Restorative cell therapy for Parkinson's disease: a quest for the perfect cell

The development of a cell therapy for the neurodegenerative disorder Parkinson's disease is a realistic ambition. It is pursued by researchers and companies alike, and spans different donor tissue types of embryonic, fetal and adult origins. In this review, we briefly outline the past and current status of research and clinical trials with cell transplantation in Parkinson's disease. We discuss studies on donor tissue derived from embryonic ventral mesencephalon and assess the current research on various forms of stem cells of both embryonic and adult origins in the quest to develop a cell-based therapy for this debilitating movement disorder.     

Challenges in cancer research and multifaceted approaches for cancer biomarker quest

Recent advances in cancer biology have subsequently led to the development of new molecularly targeted anti-cancer agents that can effectively hit cancer-related proteins and pathways. Despite better insight into genomic aberrations and diversity of cancer phenotypes, it is apparent that proteomics too deserves attention in cancer research. Currently, a wide range of proteomic technologies are being used in quest for new cancer biomarkers with effective use. These, together with newer technologies such as multiplex assays could significantly contribute to the discovery and development of selective and specific cancer biomarkers with diagnostic or prognostic values for monitoring the disease state. This review attempts to illustrate recent advances in the field of cancer biomarkers and multifaceted approaches undertaken in combating cancer.     

Proteomics of breast cancer: the quest for markers and therapeutic targets

Proteomics of breast cancer has already delivered significant data in terms of proteome profiling in addition to the identification of a few proteins of potential interest for diagnosis and treatment. With more pathological and experimental situations being studied, it now enters into a new phase dominated by the concepts of deep proteome analysis and the definition of protein-protein interaction networks leading to mammary cell deregulation and cancer progression. Together, what could be called "Systems Proteomics", integrating with information from the genomics and the physiopathology, is clearly emerging to become the frame for future investigations. However, difficulties ahead should not be underestimated. First, the proteome is complex, and current tools are still far from providing a definitive solution for its exploration. Second, breast cancer is a multifactorial disease which is so diverse that a great deal of time and efforts will be necessary to define its associated proteome modifications and translate it into practical applications for the clinic.     

The quest for a humanori

Attempts at identifying DNA replication origins in human cells have been performed with a variety of molecular genetic and biochemical approaches, with often controversial results.The combination of bromodeoxyuridine labelling, immunopurification of newly synthesized labelled DNA, measurement of the relative abundance of markers in this DNA by quantitative competitive PCR, has allowed the identification within 450 bp of the start-site of DNA replication located at the human lamin B2 gene. The origin is located near the non-transcribed spacer between two highly transcribed genes and shows evidence of a number of specific protein-DNA interactions, the most prominent of which disappears when the cells are differentiated into a non-proliferating state.     

Systems biology and combination therapy in the quest for clinical efficacy

Combinatorial control of biological processes, in which redundancy and multifunctionality are the norm, fundamentally limits the therapeutic index that can be achieved by even the most potent and highly selective drugs. Thus, it will almost certainly be necessary to use new 'targeted' pharmaceuticals in combinations. Multicomponent drugs are standard in cytotoxic chemotherapy, but their development has required arduous empirical testing. However, experimentally validated numerical models should greatly aid in the formulation of new combination therapies, particularly those tailored to the needs of specific patients. This perspective focuses on opportunities and challenges inherent in the application of mathematical modeling and systems approaches to pharmacology, specifically with respect to the idea of achieving combinatorial selectivity through use of multicomponent drugs.     

TRAIL: a potential agent for cancer therapy

Induction of apoptosis in cancer cells with chemotherapy and radiation treatment is a major strategy in cancer therapy at present. Nevertheless, innate or acquired resistance has been an obstacle for conventional clinical therapy. TNF-related apoptosis inducing ligand (TRAIL/Apo-2L) is a typical member of the TNF ligand family that induces apoptosis through activating the death receptors. In recent years, considerable attention has been focused on the potential benefits of TRAIL in cancer therapy, as the majority of cancer cells are sensitive to TRAIL-induced apoptosis, while most normal cells are TRAIL-resistant. Furthermore, the use of TRAIL in combination with chemotherapeutic agents or irradiation strengthens its apoptotic effects. In this review, we will discuss the regulation mechanism of TRAIL-induced apoptosis and the molecular basis of the synergies created by its use in combination with chemotherapeutic agents and irradiation. We also analyze in detail that TRAIL may be cytotoxic, as this is a potential obstacle to its development for being used in cancer therapy.     

