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Sample records for cell therapeutic research

  1. Genome editing in pluripotent stem cells: research and therapeutic applications

    Deleidi, Michela, E-mail: michela.deleidi@dzne.de [German Center for Neurodegenerative Diseases (DZNE) Tübingen within the Helmholtz Association, Tübingen (Germany); Hertie Institute for Clinical Brain Research, University of Tübingen (Germany); Yu, Cong [Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, New York (United States)

    2016-05-06

    Recent progress in human pluripotent stem cell (hPSC) and genome editing technologies has opened up new avenues for the investigation of human biology in health and disease as well as the development of therapeutic applications. Gene editing approaches with programmable nucleases have been successfully established in hPSCs and applied to study gene function, develop novel animal models and perform genetic and chemical screens. Several studies now show the successful editing of disease-linked alleles in somatic and patient-derived induced pluripotent stem cells (iPSCs) as well as in animal models. Importantly, initial clinical trials have shown the safety of programmable nucleases for ex vivo somatic gene therapy. In this context, the unlimited proliferation potential and the pluripotent properties of iPSCs may offer advantages for gene targeting approaches. However, many technical and safety issues still need to be addressed before genome-edited iPSCs are translated into the clinical setting. Here, we provide an overview of the available genome editing systems and discuss opportunities and perspectives for their application in basic research and clinical practice, with a particular focus on hPSC based research and gene therapy approaches. Finally, we discuss recent research on human germline genome editing and its social and ethical implications. - Highlights: • Programmable nucleases have proven efficient and specific for genome editing in human pluripotent stem cells (hPSCs). • Genome edited hPSCs can be employed to study gene function in health and disease as well as drug and chemical screens. • Genome edited hPSCs hold great promise for ex vivo gene therapy approaches. • Technical and safety issues should be first addressed to advance the clinical use of gene-edited hPSCs.

  2. Genome editing in pluripotent stem cells: research and therapeutic applications

    Deleidi, Michela; Yu, Cong

    2016-01-01

    Recent progress in human pluripotent stem cell (hPSC) and genome editing technologies has opened up new avenues for the investigation of human biology in health and disease as well as the development of therapeutic applications. Gene editing approaches with programmable nucleases have been successfully established in hPSCs and applied to study gene function, develop novel animal models and perform genetic and chemical screens. Several studies now show the successful editing of disease-linked alleles in somatic and patient-derived induced pluripotent stem cells (iPSCs) as well as in animal models. Importantly, initial clinical trials have shown the safety of programmable nucleases for ex vivo somatic gene therapy. In this context, the unlimited proliferation potential and the pluripotent properties of iPSCs may offer advantages for gene targeting approaches. However, many technical and safety issues still need to be addressed before genome-edited iPSCs are translated into the clinical setting. Here, we provide an overview of the available genome editing systems and discuss opportunities and perspectives for their application in basic research and clinical practice, with a particular focus on hPSC based research and gene therapy approaches. Finally, we discuss recent research on human germline genome editing and its social and ethical implications. - Highlights: • Programmable nucleases have proven efficient and specific for genome editing in human pluripotent stem cells (hPSCs). • Genome edited hPSCs can be employed to study gene function in health and disease as well as drug and chemical screens. • Genome edited hPSCs hold great promise for ex vivo gene therapy approaches. • Technical and safety issues should be first addressed to advance the clinical use of gene-edited hPSCs.

  3. New perspectives in human stem cell therapeutic research

    Trounson Alan

    2009-06-01

    Full Text Available Abstract Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating β islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for

  4. Synthetic biology in mammalian cells: Next generation research tools and therapeutics

    Lienert, Florian; Lohmueller, Jason J; Garg, Abhishek; Silver, Pamela A

    2014-01-01

    Recent progress in DNA manipulation and gene circuit engineering has greatly improved our ability to programme and probe mammalian cell behaviour. These advances have led to a new generation of synthetic biology research tools and potential therapeutic applications. Programmable DNA-binding domains and RNA regulators are leading to unprecedented control of gene expression and elucidation of gene function. Rebuilding complex biological circuits such as T cell receptor signalling in isolation from their natural context has deepened our understanding of network motifs and signalling pathways. Synthetic biology is also leading to innovative therapeutic interventions based on cell-based therapies, protein drugs, vaccines and gene therapies. PMID:24434884

  5. Developments in stem cell research and therapeutic cloning: Islamic ethical positions, a review.

    Fadel, Hossam E

    2012-03-01

    Stem cell research is very promising. The use of human embryos has been confronted with objections based on ethical and religious positions. The recent production of reprogrammed adult (induced pluripotent) cells does not - in the opinion of scientists - reduce the need to continue human embryonic stem cell research. So the debate continues. Islam always encouraged scientific research, particularly research directed toward finding cures for human disease. Based on the expectation of potential benefits, Islamic teachings permit and support human embryonic stem cell research. The majority of Muslim scholars also support therapeutic cloning. This permissibility is conditional on the use of supernumerary early pre-embryos which are obtained during infertility treatment in vitro fertilization (IVF) clinics. The early pre-embryos are considered in Islamic jurisprudence as worthy of respect but do not have the full sanctity offered to the embryo after implantation in the uterus and especially after ensoulment. In this paper the Islamic positions regarding human embryonic stem cell research and therapeutic cloning are reviewed in some detail, whereas positions in other religious traditions are mentioned only briefly. The status of human embryonic stem cell research and therapeutic cloning in different countries, including the USA and especially in Muslim countries, is discussed. © 2010 Blackwell Publishing Ltd.

  6. Human Pluripotent Stem Cell-Derived Cardiomyocytes as Research and Therapeutic Tools

    Ivana Acimovic

    2014-01-01

    Full Text Available Human pluripotent stem cells (hPSCs, namely, embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs, with their ability of indefinite self-renewal and capability to differentiate into cell types derivatives of all three germ layers, represent a powerful research tool in developmental biology, for drug screening, disease modelling, and potentially cell replacement therapy. Efficient differentiation protocols that would result in the cell type of our interest are needed for maximal exploitation of these cells. In the present work, we aim at focusing on the protocols for differentiation of hPSCs into functional cardiomyocytes in vitro as well as achievements in the heart disease modelling and drug testing on the patient-specific iPSC-derived cardiomyocytes (iPSC-CMs.

  7. Cell-based therapeutics from an economic perspective: primed for a commercial success or a research sinkhole?

    McAllister, Todd N; Dusserre, Nathalie; Maruszewski, Marcin; L'heureux, Nicolas

    2008-11-01

    Despite widespread hype and significant investment through the late 1980s and 1990s, cell-based therapeutics have largely failed from both a clinical and financial perspective. While the early pioneers were able to create clinically efficacious products, small margins coupled with small initial indications made it impossible to produce a reasonable return on the huge initial investments that had been made to support widespread research activities. Even as US FDA clearance opened up larger markets, investor interest waned, and the crown jewels of cell-based therapeutics went bankrupt or were rescued by corporate bailout. Despite the hard lessons learned from these pioneering companies, many of today's regenerative medicine companies are supporting nearly identical strategies. It remains to be seen whether or not our proposed tenets for investment and commercialization strategy yield an economic success or whether the original model can produce a return on investment sufficient to justify the large up-front investments. Irrespective of which approach yields a success, it is critically important that more of the second-generation products establish profitability if the field is to enjoy continued investment from both public and private sectors.

  8. Stem Cell Therapy and Breast Cancer Treatment: review of stem cell research and potential therapeutic impact against cardiotoxicities due to breast cancer treatment

    Thomas E. Sharp

    2014-11-01

    Full Text Available A new problem has emerged with the ever-increasing number of breast cancer survivors. While early screening and advances in treatment have allowed these patients to overcome their cancer, these treatments often have adverse cardiovascular side effects that can produce abnormal cardiovascular function. Chemotherapeutic and radiation therapy have both been linked to cardiotoxicity; these therapeutics can cause a loss of cardiac muscle and deterioration of vascular structure that can eventually lead to heart failure (HF. This cardiomyocyte toxicity can leave the breast cancer survivor with a probable diagnosis of dilated or restrictive cardiomyopathy (DCM or RCM. While current HF standard of care can alleviate symptoms, other than heart transplantation, there is no therapy that replaces cardiac myocytes that are killed during cancer therapies. There is a need to develop novel therapeutics that can either prevent or reverse the cardiac injury caused by cancer therapeutics. These new therapeutics should promote the regeneration of lost or deteriorating myocardium. Over the last several decades the therapeutic potential of cell-based therapy has been investigated for HF patients. In this review we discuss the progress of preclinical and clinical stem cell research for the diseased heart and discuss the possibility of utilizing these novel therapies to combat cardiotoxicity observed in breast cancer survivors.

  9. Advancing Stem Cell Biology toward Stem Cell Therapeutics

    Scadden, David; Srivastava, Alok

    2012-01-01

    Here, the International Society for Stem Cell Research (ISSCR) Clinical Translation Committee introduces a series of articles outlining the current status, opportunities, and challenges surrounding the clinical translation of stem cell therapeutics for specific medical conditions.

  10. Cell kinetics and therapeutic efficiency

    Andreeff, M.; Abenhardt, W.; Gruner, B.; Stoffner, D.; Mainz Univ.

    1976-01-01

    The study shows that cell kinetics effects correlate with the effects of cytostatic drugs in the tumour model investigated here. It should, however, be noted that even genetically related tumour cell types may react differently to the same cytostatic drug, and that the cell kinetics effects, due to the changes in the cell cycle, cannot be predicted but should be followed with a very fast method, e.g. sequential flan fluorescence cytophotometry, for optimal therapeutic results. (orig./GSE) [de

  11. Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

    Laffey, John G; Matthay, Michael A

    2017-08-01

    On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.

  12. Organoid technology for brain and therapeutics research.

    Wang, Zhi; Wang, Shu-Na; Xu, Tian-Ying; Miao, Zhu-Wei; Su, Ding-Feng; Miao, Chao-Yu

    2017-10-01

    Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics. © 2017 John Wiley & Sons Ltd.

  13. Allogenic banking of dental pulp stem cells for innovative therapeutics.

    Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

    2015-08-26

    Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.

  14. Therapeutic application of multipotent stem cells

    Mirzaei, Hamed; Sahebkar, Amirhossein; Sichani, Laleh Shiri

    2018-01-01

    Cell therapy is an emerging fields in the treatment of various diseases such as cardiovascular, pulmonary, hepatic, and neoplastic diseases. Stem cells are an integral tool for cell therapy. Multipotent stem cells are an important class of stem cells which have the ability to self-renew through...... been showed that multipotent stem cells exert their therapeutic effects via inhibition/activation of a sequence of cellular and molecular pathways. Although the advantages of multipotent stem cells are numerous, further investigation is still necessary to clarify the biology and safety of these cells...... before they could be considered as a potential treatment for different types of diseases. This review summarizes different features of multipotent stem cells including isolation, differentiation, and therapeutic applications....

  15. Merkel Cell Carcinoma Therapeutic Update.

    Cassler, Nicole M; Merrill, Dean; Bichakjian, Christopher K; Brownell, Isaac

    2016-07-01

    Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

  16. Therapeutic potential of adult stem cells

    Serakinci, Nedime; Keith, W. Nicol

    2006-01-01

    is the necessity to be able to identify, select, expand and manipulate cells outside the body. Recent advances in adult stem cell technologies and basic biology have accelerated therapeutic opportunities aimed at eventual clinical applications. Adult stem cells with the ability to differentiate down multiple...... lineages are an attractive alternative to human embryonic stem cells (hES) in regenerative medicine. In many countries, present legislation surrounding hES cells makes their use problematic, and indeed the origin of hES cells may represent a controversial issue for many communities. However, adult stem...... cells are not subject to these issues. This review will therefore focus on adult stem cells. Based on their extensive differentiation potential and, in some cases, the relative ease of their isolation, adult stem cells are appropriate for clinical development. Recently, several observations suggest...

  17. Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

    Balivada, Sivasai

    Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V

  18. Stem Cell Therapy and Breast Cancer Treatment: Review of Stem Cell Research and Potential Therapeutic Impact Against Cardiotoxicities Due to Breast Cancer Treatment

    Sharp, Thomas E.; George, Jon C.

    2014-01-01

    A new problem has emerged with the ever-increasing number of breast cancer survivors. While early screening and advances in treatment have allowed these patients to overcome their cancer, these treatments often have adverse cardiovascular side effects that can produce abnormal cardiovascular function. Chemotherapeutic and radiation therapy have both been linked to cardiotoxicity; these therapeutics can cause a loss of cardiac muscle and deterioration of vascular structure that can eventually ...

  19. Estimating the effectiveness of human-cell irradiation by protons of a therapeutic beam of the joint institute for nuclear research phasotron using cytogenetic methods

    Zaytseva, E. M.; Govorun, R. D.; Mitsin, G. V.; Molokanov, A. G.

    2011-11-01

    The effectiveness of the impact of therapeutic proton beams in human cells with respect to the criterion of formation of chromosome aberrations in human-blood lymphocytes is estimated. The physical characteristics of radiation (proton LET at the input of the object and in the region of the modified Bragg peak) and the role of the biological factor (the differences in the radiosensitivity of nondividing cells corresponding to the irradiation of normal tissues along the proton-beam path and tumor tissues) are taken into account. The relative biological effectiveness of protons is ˜1 at the beam input of the object and ˜1.2 in the Bragg peak region. Taking into account the higher radiosensitivity of dividing cells in the G 2 phase of the cell cycle, the irradiation effectiveness increases to ˜1.4.

  20. Therapeutic potential of stem cells in veterinary practice

    Nitin E Gade

    Full Text Available Stem cell research acquired great attention during last decade inspite of incredible therapeutic potential of these cells the ethical controversies exists. Stem cells have enormous uses in animal cloning, drug discovery, gene targeting, transgenic production and regenerative therapy. Stem cells are the naïve cells of body which can self-renew and differentiate into other cell types to carry out multiple functions, these properties have been utilized in therapeutic application of stem cells in human and veterinary medicine. The application of stem cells in human medicine is well established and it is commonly used for chronic and accidental injuries. In Veterinary sciences previous studies mostly focused on establishing protocols for isolation and their characterization but with advancement in array of techniques for in vitro studies, stem cells rapidly became a viable tool for regenerative therapy of chronic, debilitating and various unresponsive clinical diseases and disorders. Multipotent adult stem cells have certain advantages over embryonic stem cells like easy isolation and expansion from numerous sources, less immunogenicity and no risk of teratoma formation hence their use is preferred in therapeutics. Adult stem cells have been utilized for treatment of spinal injuries, tendonitis, cartilage defects, osteoarthritis and ligament defects, liver diseases, wounds, cardiac and bone defects in animals. The multi-potential capability of these cells can be better utilized in near future to overcome the challenges faced by the clinicians. This review will emphasize on the therapeutic utilization and success of stem cell therapies in animals. [Vet. World 2012; 5(8.000: 499-507

  1. Cancer Stem Cell Plasticity Drives Therapeutic Resistance

    Mary R. Doherty

    2016-01-01

    Full Text Available The connection between epithelial-mesenchymal (E-M plasticity and cancer stem cell (CSC properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.

  2. Cell-Specific Aptamers as Emerging Therapeutics

    Cindy Meyer

    2011-01-01

    Full Text Available Aptamers are short nucleic acids that bind to defined targets with high affinity and specificity. The first aptamers have been selected about two decades ago by an in vitro process named SELEX (systematic evolution of ligands by exponential enrichment. Since then, numerous aptamers with specificities for a variety of targets from small molecules to proteins or even whole cells have been selected. Their applications range from biosensing and diagnostics to therapy and target-oriented drug delivery. More recently, selections using complex targets such as live cells have become feasible. This paper summarizes progress in cell-SELEX techniques and highlights recent developments, particularly in the field of medically relevant aptamers with a focus on therapeutic and drug-delivery applications.

  3. Human therapeutic cloning (NTSC): applying research from mammalian reproductive cloning.

    French, Andrew J; Wood, Samuel H; Trounson, Alan O

    2006-01-01

    Human therapeutic cloning or nuclear transfer stem cells (NTSC) to produce patient-specific stem cells, holds considerable promise in the field of regenerative medicine. The recent withdrawal of the only scientific publications claiming the successful generation of NTSC lines afford an opportunity to review the available research in mammalian reproductive somatic cell nuclear transfer (SCNT) with the goal of progressing human NTSC. The process of SCNT is prone to epigenetic abnormalities that contribute to very low success rates. Although there are high mortality rates in some species of cloned animals, most surviving clones have been shown to have normal phenotypic and physiological characteristics and to produce healthy offspring. This technology has been applied to an increasing number of mammals for utility in research, agriculture, conservation, and biomedicine. In contrast, attempts at SCNT to produce human embryonic stem cells (hESCs) have been disappointing. Only one group has published reliable evidence of success in deriving a cloned human blastocyst, using an undifferentiated hESC donor cell, and it failed to develop into a hESC line. When optimal conditions are present, it appears that in vitro development of cloned and parthenogenetic embryos, both of which may be utilized to produce hESCs, may be similar to in vitro fertilized embryos. The derivation of ESC lines from cloned embryos is substantially more efficient than the production of viable offspring. This review summarizes developments in mammalian reproductive cloning, cell-to-cell fusion alternatives, and strategies for oocyte procurement that may provide important clues facilitating progress in human therapeutic cloning leading to the successful application of cell-based therapies utilizing autologous hESC lines.

  4. Gastric cancer stem cells: A novel therapeutic target

    Singh, Shree Ram

    2013-01-01

    Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer. PMID:23583679

  5. Therapeutic approaches to preventing cell death in Huntington disease.

    Kaplan, Anna; Stockwell, Brent R

    2012-12-01

    Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

    Tissot, Tazzio; Arnal, Audrey; Jacqueline, Camille; Poulin, Robert; Lefèvre, Thierry; Mery, Frédéric; Renaud, François; Roche, Benjamin; Massol, François; Salzet, Michel; Ewald, Paul; Tasiemski, Aurélie; Ujvari, Beata; Thomas, Frédéric

    2016-03-01

    Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. © 2016 WILEY Periodicals, Inc.

  7. Recent Advances in Stem Cell-Based Therapeutics for Stroke

    Napoli, Eleonora; Borlongan, Cesar V.

    2016-01-01

    Regenerative medicine for central nervous system disorders, including stroke, has challenged the non-regenerative capacity of the brain. Among the many treatment strategies tailored towards repairing the injured brain, stem cell-based therapeutics have been demonstrated as safe and effective in animal models of stroke, and are being tested in limited clinical trials. We address here key lab-to-clinic translational research that relate to efficacy, safety, and mechanism of action underlying st...

  8. Cell differentiation: therapeutical challenges in diabetes.

    Roche, Enrique; Vicente-Salar, Nestor; Arribas, Maribel; Paredes, Beatriz

    2012-01-01

    Stem cells, derived from either embryonic or adult tissues, are considered to be potential sources of insulin-secreting cells to be transplanted into type 1 and advanced stages of type 2 diabetic patients. Many laboratories have considered this possibility, resulting in a large amount of published protocols, with a wide degree of complexity among them. Our group was the first to report that it was possible to obtain insulin-secreting cells from mouse embryonic stem cells, proving the feasibility of this new challenge. The same observation was immediately reported using human embryonic stem cells. However, the resulting cell product was not properly characterised, affecting the reproducibility of the protocol by other groups. A more elaborated protocol was developed by Lumelsky and co-workers, demonstrating that neuroectodermal cells could be an alternative source for insulin-producing cells. However, the resulting cells of this protocol produced low amounts of the hormone. This aimed other groups to perform key changes in order to improve the insulin content of the resulting cells. Recently, Baetge's group has published a new protocol based on the knowledge accumulated in pancreatic development. In this protocol, human embryonic stem cells were differentiated into islet-like structures through a five step protocol, emulating the key steps during embryonic development of the endocrine pancreas. The final cell product, however, seemed to be in an immature state, thus further improvement is required. Despite this drawback, the protocol represents the culmination of work performed by different groups and offers new research challenges for the investigators in this exciting field. Concerning adult stem cells, the possibility of identifying pancreatic precursors or of reprogramming extrapancreatic derived cells are key possibilities that may circumvent the problems that appear when using embryonic stem cells, such as immune rejection and tumour formation.

  9. Therapeutic Process and Outcome: The Interplay of Research

    Campbel, Holly

    2008-01-01

    From Freud through to modern times researchers have aimed to develop a clearer understanding of therapeutic processes and outcomes. Despite this continued interest in the field, the representation of psychotherapy processes and the applicability of research findings and recommendations to the therapeutic field continue to prove difficult.…

  10. Towards the therapeutic use of vascular smooth muscle progenitor cells.

    Merkulova-Rainon, Tatyana; Broquères-You, Dong; Kubis, Nathalie; Silvestre, Jean-Sébastien; Lévy, Bernard I

    2012-07-15

    Recent advances in the development of alternative proangiogenic and revascularization processes, including recombinant protein delivery, gene therapy, and cell therapy, hold the promise of greater efficacy in the management of cardiovascular disease in the coming years. In particular, vascular progenitor cell-based strategies have emerged as an efficient treatment approach to promote vessel formation and repair and to improve tissue perfusion. During the past decade, considerable progress has been achieved in understanding therapeutic properties of endothelial progenitor cells, while the therapeutic potential of vascular smooth muscle progenitor cells (SMPC) has only recently been explored; the number of the circulating SMPC being correlated with cardiovascular health. Several endogenous SMPC populations with varying phenotypes have been identified and characterized in the peripheral blood, bone marrow, and vascular wall. While the phenotypic entity of vascular SMPC is not fully defined and remains an evolving area of research, SMPC are increasingly recognized to play a special role in cardiovascular biology. In this review, we describe the current approaches used to define vascular SMPC. We further summarize the data on phenotype and functional properties of SMPC from various sources in adults. Finally, we discuss the role of SMPC in cardiovascular disease, including the contribution of SMPC to intimal proliferation, angiogenesis, and atherosclerotic plaque instability as well as the benefits resulting from the therapeutic use of SMPC.

  11. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  12. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke.

    Wei, Ling; Wei, Zheng Z; Jiang, Michael Qize; Mohamad, Osama; Yu, Shan Ping

    2017-10-01

    One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Research progress of therapeutic vaccines for treating chronic hepatitis B.

    Li, Jianqiang; Bao, Mengru; Ge, Jun; Ren, Sulin; Zhou, Tong; Qi, Fengchun; Pu, Xiuying; Dou, Jia

    2017-05-04

    Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.

  14. 77 FR 35060 - Pfizer Therapeutic Research, Formerly Known as Warner Lambert Company, Pfizer Worldwide Research...

