Molecular and Cellular Therapies

Neural stem cells (NSCs) offer a unique and powerful tool for basic research and regenerative medicine. However, the challenges that scientists face in the comprehension of the biology and physiological function of these cells are still many. Deciphering NSCs fundamental biological aspects represents indeed a crucial step to control NSCs fate and functional integration following transplantation, and is essential for a safe and appropriate use of NSCs in injury/disease conditions. In this review, we focus on the biological properties of NSCs and discuss how these cells may be exploited to provide effective therapies for neurological disorders...

BACKGROUND: We recently synthesized a hydrophilic polymer, poly(N-(2-hydroxypropyl)methacrylamide-co-N-(3-azidopropyl)methacrylamide), p(HPMA-co-AzMA), by RAFT polymerization using a novel azide-containing methacrylamide monomer that through a post modification strategy using click chemistry enabled facile preparation of a panel of versatile and well-defined bioconjugates. In this work we screen a panel of different molecular weight (Mw) fluorescently tagged p(HPMA-co-AzMA) in healthy mice, by live bioimaging, to select an extended circulatory half-life material for investigating joint accumulation in a murine collagen antibody-induced arthritis model...

The Wnt/β-catenin signaling pathway is crucial in animal development from sponges to humans. Its activity in the adulthood is less general, with exceptions having huge medical importance. Namely, improper activation of this pathway is carcinogenic in many tissues, most notably in the colon, liver and the breast. On the other hand, the Wnt/β-catenin signaling must be re-activated in cases of tissue damage, and insufficient activation results in regeneration failure and degeneration. These both medically important implications are unified by the emerging importance of this signaling pathway in the control of proliferation of various types of stem cells, crucial for tissue regeneration and, in case of cancer stem cells - cancer progression and relapse...

Advancements in human genomics over the last two decades have shown that cancer is mediated by somatic aberration in the host genome. This discovery has incited enthusiasm among cancer researchers; many now use therapeutic approaches in genetic manipulation to improve cancer regression and find a potential cure for the disease. Such gene therapy includes transferring genetic material into a host cell through viral (or bacterial) and non-viral vectors, immunomodulation of tumor cells or the host immune system, and manipulation of the tumor microenvironment, to reduce tumor vasculature or to increase tumor antigenicity for better recognition by the host immune system...

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by the selective degeneration of defined subgroups of motoneuron in the brainstem, spinal cord and motor cortex with signature hallmarks of mitochondrial Ca(2+) overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium, and in particular low cytosolic calcium ([Ca(2+)]c) buffering and a strong interaction between metabolic mechanisms and [Ca(2+)]i have been identified predominantly in motoneuron impairment, the causes of these disruptions are unknown...

Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies...

Despite ongoing research efforts and attempts to bring new drugs into trial, the prognosis for brain tumors remains poor. Patients with the most common and lethal intracranial neoplasia, glioblastoma multiforme (GBM), have an average survival of one year with combination of surgical resection, radiotherapy and temozolomide. One of the main problems in the treatment of GBM is getting drugs across the blood brain barrier (BBB) efficiently. In an attempt to solve this problem, there are ongoing experimental and clinical trials to deliver drugs within stem cells...

Oligodendrocyte precursor cells (OPCs) have shown high promise as a transplant population to promote regeneration in the central nervous system, specifically, for the production of myelin - the protective sheath around nerve fibers. While clinical trials for these cells have commenced in some areas, there are currently key barriers to the translation of neural cell therapies. These include the ability to (a) image transplant populations in vivo; (b) genetically engineer transplant cells to augment their repair potential; and (c) safely target cells to sites of pathology...

The Wnt signaling pathway is long known to play fundamental roles in various aspects of embryonic development, but also in several homeostatic processes controlling tissue functions in adults. The complexity of this system is best underscored by the fact that the mammalian genome encodes for 19 different Wnt ligands, most but not all of them acting through an intracellular stabilization of β-catenin, representing the key molecule within the so-called canonical Wnt signaling pathway. Wnt ligands primarily bind to 10 different serpentine receptors of the Fzd family, and this binding can be positively or negatively regulated by additional molecules present at the surface of the respective target cells...

Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM...

Defining how HIV does, and does not, kill the host CD4 T cell that it infects is of paramount importance in an era when research is approaching a cure for infection. Three mutually exclusive pathways can lead to the death of HIV-infected cells during the HIV life cycle, before, coincident and after HIV integration and consequently may affect viral replication. We discuss the molecular mechanism underlying these pathways, the evidence supporting their roles in vivo, and contemplate how understanding these pathways might inform novel approaches to promote viral cure of HIV...

Progress is being made in developing neuroprotective strategies for traumatic brain injuries; however, there will never be a therapy that will fully preserve neurons that are injured from moderate to severe head injuries. Therefore, to restore neurological function, regenerative strategies will be required. Given the limited regenerative capacity of the resident neural precursors of the CNS, many investigators have evaluated the regenerative potential of transplanted precursors. Unfortunately, these precursors do not thrive when engrafted without a biomaterial scaffold...

There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease...

Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance...

Membrane transporters play critical roles in moving a variety of anticancer drugs across cancer cell membrane, thereby determining chemotherapy efficacy and/or toxicity. The retention of anticancer drugs in cancer cells is the result of net function of efflux and influx transporters. The ATP-binding cassette (ABC) transporters are mainly the efflux transporters expressing at cancer cells, conferring the chemo-resistance in various malignant tumors, which has been well documented over the past decades. However, the function of influx transporters, in particular the solute carriers (SLC) in cancer cells, has only been recently well recognized to have significant impact on cancer therapy...

Tumour cells create their own microenvironment where they closely interact with a variety of soluble and non-soluble molecules, different cells and numerous other components within the extracellular matrix (ECM). Interaction between tumour cells and the ECM is bidirectional leading to either progression or inhibition of tumourigenesis. Therefore, development of novel therapies targeted primarily to tumour microenvironment (TME) is highly rational. Here, we give a short overview of different macromolecules of the ECM and introduce mechanisms whereby they contribute to tumourigenesis within the TME...

Over recent years, there has been a great deal of interest in the prospects of stem cell-based therapies for the treatment of nervous system disorders. The eagerness of scientists, clinicians, and spin-out companies to develop new therapies led to premature clinical trials in human patients, and now the initial excitement has largely turned to skepticism. Rather than embracing a defeatist attitude or pressing blindly ahead, I argue it is time to evaluate the challenges encountered by regenerative medicine in the central nervous system and the progress that is being made to solve these problems...

BACKGROUND: Although the host gene expression in the context of HIV has been explored by several studies, it remains unclear how HIV is able to manipulate and subvert host gene machinery before and after highly active antiretroviral therapy (HAART) in the same individual. In order to define the underlying pharmaco-genomic basis of HIV control during HAART and genomic basis of immune deterioration prior to HAART initiation, we performed a genome-wide expression analysis using primary peripheral blood mononuclear cells (PBMC) derived from 14 HIV + subjects pre-highly active antiretroviral therapy (HAART) (time point-1 or TP1) with detectable plasma viremia and post-HAART (time point-2 or TP2) with effective control of plasma viremia (<40 HIV RNA copies/mL of plasma)...

Human immunodeficiency virus (HIV) is still a serious global health concern responsible for more than 25 million deaths in last three decades. More than 34 million people are living with HIV infection. Macrophages and CD4+ T cells are the principal targets of HIV-1. The pathogenesis of HIV-1 takes different routes in macrophages and CD4+ T cells. Macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time. In addition, macrophages being present in every organ system thus can disseminate virus to the different anatomical sites leading to the formation of viral sanctuaries...

Currently there is significant scientific effort being directed at developing ways to create either a sterilizing cure, or functional cure for HIV infection. Multiple approaches are being evaluated under the broad headings of gene therapy, immune based interventions, and treatments which depend upon HIV reactivation from latency to cause the death of cells which harbor the virus. Molecular and Cellular Therapies (MCT) welcomes all manuscripts devoted to increasing our understanding of determinants of affecting a cure for HIV and mechanistic studies determine the cellular and viral interventions necessary for achieving HIV cure...