Advances in ovarian cancer proteomics: the quest for biomarkers and improved therapeutic interventions

Epithelial ovarian cancer is the leading cause of cancer-related death among gynecological cancers due to the asymptomatic nature of the disease, a lack of early detection markers and the development of resistance to current chemotherapeutic agents. Currently available tests (CA-125, transvaginal ultrasound or combination of both) lack the sensitivity and specificity to be useful as an efficient screening tool for surveillance of the general population. Thus, there is an urgent need for the development and validation of new molecular markers that would be both specific and sensitive indicators of disease onset, as well as progression. Proteomic profiling has emerged as a powerful tool to study ovarian cancer in an unbiased way at the molecular level, to monitor the effects of given treatment options and for the discovery of biomarkers. In this review we discuss the challenges associated with proteomics-based biomarker discovery and some recent concepts to potentially overcome these hurdles. Recent proteomics work on ovarian cancer cells and tissues will be discussed in light of obtaining new insights into fundamental biological processes, as well as their potential integration with ongoing biomarker discovery pipelines.     

The quest for personalized B-cell depletion therapy in rheumatic disease

Although B cell depletion therapy (BCDT) is now a well-accepted therapeutic option in autoimmune rheumatic disease, a significant proportion of patients remain resistant to therapy. .19pt?>A more challenging clinical problem is the high rate of relapse after B cell reconstitution, as well as the difficulty in predicting the exact timing of that relapse. In this article, we consider the immunological mechanisms that may account for the heterogeneity of clinical response to BCDT. Understanding how BCDT alters the balance between different B cell subsets, some pathogenic and some regulatory, may help us correctly target BCDT to the right patients, and thereby improve treatment responses in rheumatic disease.The identification of autoantibodies in the serum of patients with rheumatic disease was one of the landmark studies that placed B cells at the heart of research into the pathogenesis of autoimmune disease. It is now clear that B cells contribute to autoimmunity by a range of mechanisms, both directly through the secretion of inflammatory cytokines [1] and indirectly by antigen presentation and co-stimulation to activate autoreactive T cells. However, it was only at the beginning of the last decade that attention finally turned to B cells as a potential target that may ameliorate autoimmune rheumatic disease.     

Advances in ovarian cancer proteomics: the quest for biomarkers and improved therapeutic interventions

Epithelial ovarian cancer is the leading cause of cancer-related death among gynecological cancers due to the asymptomatic nature of the disease, a lack of early detection markers and the development of resistance to current chemotherapeutic agents. Currently available tests (CA-125, transvaginal ultrasound or combination of both) lack the sensitivity and specificity to be useful as an efficient screening tool for surveillance of the general population. Thus, there is an urgent need for the development and validation of new molecular markers that would be both specific and sensitive indicators of disease onset, as well as progression. Proteomic profiling has emerged as a powerful tool to study ovarian cancer in an unbiased way at the molecular level, to monitor the effects of given treatment options and for the discovery of biomarkers. In this review we discuss the challenges associated with proteomics-based biomarker discovery and some recent concepts to potentially overcome these hurdles. Recent proteomics work on ovarian cancer cells and tissues will be discussed in light of obtaining new insights into fundamental biological processes, as well as their potential integration with ongoing biomarker discovery pipelines.     

Stem cell biology: a never ending quest for understanding

Stem cells (SC) research is an important part of biotechnology that could lead to the development of new therapeutic strategies. A lot of effort has been put to understand biology of the stem cells and to find genes and subsequently proteins that are responsible for their proliferation, self-renewal and differentiation. Different cytokines and growth factors has been used to expand stem cells, but no combination of these factors was identified that could effectively expand the most primitive stem cells. Recently, however, genes and receptors responsible for SC proliferation and differentiation have been described. Ligands for these receptors or these genes themselves are being already used for ex vivo expansion of stem cells and the first data are very promising. New markers, such as CXCR4 and CD133, have been discovered and shown to be present on surface of hematopoietic stem cells. The same markers were recently also found to be expressed on neuronal-, hepatic- or skeletal muscle-stem cells. By employing these markers several laboratories are trying to isolate stem cells for potential clinical use. New characteristics of stem cells such as transdifferentiation and cell fusion have been described. Our team has identified a population of tissue committed stem cells (TCSC). These cells are present in a bone marrow and in other tissues and they can differentiate into several cell types including cardiac, neural and liver cells.     