    2012-06-12

    ... Research, Formerly Known as Warner Lambert Company, Pfizer Worldwide Research & Development Division... December 2, 2011, applicable to workers of Pfizer Therapeutic Research, Pfizer Worldwide Research... Worldwide Research & Development Division, Antibacterial Research Unit, Pharmacokinetics, Dynamics and...

  15. [Cancer stem cells as the therapeutic target of tomorrow].

    Hatina, Jiří

    2017-02-01

    The concept of hierarchical organization of tumour cell population, with cancer stem cells positioned at the apex of the cell hierarchy, can explain at least some crucial aspects of biological and clinical behaviour of cancer, like its propensity to relapse as well as the development of therapeutic resistance. The underlying biological properties of cancer stem cells are crucially dependent on various signals, inhibition of which provides an attractive opportunity to attack pharmacologically cancer stem cells. Currently, a lot of such stemness-inhibitors undergo various phases of clinical testing. Interestingly, numerous old drugs that are in routine use in human and veterinary medicine for non-oncological indications appear to be able to specifically target cancer stem cells as well. As cancer stem cells, at least for most tumours, represent usually only a minor tumour cell fraction, it is quite probable that the main focus of the clinical use of the stemness inhibitors would consist in their rational combinations with traditional anticancer treatment modalities. A highly important goal for the future research is to identify reliable and clinically applicable predictive markers that would allow to apply these novel anticancer drugs on the individual basis within the context of personalized medicine.

  16. 78 FR 28630 - Pfizer Therapeutic Research, Pfizer Worldwide Research & Development Division, Formerly Known as...

    2013-05-15

    ... Research, Pfizer Worldwide Research & Development Division, Formerly Known as Warner Lambert Company... Groton, Connecticut location of Pfizer Therapeutic Research, Pfizer Worldwide Research & Development... Worldwide Research & Development Division, formerly known as Warner Lambert Company, Comparative Medicine...

  17. Fetal stem cells and skeletal muscle regeneration: a therapeutic approach

    Michela ePozzobon

    2014-08-01

    Full Text Available More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle specific stem cell, namely satellite cells. Muscle diseases, in particular chronic degenerative state of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continue cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is not a definitive cure in particular for genetic muscle disease. Taking this in mind, in this article we will give special consideration to muscle diseases and the use of fetal derived stem cells as new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immunemodulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies.

  18. Cell-based therapeutic strategies for multiple sclerosis.

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

    2017-11-01

    The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  19. Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

    2003-01-01

    Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching

  20. Underwater Shock Wave Research Applied to Therapeutic Device Developments

    Takayama, K.; Yamamoto, H.; Shimokawa, H.

    2013-07-01

    The chronological development of underwater shock wave research performed at the Shock Wave Research Center of the Institute of Fluid Science at the Tohoku University is presented. Firstly, the generation of planar underwater shock waves in shock tubes and their visualization by using the conventional shadowgraph and schlieren methods are described. Secondly, the generation of spherical underwater shock waves by exploding lead azide pellets weighing from several tens of micrograms to 100 mg, that were ignited by irradiating with a Q-switched laser beam, and their visualization by using double exposure holographic interferometry are presented. The initiation, propagation, reflection, focusing of underwater shock waves, and their interaction with various interfaces, in particular, with air bubbles, are visualized quantitatively. Based on such a fundamental underwater shock wave research, collaboration with the School of Medicine at the Tohoku University was started for developing a shock wave assisted therapeutic device, which was named an extracorporeal shock wave lithotripter (ESWL). Miniature shock waves created by irradiation with Q-switched HO:YAG laser beams are studied, as applied to damaged dysfunctional nerve cells in the myocardium in a precisely controlled manner, and are effectively used to design a catheter for treating arrhythmia.

  1. Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications

    Eunice Yuen-Ting Lau

    2017-01-01

    Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.

  2. Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

    Ahmad Hamad

    2013-01-01

    Full Text Available Chronic myeloid leukemia (CML is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML that have the potential to target CML stem cells and potentially provide cure for CML.

  3. Progenitor cells in the kidney: biology and therapeutic perspectives

    Rookmaaker, M.B.; Verhaar, M.C.; Zonneveld, A.J. van; Rabelink, T.J.

    2004-01-01

    Progenitor cells in the kidney: Biology and therapeutic perspectives. The stem cell may be viewed as an engineer who can read the blue print and become the building. The role of this fascinating cell in physiology and pathophysiology has recently attracted a great deal of interest. The archetype of

  4. Cell-based therapeutic strategies for multiple sclerosis

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C

    2017-01-01

    and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities......, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved...

  5. Developments in intervertebral disc disease research: pathophysiology, mechanobiology, and therapeutics.

    Weber, Kathryn T; Jacobsen, Timothy D; Maidhof, Robert; Virojanapa, Justin; Overby, Chris; Bloom, Ona; Quraishi, Shaheda; Levine, Mitchell; Chahine, Nadeen O

    2015-03-01

    Low back pain is a leading cause of disability worldwide and the second most common cause of physician visits. There are many causes of back pain, and among them, disc herniation and intervertebral disc degeneration are the most common diagnoses and targets for intervention. Currently, clinical treatment outcomes are not strongly correlated with diagnoses, emphasizing the importance for characterizing more completely the mechanisms of degeneration and their relationships with symptoms. This review covers recent studies elucidating cellular and molecular changes associated with disc mechanobiology, as it relates to degeneration and regeneration. Specifically, we review findings on the biochemical changes in disc diseases, including cytokines, chemokines, and proteases; advancements in disc disease diagnostics using imaging modalities; updates on studies examining the response of the intervertebral disc to injury; and recent developments in repair strategies, including cell-based repair, biomaterials, and tissue engineering. Findings on the effects of the omega-6 fatty acid, linoleic acid, on nucleus pulposus tissue engineering are presented. Studies described in this review provide greater insights into the pathogenesis of disc degeneration and may define new paradigms for early or differential diagnostics of degeneration using new techniques such as systemic biomarkers. In addition, research on the mechanobiology of disease enriches the development of therapeutics for disc repair, with potential to diminish pain and disability associated with disc degeneration.

  6. Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology.

    Chiba, Tetsuhiro; Iwama, Atsushi; Yokosuka, Osamu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Despite advances in its diagnosis and treatment, the prognosis of patients with advanced HCC remains unfavorable. Recent advances in stem cell biology and associated technologies have enabled the identification of minor components of tumorigenic cells, termed cancer stem cells (CSC) or tumor-initiating cells, in cancers such as HCC. Furthermore, because CSC play a central role in tumor development, metastasis and recurrence, they are considered to be a therapeutic target in cancer treatment. Hepatic CSC have been successfully identified using functional and cell surface markers. The analysis of purified hepatic CSC has revealed the molecular machinery and signaling pathways involved in their maintenance. In addition, epigenetic transcriptional regulation has been shown to be important in the development and maintenance of CSC. Although inhibitors of CSC show promise as CSC-targeting drugs, novel therapeutic approaches for the eradication of CSC are yet to be established. In this review, we describe recent progress in hepatic CSC research and provide a perspective on the available therapeutic approaches based on stem cell biology. © 2015 The Japan Society of Hepatology.

  7. Multifunctional cell therapeutics with plasmonic nanobubbles

    Lukianova-Hleb, Ekaterina Y.; Kashinath, Shruti; Lapotko, Dmitri O.

    2012-03-01

    We report our new discovery of the nanophenomenon called plasmonic nanobubbles to devise faster, safer and more accurate ways of manipulating the components of human tissue grafts. The reported work facilitates future cell and gene therapies by allowing specific cell subsets to be positively or negatively selected for culture, genetic engineering or elimination. The technology will have application for a wide range of human tissues that can be used to treat a multiplicity of human diseases.

  8. Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage.

    Gao, Liansheng; Xu, Weilin; Li, Tao; Chen, Jingyin; Shao, Anwen; Yan, Feng; Chen, Gao

    2018-01-01

    Spontaneous intracerebral hemorrhage (ICH) is one type of the most devastating cerebrovascular diseases worldwide, which causes high morbidity and mortality. However, efficient treatment is still lacking. Stem cell therapy has shown good neuroprotective and neurorestorative effect in ICH and is a promising treatment. In this study, our aim was to review the therapeutic effects, strategies, related mechanisms and safety issues of various types of stem cell for ICH treatment. Numerous studies had demonstrated the therapeutic effects of diverse stem cell types in ICH. The potential mechanisms include tissue repair and replacement, neurotrophy, promotion of neurogenesis and angiogenesis, anti-apoptosis, immunoregulation and anti-inflammation and so forth. The microenvironment of the central nervous system (CNS) can also influence the effects of stem cell therapy. The detailed therapeutic strategies for ICH treatment such as cell type, the number of cells, time window, and the routes of medication delivery, varied greatly among different studies and had not been determined. Moreover, the safety issues of stem cell therapy for ICH should not be ignored. Stem cell therapy showed good therapeutic effect in ICH, making it a promising treatment. However, safety should be carefully evaluated, and more clinical trials are required before stem cell therapy can be extensively applied to clinical use.

  9. IMPROVING THE REPORTING OF THERAPEUTIC EXERCISE INTERVENTIONS IN REHABILITATION RESEARCH.

    Page, Phil; Hoogenboom, Barb; Voight, Michael

    2017-04-01

    The foundation of evidence-based practice lies in clinical research, which is based on the utilization of the scientific method. The scientific method requires that all details of the experiment be provided in publications to support replication of the study in order to evaluate and validate the results. More importantly, clinical research can only be translated into practice when researchers provide explicit details of the study. Too often, rehabilitation exercise intervention studies lack the appropriate detail to allow clinicians to replicate the exercise protocol in their patient populations. Therefore, the purpose of this clinical commentary is to provide guidelines for optimal reporting of therapeutic exercise interventions in rehabilitation research. 5.

  10. Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

    Deming, Yuetiva; Li, Zeran; Benitez, Bruno A; Cruchaga, Carlos

    2018-06-20

    There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.

  11. 77 FR 65582 - Pfizer Therapeutic Research, Pfizer Worldwide Reasearch & Development Division, Formerly Known as...

    2012-10-29

    ... Research, Pfizer Worldwide Reasearch & Development Division, Formerly Known as Warner Lambert Company... workers of Pfizer Therapeutic Research, Pfizer Worldwide Research & Development Division, formerly known... follows: All workers of Pfizer Therapeutic Research, Pfizer Worldwide Research & Development Division...

  12. Therapeutic options in peripheral T cell lymphoma

    Yaping Zhang

    2016-04-01

    Full Text Available Abstract Peripheral T cell lymphoma (PTCL is a rare and heterogeneous group of non-Hodgkin lymphomas with a very poor prognosis. The standard first-line treatments have resulted in unsatisfactory patient outcomes. With the exception of low-risk anaplastic lymphoma kinase (ALK-positive anaplastic large cell lymphoma (ALCL, the majority of patients relapse rapidly; the current 5-year overall survival rates are only 10–30 %. Novel targeted therapies and combination chemotherapies are required for the treatment of patients with PTCL. In recent years, some retrospective and prospective studies have been performed concerning PTCL. Consequently, a number of novel agents and their relevant combination therapies have been identified, including histone deacetylase inhibitors, immunoconjugates, antifolates, monoclonal antibodies, immunomodulatory agents, nucleoside analogs, proteasome inhibitors, kinase inhibitors, bendamustine, l-asparaginase, and other targeted agents. It is hoped that these innovative approaches will finally improve outcomes in patients with PTCL. This review summarizes the currently available approaches for the treatment of PTCL with an emphasis on potential new agents, including the role of stem cell transplantation.

  13. Cuban experience with the therapeutic use of adult stem cells

    Hernandez Ramirez, Porfirio; Alfonso Simon, Amel; Aparicio Suarez, Jose L

    2011-01-01

    The basic and clinical researches carried out during past years on the stem cells and its therapeutic possibilities are at present times, one of the most interesting subjects of the contemporaneous medicine. There are advances in the study and application of adult stem cells showing remarkable advantages on the embryonic ones, since its handling is more simple, economic and they are obtained from the own subject to be treated. For the introduction in Cuba of the regenerative cellular therapy in the Institute of Hematology and Immunology the cellular sources selected were the adult stem cells derived from bone marrow and the mobilized ones to the peripheral blood. To make easy the expansion of treatment to other hospital centers, authors standardized a technique for the mobilization of the hematopoietic stem cells to peripheral blood using a granulocyte colony-stimulating factor (Filgrastim, of national production) developing a simple, economic and more tolerable method for patients. In this way, the cellular therapy has been expanded to 6 Cuban provinces and until April, 2009 562 cases with autologous adult stem cells transplant have been treated, from which the 81.7% to correspond to patients presenting with Angiology diseases with a significant reduction of major amputations. Also, the results have been very promising in the bone lesions and periodontal processes among other diseases treated. The results obtained until now may be considered as a new achievement of revolutionary science and of our national health systems and of science and technique. The method used is an economic and feasible procedure for the institutions with scarce resources

  14. The Promise and Perils of Stem Cell Therapeutics

    Daley, George Q.

    2012-01-01

    Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation for hematologic disease, essentially all other stem cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit, likely owing to our primitive state of knowledge about therapeutic mechanisms. Outside the standard cl...

  15. Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles

    Bin Zhang

    2016-02-01

    Full Text Available The intense research focus on stem and progenitor cells could be attributed to their differentiation potential to generate new cells to replace diseased or lost cells in many highly intractable degenerative diseases, such as Alzheimer disease, multiple sclerosis, and heart diseases. However, experimental and clinical studies have increasingly attributed the therapeutic efficacy of these cells to their secretion. While stem and progenitor cells secreted many therapeutic molecules, none of these molecules singly or in combination could recapitulate the functional effects of stem cell transplantations. Recently, it was reported that extracellular vesicles (EVs could recapitulate the therapeutic effects of stem cell transplantation. Based on the observations reported thus far, the prevailing hypothesis is that stem cell EVs exert their therapeutic effects by transferring biologically active molecules such as proteins, lipids, mRNA, and microRNA from the stem cells to injured or diseased cells. In this respect, stem cell EVs are similar to EVs from other cell types. They are both primarily vehicles for intercellular communication. Therefore, the differentiating factor is likely due to the composition of their cargo. The cargo of EVs from different cell types are known to include a common set of proteins and also proteins that reflect the cell source of the EVs and the physiological or pathological state of the cell source. Hence, elucidation of the stem cell EV cargo would provide an insight into the multiple physiological or biochemical changes necessary to affect the many reported stem cell-based therapeutic outcomes in a variety of experimental models and clinical trials.

  16. Therapeutic Approaches to Target Cancer Stem Cells

    Diaz, Arlhee; Leon, Kalet

    2011-01-01

    The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC

  17. Mesenchymal stem cells as therapeutic delivery vehicles targeting tumor stroma

    Serakinci, Nedime; Christensen, Rikke; Sørensen, Flemming Brandt

    2011-01-01

    The field of stem cell biology continues to evolve by characterization of further types of stem cells and by exploring their therapeutic potential for experimental and clinical applications. Human mesenchymal stem cells (hMSCs) are one of the most promising candidates simply because...... better understanding and in vivo supporting data. The homing ability of hMSCs was investigated by creating a human xenograft model by transplanting an ovarian cancer cell line into immunocompromised mice. Then, genetically engineered hMSC-telo1 cells were injected through the tail vein...

  18. Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

    Roybal, Kole T; Lim, Wendell A

    2017-04-26

    The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

  19. Prostate Stem Cell Antigen: A Prospective Therapeutic and Diagnostic Target

    Raff, Adam B.; Gray, Andrew; Kast, W. Martin

    2009-01-01

    The development of novel clinical tools to combat cancer is an intense field of research and recent efforts have been directed at the identification of proteins that may provide diagnostic, prognostic and/or therapeutic applications due to their restricted expression. To date, a number of protein candidates have emerged as potential clinical tools in the treatment of prostate cancer. Discovered over ten year ago, prostate stem cell antigen (PSCA) is a cell surface antigen that belongs to the Ly-6/Thy-1 family of glycosylphosphatidylinositol-anchored proteins. PSCA is highly overexpressed in human prostate cancer, with limited expression in normal tissues, making it an ideal target for both diagnosis and therapy. Several studies have now clearly correlated the expression of PSCA with relevant clinical benchmarks, such as Gleason score and metastasis, while others have demonstrated the efficacy of PSCA targeting in treatment through various modalities. The purpose of this review is to present the current body of knowledge about PSCA and its potential role in the treatment of human prostate cancer. PMID:18838214

  20. Cell therapeutics to treat diseases of the retina

    Natarajan S

    2008-11-01

    Full Text Available Background: The adult Bone Marrow Stem Cells (BMSCs have distinct advantages over the other types of stem cells. They are multipotent, can be stored for upto 10 years and considered to be one of the best sources of hematopoietic and mesenchymal stem cells in an adult body. Genetically inherited diseases such as Retinitis Pigmentosa and Degenerative diseases such as Age Related Macular Degeneration remain unsolved as no definitive treatment is available to repair the damages caused to the RPE and Photoreceptors as of now. In this scenario, the technique of Bone Marrow aspiration & isolation of Mono Nucleated Cells (MNCs & intra-vitreal injection of a very small volume of MNCs in human retinal disorders has been standardized and is safe and feasible for human studies (Mohanty et al and autotransplantation of RPEs from periphery to affected area are underpractice(Coffey et al. In this study we report our research work on different approaches to the above diseases using cell therapeuticsStudy 1 Materials & methods: Ciliary Pigment Epithelium was harvested from donor eyes from Aditya Jyot Eye Hospital, Mumbai and was taken to and grown at NCRM lab. The cells were grown in the earlier reported methodology of Brenda et al (Science 2004. Results: The CPE derived Retinal stem cells grew well in the lab. However, the practical difficulties of harvesting the same in patients limited our further steps in this study. Study II:? Materials & methods: Cadaver eye RPE cells were harvested and grown using polymer scaffolds after transporting them over 6 to 12 Hrs. The RPEs were grown on conventional methods and in polymer scaffolds and were subjected to RT-PCR. Results: Human RPEs were able to grow without amniotic membrane and the same was proven by RT-PCR. This would make it possible for the peripheral RPEs taken from patients to be stored and later expanded and used for replacing the diseased cells of the central portion of the retina in future, without having

  1. Therapeutic Misconception in Psychiatry Research: A Systematic Review.

    Thong, Ivan Sk; Foo, Meng Yee; Sum, Min Yi; Capps, Benjamin; Lee, Tih-Shih; Ho, Calvin; Sim, Kang

    2016-02-29

    Therapeutic misconception (TM) denotes the phenomenon in which research subjects conflate research purpose, protocols and procedures with clinical treatment. We examined the prevalence, contributory factors, clinical associations, impact, and collated solutions on TM within psychiatric research, and made suggestions going ahead. Literature search for relevant empirical research papers was conducted until February 2015. Eighty-eight reports were extracted, of which 31 were selected, summarised into different headings for discussion of implications and collated solutions of TM. We found variable and high rates of TM (ranging from 12.5% to 86%) in some psychiatry research populations. Contributory factors to TM included perceived medical roles of researchers, media, research setting and subject factors. Greater TM in affective, neurodevelopmental and psychotic spectrum conditions were associated with demographic variables (such as lower education, increased age), clinical factors (such as poor insight, cognitive deficits, increased symptoms, poorer self-rated quality of health), and social functioning (such as decreased independence). Inattention to TM may lead to frustration, negative impression and abandonment of participation in psychiatry research. Strategies such as the employment of a neutral educator during the informed consent process and education modules may be effective in addressing TM. Further research is warranted to examine the different TM facets, specific clinical correlates and more effective management strategies.

  2. Current Status of Dengue Therapeutics Research and Development.

    Low, Jenny G H; Ooi, Eng Eong; Vasudevan, Subhash G

    2017-03-01

    Dengue is a significant global health problem. Even though a vaccine against dengue is now available, which is a notable achievement, its long-term protective efficacy against each of the 4 dengue virus serotypes remains to be definitively determined. Consequently, drugs directed at the viral targets or critical host mechanisms that can be used safely as prophylaxis or treatment to effectively ameliorate disease or reduce disease severity and fatalities are still needed to reduce the burden of dengue. This review will provide a brief account of the status of therapeutics research and development for dengue. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

  3. Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis

    Feifei Li

    2017-05-01

    Full Text Available Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.

  4. Exosomes and Their Therapeutic Potentials of Stem Cells

    Chao Han

    2016-01-01

    Full Text Available Exosomes, a group of vesicles originating from the multivesicular bodies (MVBs, are released into the extracellular space when MVBs fuse with the plasma membrane. Numerous studies indicate that exosomes play important roles in cell-to-cell communication, and exosomes from specific cell types and conditions display multiple functions such as exerting positive effects on regeneration in many tissues. It is widely accepted that the therapeutic potential of stem cells may be mediated largely by the paracrine factors, so harnessing the paracrine effects of stem and progenitor cells without affecting these living, replicating, and potentially pluripotent cell populations is an advantage in terms of safety and complexity. Ascending evidence indicated that exosomes might be the main components of paracrine factors; thus, understanding the role of exosomes in each subtype of stem cells is far-reaching. In this review, we discuss the functions of exosomes from different types of stem cells and emphasize the therapeutic potentials of exosomes, providing an alternative way of developing strategies to cure diseases.

  5. Therapeutic Potential of Invariant Natural Killer T Cells in Autoimmunity

    Luc Van Kaer

    2018-03-01

    Full Text Available Tolerance against self-antigens is regulated by a variety of cell types with immunoregulatory properties, such as CD1d-restricted invariant natural killer T (iNKT cells. In many experimental models of autoimmunity, iNKT cells promote self-tolerance and protect against autoimmunity. These findings are supported by studies with patients suffering from autoimmune diseases. Based on these studies, the therapeutic potential of iNKT cells in autoimmunity has been explored. Many of these studies have been performed with the potent iNKT cell agonist KRN7000 or its structural variants. These findings have generated promising results in several autoimmune diseases, although mechanisms by which iNKT cells modulate autoimmunity remain incompletely understood. Here, we will review these preclinical studies and discuss the prospects for translating their findings to patients suffering from autoimmune diseases.

  6. European regulation for therapeutic use of stem cells.

    Ferry, Nicolas

    2017-01-01

    The regulation for the use of stem cells has evolved during the past decade with the aim of ensuring a high standard of quality and safety for human derived products throughout Europe to comply with the provision of the Lisbon treaty. To this end, new regulations have been issued and the regulatory status of stem cells has been revised. Indeed, stem cells used for therapeutic purposes can now be classified as a cell preparation, or as advanced therapy medicinal products depending on the clinical indication and on the procedure of cell preparation. Furthermore, exemptions to the European regulation are applicable for stem cells prepared and used within the hospital. The aim of this review is to give the non-specialized reader a broad overview of this particular regulatory landscape.

