both the challenges and opportunities in targeting cell surface sialylation. The review features an overview of the biological evaluation methods, computational and imaging tools, inhibitor molecular diversity, and selectivity toward ST subtypes, along with the emerging role of ST inhibitors as diagnostic tools for disease imaging.     

Early Intervention for Children with Intellectual Disabilities: Current Knowledge and Future Prospects*

The field of early intervention is vibrant, generating expectations that systematic, comprehensive, experientially based interventions will alter developmental trajectories and prevent secondary complications. In this article, the existing knowledge base in the field is reviewed. It emphasizes the importance of an overall developmental framework, what is known through intervention science and the emergence of guiding principles for programme design and development. This is followed by a discussion of future prospects for improving early intervention outcomes in four areas. First, the importance of designing studies that provide information about carefully defined subgroups is discussed. This issue of specificity of outcomes is crucial in order to determine boundaries for effectiveness and to direct attention to areas of special concern. Second, prospects for translational research are discussed with particular reference to our knowledge of the core developmental processes affected. Third, the need to focus on the increasingly apparent mental health and social competence difficulties of even young children with intellectual disabilities is considered. Finally, the complex problems and potential solutions associated with the transfer of model intervention programmes to communities as part of early intervention systems are described.     

Granulocyte colony‐stimulating factor produces a decrease in IFNγ and increase in IL‐4 when administrated to healthy donors

Hematopoietic stem cells transplantation (HSCT) is the leading curative therapy for a variety of hematological and hereditary diseases; however, graft versus host disease (GVHD), an immunologic phenomenon that is favored by Th1 cytokines and cytotoxic cells from donors, is present frequently and is one of the most important causes of transplant related mortality. Peripheral blood HSCT is the preferred source of stem cells in almost 100% of the cases of autologous HSCT and in 70% of allogeneic transplants. The best mobilizing agent to get the stem cells out from the bone marrow is the Granulocyte‐Colony Stimulating Factor (G‐CSF). In this work, our main objective was to study a possible correlation between the graft cell dose and the patient's clinical outcome. We evaluated the immunologic changes produced by G‐CSF in the lymphocyte and cytokine profiles in allogeneic HSC donors. HSC from twelve donors were mobilized with G‐CSF at 16 μg/kg/day, for 5 days. Basal Peripheral Blood (BPB), Mobilized Peripheral Blood (MPB), and aphaeresis mononuclear cells (G‐MNC) samples were taken from all donors. Using flow cytometry, we quantified CD19⁺, CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺, NK, NKT, DC1, and DC2 cells. Cytokines were determined by ELISA in culture supernatants. CD19⁺ (p = 0.001), DC1 (p < 0.002) and DC2 (p < 0.001) cells were increased in MPB with respect to BPB. An increase in Th2 cytokines such as (IL‐4) and a decrease in Th1 cytokines (IFNγ, IL‐2) were also found in MPB samples. In conclusion, Th1 and Th2 cytokines are relevant in predicting the clinical outcome after allogeneic peripheral blood HSCT. J. Clin. Apheresis 25:181–187, 2010. © 2010 Wiley‐Liss, Inc.     

Comparative Efficacy of Treatments for Previously Treated Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis

Purpose

New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM.

Combined implantation of CD34+ and CD14+ cells increases neovascularization through amplified paracrine signalling

Cell therapy strategies that use adult peripheral blood‐derived CD34⁺ progenitor cells are hampered by low cell numbers and the infrequent cellular incorporation into the neovasculature. Hence, the use of CD34⁺ cells to treat ischaemic diseases is under debate. Interaction between CD34⁺ cells and CD14⁺ cells results in superior endothelial differentiation of CD14⁺ cells in vitro, indicating that cell therapy approaches utilizing both CD34⁺ and CD14⁺ cells may be advantageous in therapeutic neovascularization. Here, human CD34⁺ and CD14⁺ cells were isolated from adult peripheral blood and implanted subcutaneously into nude mice, using matrigel as the carrier. Combined implantation of human CD34⁺ and CD14⁺ cells resulted in superior neovascularization, compared to either cell type alone, albeit incorporation of human cells into the murine vasculature was not observed. Human CD34⁺ and CD14⁺ cells produced and secreted a pentad of pro‐angiogenic mediators, such as HGF, MCP‐1 and IL‐8, bFGF and VEGFa in monoculture. The production and secretion of pro‐angiogenic mediators by CD14⁺ cells was highly amplified upon incubation with conditioned medium from CD34⁺ cells. In vivo, neovascularization of matrigel implants did not rely on the endothelial differentiation and incorporation of CD34⁺ or CD14⁺ cells, but depended on the paracrine effects of IL‐8, MCP‐1, HGF, bFGF and VEGFa secreted by implanted cells. Administration of this growth factor/cytokine pentad using matrigel as a carrier results in cell recruitment and microvessel formation equal to progenitor cell‐induced neovascularization. These data provide new insights on neovascularization by cell therapy and may contribute to new strategies for the treatment of ischaemic diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

Research Using Emergency Department–related Data Sets: Current Status and Future Directions

The 2009 Academic Emergency Medicine consensus conference focused on "Public Health in the ED: Surveillance, Screening and Intervention." One conference breakout session discussed the significant research value of health-related data sets. This article represents the proceedings from that session, primarily focusing on emergency department (ED)-related data sets and includes examples of the use of a data set based on ED visits for research purposes. It discusses types of ED-related data sets available, highlights barriers to research use of ED-related data sets, and notes limitations of these data sets. The paper highlights future directions and challenges to using these important sources of data for research, including identification of five main needs related to enhancing the use of ED-related data sets. These are 1) electronic linkage of initial and follow-up ED visits and linkage of information about ED visits to other outcomes, including costs of care, while maintaining deidentification of the data; 2) timely data access with minimal barriers; 3) complete data collection for clinically relevant and/or historical data elements, such as the external cause-of-injury code; 4) easy access to data that can be parsed into smaller jurisdictions (such as states) for policy and/or research purposes, while maintaining confidentiality; and 5) linkages between health survey data and health claims data. ED-related data sets contain much data collected directly from health care facilities, individual patient records, and multiple other sources that have significant potential impact for studying and improving the health of individuals and the population.     

