From bedside to bench to clinic trials: identifying new treatments for severe asthma

Asthmatics with a severe form of the disease are frequently refractory to standard medications such as inhaled corticosteroids, underlining the need for new treatments to prevent the occurrence of potentially life-threatening episodes. A major obstacle in the development of new treatments for severe asthma is the heterogeneous pathogenesis of the disease, which involves multiple mechanisms and cell types. Furthermore, new therapies might need to be targeted to subgroups of patients whose disease pathogenesis is mediated by a specific pathway. One approach to solving the challenge of developing new treatments for severe asthma is to use experimental mouse models of asthma to address clinically relevant questions regarding disease pathogenesis. The mechanistic insights gained from mouse studies can be translated back to the clinic as potential treatment approaches that require evaluation in clinical trials to validate their effectiveness and safety in human subjects. Here, we will review how mouse models have advanced our understanding of severe asthma pathogenesis. Mouse studies have helped us to uncover the underlying inflammatory mechanisms (mediated by multiple immune cell types that produce Th1, Th2 or Th17 cytokines) and non-inflammatory pathways, in addition to shedding light on asthma that is associated with obesity or steroid unresponsiveness. We propose that the strategy of using mouse models to address clinically relevant questions remains an attractive and productive research approach for identifying mechanistic pathways that can be developed into novel treatments for severe asthma.     

The new ParaDIgm: IgM from bench to clinic

The inaugural IgM event entitled “The new ParaDIgm: IgM from bench to clinic” brought together the increasingly active and growing IgM antibody community to discuss recent advances and challenges facing the discovery and development of IgM antibody therapies and technologies. Researchers, clinicians and biomanufacturing experts delivered 21 talks on the basic science and isolation of IgM, upstream and downstream development, and formulation and clinical development of the molecules. Participants networked around topics aimed at exploring the full potential of IgM antibodies. The meeting was held at DECHEMA Gesellschaft für Chemische Technik und Biotechnologie e. V. (Society for Chemical Engineering and Biotechnology), a non-profit scientific and technical society based in Frankfurt am Main, Germany. The meeting was sponsored by Patrys, Laureate Biopharma, Bio-Rad Laboratories, BIA Separations, Percivia and the Bio Affinity Company (BAC). The second New ParaDIgm: IgM from bench to clinic meeting, will be held on April 23–24, 2013 in Frankfurt, Germany.     

Human serum albumin: from bench to bedside

Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multi-domain macromolecule, representing the main determinant of plasma oncotic pressure and the main modulator of fluid distribution between body compartments. HSA displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds. Indeed, HSA represents the main carrier for fatty acids, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays (pseudo-)enzymatic properties. HSA is a valuable biomarker of many diseases, including cancer, rheumatoid arthritis, ischemia, post-menopausal obesity, severe acute graft-versus-host disease, and diseases that need monitoring of the glycemic control. Moreover, HSA is widely used clinically to treat several diseases, including hypovolemia, shock, burns, surgical blood loss, trauma, hemorrhage, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, nutrition support, resuscitation, and hypoalbuminemia. Recently, biotechnological applications of HSA, including implantable biomaterials, surgical adhesives and sealants, biochromatography, ligand trapping, and fusion proteins, have been reported. Here, genetic, biochemical, biomedical, and biotechnological aspects of HSA are reviewed.     

Lutein and cataract: from bench to bedside

Cataract is one of the most important leading causes of blindness in the world. Extensive research showed that oxidative stress may play an important role in the initiation and progression of a cataract and other age-related eye diseases. Extra-generation of reactive oxygen and nitrogen species in the eye tissue has been shown as one of the most important risk factors for cataracts and other age-related eye diseases. With respect to this, it can be hypothesized that dietary antioxidants may be useful in the prevention and/or mitigation of cataract. Lutein is an important xanthophyll which is widely found in different vegetables such as spinach, kale and carrots as well as some other foods such as eggs. Lutein is concentrated in the macula and suppresses the oxidative stress in the eye tissues. A plethora of literature has shown that increased lutein consumption has a close correlation with reduction in the incidence of cataract. Despite this general information, there is a negligible number of review articles considering the beneficial effects of lutein on cataracts and age-related eye diseases. The present review is aimed at discussing the role of oxidative stress in the initiation and progression of a cataract and the possible beneficial effects of lutein in maintaining retinal health and fighting cataract. We also provide a perspective on the chemistry, sources, bioavailability and safety of lutein.     

The molecular basis of erectile dysfunction: from bench to bedside

Erectile dysfunction is a common problem affecting many men across all age groups. Its etiology is multifactorial. Hormonal, vascular, neurogenic, lifestyle, and psychological entities have all been implicated as causative agents. The molecular basis underlying its etiology and progression is complex and still challenges researchers in the field. Nonetheless, newly discovered common pathways and targets of its pathogenesis have opened a new era for both prevention and active treatment of the disease. This review describes some of the known molecular mechanisms contributing to erectile dysfunction and discusses the future of gene therapy for the disease.     

无绿藻的研究进展:从基础到临床

无绿藻是一种直径约3 ～ 30 μm的单细胞生物,广泛存在于自然界和动物体表及体内,属于条件致病性真菌.目前主要通过直接镜检、真菌培养、组织病理学检查及分子生物学等手段对无绿藻进行鉴定.现已发现无绿藻属包括五个种,其中对人有致病性的仅为中型无绿藻基因型2、小型无绿藻和P.blaschkeae,其致病机制可能与外伤和免疫力低下有关.随着研究的深入,越来越多的无绿藻病被临床确诊.根据不同的类型及其临床表现,对无绿藻病的治疗也有所区别.为了提高对无绿藻这一条件真菌及其致病性的认识,该文对其生物学特性、鉴定方法、致病性、临床表现等研究进展做一简要综述.     