  7. BiovaxID, a personalized therapeutic vaccine against B-cell lymphomas

    Reiniš, Milan

    2008-01-01

    Roč. 10, č. 5 (2008), s. 526-534 ISSN 1464-8431 Institutional research plan: CEZ:AV0Z50520514 Keywords : B-cell lymphomas * tumor antigen * therapeutic vaccine Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.913, year: 2008

  8. Therapeutic potential of stem cells in auditory hair cell repair

    Ryuji Hata

    2009-01-01

    Full Text Available The prevalence of acquired hearing loss is very high. About 10% of the total population and more than one third of the population over 65 years suffer from debilitating hearing loss. The most common type of hearing loss in adults is idiopathic sudden sensorineural hearing loss (ISSHL. In the majority of cases, ISSHL is permanent and typically associated with loss of sensory hair cells in the organ of Corti. Following the loss of sensory hair cells, the auditory neurons undergo secondary degeneration. Sensory hair cells and auditory neurons do not regenerate throughout life, and loss of these cells is irreversible and cumulative. However, recent advances in stem cell biology have gained hope that stem cell therapy comes closer to regenerating sensory hair cells in humans. A major advance in the prospects for the use of stem cells to restore normal hearing comes with the recent discovery that hair cells can be generated ex vivo from embryonic stem (ES cells, adult inner ear stem cells and neural stem cells. Furthermore, there is increasing evidence that stem cells can promote damaged cell repair in part by secreting diffusible molecules such as growth factors. These results suggest that stem-cell-based treatment regimens can be applicable to the damaged inner ear as future clinical applications.Previously we have established an animal model of cochlear ischemia in gerbils and showed progressive hair cell loss up to 4 days after ischemia. Auditory brain stem response (ABR recordings have demonstrated that this gerbil model displays severe deafness just after cochlear ischemia and gradually recovers thereafter. These pathological findings and clinical manifestations are reminiscent of ISSHL in humans. In this study, we have shown the effectiveness of stem cell therapy by using this animal model of ISSHL.

  9. Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials.

    Esensten, Jonathan H; Bluestone, Jeffrey A; Lim, Wendell A

    2017-01-24

    Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field.

  10. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-19

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

  11. Breast cancer stem cells, EMT and therapeutic targets

    Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

    2014-10-10

    Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.

  12. Dye solar cell research

    Cummings, F

    2009-11-01

    Full Text Available Cummings Energy and Processes Materials Science and Manufacturing Council for Scientific and Industrial Research P.O. Box 395 Pretoria 0001, South Africa 27 November 2009 CONTENT head2rightBackground head2rightCSIR Dye Solar Cell Research head2... rightCollaborations and Links © CSIR 2007 www.csir.co.za head2rightAcknowledgements BACKGROUND head2rightSA is dry: Annual rainfall average of 450 mm compared with a world average of 860 mm head2rightOn upside, we have some...

  13. Nanoparticle-labeled stem cells: a novel therapeutic vehicle

    Abir O El-Sadik

    2010-03-01

    Full Text Available Abir O El-Sadik1, Afaf El-Ansary2, Sherif M Sabry31Stem Cell Unit, Anatomy Department, College of Medicine, Health Science Colleges; 2Biochemistry Department, Science College, King Saud University; 3Anatomy Department, Faculty of Medicine, Cairo University, Cairo, EgyptAbstract: Nanotechnology has been described as a general purpose technology. It has already generated a range of inventions and innovations. Development of nanotechnology will provide clinical medicine with a range of new diagnostic and therapeutic opportunities such as medical imaging, medical diagnosis, drug delivery, and cancer detection and management. Nanoparticles such as manganese, polystyrene, silica, titanium oxide, gold, silver, carbon, quantum dots, and iron oxide have received enormous attention in the creation of new types of analytical tools for biotechnology and life sciences. Labeling of stem cells with nanoparticles overcame the problems in homing and fixing stem cells to their desired site and guiding extension of stem cells to specific directions. Although the biologic effects of some nanoparticles have already been assessed, information on toxicity and possible mechanisms of various particle types remains inadequate. The aim of this review is to give an overview of the mechanisms of internalization and distribution of nanoparticles inside stem cells, as well as the influence of different types of nanoparticles on stem cell viability, proliferation, differentiation, and cytotoxicity, and to assess the role of nanoparticles in tracking the fate of stem cells used in tissue regeneration.Keywords: nanoparticles, stem cells, uptake, differentiation, cytotoxicity, tracking

  14. Engineering Specificity and Function of Therapeutic Regulatory T Cells

    Jenny L. McGovern

    2017-11-01

    Full Text Available Adoptive therapy with polyclonal regulatory T cells (Tregs has shown efficacy in suppressing detrimental immune responses in experimental models of autoimmunity and transplantation. The lack of specificity is a potential limitation of Treg therapy, as studies in mice have demonstrated that specificity can enhance the therapeutic potency of Treg. We will discuss that vectors encoding T cell receptors or chimeric antigen receptors provide an efficient gene-transfer platform to reliably produce Tregs of defined antigen specificity, thus overcoming the considerable difficulties of isolating low-frequency, antigen-specific cells that may be present in the natural Treg repertoire. The recent observations that Tregs can polarize into distinct lineages similar to the Th1, Th2, and Th17 subsets described for conventional T helper cells raise the possibility that Th1-, Th2-, and Th17-driven pathology may require matching Treg subsets for optimal therapeutic efficacy. In the future, genetic engineering may serve not only to enforce FoxP3 expression and a stable Treg phenotype but it may also enable the expression of particular transcription factors that drive differentiation into defined Treg subsets. Together, established and recently developed gene transfer and editing tools provide exciting opportunities to produce tailor-made antigen-specific Treg products with defined functional activities.

  15. Fuel Cell Research

    Weber, Peter M. [Brown University

    2014-03-30

    Executive Summary In conjunction with the Brown Energy Initiative, research Projects selected for the fuel cell research grant were selected on the following criteria: They should be fundamental research that has the potential to significantly impact the nation’s energy infrastructure. They should be scientifically exciting and sound. They should synthesize new materials, lead to greater insights, explore new phenomena, or design new devices or processes that are of relevance to solving the energy problems. They involve top-caliper senior scientists with a record of accomplishment, or junior faculty with outstanding promise of achievement. They should promise to yield at least preliminary results within the given funding period, which would warrant further research development. They should fit into the overall mission of the Brown Energy Initiative, and the investigators should contribute as partners to an intellectually stimulating environment focused on energy science. Based on these criteria, fourteen faculty across three disciplines (Chemistry, Physics and Engineering) and the Charles Stark Draper Laboratory were selected to participate in this effort.1 In total, there were 30 people supported, at some level, on these projects. This report highlights the findings and research outcomes of the participating researchers.

  16. On Informatics Diagnostics and Informatics Therapeutics - Good Medical Informatics Research Is Needed Here.

    Haux, Reinhold

    2017-01-01

    In the era of digitization some new procedures play an increasing role for diagnosis as well as for therapy: informatics diagnostics and informatics therapeutics. Challenges for such procedures are described. It is discussed, when research on such diagnostics and therapeutics can be regarded as good research. Examples are mentioned for informatics diagnostics and informatics therapeutics, which are based on health-enabling technologies.

  17. Information on Stem Cell Research

    ... Home » Current Research » Focus on Research Focus on Stem Cell Research Stem cells possess the unique ability to differentiate into ... virus infection. To search the complete list of stem cell research projects funded by NIH please go to NIH ...

  18. Participatory Action Research with therapeutic arts practitioners : Research capacity building in a pediatric hospital

    Lind, Candace; Cantell, Marja; Baggott, Sandy; Houde, Marc; Coupal, Stephanie

    2015-01-01

    The therapeutic arts (TA) encompass a vast area of practices including art, music, drama, dance, and horticultural therapy in multiple settings. However, TA often lack recognition in hospital settings and may be viewed as expendable programming. Credibility and visibility obtained through research

  19. Research from therapeutic radiographers: An audit of research capacity within the UK

    Probst, H.; Harris, R.; McNair, H.A.; Baker, A.; Miles, E.A.; Beardmore, C.

    2015-01-01

    Research from Allied Health Professionals (AHPs) is anecdotally known to lag behind that of other professions. The developing research landscape within other therapies and internationally led us to question how UK practice in therapeutic radiography was developing. The aim of the survey was to audit research capacity across therapy radiography in the UK. Method: An electronic survey was sent to Radiotherapy Service Managers (RSM) and research leads in each of the radiotherapy centres in the UK. An adapted version of the ‘Auditing Research Capacity’ tool (ARC © tool) was used as the basis of the questionnaire. Results: A total of 45 RSM responded to the survey (67% response rate) and 30 Research radiographers (RR) (45% response rate). A total of 51 RR were in post equating to 40.3 whole time equivalents and averaging 1 RR per centre. Variation was evident in the commitment to the development of a research culture identified by practices such as linking research to the business planning cycle, inclusion of research in recruitment and advertising materials, or having a nominated therapeutic radiographer lead on research for the department. Over a third of responding centres did not have a research strategy and training for RRs was limited; specifically in areas such as writing funding bids, writing for publication and the research and governance process. Conclusion: A number of short and long-term strategies are proposed that should enhance a positive research culture and improve research capacity for therapeutic radiography led research. These include utilisation of the existing infrastructure provided by the National Institute for Health Research, a lead or co-ordinator for research activity with a remit to motivate others. Development of links and networks, and the development of a research strategy linked to wider Trust research priorities. The research strategy should include mentoring or developing appropriate research skills for those engaged in research

  20. Liver cell-targeted delivery of therapeutic molecules.

    Kang, Jeong-Hun; Toita, Riki; Murata, Masaharu

    2016-01-01

    The liver is the largest internal organ in mammals and is involved in metabolism, detoxification, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune/inflammatory responses. Hepatitis, alcoholic or non-alcoholic liver disease, hepatocellular carcinoma, hepatic veno-occlusive disease, and liver fibrosis and cirrhosis are the most common liver diseases. Safe and efficient delivery of therapeutic molecules (drugs, genes or proteins) into the liver is very important to increase the clinical efficacy of these molecules and to reduce their side effects in other organs. Several liver cell-targeted delivery systems have been developed and tested in vivo or ex vivo/in vitro. In this review, we discuss the literature concerning liver cell-targeted delivery systems, with a particular emphasis on the results of in vivo studies.

  1. Novel therapeutic options for relapsed hairy cell leukemia.

    Jain, Preetesh; Polliack, Aaron; Ravandi, Farhad

    2015-01-01

    The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification of BRAFV600E mutations and the role of aberrant MEK kinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL.

  2. Therapeutic targeting strategies using endogenous cells and proteins.

    Parayath, Neha N; Amiji, Mansoor M

    2017-07-28

    Targeted drug delivery has become extremely important in enhancing efficacy and reducing the toxicity of therapeutics in the treatment of various disease conditions. Current approaches include passive targeting, which relies on naturally occurring differences between healthy and diseased tissues, and active targeting, which utilizes various ligands that can recognize targets expressed preferentially at the diseased site. Clinical translation of these mechanisms faces many challenges including the immunogenic and toxic effects of these non-natural systems. Thus, use of endogenous targeting systems is increasingly gaining momentum. This review is focused on strategies for employing endogenous moieties, which could serve as safe and efficient carriers for targeted drug delivery. The first part of the review involves cells and cellular components as endogenous carriers for therapeutics in multiple disease states, while the second part discusses the use of endogenous plasma components as endogenous carriers. Further understanding of the biological tropism with cells and proteins and the newer generation of delivery strategies that exploits these endogenous approaches promises to provide better solutions for site-specific delivery and could further facilitate clinical translations. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications.

    Moravek, Molly B; Yin, Ping; Ono, Masanori; Coon, John S; Dyson, Matthew T; Navarro, Antonia; Marsh, Erica E; Chakravarti, Debabrata; Kim, J Julie; Wei, Jian-Jun; Bulun, Serdar E

    2015-01-01

    Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention. A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript. Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and

  4. Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics.

    Gamwell, Lisa F; Gambaro, Karen; Merziotis, Maria; Crane, Colleen; Arcand, Suzanna L; Bourada, Valerie; Davis, Christopher; Squire, Jeremy A; Huntsman, David G; Tonin, Patricia N; Vanderhyden, Barbara C

    2013-02-21

    The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by > 75% after infection with oncolytic viruses. These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53 mutations. Although BIN-67 cells are

  5. Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

    Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha

    2013-09-15

    This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.

  6. Therapeutic Potential of Umbilical Cord Blood Stem Cells on Brain Damage of a Model of Stroke

    Mohammad Reza Nikravesh

    2011-11-01

    Full Text Available Introduction: Human cord blood-derived stem cells are a rich source of stem cells as well as precursors. With regard to the researchers have focused on the therapeutic potential of stem cell in the neurological disease such as stroke, the aim of this study was the investiga-tion of the therapeutic effects of human cord blood-derived stem cells in cerebral ischemia on rat. Methods: This study was carried out on young rats. Firstly, to create a laboratory model of ischemic stroke, carotid artery of animals was occluded for 30 minutes. Then, umbilical cord blood cells were isolated and labeled using bromodeoxyuridine and 2×105 cells were injected into the experimental group via the tail vein. Rats with hypoxic condi-tions were used as a sham group. A group of animals did not receive any injection or sur-geries were used as a control. Results: Obtained results were evaluated based on behavior-al responses and immunohistochemistry, with emphasis on areas of putamen and caudate nucleus in the control, sham and experimental groups. Our results indicated that behavioral recovery was observed in the experimental group compared to the either the sham or the control group. However, histological studies demonstrated a low percent of tissue injury in the experimental group in comparison with the sham group. Conclusion: Stem cell trans-plantation is beneficial for the brain tissue reparation after hypoxic ischemic cell death.

  7. Cellular Therapeutics for Heart Failure: Focus on Mesenchymal Stem Cells

    Amitabh C. Pandey

    2017-01-01

    Full Text Available Resulting from a various etiologies, the most notable remains ischemia; heart failure (HF manifests as the common end pathway of many cardiovascular processes and remains among the top causes for hospitalization and a major cause of morbidity and mortality worldwide. Current pharmacologic treatment for HF utilizes pharmacologic agents to control symptoms and slow further deterioration; however, on a cellular level, in a patient with progressive disease, fibrosis and cardiac remodeling can continue leading to end-stage heart failure. Cellular therapeutics have risen as the new hope for an improvement in the treatment of HF. Mesenchymal stem cells (MSCs have gained popularity given their propensity of promoting endogenous cellular repair of a myriad of disease processes via paracrine signaling through expression of various cytokines, chemokines, and adhesion molecules resulting in activation of signal transduction pathways. While the exact mechanism remains to be completely elucidated, this remains the primary mechanism identified to date. Recently, MSCs have been incorporated as the central focus in clinical trials investigating the role how MSCs can play in the treatment of HF. In this review, we focus on the characteristics of MSCs that give them a distinct edge as cellular therapeutics and present results of clinical trials investigating MSCs in the setting of ischemic HF.

  8. [Mantle cell lymphoma: Towards a personalized therapeutic strategy?].

    Navarro Matilla, Belén; García-Marco, José A

    2015-06-22

    Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  9. Mechanisms of therapeutic resistance in cancer (stem cells with emphasis on thyroid cancer cells.

    Sabine eHombach-Klonisch

    2014-03-01

    Full Text Available Tissue invasion, metastasis and therapeutic resistance to anti-cancer treatments are common and main causes of death in cancer patients. Tumor cells mount complex and still poorly understood molecular defense mechanisms to counteract and evade oxygen deprivation, nutritional restrictions as well as radio- and chemotherapeutic treatment regimens aimed at destabilizing their genomes and important cellular processes. In thyroid cancer, as in other tumors, such defense strategies include the reactivation in cancer cells of early developmental programs normally active exclusively in stem cells, the stimulation of cancer stem-like cells resident within the tumor tissue and the recruitment of bone marrow-derived progenitors into the tumor (Thomas et al., 2008;Klonisch et al., 2009;Derwahl, 2011. Metastasis and therapeutic resistance in cancer (stem cells involves the epithelial-to-mesenchymal transition- (EMT- mediated enhancement in cellular plasticity, which includes coordinated dynamic biochemical and nuclear changes (Ahmed et al., 2010. The purpose of the present review is to provide an overview of the role of DNA repair mechanisms contributing to therapeutic resistance in thyroid cancer and highlight the emerging roles of autophagy and damage associated molecular pattern (DAMP responses in EMT and chemoresistance in tumor cells. Finally, we use the stem cell factor and nucleoprotein High Mobility Group A2 (HMGA2 as an example to demonstrate how factors intended to protect stem cells are wielded by cancer (stem cells to gain increased transformative cell plasticity which enhances metastasis, therapeutic resistance and cell survival. Wherever possible, we have included information on these cellular processes and associated factors as they relate to thyroid cancer cells.

  10. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

    Adrian Biddle

    2016-02-01

    Full Text Available Cancer stem cells (CSCs drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT and mesenchymal-to-epithelial transition (MET to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC, we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/−CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

  11. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.

    Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C

    2016-02-01

    Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

  12. Therapeutic strategies in Sickle Cell Anemia: The past present and future.

    Fernandes, Queenie

    2017-06-01

    Sickle Cell Anemia (SCA) was one of the first hemoglobinopathies to be discovered. It is distinguished by the mutation-induced expression of a sickle cell variant of hemoglobin (HbS) that triggers erythrocytes to take a characteristic sickled conformation. The complex physiopathology of the disease and its associated clinical complications has initiated multi-disciplinary research within its field. This review attempts to lay emphasis on the evolution, current standpoint and future scope of therapeutic strategies in SCA. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Therapeutic Potential, Challenges and Future Perspective of Cancer Stem Cells in Translational Oncology: A Critical Review.

    Shukla, Gaurav; Khera, Harvinder Kour; Srivastava, Amit Kumar; Khare, Piush; Patidar, Rahul; Saxena, Rajiv

    2017-01-01

    Stem cell research is a rapidly developing field that offers effective treatment for a variety of malignant and non-malignant diseases. Stem cell is a regenerative medicine associated with the replacement, repair, and restoration of injured tissue. Stem cell research is a promising field having maximum therapeutic potential. Cancer stem cells (CSCs) are the cells within the tumor that posses capacity of selfrenewal and have a root cause for the failure of traditional therapies leading to re-occurrence of cancer. CSCs have been identified in blood, breast, brain, and colon cancer. Traditional therapies target only fast growing tumor mass, but not slow-dividing cancer stem cells. It has been shown that embryonic pathways such as Wnt, Hedgehog and Notch, control self-renewal capacity and involved in cancer stem cell maintenance. Targeting of these pathways may be effective in eradicating cancer stem cells and preventing chemotherapy and radiotherapy resistance. Targeting CSCs has become one of the most effective approaches to improve the cancer survival by eradicating the main root cause of cancer. The present review will address, in brief, the importance of cancer stem cells in targeting cancer as better and effective treatment along with a concluding outlook on the scope and challenges in the implication of cancer stem cells in translational oncology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Cancer Stem Cell Hypothesis for Therapeutic Innovation in Clinical Oncology? Taking the Root Out, Not Chopping the Leaf.

    Dzobo, Kevin; Senthebane, Dimakatso Alice; Rowe, Arielle; Thomford, Nicholas Ekow; Mwapagha, Lamech M; Al-Awwad, Nasir; Dandara, Collet; Parker, M Iqbal

    2016-12-01

    Clinical oncology is in need of therapeutic innovation. New hypotheses and concepts for translation of basic research to novel diagnostics and therapeutics are called for. In this context, the cancer stem cell (CSC) hypothesis rests on the premise that tumors comprise tumor cells and a subset of tumor-initiating cells, CSCs, in a quiescent state characterized by slow cell cycling and expression of specific stem cell surface markers with the capability to maintain a tumor in vivo. The CSCs have unlimited self-renewal abilities and propagate tumors through division into asymmetric daughter cells. This differentiation is induced by both genetic and environmental factors. Another characteristic of CSCs is their therapeutic resistance, which is due to their quiescent state and slow dividing. Notably, the CSC phenotype differs greatly between patients and different cancer types. The CSCs may differ genetically and phenotypically and may include primary CSCs and metastatic stem cells circulating within the blood system. Targeting CSCs will require the knowledge of distinct stem cells within the tumor. CSCs can differentiate into nontumorigenic cells and this has been touted as the source of heterogeneity observed in many solid tumors. The latter cannot be fully explained by epigenetic regulation or by the clonal evolution theory. This heterogeneity markedly influences how tumors respond to therapy and prognosis. The present expert review offers an analysis and synthesis of the latest research and concepts on CSCs, with a view to truly disruptive innovation for future diagnostics and therapeutics in clinical oncology.

  15. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    Jhanwar-Uniyal, Meena; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj

    2015-01-01

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM

  16. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    Jhanwar-Uniyal, Meena, E-mail: meena_jhanwar@nymc.edu; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj [Department of Neurosurgery, New York Medical College, Valhalla, NY 10595 (United States)

    2015-03-25

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

  17. Merkel Cell Carcinoma: Chemotherapy and Emerging New Therapeutic Options

    Desch, L.; Kunstfeld, R.

    2013-01-01

    Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor that typically occurs in elderly, immunosuppressed patients. Infection with Merkel cell virus (MCV) and immunosuppression play an important role in the development of MCC. Different staging systems make it difficult to compare the existing clinical data. Furthermore, there predominantly exist single case reports and case series, but no randomized controlled trials. However, it is necessary to develop further therapy options because MCC tends to grow rapidly and metastasizes early. In the metastatic disease, therapeutic attempts were made with various chemotherapeutic combination regimens. Because of the high toxicity of these combinations, especially those established in SCLC, and regarding the unsatisfying results, the challenge is to balance the pros and cons of chemotherapy individually and carefully. Up to now, emerging new therapy options as molecular-targeted agents, for example, pipebuzone, imatinib, or somatostatin analogues as well as immunologic als, for example, imiquimod and interferons, also showed less success concerning the disease-free response rates. According to the literature, neither chemotherapy nor molecular-targeted agents or immunotherapeutic strategies have shown promising effects in the therapy of the metastatic disease of MCC so far. There is a great demand for randomized controlled studies and a need for an MCC registry and multicenter clinical trials due to the tumors curiosity.