Implantable Defibrillator Diagnostic Storage Capabilities: Evolution, Current Status, and Future Utilization

There has been a rapid and significant evolution in the stored diagnostic information available from implantable cardioverter defibrillatars (ICDs). The diagnostic information available in current generation ICDs has greatly enhanced the clinicians' ability to determine the rhythm triggering device therapy as well as to identify potential problems with the ICD system. Furthermore, this information may be useful in identifying triggers of ventricular arrhythmias in patients at high risk for sudden death. The history, evolution, value, and limitations of the stored diagnostic capabilities of implantable defibrillators are discussed.     

Chronic Daily Headache in Children and Adolescents:Current Status and Recommendations for the Future

The Pediatric Committee of the American Association for the Study of Headache was created in 1994 to develop a plan for comprehensively addressing global issues of headache in childhood. It was the impression of clinicians and researchers with an interest in childhood headaches that a clearer focus was needed to facilitate progress in the study and management of pediatric headache. It was further felt that approaches to treatment and outcomes, as well as assessment and classification schema for pediatric patients needed to be examined separately. The goal of the committee is to integrate anecdotal, clinical, and research expertise into a plan for addressing headaches in the pediatric population in the future. During the last 5 years, substantial attention has been devoted to chronic daily headache, primarily in adult populations. It is the purpose of this paper to review the literature of chronic daily headache in children, and propose areas for further exploration, given the recent emergence of interest in this diagnostic entity.     

Antibody-based candidate therapeutics against HIV-1: implications for virus eradication and vaccine design

Introduction: The currently available anti-HIV-1 drugs can control the infection but do not eradicate the virus. Their long-term use can lead to side effects and resistance to therapy. Therefore, eradication of the virus has been a major goal of research. Biological therapeutics including broadly neutralizing monoclonal antibodies (bnAbs) are promising tools to reach this goal. They could also help design novel vaccine immunogens potentially capable of eliciting bnAbs targeting the HIV-1 envelope glycoproteins (Envs).

Areas covered: We review HIV-1 bnAbs and their potential as candidate prophylactics and therapeutics used individually, in combination, or as bispecific fusion proteins. We also discuss their potential use in the ‘activation-elimination' approach for HIV-1 eradication in infected patients receiving antiretroviral treatment as well as current vaccine design efforts based on understanding of interactions of candidate vaccine immunogens with matured bnAbs and their putative germline predecessors, and related antibody maturation pathways.

Expert opinion: Exploration of HIV-1 bnAbs has provided and will continue to provide useful knowledge that helps develop novel types of biotherapeutics and vaccines. It is possible that bnAb-based candidate therapeutics could help eradicate HIV-1. Development of vaccine immunogens capable of eliciting potent bnAbs in humans remains a fundamental challenge.     

HER3, serious partner in crime: Therapeutic approaches and potential biomarkers for effect of HER3-targeting

The human epidermal growth factor receptor (HER) family members are targeted by a growing numbers of small molecules and monoclonal antibodies. Resistance against the epidermal growth factor receptor (EGFR) and HER2-targeting agents is a clinically relevant problem forcing research on optimizing targeting of the HER family. In view of its overexpression in tumors, and compensatory role in HER signaling, HER3 has gained much interest as a potential additional target within the HER family. It is the only member of the HER family lacking intrinsic tyrosine kinase activity and therefore its role in cancer has long been underestimated. Drugs that block HER3 or interfere with HER3 dimer signaling, including fully human anti-HER3 antibodies, bispecific antibodies and tyrosine kinase inhibitors (TKIs), are currently becoming available. Several compounds have already entered clinical trial. In the meantime potential biomarkers are tested such as tumor analysis of HER3 expression, functional assays for downstream effector molecules and molecular imaging techniques. This review describes the biology and relevance of HER3 in cancer, agents targeting HER3 and potential biomarkers for effect of HER3-targeting.     

Use of Targeted Therapeutics in Epithelial Ovarian Cancer: A Review of Current Literature and Future Directions

Purpose

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions.

Severe acute respiratory syndrome coronavirus entry into host cells: Opportunities for therapeutic intervention

A novel human coronavirus (CoV) has been identified as the etiological agent that caused the severe acute respiratory syndrome (SARS) outbreak in 2003. The spike (S) protein of this virus is a type I surface glycoprotein that mediates binding of the virus to the host receptor and the subsequent fusion between the viral and host membranes. Because of its critical role in viral entry, the S protein is an important target for the development of anti-SARS CoV therapeutics and prophylactics. This article reviews the structure and function of the SARS CoV S protein in the context of its role in virus entry. Topics that are discussed include: the interaction between the S1 domain of the SARS spike protein and the cellular receptor, angiotensin converting enzyme 2 (ACE2), and the structural features of the ectodomain of ACE2; the antigenic determinants presented by the S protein and the nature of neutralizing monoclonal antibodies that are elicited in vivo; the structure of the 4,3-hydrophobic heptad repeats HR1 and HR2 of the S2 domain and their interaction to form a six-helical bundle during the final stages of fusion. Opportunities for the design and development of anti-SARS agents based on the inhibition of receptor binding, the therapeutic uses of S-directed monoclonal antibodies and inhibitors of HR1-HR2 complex formation are presented.