Glycolysis in cancer: a potential target for therapy

Clinical imaging of primary and metastatic cancers with Fluoro deoxy-d-Glucose Positron Emission Tomography (FdG PET) has clearly demonstrated that increased glucose flux compared to normal tissue is a common trait of human malignancies (Gambhir, 2002) This is a consequence of a shift of glucose metabolism to less efficient glycolytic pathways in response to regional hypoxia and evolution of aerobic glycolysis in many cancer phenotypes. This distinctive metabolic profile presents an inviting target for cancer treatment and prevention. Here, we summarize the therapeutic strategies under investigation to exploit or interrupt tumor glycolytic metabolism. Although a number of approaches are under investigation, none has been sufficiently successful to warrant widespread clinical application. We point out that the environmental heterogeneity and evolutionary capacity of tumor cells that likely led to development of upregulated glycolysis could also promote adaptive strategies that confer resistance to therapies designed to inhibit glucose metabolism.     

Genetic transformation of mosquitoes: a quest for malaria control

Malaria inflicts an enormous toll in human lives and this burden is increasing. Present means to fight the disease, such as drugs and insecticides, are insufficient. Moreover, an effective vaccine has not yet been developed. This review examines an alternative strategy for malaria control, namely the genetic modification of mosquitoes to make them inefficient vectors for the parasite. The article summarises progress made toward the development of transposable element vectors for germ line transformation and the search for mosquito markers of transformation. Also reviewed is the search for anti-malarial effector genes whose products can inhibit development of the parasite in the mosquito with minimal fitness burden. While much progress has been made, much work remains to be done. Future research directions are discussed.     

The quest for florigen: a review of recent progress

The photoperiodic induction of flowering is a systemic process requiring translocation of a floral stimulus from the leaves to the shoot apical meristem. In response to this stimulus, the apical meristem stops producing leaves to initiate floral development; this switch in morphogenesis involves a change in the identity of the primordia initiated and in phyllotaxis. The physiological study of the floral transition has led to the identification of several putative floral signals such as sucrose, cytokinins, gibberellins, and reduced N-compounds that are translocated in the phloem sap from leaves to the shoot apical meristem. On the other hand, the genetic approach developed more recently in Arabidopsis thaliana allowed the discovery of many genes that control flowering time. These genes function in 'cascades' within four promotive pathways, the 'photoperiodic', 'autonomous', 'vernalization', and 'gibberellin' pathways, which all converge on the 'integrator' genes SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1) and FLOWERING LOCUS T (FT). Recently, several studies have highlighted a role for a product of FT as a component of the floral stimulus or 'florigen'. These recent advances and the proposed mode of action of FT are discussed here.     

Mouse models of Alzheimer's disease: a quest for plaques and tangles

Many genetically altered mice have been designed to help understand the role of specific gene mutations in the pathogenesis of Alzheimer's disease (AD) based on the realization that specific mutations in the genes for amyloid precursor protein--the presenilins and tau--are associated with early-onset familial AD or, in the case of tau mutations, other neurodegenerative diseases with neurofibrillary tangles. However, attempts to reproduce the neuropathology of AD in the mouse have been frustrating. Transgenic designs emphasizing amyloid precursor protein produced mice that develop amyloid plaques, but neurodegeneration and neurofibrillary tangles failed to form. Strategies emphasizing tau resulted in increased phosphorylation of tau and tangle formation, although amyloid plaques were absent. Nevertheless, crossing transgenic animals expressing mutated tau and amyloid precursor protein has produced a mouse that closely recapitulates the neuropathology of AD. A review of the various murine models, their role in understanding the pathogenesis of AD and their use in testing therapeutic regimens, is provided.     

Polymersomes: a new multi-functional tool for cancer diagnosis and therapy

Nanoparticles are being developed as delivery vehicles for therapeutic pharmaceuticals and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties that make them ideal for these applications. Synthetic control over block copolymer chemistry enables tunable design of polymersome material properties. The polymersome architecture, with its large hydrophilic reservoir and its thick hydrophobic lamellar membrane, provides significant storage capacity for both water soluble and insoluble substances (such as drugs and imaging probes). Further, the brush-like architecture of the polymersome outer shell can potentially increase biocompatibility and blood circulation times. A further recent advance is the development of multi-functional polymersomes that carry pharmaceuticals and imaging agents simultaneously. The ability to conjugate biologically active ligands to the brush surface provides a further means for targeted therapy and imaging. Hence, polymersomes hold enormous potential as nanostructured biomaterials for future in vivo drug delivery and diagnostic imaging applications.