  18. Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

    Jaume Folch

    2016-01-01

    Full Text Available Alzheimer’s disease (AD currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC. PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5. Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

  19. Insights into cell-free therapeutic approach: Role of stem cell "soup-ernatant".

    Raik, Shalini; Kumar, Ajay; Bhattacharyya, Shalmoli

    2018-03-01

    Current advances in medicine have revolutionized the field of regenerative medicine dramatically with newly evolved therapies for repair or replacement of degenerating or injured tissues. Stem cells (SCs) can be harvested from different sources for clinical therapeutics, which include fetal tissues, umbilical cord blood, embryos, and adult tissues. SCs can be isolated and differentiated into desired lineages for tissue regeneration and cell replacement therapy. However, several loopholes need to be addressed properly before this can be extended for large-scale therapeutic application. These include a careful approach for patient safety during SC treatments and tolerance of recipients. SC treatments are associated with a number of risk factors and require successful integration and survival of transplanted cells in the desired microenvironment with concurrent tissue regeneration. Recent studies have focused on developing alternatives that can replace the cell-based therapy using paracrine factors. The development of stem "cell free" therapies can be devoted mainly to the use of soluble factors (secretome), extracellular vesicles, and mitochondrial transfer. The present review emphasizes on the paradigms related to the use of SC-based therapeutics and the potential applications of a cell-free approach as an alternative to cell-based therapy in the area of regenerative medicine. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  20. [Transgenic cell cultures that synthesize neurotrophic factors and the possibility of therapeutic use of its cells].

    Pavlova, G V; Kanaĭkina, N N; Panteleev, D Iu; Okhotin, V E; Revishchin, A V

    2012-01-01

    Under the leadership of Corresponding Member of the Russian Academy of Sciences L.I. Korochkin, the Laboratory of Neurogenetics and Developmental Genetics (Institute of Gene Biology, Russian Academy of Sciences) for many years has been conducting studies of nervous system development, neural cell differentiation, and application of gene and cell technology to cure neurodegenerative diseases. The results of the study initiated by L.I. Korochkin and continued by his scientific successors support the direction of allocation of transgenic neurotrofic factors and heat-shock proteins as neuroprotectors for cell therapy. Potential for usage of promoter of HSP70 heat-shock gene of Drosophila to create transgenic constructs for therapy has been shown. Further improvement of technology of nonvirus transfer for therapeutic genes, as well as production of multicomponent genetic constructs coding several therapeutic factors with synergy effect, would stimulate creation of efficient cell medicals to cure neurodegenerative diseases.

  1. Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential

    Tom J. Burdon

    2011-01-01

    Full Text Available During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.

  2. Updates on Nutraceutical Sleep Therapeutics and Investigational Research

    Michael Yurcheshen

    2015-01-01

    Full Text Available Approximately 50% of the population will suffer from a sleep disorder over the course of their lifetime. There is increasing interest in nutraceuticals for these conditions. The quality of the evidence for the safety and effectiveness of using these supplements to treat sleep disorders varies substantially. In this review, we discuss the data about the effectiveness and safety of six commonly used plant-based sleep therapeutics: caffeine, chamomile, cherries, kava kava, L-tryptophan, marijuana, and valerian. We explore both historical uses of each substance and the current state of the literature.

  3. VITAMIN D3: RESEARCH BREAKTHROUGHS AND THERAPEUTIC USE

    Pohorila М.S.

    2017-12-01

    Full Text Available Vitamin D3 (cholecalciferol, the natural form of vitamin D, is produced in the skin from 7-dehydrocholesterol. The synthesis of vitamin D in the skin is the most important source of vitamin D. Vitamin D can also be taken through nutrition, in the diet, but it is present in only a few food sources, containing relevant levels of vitamin D. 1,25-dihydroxyvitamin D3 [1,25(OH2D3] is the hormonally active form of vitamin D. Novel researches show it generates a number of extraskeletal biological responses including inhibition of variety types cancer progression, effects on cardiovascular disorders and mediates a protection against a number of inflammatory, autoimmune and infection diseases The biological actions of 1,25(OH2D3 are mediated by the VDR. The genomic mechanism of 1,25(OH2D3 action involves the direct binding of 1,25(OH2D3 activated VDR/RXR to specific DNA sequences in and around target genes resulting in either activation or repression of transcription [7] VDR modulates the expression of genes involved in immune function and cytokine production. The VDR and CYP27B1, the enzyme located in kidneys and target organs, are present in immune competent cells, bronchial and pulmonary epithelial cells, among others, and is up-regulated following the ligation of specific toll-like receptors by extracellular pathogens, implicating vitamin D in innate immunity. By binding the VDR, calcitriol induces several endogenous antimicrobial peptides (AMP in monocytes, neutrophils and epithelial cells including cathelicidin LL-37, α-defensin, β defensing and neutrophil gelatinase-associated lipocalin and up-regulates nitric oxide (NO synthase. Since the inflammatory response associated with infections such influenza, pneumonia and sepsis increases both clinical severity and mortality, the ability to reduce inflammation may allow vitamin D to decrease mortality and disease burden in certain infections. Notwithstanding the width of possible vitamin D application

  4. Perspective on Cancer Therapeutics Utilizing Analysis of Circulating Tumor Cells

    Keun-Yeong Jeong

    2018-04-01

    Full Text Available Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment—such as surgery, chemotherapy, and/or radiation therapy—is selected. A new assay has been developed that detects circulating tumor cells (CTCs. Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics.

  5. Regulatory B cells: an exciting target for future therapeutics in transplantation

    Alexandre eNouël

    2014-01-01

    Full Text Available Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrates on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell-depleting Ab, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg cells -or B10 cells- has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches.

  6. Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis

    Aleksandar Arsenijevic

    2017-01-01

    Full Text Available Primary biliary cholangitis (PBC is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.

  7. Introduction to thematic minireview series: Development of human therapeutics based on induced pluripotent stem cell (iPSC) technology.

    Rao, Mahendra; Gottesfeld, Joel M

    2014-02-21

    With the advent of human induced pluripotent stem cell (hiPSC) technology, it is now possible to derive patient-specific cell lines that are of great potential in both basic research and the development of new therapeutics for human diseases. Not only do hiPSCs offer unprecedented opportunities to study cellular differentiation and model human diseases, but the differentiated cell types obtained from iPSCs may become therapeutics themselves. These cells can also be used in the screening of therapeutics and in toxicology assays for potential liabilities of therapeutic agents. The remarkable achievement of transcription factor reprogramming to generate iPSCs was recognized by the award of the Nobel Prize in Medicine to Shinya Yamanaka in 2012, just 6 years after the first publication of reprogramming methods to generate hiPSCs (Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Cell 131, 861-872). This minireview series highlights both the promises and challenges of using iPSC technology for disease modeling, drug screening, and the development of stem cell therapeutics.

  8. Therapeutic research on children in low–income countries

    Whyte, Susan Reynolds

    2015-01-01

    -established institutions in Africa show that parents eagerly have their children ‘join’ such projects. They assess benefits and risks less in research terms and more through overall trust in care provided previously by such institutions in the community. Bioethics should go beyond concern with protecting individual......Social scientists undertaking studies in developing countries focus on ‘trial communities’: networks of funders, institutions, researchers, clinical staff, fieldworkers, and study participants. Whereas bioethicists consider universal ethical requirements, social scientists examine ethical practices...... subjects from research risks and should view clinical care and research functions as indistinguishable for many who seek sustained support for the children’s health....

  9. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

    Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

    2015-01-01

    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID:25142460

  10. Experimental Methodology used by Cell Cultures Laboratory from INRMFB to assess the therapeutic effect of natural factors

    Munteanu Constantin

    2010-11-01

    Full Text Available The experimental study design on cell cultures allows the direct biological evaluation at the cellular level, of the therapeutic effect that natural factors can play over the organism.Techniques for obtaining cell cultures requires a complex and laborious task that starts from live tissue sampling, continuous with isolation of cells and their preparation for sowing a culture plate. This preparation involves mechanical and enzymatic action from the researcher on biological material. Derived cell cultures are monitored morphologically by high-performance inverted biological microscope, with video camera for image acquisition. In the final stage, the cells are scraped, and through biochemical and molecular techniques, the therapeutic efficiency hypothesis of the investigated natural factor is verified experimentally. The cell cultures can be crioconservated in special containers with liquid nitrogen.

  11. Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells.

    Reenu Punia

    Full Text Available Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC cells.During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on

  12. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.

    Hira, Vashendriya V V; Van Noorden, Cornelis J F; Carraway, Hetty E; Maciejewski, Jaroslaw P; Molenaar, Remco J

    2017-08-01

    Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Bioprinting for stem cell research

    Tasoglu, Savas; Demirci, Utkan

    2012-01-01

    Recently, there has been a growing interest to apply bioprinting techniques to stem cell research. Several bioprinting methods have been developed utilizing acoustics, piezoelectricity, and lasers to deposit living cells onto receiving substrates. Using these technologies, spatially defined gradients of immobilized proteins can be engineered to direct stem cell differentiation into multiple subpopulations of different lineages. Stem cells can also be patterned in a high-throughput manner onto flexible implementation patches for tissue regeneration or onto substrates with the goal of accessing encapsulated stem cell of interest for genomic analysis. Here, we review recent achievements with bioprinting technologies in stem cell research, and identify future challenges and potential applications including tissue engineering and regenerative medicine, wound healing, and genomics. PMID:23260439

  14. Production Methods for a Mesenchymal Stem Cell Therapeutic as a Medical Defense Countermeasure

    2012-02-01

    mesenchymal stem cell (MSC) efficacy in a variety of injury models demonstrate the unique qualities of this reparative cell population to adapt to the...therapeutic product. Characterization of stem cell properties of culture-expanded MSCs is shown by in vitro differentiation to form mature cell types. The

  15. Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering

    Seung Taek Ji

    2017-01-01

    Full Text Available The primary cause of death among chronic diseases worldwide is ischemic cardiovascular diseases, such as stroke and myocardial infarction. Recent evidence indicates that adult stem cell therapies involving cardiovascular regeneration represent promising strategies to treat cardiovascular diseases. Owing to their immunomodulatory properties and vascular repair capabilities, mesenchymal stem cells (MSCs are strong candidate therapeutic stem cells for use in cardiovascular regeneration. However, major limitations must be overcome, including their very low survival rate in ischemic lesion. Various attempts have been made to improve the poor survival and longevity of engrafted MSCs. In order to develop novel therapeutic strategies, it is necessary to first identify stem cell modulators for intracellular signal triggering or niche activation. One promising therapeutic strategy is the priming of therapeutic MSCs with stem cell modulators before transplantation. Another is a tissue engineering-based therapeutic strategy involving a cell scaffold, a cell-protein-scaffold architecture made of biomaterials such as ECM or hydrogel, and cell patch- and 3D printing-based tissue engineering. This review focuses on the current clinical applications of MSCs for treating cardiovascular diseases and highlights several therapeutic strategies for promoting the therapeutic efficacy of MSCs in vitro or in vivo from cell priming to tissue engineering strategies, for use in cardiovascular regeneration.

  16. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor.

    Wu, Chia-Yung; Roybal, Kole T; Puchner, Elias M; Onuffer, James; Lim, Wendell A

    2015-10-16

    There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control. Copyright © 2015, American Association for the Advancement of Science.

  17. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor

    Wu, Chia-Yung; Roybal, Kole T.; Puchner, Elias M.; Onuffer, James; Lim, Wendell A.

    2016-01-01

    There is growing promise in using engineered cells as therapeutic agents. For example, synthetic Chimeric Antigen Receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, excessive activity and poor control over such engineered T cells can cause severe toxicities. We present the design of “ON-switch” CARs that enable small molecule-control over T cell therapeutic functions, while still retaining antigen specificity. In these split receptors, antigen binding and intracellular signaling components only assemble in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate both cell autonomous recognition and user control. PMID:26405231

  18. Cancer stem cell markers in common cancers - therapeutic implications

    Klonisch, Thomas; Wiechec, Emilia; Hombach-Klonisch, Sabine

    2008-01-01

    Rapid advance in the cancer stem cell field warrants optimism for the development of more reliable cancer therapies within the next 2-3 decades. Below, we characterize and compare the specific markers that are present on stem cells, cancer cells and cancer stem cells (CSC) in selected tissues...

  19. Applications of Shock Wave Research to Developments of Therapeutic Devices.

    Takayama, Kazuyoshi

    2007-06-01

    Underwater shock wave research applied to medicine started in 1980 by exploding micro lead azide pellets in water. Collaboration with urologists in the School of Medicine, Tohoku University at the same time was directed to disintegration of kidney stones by controlling shock waves. We initially proposed a miniature truncated ellipsoidal cavity for generating high-pressures enough to disintegrate the stone but gave up the idea, when encountering the Dornie Systems' invention of an extracorporeal shock wave lithotripter (ESWL). Then we confirmed its effectiveness by using 10 mg silver azide pellets and constructed our own lithotripter, which was officially approved for a clinical use in 1987. Tissue damage during ESWL was attributable to bubble collapse and we convinced it could be done in a controlled fashion. In 1996, we used 160 mJ pulsed Ho:YAG laser beam focusing inside a catheter for shock generation and applied it to the revascularization of cerebral embolism, which is recently expanded to the treatment of pulmonary infarction. Micro water jets discharged in air were so effective to dissect soft tissues preserving small blood vessels. Animal experiments are successfully performed with high frequency water jets driven by an actuator-assisted micro-pump. A metal foil is deformed at high speed by a Q-switched Nd:YAG laser beam loading. We used this technique to project micro-particles or dry drugs attached on its reverse side and extended it to a laser ablation assisted dry drug delivery or DNA introductory system.

  20. Therapeutic strategies involving uterine stem cells in reproductive medicine.

    Simoni, Michael; Taylor, Hugh S

    2018-04-12

    The current review provides an update on recent advances in stem cell biology relevant to female reproduction. Stem cells are undifferentiated cells that often serve as a reservoir of cells to regenerate tissue in settings or injury or cell loss. The endometrium has progenitor stem cells that can replace all of the endometrium during each menstrual cycle. In addition, multipotent endometrial cells replace these progenitor cells when depleted. Recruitment of stem cells from outside of the uterus occurs in setting of increased demand such as ischemia or injury. Bone marrow-derived multipotent stem cells are recruited to the uterus by estrogen or injury-induced expression of the chemokine CXCL12. In the setting of overwhelming injury, especially in the setting of low estrogen levels, there may be insufficient stem cell recruitment to adequately repair the uterus resulting in conditions such as Asherman syndrome or other endometrial defects. In contrast, excessive recruitment of stem cells underlies endometriosis. Enhanced understanding of stem-cell mobilization, recruitment, and engraftment has created the possibility of improved therapy for endometrial defects and endometriosis through enhanced manipulation of stem-cell trafficking. Further, the normal endometrium is a rich source of multipotent stem cells that can be used for numerous applications in regenerative medicine beyond reproduction. A better understanding of reproductive stem-cell biology may allow improved treatment of endometrial disease such as Asherman syndrome and other endometrial receptivity defects. Inhibiting stem-cell mobilization may also be helpful in endometriosis therapy. Finally, endometrial derived multipotent stem cells may play a crucial role in cell therapy for regenerative medicine.

  1. Radiation Interaction with Therapeutic Drugs and Cell Membranes

    Martin, Diana I.; Manaila, Elena N.; Matei, Constantin I.; Iacob, Nicusor I.; Ighigeanu, Daniel I.; Craciun, Gabriela D.; Moisescu, Mihaela I.; Savopol, Tudor D.; Kovacs, Eugenia A.; Cinca, Sabin A.; Margaritescu, Irina D.

    2007-01-01

    This transient permeabilized state of the cell membrane, named the 'cell electroporation' (CE) can be used to increase cells uptake of drugs that do not readily pass cell membrane, thus enabling their cytotoxicity. The anticancer drugs, such as bleomycin (BL) and cisplatin, are the most candidates for the combined use with ionizing and non-ionizing radiation fields. The methods and installations for the cell electroporation by electron beam (EB) and microwave (MW) irradiation are presented. The viability tests of the human leukocytes under EB and MW exposure with/without the BL in the cell cultures are discussed

  2. Microencapsulation of Hepatocytes and Mesenchymal Stem Cells for Therapeutic Applications.

    Meier, Raphael P H; Montanari, Elisa; Morel, Philippe; Pimenta, Joël; Schuurman, Henk-Jan; Wandrey, Christine; Gerber-Lemaire, Sandrine; Mahou, Redouan; Bühler, Leo H

    2017-01-01

    Encapsulated hepatocyte transplantation and encapsulated mesenchymal stem cell transplantation are newly developed potential treatments for acute and chronic liver diseases, respectively. Cells are microencapsulated in biocompatible semipermeable alginate-based hydrogels. Microspheres protect cells against antibodies and immune cells, while allowing nutrients, small/medium size proteins and drugs to diffuse inside and outside the polymer matrix. Microencapsulated cells are assessed in vitro and designed for experimental transplantation and for future clinical applications.Here, we describe the protocol for microencapsulation of hepatocytes and mesenchymal stem cells within hybrid poly(ethylene glycol)-alginate hydrogels.

  3. International Society for Stem Cell Research

    ... renowned stem cell and regenerative medicine community. More stem cell research Take a closer look Recent Blogs View ... story independent nonprofit organization & the voice of the stem cell research community The International Society for Stem Cell ...

  4. Therapeutic opportunities: Telomere maintenance in inducible pluripotent stem cells

    Gourronc, Francoise A. [Department of Microbiology, University of Iowa (United States); Klingelhutz, Aloysius J., E-mail: al-klingelhutz@uiowa.edu [Department of Microbiology, University of Iowa (United States)

    2012-02-01

    It has been demonstrated that exogenous expression of a combination of transcription factors can reprogram differentiated cells such as fibroblasts and keratinocytes into what have been termed induced pluripotent stem (iPS) cells. These iPS cells are capable of differentiating into all the tissue lineages when placed in the right environment and, in the case of mouse cells, can generate chimeric mice and be transmitted through the germline. Safer and more efficient methods of reprogramming are rapidly being developed. Clearly, iPS cells present a number of exciting possibilities, including disease modeling and therapy. A major question is whether the nuclei of iPS cells are truly rejuvenated or whether they might retain some of the marks of aging from the cells from which they were derived. One measure of cellular aging is the telomere. In this regard, recent studies have demonstrated that telomeres in iPS cells may be rejuvenated. They are not only elongated by reactivated telomerase but they are also epigenetically modified to be similar but not identical to embryonic stem cells. Upon differentiation, the derivative cells turn down telomerase, the telomeres begin to shorten again, and the telomeres and the genome are returned to an epigenetic state that is similar to normal differentiated somatic cells. While these preliminary telomere findings are promising, the overall genomic integrity of reprogrammed cells may still be problematic and further studies are needed to examine the safety and feasibility of using iPS cells in regenerative medicine applications.

  5. Therapeutic opportunities: Telomere maintenance in inducible pluripotent stem cells

    Gourronc, Francoise A.; Klingelhutz, Aloysius J.

    2012-01-01

    It has been demonstrated that exogenous expression of a combination of transcription factors can reprogram differentiated cells such as fibroblasts and keratinocytes into what have been termed induced pluripotent stem (iPS) cells. These iPS cells are capable of differentiating into all the tissue lineages when placed in the right environment and, in the case of mouse cells, can generate chimeric mice and be transmitted through the germline. Safer and more efficient methods of reprogramming are rapidly being developed. Clearly, iPS cells present a number of exciting possibilities, including disease modeling and therapy. A major question is whether the nuclei of iPS cells are truly rejuvenated or whether they might retain some of the marks of aging from the cells from which they were derived. One measure of cellular aging is the telomere. In this regard, recent studies have demonstrated that telomeres in iPS cells may be rejuvenated. They are not only elongated by reactivated telomerase but they are also epigenetically modified to be similar but not identical to embryonic stem cells. Upon differentiation, the derivative cells turn down telomerase, the telomeres begin to shorten again, and the telomeres and the genome are returned to an epigenetic state that is similar to normal differentiated somatic cells. While these preliminary telomere findings are promising, the overall genomic integrity of reprogrammed cells may still be problematic and further studies are needed to examine the safety and feasibility of using iPS cells in regenerative medicine applications.

  6. Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility?

    Easley, Charles A; Simerly, Calvin R; Schatten, Gerald

    2013-07-01

    Recent advances in assisted reproduction treatment have enabled some couples with severe infertility issues to conceive, but the methods are not successful in all cases. Notwithstanding the significant financial burden of assisted reproduction treatment, the emotional scars from an inability to conceive a child enacts a greater toll on affected couples. While methods have circumvented some root causes for male and female infertility, often the underlying causes cannot be treated, thus true cures for restoring a patient's fertility are limited. Furthermore, the procedures are only available if the affected patients are able to produce gametes. Patients rendered sterile by medical interventions, exposure to toxicants or genetic causes are unable to utilize assisted reproduction to conceive a child - and often resort to donors, where permitted. Stem cells represent a future potential avenue for allowing these sterile patients to produce offspring. Advances in stem cell biology indicate that stem cell replacement therapies or in-vitro differentiation may be on the horizon to treat and could cure male and female infertility, although significant challenges need to be met before this technology can reach clinical practice. This article discusses these advances and describes the impact that these advances may have on treating infertility. Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  7. Therapeutic action of taurine on the postirradiation recovery of the yeast cells

    Benevolenskij, V.N.; Yartsev, E.I.; Novosteltseva, S.D.; Yakovlev, V.G.

    1975-01-01

    It has been shown on X-irradiated Saccharomyces ellipsoides cells that taurine-potassium phosphate applied after the exposure has a therapeutic action, that is, it intensifies the natural process of intracellular dark repair

  8. Therapeutic Evaluation of Mesenchymal Stem Cells in Chronic Gut Inflammation

    2017-11-01

    innate lymphoid cells (ILCs). ILCs arise from hematolym- phoid progenitor cells and may be categorized as cytotoxic ILCs which are represented by natural...20–32. thophC. Reinoso Webb et al. / Pa [39] G. Eberl, J.P. Di Santo, E. Vivier, The brave new world of innate lymphoid cells , Nat. Immunol. 16 (2015...Koni, F.D. Bushman, C.O. Elson, G. Eberl, D. Artis, G.F. Sonnenberg, Innate lymphoid cells regulate CD4+ T- cell responses to intestinal commensal

  9. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

    Hiroshi Katoh

    2015-01-01

    Full Text Available Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs. Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

  10. Myeloid derived suppressor cells as therapeutic target in hematological malignancies

    Kim eDe Veirman

    2014-12-01

    Full Text Available Myeloid derived suppressor cells (MDSC are a heterogeneous population of immature myeloid cells that accumulate during pathological conditions such as cancer and are associated with a poor clinical outcome. MDSC expansion hampers the host anti-tumor immune response by inhibition of T cell proliferation, cytokine secretion and recruitment of regulatory T cells. In addition, MDSC exert non-immunological functions including the promotion of angiogenesis, tumor invasion and metastasis. Recent years, MDSC are considered as a potential target in solid tumors and hematological malignancies to enhance the effects of currently used immune modulating agents. This review focuses on the characteristics, distribution, functions, cell-cell interactions and targeting of MDSC in hematological malignancies including multiple myeloma, lymphoma and leukemia.