Tissue engineering for full-thickness burns: a dermal substitute from bench to bedside

Our aim was to obtain a viable and easily available dermal substitute (DS) for the definitive coverage of full-thickness burns. A DS composed of a collagen-glycosaminoglycan-chitosan dermal matrix (DM) colonized with foreskin fibroblasts (FF) is described. FF-colonized DS were compared to the DM seeded with adult dermal fibroblasts (DF). FF-colonized DS expressed more fibrillin and tropoelastin than that with DF. Reconstructed skin obtained with both FF- and DF-colonized DS similarly expressed laminin-5 and collagen VII at the dermal-epidermal junction. Both FF- and DF-colonized DS produced cutaneous wound healing mediators in a dose-dependent manner in the presence of platelet lysate. After freeze-thawing, the FF-colonized DS were recovered in culture and retained their ability to produce vascular endothelial growth factor. Grafting of DS into nude rats achieved a complete healing of a dermal-epidermal lesion with a good epidermalization.     

Mitochondrial gene therapy: The tortuous path from bench to bedside

The association of mitochondrial dysfunction with a variety of human diseases and disabilities has been documented. Mitochondrial gene therapy (MGT) seeks to correct the genetic defect in mitochondrial DNA. For successful MGT, an appreciation of the nature of the dysfunction and of the complexities of mitochondrial disease is necessary. This review summarizes the current status of various MGT protocols described in the literature. Although there are many technical difficulties to be overcome, there are indications that some of them will find clinical applications in the near future.     

The human ATP-binding cassette transporter genes: from the bench to the bedside

ATP-binding cassette (ABC) transporter genes are ubiquitously present in most organisms from bacteria to man. This gene family is the largest one known as of yet. Still growing, the number of human ABC transporters counts currently 47 members which belong to seven subfamilies. ABC transporters share a similar molecular architecture: (1) Full-structured transporters harbor two symmetric halves each consisting of one nucleotide binding domain (NBD) and one transmembrane domain (TMD). (2) Half-transporters with one NBD and one TMD homo- or heterodimerize to functional transporter complexes. ABC transporters are "traffic ATPases" which hydrolyze ATP and which transport a wide array of molecules or conduct the transport of molecules by stimulating other translocation mechanisms. Many ABC transporters are involved in human inherited or sporadic diseases such as cystic fibrosis, adrenoleukodystrophy, Stargardt's disease, drug-resistant tumors, Dubin-Johnson syndrome, Byler's disease, progressive familiar intrahepatic cholestasis, X-linked sideroblastic anemia and ataxia, persistent hyperinsulimenic hypoglycemia of infancy, and others. The present review summarizes the current findings in basic research and the efforts for bridging the gap to clinical applications in therapy and diagnostics.     

Advances in infection and immunity: from bench to bedside

This report summarizes recent advances on host-pathogen interactions, innate and adaptive responses to infection, as well as novel strategies for the control of infectious diseases.     

泛素介导的蛋白质降解系统——从基础研究到临床应用

20世纪60～80年代,大多数生物科研人员都致力于核酸和遗传信息传递的研究。蛋白质降解被认为是非特异的过程,因此没有人感兴趣。泛素修饰的发现使蛋白质降解领域发生革命性的变化,人们逐渐认识到蛋白质降解是一个特异的受严格调控的过程。细胞内蛋白质降解事件的发生会调节许多生命过程,如细胞增殖、分化、衰老和死亡。细胞内蛋白质降解调控异常也会引发多种疾病,包括癌症和神经退行性疾病。人们对细胞内蛋白质降解的研究已经取得一定成果,但是还有很多问题没有解决,全面解读该过程还需要更多的努力和探索。     

Dendritic cells: On the move from bench to bedside.

As dendritic cells increasingly become the adjuvant of choice in new approaches to cancer immunotherapy, a degree of protocol standardization is required to aid future large-scale clinical trials.     

Emergency bedside cesarean delivery: lessons learned in teamwork and patient safety

ABSTRACT: BACKGROUND: Maternal cardiovascular and pulmonary events during labor and delivery may result in adverse maternal and fetal outcome. Potential etiologies include primary cardiac events, pulmonary embolism, eclampsia, maternal hemorrhage, and adverse medication events. Remifentanil patient-controlled analgesia is an alternative when conventional neuraxial analgesia for labor is contraindicated. Although remifentanil is a commonly used analgesic, its use for labor analgesia is not clearly defined. CASE PRESENTATION: We present an unexpected and unique case of remifentanil toxicity resulting in the need for an emergent bedside cesarean delivery. A 30-year-old G3P2 woman receiving subcutaneous heparin anticoagulation due to a recent deep vein thrombosis developed cardiopulmonary arrest during labor induction due to remifentanil toxicity. CONCLUSION: A rapid discussion among the attending obstetric, anesthesia, and nursing teams resulted in consensus to perform an emergent bedside cesarean delivery resulting in an excellent fetal outcome. During maternal cardiopulmonary arrest, a prompt decision to perform a bedside cesarean delivery is essential to avoid significant maternal and fetal morbidity. Under these conditions, rapid collaboration among obstetric, anesthesia, and nursing personnel, and an extensive multi-layered safety process are integral components to optimize maternal and fetal outcomes.     

Pro-inflammatory cytokines in acute coronary syndromes: from bench to bedside

Cytokines are produced in a variety of tissues and regulate the expression of a number of inflammatory molecules, leading to destabilization and finally rupture of vulnerable atheromatic plaques. They also participate in the pathophysiology of acute coronary syndromes (ACS) by direct effects on myocardial contractility and apoptosis. At a clinical level, circulating cytokines have a prognostic role since they are useful markers predicting future coronary events in patients with advanced atherosclerosis and in patients after ACS.