  11. Therapeutic Application of Pluripotent Stem Cells: Challenges and Risks

    Ulrich Martin

    2017-12-01

    Full Text Available Stem-cell-based therapies are considered to be promising and innovative but complex approaches. Induced pluripotent stem cells (iPSCs combine the advantages of adult stem cells with the hitherto unique characteristics of embryonic stem cells (ESCs. Major progress has already been achieved with regard to reprogramming technology, but also regarding targeted genome editing and scalable expansion and differentiation of iPSCs and ESCs, in some cases yielding highly enriched preparations of well-defined cell lineages at clinically required dimensions. It is noteworthy, however, that for many applications critical requirements such as the targeted specification into distinct cellular subpopulations and a proper cell maturation remain to be achieved. Moreover, current hurdles such as low survival rates and insufficient functional integration of cellular transplants remain to be overcome. Nevertheless, PSC technologies obviously have come of age and matured to a stage where various clinical applications of PSC-based cellular therapies have been initiated and are conducted.

  12. Stem cell aging: mechanisms, regulators and therapeutic opportunities

    Oh, Juhyun; Lee, Yang David; Wagers, Amy J

    2014-01-01

    Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic ‘memory’ that is indelibly written or one that can be reset. PMID:25100532

  13. Stem cells of umbilical blood cord – therapeutic use

    Beata Bielec

    2015-07-01

    Full Text Available For many years, the transplantation of hematopoietic stem cells has been used to treat some diseases of the hematopoietic system. For a very long time, only bone marrow was used as a source of hematopoietic stem cells for this method of treatment. However, to comply with allogeneic bone marrow transplantation, an antigenically compatible donor is necessary. Transplantations from unrelated donors are associated with increased risk of a graft-versus-host reaction, transplant rejection and, consequently, increased mortality. Many years ago, it was found that umbilical cord blood as well as bone marrow and peripheral blood contains hematopoietic stem cells and mesenchymal cells able to differentiate into different cell types and that the umbilical cord blood can be a source of stem cells for transplantation. Following this discovery, numerous attempts were made for its potential use in the treatment of hematologic diseases, metabolic diseases as well as regenerative medicine. Umbilical cord blood stem cells exhibit intermediate characteristics between embryonic and adult stem cells. They are distinguished from the latter by telomere length, telomerase activity, and lower risk of accumulation of DNA mutations or chromosomal aberrations. The only transplantation limitation appears to be the amount of cord blood collected, which on average is sufficient for transplantation in a 40-50 kg child. Collection of cord blood is a simple, short-lasting treatment, not causing any danger for a newborn or the mother. Umbilical cord blood is obtained during labor, and then frozen and stored at cord blood banks all over the world.

  14. Multipotency and therapeutic potential of NG2 cells.

    Valný, Martin; Honsa, Pavel; Kriška, Ján; Anděrová, Miroslava

    2017-01-01

    Roč. 141, SI (2017), s. 42-55 ISSN 0006-2952 R&D Projects: GA ČR(CZ) GA17-04034S Institutional support: RVO:68378041 Keywords : NG2 cells * oligodendrocyte precursor cells (OPC) * myelin plasticity Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 4.581, year: 2016

  15. Survivin is a therapeutic target in Merkel cell carcinoma

    Arora, Reety; Shuda, Masahiro; Guastafierro, Anna; Feng, Huichen; Toptan, Tuna; Tolstov, Yanis; Normolle, Daniel; Vollmer, Laura L; Vogt, Andreas; Dömling, Alexander; Brodsky, Jeffrey L; Chang, Yuan; Moore, Patrick S

    2012-01-01

    Merkel cell polyomavirus (MCV) causes ~80% of primary and metastatic Merkel cell carcinomas (MCCs). By comparing digital transcriptome subtraction deep-sequencing profiles, we found that transcripts of the cellular survivin oncoprotein [BIRC5a (baculoviral inhibitor of apoptosis repeat-containing

  16. Micronutrients as therapeutic tools in the management of sickle cell ...

    Sickle cell disease, malaria and diabetes are among the diseases plaguing a good population of the developing world and the cost implication for their management is very high. Sickle cell disease and malari have anemia as a common factor and immunological disturbances are also prevalent in these disease conditions.

  17. Toward a new generation of therapeutics: artificial cell targeted delivery of live cells for therapy.

    Prakash, Satya; Martoni, Christopher

    2006-01-01

    Scientific evidence in the prevention and treatment of various disorders is accumulating regarding probiotics. The health benefits supported by adequate clinical data include increased resistance to infectious disease, decreased duration of diarrhea, management of inflammatory bowel disease, reduction of serum cholesterol, prevention of allergy, modulation of cytokine gene expression, and suppression of carcinogen production. Recent ventures in metabolic engineering and heterologous protein expression have enhanced the enzymatic and immunomodulatory effects of probiotics and, with time, may allow more active intervention among critical care patients. In addition, a number of approaches are currently being explored, including the physical and chemical protection of cells, to increase probiotic viability and its health benefits. Traditional immobilization of probiotics in gel matrices, most notably calcium alginate and kappa-carrageenan, has frequently been employed, with noted improvements in viability during freezing and storage. Conflicting reports exist, however, on the protection offered by immobilization from harsh physiologic environments. An alternative approach, microencapsulation in "artificial cells," builds on immobilization technologies by combining enhanced mechanical stability of the capsule membrane with improved mass transport, increased cell loading, and greater control of parameters. This review summarizes the current clinical status of probiotics, examines the promises and challenges of current immobilization technologies, and presents the concept of artificial cells for effective delivery of therapeutic bacterial cells.

  18. [Cell-based therapies - an innovative therapeutic option in ophthalmology: Treating corneal diseases with stem cells].

    Bakker, Ann-Christin; Langer, Barbara

    2015-11-01

    Pathological changes and disorders of the cornea are a major cause of severe visual impairment and blindness. Replacement of a pathologically altered cornea with healthy corneal tissue from the eye of a suitable donor is among the most common and successful transplantation procedures in medicine. In Germany, approximately 5000-6000 corneal transplantations are performed each year, but the total demand per year is estimated to be twice as high. With a success rate of 90%, the outcome of cornea transplantation is very favourable. However, long-term maintenance and regeneration of a healthy new cornea requires tissue-specific corneal stem cells residing at the basal layer of the limbus, which is the annular transition zone between the cornea and sclera. When this important limbal stem cell population is destroyed or dysfunctional, a pathological condition known as limbal stem cell deficiency (LSCD) manifests. Limbal stem cell deficiency describes conditions associated with impaired corneal wound healing and regeneration. In this situation, transplantation of healthy limbal stem cells is the only curative treatment approach for restoration of an intact and functional ocular surface. To date, treatment of LSCD presents a great challenge for ophthalmologists. However, innovative, cell-therapeutic approaches may open new, promising treatment perspectives. In February 2015, the European Commission granted marketing authorization to the first stem cell-based treatment in the European Union. The product named Holoclar® is an advanced therapy medicinal product (ATMP) for the treatment of moderate to severe LSCD due to physical and chemical burns in adults. Further cell-based treatment approaches are in clinical development.

  19. The Impact of Endometriosis across the Lifespan of Women: Foreseeable Research and Therapeutic Prospects

    C. L. Hughes

    2015-01-01

    Full Text Available In addition to estrogen dependence, endometriosis is characterized by chronic pelvic inflammation. The impact of the chronic pelvic inflammatory state on other organ systems and women’s health is unclear. Endometriosis associated chronic inflammation and potential adverse health effects across the lifespan render it imperative for renewed research vigor into the identification of novel biomarkers of disease and therapeutic options. Herein we propose a number of opportunities for research and development of new therapeutics to address the unmet needs in the treatment of endometriosis per se and its ancillary risks for other diseases in women across the lifespan.

  20. CELL-SELEX: Novel Perspectives of Aptamer-Based Therapeutics

    Hans P. Wendel

    2008-04-01

    Full Text Available Aptamers, single stranded DNA or RNA molecules, generated by a method called SELEX (systematic evolution of ligands by exponential enrichment have been widely used in various biomedical applications. The newly developed Cell-SELEX (cell based-SELEX targeting whole living cells has raised great expectations for cancer biology, -therapy and regenerative medicine. Combining nanobiotechnology with aptamers, this technology opens the way to more sophisticated applications in molecular diagnosis. This paper gives a review of recent developments in SELEX technologies and new applications of aptamers.

  1. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma

    Bag?, Juli R.; Alfonso-Pecchio, Adolfo; Okolie, Onyi; Dumitru, Raluca; Rinkenbaugh, Amanda; Baldwin, Albert S.; Miller, C. Ryan; Magness, Scott T.; Hingtgen, Shawn D.

    2016-01-01

    Transdifferentiation (TD) is a recent advancement in somatic cell reprogramming. The direct conversion of TD eliminates the pluripotent intermediate state to create cells that are ideal for personalized cell therapy. Here we provide evidence that TD-derived induced neural stem cells (iNSCs) are an efficacious therapeutic strategy for brain cancer. We find that iNSCs genetically engineered with optical reporters and tumouricidal gene products retain the capacity to differentiate and induced ap...

  2. Psychiatric therapeutic applications of virtual reality technology (VRT): research prospectus and phenomenological critique.

    Bloom, R W

    1997-01-01

    There is theoretical and empirical research supporting the hypothesis that virtual reality technology (VRT) can be efficaciously applied to attenuate the symptoms of mental disorders (Baer, 1996; Rothbaum et al, 1995a, 1995b; Rothbaum et al, 1996.) Yet there is also research suggesting psychiatric therapeutic applications of VRT may induce noxious or unexpected psychological consequences (Kolasinski, 1996; Muscott & Gifford, 1994; Regan & Price, 1994; Regan & Ramsey, 1996; Strickland, 1995.) A prudent conclusion would be to advocate ever more sophisticated studies on psychiatric therapeutic applications of VRT concerning (1) increasing the overall socioadaptiveness of patients, (2) the robustness of moderating, modifying, or other intermediary variables effecting or affecting VRT therapeutic efficacy, and (3) variables, processes, and hypotheses generated from VRT applications in non-psychiatric fields.

  3. Nanotechnology solutions for Alzheimer's disease: advances in research tools, diagnostic methods and therapeutic agents.

    Nazem, Amir; Mansoori, G Ali

    2008-03-01

    A century of research has passed since the discovery and definition of Alzheimer's disease (AD), the primary common dementing disorder worldwide. However, AD lacks definite diagnostic approaches and effective cure at the present. Moreover, the currently available diagnostic tools are not sufficient for an early screening of AD in order to start preventive approaches. Recently the emerging field of nanotechnology has promised new techniques to solve some of the AD challenges. Nanotechnology refers to the techniques of designing and manufacturing nanosize (1-100 nm) structures through controlled positional and/or self-assembly of atoms and molecules. In this report, we present the promises that nanotechnology brings in research on the AD diagnosis and therapy. They include its potential for the better understanding of the AD root cause molecular mechanisms, AD's early diagnoses, and effective treatment. The advances in AD research offered by the atomic force microscopy, single molecule fluorescence microscopy and NanoSIMS microscopy are examined here. In addition, the recently proposed applications of nanotechnology for the early diagnosis of AD including bio-barcode assay, localized surface plasmon resonance nanosensor, quantum dot and nanomechanical cantilever arrays are analyzed. Applications of nanotechnology in AD therapy including neuroprotections against oxidative stress and anti-amyloid therapeutics, neuroregeneration and drug delivery beyond the blood brain barrier (BBB) are discussed and analyzed. All of these applications could improve the treatment approach of AD and other neurodegenerative diseases. The complete cure of AD may become feasible by a combination of nanotechnology and some other novel approaches, like stem cell technology.

  4. The Multifaceted Uses and Therapeutic Advantages of Nanoparticles for Atherosclerosis Research.

    DiStasio, Nicholas; Lehoux, Stephanie; Khademhosseini, Ali; Tabrizian, Maryam

    2018-05-08

    Nanoparticles are uniquely suited for the study and development of potential therapies against atherosclerosis by virtue of their size, fine-tunable properties, and ability to incorporate therapies and/or imaging modalities. Furthermore, nanoparticles can be specifically targeted to the atherosclerotic plaque, evading off-target effects and/or associated cytotoxicity. There has been a wealth of knowledge available concerning the use of nanotechnologies in cardiovascular disease and atherosclerosis, in particular in animal models, but with a major focus on imaging agents. In fact, roughly 60% of articles from an initial search for this review included examples of imaging applications of nanoparticles. Thus, this review focuses on experimental therapy interventions applied to and observed in animal models. Particular emphasis is placed on how nanoparticle materials and properties allow researchers to learn a great deal about atherosclerosis. The objective of this review was to provide an update for nanoparticle use in imaging and drug delivery studies and to illustrate how nanoparticles can be used for sensing and modelling, for studying fundamental biological mechanisms, and for the delivery of biotherapeutics such as proteins, peptides, nucleic acids, and even cells all with the goal of attenuating atherosclerosis. Furthermore, the various atherosclerosis processes targeted mainly for imaging studies have been summarized in the hopes of inspiring new and exciting targeted therapeutic and/or imaging strategies.

  5. Mesenchymal stem cells (MSCs) as skeletal therapeutics-an update

    Saeed, H.; Ahsan, M.; Saleem, Z.

    2016-01-01

    Mesenchymal stem cells hold the promise to treat not only several congenital and acquired bone degenerative diseases but also to repair and regenerate morbid bone tissues. Utilizing MSCs, several lines of evidences advocate promising clinical outcomes in skeletal diseases and skeletal tissue repair....../regeneration. In this context, both, autologous and allogeneic cell transfer options have been utilized. Studies suggest that MSCs are transplanted either alone by mixing with autogenous plasma/serum or by loading onto repair/induction supportive resorb-able scaffolds. Thus, this review is aimed at highlighting a wide range...

  6. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson's disease treatment.

    Kojima, Ryosuke; Bojar, Daniel; Rizzi, Giorgio; Hamri, Ghislaine Charpin-El; El-Baba, Marie Daoud; Saxena, Pratik; Ausländer, Simon; Tan, Kelly R; Fussenegger, Martin

    2018-04-03

    Exosomes are cell-derived nanovesicles (50-150 nm), which mediate intercellular communication, and are candidate therapeutic agents. However, inefficiency of exosomal message transfer, such as mRNA, and lack of methods to create designer exosomes have hampered their development into therapeutic interventions. Here, we report a set of EXOsomal transfer into cells (EXOtic) devices that enable efficient, customizable production of designer exosomes in engineered mammalian cells. These genetically encoded devices in exosome producer cells enhance exosome production, specific mRNA packaging, and delivery of the mRNA into the cytosol of target cells, enabling efficient cell-to-cell communication without the need to concentrate exosomes. Further, engineered producer cells implanted in living mice could consistently deliver cargo mRNA to the brain. Therapeutic catalase mRNA delivery by designer exosomes attenuated neurotoxicity and neuroinflammation in in vitro and in vivo models of Parkinson's disease, indicating the potential usefulness of the EXOtic devices for RNA delivery-based therapeutic applications.

  7. Mass Spectrometry for Research and Application in Therapeutic Drug Monitoring or Clinical and Forensic Toxicology.

    Maurer, Hans H

    2018-04-30

    This paper reviews current applications of various hyphenated low- and high-resolution mass spectrometry techniques in the field of therapeutic drug monitoring and clinical/forensic toxicology in both research and practice. They cover gas chromatography, liquid chromatography, matrix-assisted laser desorption ionization, or paper spray ionization coupled to quadrupole, ion trap, time-of-flight, or Orbitrap mass analyzers.

  8. Delphi process yielded consensus on terminology and research agenda for therapeutic footwear for neuropathic foot.

    Dahmen, R.; van der Wilden, G.J.; Lankhorst, G.J.; Boers, M.

    2008-01-01

    Objective: To investigate areas of consensus and disagreement among Dutch physiatrists concerning prescription of therapeutic footwear for the neuropathic foot and to develop a research agenda. Study Design and Setting: Forty participants were physiatrists and experts in the field of orthopedic shoe

  9. Therapeutic Evaluation of Mesenchymal Stem Cells in Chronic Gut Inflammation

    2014-09-01

    expression was induced by more than 140- fold following cytokine activation (Figure 4) Again, this is very exciting as our collaborator (Dr. Darwin ...Contribution: Dr. Koboziev performs all cell preparations, molecular and in vitro assays and assists with the flow cytometry studies and animal model Funding

  10. Therapeutic potential and challenges of Natural killer cells in treatment of solid tumors

    Andrea eGras Navarro

    2015-04-01

    Full Text Available Natural killer (NK cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing requiring one–to-one target engagement and site directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells (CSCs and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME and augment adaptive immune responses by promoting differentiation, activation and/ or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.

  11. PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

    Esperanza Martín-Sánchez

    Full Text Available Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL. The Proviral Integration site of Moloney murine leukemia virus (PIM kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs and pharmacologically (mainly with the pan-PIM inhibitor (PIMi ETP-39010 in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

  12. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Zhong SHI

    2015-02-01

    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

  13. The Mircen project, neuro-degenerative disease: mechanisms, therapeutics and imaging research Unit URA Cea Cnrs 2210

    Hantraye, Ph.

    2006-01-01

    During the post-genomic era, significant advances in our understanding of the molecular basis of disease have been made. The power of functional and molecular imaging in translating this knowledge into effective therapy is now being more and more recognized. Thus, molecular imaging plays a vital role in the early identification of disease-related molecular markers, in the development of molecular-targeted therapies, and in monitoring phenotypic response to therapy both in experimental animals and in human patients. In this context, MIRCen (acronym for Molecular Imaging Research Center ) provides a comprehensive resource available to empower basic, translational, and clinical research through the application of imaging and drug, cell, and gene based technologies. The MIR center will be dedicated to the development of pre-clinical trials for the treatment of various seriously debilitating diseases such as neuro-degenerative diseases, cardiac and hepatic disorders, and infectious diseases (AIDS). Despite the fact that many of these pathologies are still incurable, recent advances in drug, cell and gene therapy point to the feasibility of new therapeutic approaches. The long term goals of MIRCen are therefore to develop and validate: - pertinent animal models for neuro-degenerative, hepatic, cardiac and infectious diseases in rodents as well as non-human primates, - novel technologies for in vivo sensing and imaging of disease-related molecular events,- drug, gene and cell based palliative and or curative therapeutic strategies aiming at protecting and /or restoring damaged or lost functions. (author)

  14. Musings on genome medicine: is there hope for ethical and safe stem cell therapeutics?

    Rao, Mahendra; Condic, Maureen L

    2009-07-14

    Although most stem cell therapy has been non-controversial, therapy based on pluripotent stem cells has raised both ethical and safety concerns. Despite these concerns, the use of cells derived from pluripotent stem cells has recently been approved for clinical trials. We suggest that recent advances in the field have provided avenues to develop pluripotent cells that raise far fewer ethical concerns. Moreover, advances in cell sorting, gene modification and screening have allowed the development of safer therapeutic approaches. Continued advances in this rapidly evolving field are likely to allow therapy to be delivered in a safe and effective manner without socially divisive ethical controversy in the not-so-distant future.

  15. Nuclear data for the production of therapeutic radionuclides. Summary report of third research coordination meeting

    Sublet, J.-Ch.; Capote Noy, R.

    2006-08-01

    A summary is given of the Third Research Coordination Meeting on Nuclear Data for the Production of Therapeutic Radionuclides. The new library of evaluated cross-section will cover reactor and accelerator production of therapeutic radionuclides to appropriate specific activities and purity, along with the relevant decay data. A few new reactions were added at this meeting. Technical discussions and the resulting work plan to conclude the data evaluation activities are summarized for every reaction path. Timescales and agreed actions to deliver the database and Technical Report are also given. (author)

  16. Mesenchymal stem cell-derived microparticles: a promising therapeutic strategy.

    Tan, Xi; Gong, Yong-Zhen; Wu, Ping; Liao, Duan-Fang; Zheng, Xi-Long

    2014-08-18

    Mesenchymal stem cells (MSCs) are multipotent stem cells that give rise to various cell types of the mesodermal germ layer. Because of their unique ability to home in on injured and cancerous tissues, MSCs are of great potential in regenerative medicine. MSCs also contribute to reparative processes in different pathological conditions, including cardiovascular diseases and cancer. However, many studies have shown that only a small proportion of transplanted MSCs can actually survive and be incorporated into host tissues. The effects of MSCs cannot be fully explained by their number. Recent discoveries suggest that microparticles (MPs) derived from MSCs may be important for the physiological functions of their parent. Though the physiological role of MSC-MPs is currently not well understood, inspiring results indicate that, in tissue repair and anti-cancer therapy, MSC-MPs have similar pro-regenerative and protective properties as their cellular counterparts. Thus, MSC-MPs represent a promising approach that may overcome the obstacles and risks associated with the use of native or engineered MSCs.

  17. [Xenogeneic cell therapeutics: Treatment of type 1 diabetes using porcine pancreatic islets and islet cells].

    Godehardt, Antonia W; Schilling-Leiß, Dagmar; Sanzenbacher, Ralf; Tönjes, Ralf R

    2015-11-01

    In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.

  18. Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation.

    Faravelli, Irene; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Zanetta, Chiara; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-09-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3-5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.

  19. Stem cell research in pakistan; past, present and future.

    Zahra, Sayeda Anum; Muzavir, Sayed Raheel; Ashraf, Sadia; Ahmad, Aftab

    2015-05-01

    Stem cells have proved to have great therapeutic potential as stem cell treatment is replacing traditional ways of treatment in different disorders like cancer, aplastic anemia, stroke, heart disorders. The developed and developing countries are investing differently in this area of research so research output and clinical translation of research greatly vary among developed and developing countries. Present study was done to investigate the current status of stem cells research in Pakistan and ways to improve it. Many advanced countries (USA, UK and Canada etc.) are investing heavily in stem cell research and treatment. Different developing countries like Iran, Turkey and India are also following the developed countries and investing a lot in stem cells research. Pakistan is also making efforts in establishing this field to get desired benefits but unfortunately the progress is at very low pace. If Government plays an active role along with private sector, stem cell research in Pakistan can be boosted up. The numbers of publications from Pakistan are very less compared to developed and neighboring countries and Pakistan also has very less number of institutes working in this area of research. Stem cells research is at its initial stages in Pakistan and there is great need to bring Government, academia and industry together so they could make serious efforts to promote research in this very important field. This will help millions of patients suffering from incurable disorders and will also reduce economic loss.

  20. Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411

    Holmboe, Sif; Hansen, Pernille Lund; Thisgaard, Helge

    2017-01-01

    Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somato...

  1. Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

    Louise A. Mesentier-Louro

    2016-01-01

    Full Text Available Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

  2. Therapeutic effect of mesenchymal multipotent stromal cells on memory in animals with Alzheimer-type neurodegeneration.

    Bobkova, N V; Poltavtseva, R A; Samokhin, A N; Sukhikh, G T

    2013-11-01

    Transplantation of human mesenchymal multipotent stromal cells improved spatial memory in bulbectomized mice with Alzheimer-type neurodegeneration. The positive effect was observed in 1 month after intracerebral transplantation and in 3 months after systemic injection of mesenchymal multipotent stromal cells. No cases of malignant transformation were noted. These findings indicate prospects of using mesenchymal multipotent stromal cells for the therapy of Alzheimer disease and the possibility of their systemic administration for attaining the therapeutic effect.

  3. Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411.

    Sif Holmboe

    Full Text Available Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.

  4. Therapeutic targeting of the p53 pathway in cancer stem cells

    Prabhu, Varun V.; Allen, Joshua E.; Hong, Bo; Zhang, Shengliang; Cheng, Hairong; El-Deiry, Wafik S.

    2013-01-01

    Introduction Cancer stem cells are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance, and therapeutic resistance. Restoring wild-type p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target cancer stem cells. Areas covered Therapeutic approaches to restore the function of wild-type p53, cancer and normal stem cell biology in relation to p53, and the downstream effects of p53 on cancer stem cells. Expert opinion The restoration of wild-type p53 function by targeting p53 directly, its interacting proteins, or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and cancer stem cells based on the current evidence linking p53 signaling with these populations. PMID:22998602

  5. Nuclear data for production of therapeutic radionuclides. Summary report of second research coordination meeting

    Sublet, J.-Ch.; Capote Noy, R.

    2004-11-01

    A summary is given of the Second Research Coordination Meeting on Nuclear Data for Production of Therapeutic Radionuclides. The new library of evaluated cross section will cover the reactor and/or accelerator production of therapeutic radionuclides to appropriate specific activities and purity along with the relevant decay data. There are a significant number of radioisotopes in use or being proposed for therapeutic applications. As a consequence of the work undertaken during the course of this CRP, the resulting completeness and accuracy of the nuclear data for the production of these nuclides to appropriate specific activities and purity along with the re-definition of their decay data should be adequate for safe and efficient medical applications. The radioisotopes to be considered in the CRP were divided into two categories: Established Radioisotopes (therapeutic radioisotopes that have established clinical uses) and Emerging Radioisotopes (less-commonly used but potentially interesting radioisotopes for which medical applications have been demonstrated). Experimental data compilations and selection and preliminary evaluations for each of the reactions were extensively discussed during the meeting. The recommendations for both established and emerging radionuclides, and validation/testing of the cross section library are summarized. Technical discussions and the resulting work plan of the Coordinated Research Programme are summarized for every reaction path to be evaluated, along with actions and deadlines. Participants' contributions to the RCM are also attached. (author)

  6. The therapeutic alliance in internet interventions: A narrative review and suggestions for future research.

    Berger, Thomas

    2017-09-01

    Research on Internet interventions has grown rapidly over the recent years and evidence is growing that Internet-based treatments often result in similar outcomes as conventional face-to-face psychotherapy. Yet there are still unanswered concerns such as whether a therapeutic alliance can be established over the Internet and whether the alliance is important in this new treatment format. A narrative review of studies formally assessing the therapeutic alliance in Internet interventions was conducted. It is the first review summarizing findings on the therapeutic alliance that (i) distinguishes between different forms of Internet interventions and (ii) does not restrict itself to specific Internet-based treatment formats such as guided self-help treatments, e-mail or videoconferencing therapies. Independent of communication modalities, diagnostic groups and amount of contact between clients and therapists, client-rated alliance scores were high, roughly equivalent to alliance ratings found in studies on face-to-face therapy. Mixed results were found regarding the therapist-rated alliance and alliance-outcome associations. The review points to the limitations of the available evidence and identifies unanswered questions. It is concluded that one of the major tasks for future research is to identify unique characteristics of the therapeutic alliance in the different treatment formats.

  7. Fuel Cell Manufacturing Research and Development | Hydrogen and Fuel Cells

    | NREL Fuel Cell Manufacturing Research and Development Fuel Cell Manufacturing Research and Development NREL's fuel cell manufacturing R&D focuses on improving quality-inspection practices for high costs. A researcher monitoring web-line equipment in the Manufacturing Laboratory Many fuel cell

  8. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain.

    Lee, Se Jeong; Kang, Won Young; Yoon, Yeup; Jin, Ju Youn; Song, Hye Jin; Her, Jung Hyun; Kang, Sang Mi; Hwang, Yu Kyeong; Kang, Kyeong Jin; Joo, Kyeung Min; Nam, Do-Hyun

    2015-12-24

    Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain. Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgamma(null) (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro. Patient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects. Our results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.

  9. Physical urticarias: mast cell disfunction. Preventive, diagnostic and therapeutical approach

    Mario Geller

    2007-09-01

    Full Text Available Objective: To present and discuss the current classification of physicalurticarias based on immunologic and pathophysiological mechanisms.To describe clinical symptoms, triggering and worsening factors,different diagnostic tools, and to list the available pharmacologicaltherapeutic approaches as well as the methods of physicaldesensitization. Methods: The literature search was carried out usingMedline. Forty studies were evaluated including case-control series,meta-analyses, case reports and reviews in the English language. Thekeywords used were physical urticarias, classification, and physicaldesensitization. A didactic diagnostic classification of differentgroups of physical urticarias was made, as well as a description ofthe several modalities of these dermatatologic conditions causedby physical stimuli, as localized or diffuse, classical or atypical,acquired or familial, with or without IgE involvement. The geneticpredisposing factors were determined. Results: Physical urticaria isdue to mast cell dysfunction with lowered threshold for the releaseof cytoplasmic anaphylactic mediators triggered by physical factors.These precipitating environmental physical factors include cold, heat,mechanical stimuli, exercises, exposure to sunlight and skin contactwith water. Conclusions: Physical urticarias occur in approximately17% of chronic urticaria patients and different forms may coexist inthe same individual. Treatments include prevention, antihistamines(classical and non-sedating presentations and, occasionally,corticosteroids, dapsone and other anti-inflammatory drugs, and thepotential use of specific physical desensitization.

  10. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

    Daria S. Chulpanova

    2018-03-01

    Full Text Available Mesenchymal stem cells (MSCs are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs, which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.

  11. ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles.

    Bonafede, Roberta; Mariotti, Raffaella

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.

  12. In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides.

    Bolhassani, Azam; Jafarzade, Behnaz Sadat; Mardani, Golnaz

    2017-01-01

    The failure of proteins to penetrate mammalian cells or target tumor cells restricts their value as therapeutic tools in a variety of diseases such as cancers. Recently, protein transduction domains (PTDs) or cell penetrating peptides (CPPs) have been shown to promote the delivery of therapeutic proteins or peptides into live cells. The successful delivery of proteins mainly depends on their physicochemical properties. Although, linear cell penetrating peptides are one of the most effective delivery vehicles; but currently, cyclic CPPs has been developed to potently transport bioactive full-length proteins into cells. Up to now, several small protein transduction domains from viral proteins including Tat or VP22 could be fused to other peptides or proteins to entry them in various cell types at a dose-dependent approach. A major disadvantage of PTD-fusion proteins is primary uptake into endosomal vesicles leading to inefficient release of the fusion proteins into the cytosol. Recently, non-covalent complex formation (Chariot) between proteins and CPPs has attracted a special interest to overcome some delivery limitations (e.g., toxicity). Many preclinical and clinical trials of CPP-based delivery are currently under evaluation. Generally, development of more efficient protein transduction domains would significantly increase the potency of protein therapeutics. Moreover, the synergistic or combined effects of CPPs with other delivery systems for protein/peptide drug delivery would promote their therapeutic effects in cancer and other diseases. In this review, we will describe the functions and implications of CPPs for delivering the therapeutic proteins or peptides in preclinical and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Nanotechnology in stem cells research: advances and applications.

    Deb, Kaushik Dilip; Griffith, May; Muinck, Ebo De; Rafat, Mehrdad

    2012-01-01

    Human beings suffer from a myriad of disorders caused by biochemical or biophysical alteration of physiological systems leading to organ failure. For a number of these conditions, stem cells and their enormous reparative potential may be the last hope for restoring function to these failing organ or tissue systems. To harness the potential of stem cells for biotherapeutic applications, we need to work at the size scale of molecules and processes that govern stem cells fate. Nanotechnology provides us with such capacity. Therefore, effective amalgamation of nanotechnology and stem cells - medical nanoscience or nanomedicine - offers immense benefits to the human race. The aim of this paper is to discuss the role and importance of nanotechnology in stem cell research by focusing on several important areas such as stem cell visualization and imaging, genetic modifications and reprogramming by gene delivery systems, creating stem cell niche, and similar therapeutic applications.

  14. Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

    Jones, Melissa K.; Lu, Bin; Girman, Sergey; Wang, Shaomei

    2017-01-01

    Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments. PMID:28111323

  15. Antecedents and Consequences of Therapeutic Communication in Iranian Nursing Students: A Qualitative Research

    Abdolrahimi, Mahbobeh; Ghiyasvandian, Shahrzad; Zakerimoghadam, Masoumeh; Ebadi, Abbas

    2017-01-01

    In recent years, particular attention has been paid to nursing students’ therapeutic communication (TC) with patients, due to a strong emphasis on patient-centered education in the Iranian healthcare reform. However, various studies have highlighted the poor communication of future nurses. Therefore, researchers have used qualitative methodology to shed light on the antecedents and consequences of nursing students’ TC and promote it. We carried out a conventional content analysis using semist...

  16. Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives.

    Bose, Bipasha; Sen, Utsav; Shenoy P, Sudheer

    2018-01-01

    Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  17. STEM CELL RESEARCH-CONCEPT AND CONTROVERSIES

    Dr. E. P. Gharoro

    cells, heart cells, brain cells, etc.). Some researchers regard them as offering the greatest potential for the .... anaemia, heart damage, corneal damage, etc. To be useful for transplant purposes, stem cells must ... activity in the brain was demonstrated contradicting caja's “no new neurons” dogma. However, research into.

  18. Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases.

    Harrell, C Randall; Simovic Markovic, Bojana; Fellabaum, Crissy; Arsenijevic, Aleksandar; Djonov, Valentin; Arsenijevic, Nebojsa; Volarevic, Vladislav

    2018-05-18

    Mesenchymal stem cells (MSCs) were, due to their immunomodulatory and pro-angiogenic characteristics, extensively explored as new therapeutic agents in cell-based therapy of uveitis, glaucoma, retinal and ocular surface diseases.Since it was recently revealed that exosomes play an important role in biological functions of MSCs, herewith we summarized current knowledge about the morphology, structure, phenotype and functional characteristics of MSC-derived exosomes emphasizing their therapeutic potential in the treatment of eye diseases.MSC-derived exosomes were as efficient as transplanted MSCs in limiting the extent of eye injury and inflammation. Immediately after intravitreal injection, MSC-derived exosomes, due to nano-dimension, diffused rapidly throughout the retina and significantly attenuated retinal damage and inflammation. MSC-derived exosomes successfully delivered trophic and immunomodulatory factors to the inner retina and efficiently promoted survival and neuritogenesis of injured retinal ganglion cells. MSC-derived exosomes efficiently suppressed migration of inflammatory cells, attenuated detrimental Th1 and Th17 cell-driven immune response and ameliorated experimental autoimmune uveitis. MSC-derived exosomes were able to fuse with the lysosomes within corneal cells, enabling delivering of MSC-derived active β-glucuronidase and consequent catabolism of accumulated glycosaminoglycans, indicating their therapeutic potential in the treatment of Mucopolysaccharidosis VII (Sly Syndrome). Importantly, beneficent effects were noticed only in animals that received MSC-derived exosomes and were not seen after therapy with fibroblasts-derived exosomes confirming specific therapeutic potential of MSCs and their products in the treatment of eye diseases.In conclusion, MSC-derived exosomes represent potentially new therapeutic agents in the therapy of degenerative and inflammatory ocular diseases.

  19. Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review.

    Mousavizadeh, Ali; Jabbari, Ali; Akrami, Mohammad; Bardania, Hassan

    2017-10-01

    Cell targeting peptides (CTP) are small peptides which have high affinity and specificity to a cell or tissue targets. They are typically identified by using phage display and chemical synthetic peptide library methods. CTPs have attracted considerable attention as a new class of ligands to delivery specifically therapeutic and diagnostic agents, because of the fact they have several advantages including easy synthesis, smaller physical sizes, lower immunogenicity and cytotoxicity and their simple and better conjugation to nano-carriers and therapeutic or diagnostic agents compared to conventional antibodies. In this systematic review, we will focus on the basic concepts concerning the use of cell-targeting peptides (CTPs), following the approaches of selecting them from peptide libraries. We discuss several developed strategies for cell-specific delivery of different cargos by CTPs, which are designed for drug delivery and diagnostic applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells.

    Kang, N-H; Hwang, K-A; Kim, S U; Kim, Y-B; Hyun, S-H; Jeung, E-B; Choi, K-C

    2012-08-01

    As stem cells are capable of self-renewal and can generate differentiated progenies for organ development, they are considered as potential source for regenerative medicine and tissue replacement after injury or disease. Along with this capacity, stem cells have the therapeutic potential for treating human diseases including cancers. According to the origins, stem cells are broadly classified into two types: embryonic stem cells (ESCs) and adult stem cells. In terms of differentiation potential, ESCs are pluripotent and adult stem cells are multipotent. Amnion, which is a membranous sac that contains the fetus and amniotic fluid and functions in protecting the developing embryo during gestation, is another stem cell source. Amnion-derived stem cells are classified as human amniotic membrane-derived epithelial stem cells, human amniotic membrane-derived mesenchymal stem cells and human amniotic fluid-derived stem cells. They are in an intermediate stage between pluripotent ESCs and lineage-restricted adult stem cells, non-tumorigenic, and contribute to low immunogenicity and anti-inflammation. Furthermore, they are easily available and do not cause any controversial issues in their recovery and applications. Not only are amnion-derived stem cells applicable in regenerative medicine, they have anticancer capacity. In non-engineered stem cells transplantation strategies, amnion-derived stem cells effectively target the tumor and suppressed the tumor growth by expressing cytotoxic cytokines. Additionally, they also have a potential as novel delivery vehicles transferring therapeutic genes to the cancer formation sites in gene-directed enzyme/prodrug combination therapy. Owing to their own advantageous properties, amnion-derived stem cells are emerging as a new candidate in anticancer therapy.

  1. [Ethical aspects of regenerative medicine, with special reference to embryonic stem cells and therapeutic cloning].

    Imura, Hiroo

    2003-03-01

    Regenerative medicine is expected to be new therapeutic means for treating incurable diseases but requires serious bioethical consideration. Embryonic stem(ES) cells, that are pleuripotent cells suitable to regenerative medicine, can be used in Japan for investigative use under a strict control by guide-lines. On the other hand, use of embryo produced by nuclear transfer has not been allowed in Japan and further serious consideration is required. Some other ethical aspects of regenerative medicine are also discussed.

  2. Therapeutic iodine 125 for hyperthyroidism: evidence for a special radiobiological effect on the follicular cell

    Gray, H.W.; Greig, W.R.; Gillespie, F.C.; Western Regional Hospital Board, Glasgow

    1982-01-01

    An IV perchlorate test was used qualitatively to detect a functional abnormality of the colloid-follicular cell interface in patients given 131 I or 125 I for hyperthyroidism. Radiation damage, manifest as abnormal iodide organification, was more prolonged after 125 I and more often accompanied by unremitting hyperthyroidism than after 131 I. These results conform with theoretical and laboratory data which predict a gradient of deposited radiation across the human follicular cell after therapeutic 125 I. (author)

  3. The significance of the host inflammatory response on the therapeutic efficacy of cell therapies utilising human adult stem cells

    Navarro, Melba; Pu, Fanrong; Hunt, John A.

    2012-01-01

    Controlling the fate of implanted hMSCs is one of the major drawbacks to be overcome to realize tissue engineering strategies. In particular, the effect of the inflammatory environment on hMSCs behaviour is poorly understood. Studying and mimicking the inflammatory process in vitro is a very complex and challenging task that involves multiple variables. This research addressed the questions using in vitro co-cultures of primary derived hMSCs together with human peripheral blood mononucleated cells (PBMCs); the latter are key agents in the inflammatory process. This work explored the in vitro phenotypic changes of hMSCs in co-culture direct contact with monocytes and lymphocytes isolated from blood using both basal and osteogenic medium. Our findings indicated that hMSCs maintained their undifferentiated phenotype and pluripotency despite the contact with PBMCs. Moreover, hMSCs demonstrated increased proliferation and were able to differentiate specifically down the osteogenic lineage pathway. Providing significant crucial evidence to support the hypothesis that inflammation and host defence mechanisms could be utilised rather than avoided and combated to provide for the successful therapeutic application of stem cell therapies.

  4. Fuel cells: Trends in research and applications

    Appleby, A. J.

    Various aspects of fuel cells are discussed. The subjects addressed include: fuel cells for electric power production; phosphoric acid fuel cells; long-term testing of an air-cooled 2.5 kW PAFC stack in Italy; status of fuel cell research and technology in the Netherlands, Bulgaria, PRC, UK, Sweden, India, Japan, and Brazil; fuel cells from the manufacturer's viewpoint; and fuel cells using biomass-derived fuels. Also examined are: solid oxide electrolye fuel cells; aluminum-air batteries with neutral chloride electrolyte; materials research for advanced solid-state fuel cells at the Energy Research Laboratory in Denmark; molten carbonate fuel cells; the impact of the Siemens program; fuel cells at Sorapec; impact of fuel cells on the electric power generation systems in industrial and developing countries; and application of fuel cells to large vehicles.

  5. Derivation of porcine pluripotent stem cells for biomedical research.

    Shiue, Yow-Ling; Yang, Jenn-Rong; Liao, Yu-Jing; Kuo, Ting-Yung; Liao, Chia-Hsin; Kang, Ching-Hsun; Tai, Chein; Anderson, Gary B; Chen, Lih-Ren

    2016-07-01

    Pluripotent stem cells including embryonic stem cells (ESCs), embryonic germ cells (EGCs), and induced pluripotent stem cells (iPSCs) are capable of self-renew and limitlessly proliferating in vitro with undifferentiated characteristics. They are able to differentiate in vitro, spontaneously or responding to suitable signals, into cells of all three primary germ layers. Consequently, these pluripotent stem cells will be valuable sources for cell replacement therapy in numerous disorders. However, the promise of human ESCs and EGCs is cramped by the ethical argument about destroying embryos and fetuses for cell line creation. Moreover, there are still carcinogenic risks existing toward the goal of clinical application for human ESCs, EGCs, and iPSCs. Therefore, a suitable animal model for stem cell research will benefit the further development of human stem cell technology. The pigs, on the basis of their similarity in anatomy, immunology, physiology, and biochemical properties, have been wide used as model animals in the study of various human diseases. The development of porcine pluripotent stem cell lines will hold the opportunity to provide an excellent material for human counterpart to the transplantation in biomedical research and further development of cell-based therapeutic strategy. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Translational research in addiction: toward a framework for the development of novel therapeutics.

    Paterson, Neil E

    2011-06-15

    The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation. 2011 Elsevier Inc. All rights reserved.

  7. Therapeutic Ultrasound Research And Development From An Industrial And Commercial Perspective

    Seip, Ralf

    2009-04-01

    The objective of this paper is to share the challenges and opportunities as viewed from an industrial and commercial perspective that one encounters when performing therapeutic ultrasound research, development, manufacturing, and sales activities. Research in therapeutic ultrasound has become an active field in the last decade, spurred by technological advances in the areas of transducer materials, control electronics, treatment monitoring techniques, an ever increasing number of clinical applications, and private and governmental funding opportunities. The development of devices and methods utilizing therapeutic ultrasound to cure or manage disease is being pursued by startup companies and large established companies alike, driven by the promise of profiting at many levels from this new and disruptive technology. Widespread penetration within the clinical community remains elusive, with current approaches focusing on very specific applications and niche markets. Challenges include difficulties in securing capital to develop the technology and undertake costly clinical trials, a regulatory landscape that varies from country to country, resistance from established practitioners, and difficulties in assembling a team with the right mix of technological savvy and business expertise. Success is possible and increasing, however, as evidenced by several companies, initiatives, and products with measurable benefits to the patient, clinician, and companies alike.

  8. Therapeutic Ultrasound Research And Development From An Industrial And Commercial Perspective

    Seip, Ralf

    2009-01-01

    The objective of this paper is to share the challenges and opportunities as viewed from an industrial and commercial perspective that one encounters when performing therapeutic ultrasound research, development, manufacturing, and sales activities. Research in therapeutic ultrasound has become an active field in the last decade, spurred by technological advances in the areas of transducer materials, control electronics, treatment monitoring techniques, an ever increasing number of clinical applications, and private and governmental funding opportunities. The development of devices and methods utilizing therapeutic ultrasound to cure or manage disease is being pursued by startup companies and large established companies alike, driven by the promise of profiting at many levels from this new and disruptive technology. Widespread penetration within the clinical community remains elusive, with current approaches focusing on very specific applications and niche markets. Challenges include difficulties in securing capital to develop the technology and undertake costly clinical trials, a regulatory landscape that varies from country to country, resistance from established practitioners, and difficulties in assembling a team with the right mix of technological savvy and business expertise. Success is possible and increasing, however, as evidenced by several companies, initiatives, and products with measurable benefits to the patient, clinician, and companies alike.

  9. The Role and Potential Therapeutic Application of Myeloid-Derived Suppressor Cells in Allo- and Autoimmunity

    Qi Zhang

    2015-01-01

    Full Text Available Myeloid-derived suppressor cells (MDSCs are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells. They have been identified as a cell population that may affect the activation of CD4+ and CD8+ T-cells to regulate the immune response negatively, which makes them attractive targets for the treatment of transplantation and autoimmune diseases. Several studies have suggested the potential suppressive effect of MDSCs on allo- and autoimmune responses. Conversely, MDSCs have also been found at various stages of differentiation, accumulating during pathological situations, not only during tumor development but also in a variety of inflammatory immune responses, bone marrow transplantation, and some autoimmune diseases. These findings appear to be contradictory. In this review, we summarize the roles of MDSCs in different transplantation and autoimmune diseases models as well as the potential to target these cells for therapeutic benefit.

  10. [Research on Depression in the GDR - Historical Lines of Development and Therapeutic Approaches].

    Thormann, J; Himmerich, H; Steinberg, H

    2014-02-01

    Historical research has raised the issue of whether GDR psychiatry was isolated from Western influences to such an extent that an autonomous East German psychiatry developed. Taking a chronological approach and being based on a clearly defined range of topics, the objective of this paper is to identify specific contributions made by GDR psychiatry to academic research as well as the degree of its international orientation by focusing on the treatment and research on depression. We have performed a systematic review of the East German psychiatric journal "Psychiatrie, Neurologie und medizinische Psychologie" and a screening of all psychiatric textbooks that appeared in the GDR. Although East German psychiatry was oriented towards Soviet as well as Western developments, some internationally used therapeutic or conceptual innovations reached East German clinics only with some delay. Yet, East German psychiatrists have also contributed their own, independent nosological and therapeutic concepts to research on depression. Pivotal figures included, among others, R. Lemke (Jena), D. Müller-Hegemann (Leipzig) or K. Leonhard (Berlin). With regard to research on depression one cannot truly speak of an autonomous East German psychiatry. Developments in East and West were largely running in parallel. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

    Idit Dotan

    Full Text Available The incidence of papillary thyroid carcinoma (PTC has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Thyroid Stimulating Hormone Receptor (TSHR was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with

  12. Nuclear data for the production of therapeutic radionuclides. Summary report of first research coordination meeting

    Sublet, J.-Ch.; Paviotti-Corcuera, R.

    2003-06-01

    Presentations, discussions and conclusions from the First Co-ordination Meeting on Nuclear Data for the Production of Therapeutic Radionuclides are summarised in this report. The main purpose of the meeting was to discuss scientific and technical matters related to the subject and to co-ordinate related tasks. Programmes of work were agreed and assigned, and deadlines were set. Participants emphasized the importance of the completeness and accuracy of the resulting nuclear data for the production of these radionuclides to appropriate specific activities and purity along with the relevant decay data. The recommended data from this Coordinated Research Project should meet the requirements for the safe and efficacious application of therapeutic treatments in nuclear medicine. (author)

  13. CIMAvax-EGF®: Therapeutic Vaccine Against Non-small Cell Lung Cancer in Advanced Stages

    Diana Rosa Fernández Ruiz

    2017-02-01

    Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.

  14. Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

    Kyeung Min Joo

    Full Text Available Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

  15. [Nuclear transfer and therapeutic cloning].

    Xu, Xiao-Ming; Lei, An-Min; Hua, Jin-Lian; Dou, Zhong-Ying

    2005-03-01

    Nuclear transfer and therapeutic cloning have widespread and attractive prospects in animal agriculture and biomedical applications. We reviewed that the quality of oocytes and nuclear reprogramming of somatic donor cells were the main reasons of the common abnormalities in cloned animals and the low efficiency of cloning and showed the problems and outlets in therapeutic cloning, such as some basic problems in nuclear transfer affected clinical applications of therapeutic cloning. Study on isolation and culture of nuclear transfer embryonic stem (ntES) cells and specific differentiation of ntES cells into important functional cells should be emphasized and could enhance the efficiency. Adult stem cells could help to cure some great diseases, but could not replace therapeutic cloning. Ethics also impeded the development of therapeutic cloning. It is necessary to improve many techniques and reinforce the research of some basic theories, then somatic nuclear transfer and therapeutic cloning may apply to agriculture reproduction and benefit to human life better.

  16. Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders.

    Viganò, Marco; Sansone, Valerio; d'Agostino, Maria Cristina; Romeo, Pietro; Perucca Orfei, Carlotta; de Girolamo, Laura

    2016-12-16

    Musculoskeletal disorders are regarded as a major cause of worldwide morbidity and disability, and they result in huge costs for national health care systems. Traditional therapies frequently turned out to be poorly effective in treating bone, cartilage, and tendon disorders or joint degeneration. As a consequence, the development of novel biological therapies that can treat more effectively these conditions should be the highest priority in regenerative medicine. Mesenchymal stem cells (MSCs) represent one of the most promising tools in musculoskeletal tissue regenerative medicine, thanks to their proliferation and differentiation potential and their immunomodulatory and trophic ability. Indeed, MSC-based approaches have been proposed for the treatment of almost all orthopedic conditions, starting from different cell sources, alone or in combination with scaffolds and growth factors, and in one-step or two-step procedures. While all these approaches would require cell harvesting and transplantation, the possibility to stimulate the endogenous MSCs to enhance their tissue homeostasis activity represents a less-invasive and cost-effective therapeutic strategy. Nowadays, the role of tissue-specific resident stem cells as possible therapeutic target in degenerative pathologies is underinvestigated. Biophysical stimulations, and in particular extracorporeal shock waves treatment and pulsed electromagnetic fields, are able to induce proliferation and support differentiation of MSCs from different origins and affect their paracrine production of growth factors and cytokines. The present review reports the attempts to exploit the resident stem cell potential in musculoskeletal pathologies, highlighting the role of MSCs as therapeutic target of currently applied biophysical treatments.

  17. IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

    Schinke, Carolina; Giricz, Orsolya; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Barreryo, Laura; Bhagat, Tushar; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit

    2015-05-14

    Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. © 2015 by The American Society of Hematology.

  18. Strategy to prime the host and cells to augment therapeutic efficacy of progenitor cells for patients with myocardial infarction

    Jeehoon Kang

    2016-11-01

    Full Text Available Cell therapy in myocardial infarction (MI is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming peripheral blood mononuclear cells or patients, as for cell therapy of MI.

  19. Therapeutic Effect of Ligustilide-Stimulated Adipose-Derived Stem Cells in a Mouse Thromboembolic Stroke Model.

    Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Lin, Shinn-Zong; Huang, Pi-Chun; Lin, Po-Cheng; Chang, Fu-Kuei; Liu, Shih-Ping

    2016-01-01

    Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis, exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.

  20. Pathological and therapeutic roles of innate lymphoid cells in diverse diseases.

    Kim, Jisu; Kim, Geon; Min, Hyeyoung

    2017-11-01

    Innate lymphoid cells (ILCs) are a recently defined type of innate-immunity cells that belong to the lymphoid lineage and have lymphoid morphology but do not express an antigen-specific B cell or T-cell receptor. ILCs regulate immune functions prior to the formation of adaptive immunity and exert effector functions through a cytokine release. ILCs have been classified into three groups according to the transcription factors that regulate their development and function and the effector cytokines they produce. Of note, ILCs resemble T helper (Th) cells, such as Th1, Th2, and Th17 cells, and show a similar dependence on transcription factors and distinct cytokine production. Despite their short history in immunology, ILCs have received much attention, and numerous studies have revealed biological functions of ILCs including host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. Here, we describe recent findings about the roles of ILCs in the pathogenesis of various diseases and potential therapeutic targets.

  1. Setting FIRES to Stem Cell Research

    Miller, Roxanne Grietz

    2005-01-01

    The goal of this lesson is to present the basic scientific knowledge about stem cells, the promise of stem cell research to medicine, and the ethical considerations and arguments involved. One of the challenges of discussing stem cell research is that the field is constantly evolving and the most current information changes almost daily. Few…

  2. Adjuvant effects of therapeutic glycolipids administered to a cohort of NKT cell-diverse pigs.

    Artiaga, Bianca L; Whitener, Robert L; Staples, Charles R; Driver, John P

    2014-11-15

    CD1d-restricted natural killer T (NKT) cells are a unique lymphocyte population that makes important contributions to host defense against numerous microbial pathogens. The powerful immunomodulatory effects of these cells can be exploited in mice by cognate antigens for multiple therapeutic purposes, including for protection from infectious diseases and as adjuvants to improve vaccines against microbial organisms. These applications have potential to treat and prevent infectious diseases in livestock species that express NKT cells, including pigs. In this study, immune tissues from commercial swine of mixed genetic background were compared for NKT cell frequency, cytokine secretion and subset ratios. Pigs were also injected with the model antigen hen-egg lysozyme (HEL) in conjunction with one of three glycosphingolipids, alpha-galactosylceramide (αGC), OCH and C-glycoside that selectively activate NKT cells, to assess the adjuvant potential of each. There was significant variation between individual pigs for all NKT cell parameters measured. The NKT cell agonists elicited HEL-specific immune responses of different quality, but only αGC increased the systemic concentration of NKT cells. Peripheral blood NKT cell frequency measured prior to treatment was a poor predictor of how individual animals responded to NKT cell therapy. However, our results show that although NKT cells vary considerably between pigs, there exists considerable potential to harness these cells to protect swine from infectious diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. The Impact of CRISPR/Cas9 Technology on Cardiac Research: From Disease Modelling to Therapeutic Approaches

    Pramstaller, Peter P.; Hicks, Andrew A.; Rossini, Alessandra

    2017-01-01

    Genome-editing technology has emerged as a powerful method that enables the generation of genetically modified cells and organisms necessary to elucidate gene function and mechanisms of human diseases. The clustered regularly interspaced short palindromic repeats- (CRISPR-) associated 9 (Cas9) system has rapidly become one of the most popular approaches for genome editing in basic biomedical research over recent years because of its simplicity and adaptability. CRISPR/Cas9 genome editing has been used to correct DNA mutations ranging from a single base pair to large deletions in both in vitro and in vivo model systems. CRISPR/Cas9 has been used to increase the understanding of many aspects of cardiovascular disorders, including lipid metabolism, electrophysiology and genetic inheritance. The CRISPR/Cas9 technology has been proven to be effective in creating gene knockout (KO) or knockin in human cells and is particularly useful for editing induced pluripotent stem cells (iPSCs). Despite these progresses, some biological, technical, and ethical issues are limiting the therapeutic potential of genome editing in cardiovascular diseases. This review will focus on various applications of CRISPR/Cas9 genome editing in the cardiovascular field, for both disease research and the prospect of in vivo genome-editing therapies in the future. PMID:29434642

  4. The potential therapeutic value for bereaved relatives participating in research: An exploratory study.

    Germain, Alison; Mayland, Catriona R; Jack, Barbara A

    2016-10-01

    Conducting research with the bereaved presents an immediate ethical challenge, as they are undoubtedly a vulnerable group, associated with high levels of distress and susceptible to both physical and mental health issues. A comprehensive understanding of the potential therapeutic benefits for bereaved relatives participating in palliative care research is limited, and therefore the ethics of engaging this group remain questionable. This paper describes a secondary analysis of qualitative data collected in the Care of the Dying Evaluation (CODE) project, examining the experiences of patients who died at home. It explores the motivations and potential benefits for bereaved relatives participating in research with reference to the recently developed concepts in bereavement theory. Cognitive interviews were conducted with 15 bereaved relatives and secondary analysis using a content analysis framework was employed to classify the data. The results center around six recurring concepts identified as adaptive in current bereavement theory: an opportunity to share the narrative accounts of the final hours of their relative's life; a search for sense and meaning in loss; an ongoing bond/attachment with the deceased; altruistic motivations; oscillation between loss and restorative orientations; and a sense of resilience. Overall, the participants found that taking part in the research was valuable and that it could be described as offering therapeutic benefits. The need for bereaved relatives to take part in research studies should be encouraged, as they provide an accurate proxy for the patient's experience of end-of-life care while also providing a valuable account of their own perspective as family member and carer. In addition, we highlight the need for ethics committees to be aware of the potential benefits for bereaved relatives participating in research of this kind.

  5. Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential.

    Atesok, Kivanc; Fu, Freddie H; Sekiya, Ichiro; Stolzing, Alexandra; Ochi, Mitsuo; Rodeo, Scott A

    2017-02-01

    The purpose of this study was to summarize the current evidence on the use of stem cells in the elderly population with degenerative orthopaedic pathologies and to highlight the pathophysiologic mechanisms behind today's therapeutic challenges in stem cell-based regeneration of destructed tissues in the elderly patients with osteoarthritis (OA), degenerative disc disease (DDD), and tendinopathies. Clinical and basic science studies that report the use of stem cells in the elderly patients with OA, DDD, and tendinopathies were identified using a PubMed search. The studies published in English have been assessed, and the best and most recent evidence was included in the current study. Evidence suggests that, although short-term results regarding the effects of stem cell therapy in degenerative orthopaedic pathologies can be promising, stem cell therapies do not appear to reverse age-related tissue degeneration. Causes of suboptimal outcomes can be attributed to the decrease in the therapeutic potential of aged stem cell populations and the regenerative capacity of these cells, which might be negatively influenced in an aged microenvironment within the degenerated tissues of elderly patients with OA, DDD, and tendinopathies. Clinical protocols guiding the use of stem cells in the elderly patient population are still under development, and high-level randomized controlled trials with long-term outcomes are lacking. Understanding the consequences of age-related changes in stem cell function and responsiveness of the in vivo microenvironment to stem cells is critical when designing cell-based therapies for elderly patients with degenerative orthopaedic pathologies.

  6. Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations

    Luis Alberto de Pádua Covas Lage

    2015-08-01

    Full Text Available Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term "peripheral T-cell lymphomas". According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, angioimmunoblastic T-cell lymphoma (AITL, anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+, and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK-. Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.

  7. Poly ADP-ribose polymerase-1 as a potential therapeutic target in Merkel cell carcinoma.

    Ferrarotto, Renata; Cardnell, Robert; Su, Shirley; Diao, Lixia; Eterovic, A Karina; Prieto, Victor; Morrisson, William H; Wang, Jing; Kies, Merrill S; Glisson, Bonnie S; Byers, Lauren Averett; Bell, Diana

    2018-03-23

    Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP-ribose polymerase-1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma. We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome-sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines. Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA-damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV-negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression. Based on PARP1 overexpression, DNA-damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma. © 2018 Wiley Periodicals, Inc.

  8. Multifunctional quantum dots-based cancer diagnostics and stem cell therapeutics for regenerative medicine.

    Onoshima, Daisuke; Yukawa, Hiroshi; Baba, Yoshinobu

    2015-12-01

    A field of recent diagnostics and therapeutics has been advanced with quantum dots (QDs). QDs have developed into new formats of biomolecular sensing to push the limits of detection in biology and medicine. QDs can be also utilized as bio-probes or labels for biological imaging of living cells and tissues. More recently, QDs has been demonstrated to construct a multifunctional nanoplatform, where the QDs serve not only as an imaging agent, but also a nanoscaffold for diagnostic and therapeutic modalities. This review highlights the promising applications of multi-functionalized QDs as advanced nanosensors for diagnosing cancer and as innovative fluorescence probes for in vitro or in vivo stem cell imaging in regenerative medicine. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-01-01

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response

  10. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    Waters, Katrina M. [Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Sontag, Ryan L. [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States); Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov [Systems Toxicology Groups, Pacific Northwest National Laboratory, Richland, WA 99354 (United States)

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  11. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

    Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Na?ra; Rau, Fr?d?rique; Jollet, Arnaud; Edom-Vovard, Fr?d?rique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois

    2017-01-01

    International audience; Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded rep...

  12. Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations

    Lunov, Oleg; Zablotskyy, Vitaliy A.; Churpita, Olexandr; Chánová, Eliška; Syková, Eva; Dejneka, Alexandr; Kubinová, Šárka

    2014-01-01

    Roč. 4, NOV (2014), "7129-1"-"7129-11" ISSN 2045-2322 R&D Projects: GA MŠk LO1309 Grant - others:AV ČR(CZ) M100101219 Institutional support: RVO:68378271 ; RVO:61389013 ; RVO:68378041 Keywords : cell death * non-thermal plasma * therapeutic perspectives Subject RIV: BO - Biophysics; FH - Neurology (UEM-P); CD - Macromolecular Chemistry (UMCH-V) Impact factor: 5.578, year: 2014

  13. Therapeutic potential of the metabolic modulator Metformin on osteosarcoma cancer stem-like cells.

    Paiva-Oliveira, Daniela I; Martins-Neves, Sara R; Abrunhosa, Antero J; Fontes-Ribeiro, Carlos; Gomes, Célia M F

    2018-01-01

    Osteosarcoma is the most common primary bone tumour appearing in children and adolescents. Recent studies demonstrate that osteosarcoma possesses a stem-like cell subset, so-called cancer stem-like cells, refractory to conventional chemotherapeutics and pointed out as responsible for relapses frequently observed in osteosarcoma patients. Here, we explored the therapeutic potential of Metformin on osteosarcoma stem-like cells, alone and as a chemosensitizer of doxorubicin. Stem-like cells were isolated from human osteosarcoma cell lines, MNNG/HOS and MG-63, using the sphere-forming assay. Metformin cytotoxicity alone and combined with doxorubicin were evaluated using MTT/BrdU assays. Protein levels of AMPK and AKT were evaluated by Western Blot. Cellular metabolic status was assessed based on [ 18 F]-FDG uptake and lactate production measurements. Sphere-forming efficiency and expression of pluripotency transcription factors analysed by qRT-PCR were tested as readout of Metformin effects on stemness features. Metformin induced a concentration-dependent decrease in the metabolic activity and proliferation of sphere-forming cells and improved doxorubicin-induced cytotoxicity. This drug also down-regulated the expression of master regulators of pluripotency (OCT4, SOX2, NANOG), and decreased spheres' self-renewal ability. Metformin effects on mitochondria led to the activation and phosphorylation of the energetic sensor AMPK along with an upregulation of the pro-survival AKT pathway in both cell populations. Furthermore, Metformin-induced mitochondrial stress increased [ 18 F]-FDG uptake and lactate production in parental cells but not in the quiescent stem-like cells, suggesting the inability of the latter to cope with the energy crisis induced by metformin. This preclinical study suggests that Metformin may be a potentially useful therapeutic agent and chemosensitizer of osteosarcoma stem-like cells to doxorubicin.

  14. Identification of unique expression signatures and therapeutic targets in esophageal squamous cell carcinoma

    Yan Wusheng

    2012-01-01

    Full Text Available Abstract Background Esophageal squamous cell carcinoma (ESCC, the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB, normal differentiated squamous epithelium (ND, and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets. Results As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA were verified to be dysregulated in the same pattern at both the mRNA and protein levels. Conclusions These data reveal insight into genes and

  15. Therapeutic potential of umbilical cord blood cells for type 1 diabetes mellitus.

    He, Binbin; Li, Xia; Yu, Haibo; Zhou, Zhiguang

    2015-11-01

    Type 1 diabetes mellitus (T1DM) is a chronic disorder that results from autoimmune-mediated destruction of pancreatic islet β-cells. However, to date, no conventional intervention has successfully treated the disease. The optimal therapeutic method for T1DM should effectively control the autoimmunity, restore immune homeostasis, preserve residual β-cells, reverse β-cell destruction, and protect the regenerated insulin-producing cells against re-attack. Umbilical cord blood is rich in regulatory T (T(reg)) cells and multiple types of stem cells that exhibit immunomodulating potential and hold promise in their ability to restore peripheral tolerance towards pancreatic islet β-cells through remodeling of immune responses and suppression of autoreactive T cells. Recently, reinfusion of autologous umbilical cord blood or immune cells from cord blood has been proposed as a novel therapy for T1DM, with the advantages of no risk to the donors, minimal ethical concerns, a low incidence of graft-versus-host disease and easy accessibility. In this review, we revisit the role of autologous umbilical cord blood or immune cells from cord blood-based applications for the treatment of T1DM. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  16. The intersection of cancer, cancer stem cells, and the immune system: therapeutic opportunities.

    Silver, Daniel J; Sinyuk, Maksim; Vogelbaum, Michael A; Ahluwalia, Manmeet S; Lathia, Justin D

    2016-02-01

    During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. The therapeutic implications of plasticity of the cancer stem cell phenotype.

    Kevin Leder

    2010-12-01

    Full Text Available The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.

  18. Enzymatic detachment of therapeutic mesenchymal stromal cells grown on glass carriers in a bioreactor.

    Salzig, Denise; Schmiermund, Alexandra; P Grace, Pablo; Elseberg, Christiane; Weber, Christian; Czermak, Peter

    2013-01-01

    Cell therapies require the in vitro expansion of adherent cells such as mesenchymal stromal cells (hMSCs) in bioreactor systems or other culture environments, followed by cell harvest. As hMSCs are strictly adherent cells, cell harvest requires cell detachment. The use of hMSCs for cell therapy requires GMP production in accordance with the guidelines for advanced therapeutic medical products. Therefore, several GMP-conform available proteolytic enzymes were investigated for their ability to promote hMSC detachment. An allogeneic hMSC cell line (hMSC-TERT) that is used in clinical trials in the form of alginate cell capsules was chosen as a model. This study investigated the influence of several factors on the outcome of proteolytic hMSC-TERT detachment. Therefore, hMSC-TERT detachment was analyzed in different cultivation systems (static, dynamic) and in combination with further cell processing including encapsulation. Only two of the commercially available enzymes (AccutaseTM, TrypZeanTM) that fulfill all process requirements (commercial availability, cost, GMP conditions during manufacturing and non-animal origin) are found to be generally suitable for detaching hMSC-TERT. Combining cell detachment with encapsulation demonstrated a high impact of the experimental set up on cell damage. It was preferable to reduce the temperature during detachment and limit the detachment time to a maximum of 20 minutes. Cell detachment in static systems was not comparable with detachment in dynamic systems. Detachment yields in dynamic systems were lower and cell damage was higher for the same experimental conditions. Finally, only TrypZeanTM seemed to be suitable for the detachment of hMSC-TERT from dynamic reactor systems.

  19. Development of gastroenterology and hepatology in Iran: Part II- advances in research and therapeutic modalities.

    Saberifiroozi, Mehdi; Mir-Madjlessi, Seid-Hossein

    2009-09-01

    Following the establishment of Gastroenterology and Hepatology Fellowship Programs in 1987, significant developments in research and health care delivery have been achieved. The number of published articles has increased significantly and now more than 10 approved research centers are involved in several longitudinal and population based studies in GI epidemiology, viral hepatitis and GI oncology around the country. Before 1987 less than 50 gastroenterologists were working in the country, but now more than 300 gastroenterologists are involved in public and private health care delivery systems. Advanced diagnostic and therapeutic endoscopic procedures and complex surgical procedures such as liver transplantation are a routine now. These achievements are indicative of hard work and determination of dedicated physicians after the Islamic Revolution, and the support of governmental and non-governmental sectors. The future prospect of development in the discipline of gastroenterology and hepatology in Iran seems to be very encouraging.

  20. Cell Phones: Current Research Results

    ... NAS Report - Identification of Research Needs Relating to Potential Biological or Adverse Health Effects of Wireless Communication Devices World Health Organization: Electromagnetic Fields and Public Health: Mobile Phones International Agency for Research on Cancer Press ...

  1. Guidelines for human embryonic stem cell research

    Committee on Guidelines for Human Embryonic Stem Cell Research; National Research Council; Board on Health Sciences Policy; Institute of Medicine; Division on Earth and Life Studies; National Research Council

    2005-01-01

    .... Given limited federal involvement, privately funded hES cell research has thus far been carried out under a patchwork of existing regulations, many of which were not designed with this research specifically in mind...

  2. Guidelines for human embryonic stem cell research

    Committee on Guidelines for Human Embryonic Stem Cell Research, National Research Council

    2005-01-01

    Since 1998, the volume of research being conducted using human embryonic stem (hES) cells has expanded primarily using private funds because of restrictions on the use of federal funds for such research...

  3. Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer.

    Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin

    2017-08-10

    One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Regulation of matriptase and HAI-1 system, a novel therapeutic target in human endometrial cancer cells.

    Sun, Pengming; Xue, Lifang; Song, Yiyi; Mao, Xiaodan; Chen, Lili; Dong, Binhua; Braicu, Elena Loana; Sehouli, Jalid

    2018-02-27

    The effects of specific and non-specific regulation of matriptase on endometrial cancer cells in vitro were investigated. Messenger ribonucleic acid (mRNA) and protein expression of matriptase and hepatocyte growth factor activator inhibitor-1 (HAI-1) in RL-952, HEC-1A, and HEC-1B endometrial cancer cells were detected by real-time quantitative PCR (RT-qPCR) and western blot. The cells were infected with lentivirus-mediated small-interfering RNA (siRNA) targeted on matriptase (MA-siRNA) or treated with different cisplatin (DDP) concentrations. After treatment, invasion, migration, and cellular apoptosis were analyzed. Matriptase mRNA and protein expression significantly decreased to 80% after infection with MA-siRNA ( P scratch and trans-well chamber assays showed significant inhibition of invasiveness and metastasis. Upon incubation with cisplatin at concentrations higher than the therapeutic dose for 24 h, the expressions of matriptase and HAI-1 significantly decreased ( P endometrial cancer cells were significantly decreased ( P endometrial cancer cells showed promising therapeutic features.

  5. New Therapeutic Approaches to Prevent or Delay Beta-Cell Failure in Diabetes

    Ionica Floriana Elvira

    2015-09-01

    Full Text Available Background and aims: The most recent estimates of International Diabetes Federation indicate that 382 million people have diabetes, and the incidence of this disease is increasing. While in type 1 diabetes mellitus (T1DM beta-cell death is autoimmunemediated, type 2 diabetes mellitus (T2DM results from an interaction between genetic and environmental factors that impair beta-cell function and insulin action. Many people with T2DM remain unaware of their illness for a long time because symptoms may take years to appear or be recognized, while the body is affected by excess blood glucose. These patients are often diagnosed only when diabetes complications have already developed. The aim of this article was to perform a review based on literature data on therapeutic modalities to prevent/delay beta cell function decline. Material and Methods: We searched MEDLINE from 2000 to the present to identify the therapeutic approaches to prevent or delay beta-cell failure in patients with T2DM. Results and conclusions: Several common polymorphisms in genes linked to monogenic forms of diabetes appear to influence the response to T2DM pharmacotherapy. Recent studies report the role of the G protein coupled receptor 40 (GPR40, also known as Free Fatty Acids Receptor 1 (FFAR1 in the regulation of beta-cell function- CNX-011-67 (a GPR40 agonist has the potential to provide good and durable glycemic control in T2DM patients.

  6. Natural Killer (NK- and T-Cell Engaging Antibody-Derived Therapeutics

    Christoph Stein

    2012-06-01

    Full Text Available Unmodified antibodies (abs have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK- and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

  7. Optimization of Intracellular Transportation of Gene Therapeutic DNA in Small Cell Lung Cancer (Ph.d.)

    Cramer, Frederik

    2013-01-01

    Small cell lung cancer (SCLC) is a highly malignant disease characterized as being very aggressive and metastasizing at a rapid pace. The malevolent pace of SCLC cell migration results in almost three out of four SCLC patients having disseminated SCLC at the time of diagnosis. Unfortunately...... has to be able to repeated systemic delivery of gene therapy to cancer cells in a both safe and efficient way. Non-viral delivery vectors fulfill many of these requirements except the latter. It is currently very difficult to systemically transport sufficient amounts of therapeutic DNA, by a non......-viral delivery system, to the nuclei of the SCLC cells. As a result, the gene therapy expression obtained is too low to have any clinical relevance. We have at the Department of Radiation Biology developed a transcriptionally targeting suicide gene therapy system which is built on a double stranded DNA plasmid...

  8. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP).

    Brennan, Tracy A; Lindborg, Carter M; Bergbauer, Christian R; Wang, Haitao; Kaplan, Frederick S; Pignolo, Robert J

    2018-04-01

    Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies. Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions. This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy.

    Tang, Xiang-Jun; Sun, Xu-Yong; Huang, Kuan-Ming; Zhang, Li; Yang, Zhuo-Shun; Zou, Dan-Dan; Wang, Bin; Warnock, Garth L; Dai, Long-Jun; Luo, Jie

    2015-12-29

    Chimeric antigen receptor (CAR)-based T-cell adoptive immunotherapy is a distinctively promising therapy for cancer. The engineering of CARs into T cells provides T cells with tumor-targeting capabilities and intensifies their cytotoxic activity through stimulated cell expansion and enhanced cytokine production. As a novel and potent therapeutic modality, there exists some uncontrollable processes which are the potential sources of adverse events. As an extension of this impactful modality, CAR-T cell-derived exosomes may substitute CAR-T cells to act as ultimate attackers, thereby overcoming some limitations. Exosomes retain most characteristics of parent cells and play an essential role in intercellular communications via transmitting their cargo to recipient cells. The application of CAR-T cell-derived exosomes will make this cell-based therapy more clinically controllable as it also provides a cell-free platform to diversify anticancer mediators, which responds effectively to the complexity and volatility of cancer. It is believed that the appropriate application of both cellular and exosomal platforms will make this effective treatment more practicable.

  10. Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial

    Berntsen, Annika; Trepiakas, Redas; Wenandy, Lynn

    2008-01-01

    Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment...... with a DC-based vaccine in patients with metastatic renal cell carcinoma. Twenty-seven patients with progressive cytokine-refractory metastatic renal cell carcinoma were vaccinated with DCs loaded with either a cocktail of survivin and telomerase peptides or tumor lysate depending on their HLA-A2 haplotype......, and low-dose IL-2 was administered concomitantly. Tumor response, immune response, and serum IL-6 and YKL-40 were measured during treatment. Vaccine generation was successful in all patients and no serious adverse events were observed. None of the patients had an objective response but 13/27 patients...

  11. Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database.

    Kalathur, Ravi Kiran Reddy; Hernández-Prieto, Miguel A; Futschik, Matthias E

    2012-06-28

    Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling). For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are associated with HD, at http://hdtt.sysbiolab.eu Additionally

  12. Huntington's Disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database

    Kalathur Ravi Kiran

    2012-06-01

    Full Text Available Abstract Background Huntington’s disease (HD is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. Methods To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. Results Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling, but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling. For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are

  13. Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma—A Review

    Siriwardena, Samadarani B. S. M.; Tsunematsu, Takaaki; Qi, Guangying; Ishimaru, Naozumi; Kudo, Yasusei

    2018-01-01

    It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. PMID:29758011

  14. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers.

    Michael P Stany

    Full Text Available Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

  15. Cell culture techniques in honey bee research

    Cell culture techniques are indispensable in most if not all life science disciplines to date. Wherever cell culture models are lacking scientific development is hampered. Unfortunately this has been and still is the case in honey bee research because permanent honey bee cell lines have not yet been...

  16. Antecedents of cell aging research.

    Hayflick, L

    1989-01-01

    Our observation that normal human and animal cells have a limited capacity to divide and function in vitro overturned a dogma held since the turn of the century. The dogma held that cultured normal cells are immortal and gerontologists interpreted this to mean that aging, therefore, could not be the result of intracellular events. We concluded that longevity and aging do result from intracellular events, and, in the subsequent 30 years, the validity of our finding has been widely confirmed. Other major findings have been made: (a) The number of population doublings and functional events that a cultured normal cell can undergo is inversely proportional to donor age and, probably, directly proportional to species longevity; (b) the limit on cell division and function also occurs in vivo when normal cells are transplanted seriatim; (c) as cell doublings or functional events reach their limit, changes occur in hundreds of variables from the molecular to the whole cell. Most importantly, many of these changes are identical to those seen in intact humans and animals as they age; (d) WI-38, the first widely distributed normal human cell strain has retained its memory of population doubling level during 27 years of cryogenic storage. This is the longest time that any normal human cell has ever been preserved. Evidence that longevity is determined by genetic events is overwhelming but evidence that age changes are the result of gene expression is not. Normal age changes must be distinguished from disease. Because few feral animals ever become old, natural selection could not have favored the development of a genetically programmed aging process. In the 2 or 3 million years of human existence, too few old humans existed to have provided a selective advantage favoring the development of a genetic program that would determine age changes. The selective advantage of maintaining physiological vigor for as long as possible in order to insure maximum reproductive success may be

  17. Smoking, nicotine and psychiatric disorders: evidence for therapeutic role, controversies and implications for future research.

    Dursun, S M; Kutcher, S

    1999-02-01

    Researchers interested in investigating the possible therapeutic effects and the mechanisms of action of nicotine in neuropsychiatric disorders face a social-scientific-ethical dilemma. This dilemma comprises three components: (1) the known addictive potential of nicotine makes careful evaluation of the therapeutic potential of this compound socially unattractive; (2) the potential misuse of scientifically determined data by the tobacco 'lobby' creates ethical concerns; and (3) the possible confusion between the differential effects of nicotine in human smokers versus non-smokers creates difficulties in study designs in voluntary human subjects. Therefore, it is imperative that, at the onset of this review, the authors stress that they do not advocate cigarette-smoking as a route of nicotine intake under any circumstances on the basis that controlled dosing of nicotine may be of potential benefit in some neuropsychiatric disorders. In this article, we review the psychopharmacology of nicotine and its effects in a variety of neuropsychiatric disorders including schizophrenia, depression, anxiety and Tourette's syndrome. Possible mechanisms of action of nicotine directly or indirectly via its interaction with other neurotransmitter systems (i.e. serotonin, dopamine and noradrenaline) in relation to its potential role in these disorders are discussed. It is postulated that new drugs may need to be developed that selectively interact with nicotinic receptors without addiction potential.

  18. Widening and Elaboration of Consecutive Research into Therapeutic Antioxidant Enzyme Derivatives

    Alexander V. Maksimenko

    2016-01-01

    Full Text Available Undiminishing actuality of enzyme modification for therapeutic purposes has been confirmed by application of modified enzymes in clinical practice and numerous research data on them. Intravenous injection of the superoxide dismutase-chondroitin sulfate-catalase (SOD-CHS-CAT conjugate in preventive and medicative regimes in rats with endotoxin shock induced with a lipopolysaccharide bolus has demonstrated that antioxidant agents not only effectively prevent damage caused by oxidative stress (as believed previously but also can be used for antioxidative stress therapy. The results obtained emphasize the importance of investigation into the pathogenesis of vascular damage and the role of oxidative stress in it. The effects of intravenous medicative injection of SOD-CHS-CAT in a rat model of endotoxin shock have demonstrated a variety in the activity of this conjugate in addition to prevention of NO conversion in peroxynitrite upon interaction with O2∙- superoxide radical. Together with the literature data, these findings offer a prospect for the study of NO-independent therapeutic effects of SOD-CHS-CAT, implying the importance of a better insight into the mechanisms of the conjugate activity in modeled cardiovascular damage involving vasoactive agents other than NO.

  19. From Research to Application: Supportive and Therapeutic Environments for People Living With Dementia.

    Calkins, Margaret P

    2018-01-18

    The evidence about the role the designed and built environment plays in supporting individuals living with dementia has been steadily mounting for almost 40 years. Beginning with the work of M. Powell Lawton at the Weiss Pavilion at the Philadelphia Geriatric Center, there are now dozens of researchers who are exploring how the environment can be either supportive and therapeutic, indeed even serving as a prosthetic for various changes in cognition, or be a barrier to independent functioning and high quality of life. Two recent literature reviews published on the impact of environmental factors and characteristics on individuals living with dementia clearly delineate evidence that the environment can have a therapeutic or a debilitating impact on individuals living with dementia. Rather than duplicate these excellent reviews, this article puts the knowledge gleaned from this research into the shifting context that is long-term care. This article begins with an exploration of the evolution of approaches to the design of spaces for individuals living with dementia from traditional or medical models, to special care units (SCUs), to person-centered care (PCC), which is the organizing theme of this supplemental issue. A novel, person-centered way of conceptualizing the domains of environmental systems is then presented and used as the framework for structuring recommendations and creating supportive and therapeutic environments for individuals living with dementia. Although there are distinct pathophysiological and behavioral manifestations of different forms of dementia, there is almost no evidence that suggests alternative environmental characteristics are better for one type of dementia over another. Thus, this article will refer to "individuals living with dementia" as opposed to Alzheimer's disease or other specific forms of dementia. Further, this article only addresses residential environments: homes in the community, independent and assisted living residences

  20. Ethical Issues in Stem Cell Research

    Lo, Bernard; Parham, Lindsay

    2009-01-01

    Stem cell research offers great promise for understanding basic mechanisms of human development and differentiation, as well as the hope for new treatments for diseases such as diabetes, spinal cord injury, Parkinson’s disease, and myocardial infarction. However, human stem cell (hSC) research also raises sharp ethical and political controversies. The derivation of pluripotent stem cell lines from oocytes and embryos is fraught with disputes about the onset of human personhood. The reprogramm...

  1. Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?

    Abreu, Soraia C; Weiss, Daniel J; Rocco, Patricia R M

    2016-04-14

    Extracellular vesicles (EVs) are plasma membrane-bound fragments released from several cell types, including mesenchymal stromal cells (MSCs), constitutively or under stimulation. EVs derived from MSCs and other cell types transfer molecules (such as DNA, proteins/peptides, mRNA, microRNA, and lipids) and/or organelles with reparative and anti-inflammatory properties to recipient cells. The paracrine anti-inflammatory effects promoted by MSC-derived EVs have attracted significant interest in the regenerative medicine field, including for potential use in lung injuries. In the present review, we describe the characteristics, biological activities, and mechanisms of action of MSC-derived EVs. We also review the therapeutic potential of EVs as reported in relevant preclinical models of acute and chronic respiratory diseases, such as pneumonia, acute respiratory distress syndrome, asthma, and pulmonary arterial hypertension. Finally, we discuss possible approaches for potentiating the therapeutic effects of MSC-derived EVs so as to enable use of this therapy in clinical practice.

  2. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Julia Pollak

    Full Text Available Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  3. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  4. Therapeutic cloning in the mouse

    Mombaerts, Peter

    2003-01-01

    Nuclear transfer technology can be applied to produce autologous differentiated cells for therapeutic purposes, a concept termed therapeutic cloning. Countless articles have been published on the ethics and politics of human therapeutic cloning, reflecting the high expectations from this new opportunity for rejuvenation of the aging or diseased body. Yet the research literature on therapeutic cloning, strictly speaking, is comprised of only four articles, all in the mouse. The efficiency of derivation of embryonic stem cell lines via nuclear transfer is remarkably consistent among these reports. However, the efficiency is so low that, in its present form, the concept is unlikely to become widespread in clinical practice. PMID:12949262

  5. Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008: The need of Asian pharmaceutical researchers' cooperation.

    Nakata, M; Tang, W

    2008-10-01

    The Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008 (JCMWDDT 2008) was held from September 29 to October 1, 2008 at The University of Tokyo, Tokyo, Japan. JCMWDDT is an international workshop that is mainly organized by Asian editorial members of Drug Discoveries & Therapeutics (http://www.ddtjournal.com/home) for the purpose of promoting research exchanges in the field of drug discovery and therapeutic. This year's JCMWDDT is the second workshop and focused particularly on novel development and technological innovation of anti-influenza agents. The workshop began with an announcement by the Japanese Co-chairperson, Dr. Sekimizu (Department of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan; Editorin- Chief of Drug Discoveries & Therapeutics, DDT) followed by a speech by the Chinese Co-chairperson, Dr. Wenfang Xu (School of Pharmaceutical Sciences, Shandong University, Shandong, China; Editor in China Office of DDT), with additional speeches by Dr. Norio Matsuki (The University of Tokyo, Japan; Editor of DDT) and Dr. Guanhua Du (Chinese Academy of Medical Science, China; Editor of DDT). Fifty-nine titles were presented in 6 specialized sessions (Research Advances in Drug Discoveries and Therapeutics, Drug Synthesis/Clinical Therapeutics, Medicinal Chemistry/Natural Products, Anti-influenza Drugs, Anti-infection/antiviral Drugs, Biochemistry/Molecular Biology /Pharmacology) and a poster session (Drug Discov Ther 2008; 2, Suppl; available at http://www.ddtjournal.com/Announce/index.htm). An annual outbreak of avian influenza in Asian countries including China and Japan has sparked fears that the virus will mutate and then cause an epidemic in humans. Therefore, Asian researchers need to work together to control this infection. This year's JCMWDDT helped provide an opportunity to reiterate the crucial role of medicinal chemistry in conquering influenza and created an environment for cooperative

  6. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

    Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F.

    2017-01-01

    ABSTRACT Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. PMID:28188264

  7. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

    Ludovic Arandel

    2017-04-01

    Full Text Available Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.

  8. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds.

    Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F; Furling, Denis

    2017-04-01

    Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. © 2017. Published by The Company of Biologists Ltd.

  9. Effects of fotemustine or dacarbasine on a melanoma cell line pretreated with therapeutic proton irradiation

    Privitera Giuseppe

    2009-04-01

    Full Text Available Abstract Background Considering that HTB140 melanoma cells have shown a poor response to either protons or alkylating agents, the effects of a combined use of these agents have been analysed. Methods Cells were irradiated in the middle of the therapeutic 62 MeV proton spread out Bragg peak (SOBP. Irradiation doses were 12 or 16 Gy and are those frequently used in proton therapy. Four days after irradiation cells were treated with fotemustine (FM or dacarbazine (DTIC. Drug concentrations were 100 and 250 μM, values close to those that produce 50% of growth inhibition. Cell viability, proliferation, survival and cell cycle distribution were assessed 7 days after irradiation that corresponds to more than six doubling times of HTB140 cells. In this way incubation periods providing the best single effects of drugs (3 days and protons (7 days coincided at the same time. Results Single proton irradiations have reduced the number of cells to ~50%. FM caused stronger cell inactivation due to its high toxicity, while the effectiveness of DTIC, that was important at short term, almost vanished with the incubation of 7 days. Cellular mechanisms triggered by proton irradiation differently influenced the final effects of combined treatments. Combination of protons and FM did not improve cell inactivation level achieved by single treatments. A low efficiency of the single DTIC treatment was overcome when DTIC was introduced following proton irradiation, giving better inhibitory effects with respect to the single treatments. Most of the analysed cells were in G1/S phase, viable, active and able to replicate DNA. Conclusion The obtained results are the consequence of a high resistance of HTB140 melanoma cells to protons and/or drugs. The inactivation level of the HTB140 human melanoma cells after protons, FM or DTIC treatments was not enhanced by their combined application.

  10. Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination.

    Meyer, Sonja Izquierdo; Fuglsang, Katrine; Blaakaer, Jan

    2014-12-01

    This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. A focused and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two to four times. The vaccines contained different combinations of HPV16 and HPV18 and early proteins, E6 and E7. The primary outcome was the cell-mediated immune response. Correlation to clinical outcome (histopathology) and human leukocyte antigen genes were secondary endpoints. All vaccines triggered a detectable cell-mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). Prophylactic HPV vaccines have been introduced to reduce the incidence of cervical cancer in young women. Women already infected with HPV could benefit from a therapeutic HPV vaccination. Hence, it is important to continue the development of therapeutic HPV vaccines to lower the rate of HPV-associated malignancies and crucial to evaluate vaccine efficacy clinically. This clinical review represents an attempt to elucidate the theories supporting the development of an HPV vaccine with a therapeutic effect on human papillomavirus-induced malignancies of the cervix. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

  11. A network biology approach evaluating the anticancer effects of bortezomib identifies SPARC as a therapeutic target in adult T-cell leukemia cells

    Yu Zhang

    2008-10-01

    Full Text Available Junko H Ohyashiki1, Ryoko Hamamura2, Chiaki Kobayashi2, Yu Zhang2, Kazuma Ohyashiki21Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan; 2First Department of Internal Medicine, Tokyo Medical University, Tokyo, JapanAbstract: There is a need to identify the regulatory gene interaction of anticancer drugs on target cancer cells. Whole genome expression profiling offers promise in this regard, but can be complicated by the challenge of identifying the genes affected by hundreds to thousands of genes that induce changes in expression. A proteasome inhibitor, bortezomib, could be a potential therapeutic agent in treating adult T-cell leukemia (ATL patients, however, the underlying mechanism by which bortezomib induces cell death in ATL cells via gene regulatory network has not been fully elucidated. Here we show that a Bayesian statistical framework by VoyaGene® identified a secreted protein acidic and rich in cysteine (SPARC gene, a tumor-invasiveness related gene, as a possible modulator of bortezomib-induced cell death in ATL cells. Functional analysis using RNAi experiments revealed that inhibition of the expression SPARC by siRNA enhanced the apoptotic effect of bortezomib on ATL cells in accordance with an increase of cleaved caspase 3. Targeting SPARC may help to treat ATL patients in combination with bortezomib. This work shows that a network biology approach can be used advantageously to identify the genetic interaction related to anticancer effects.Keywords: network biology, adult T cell leukemia, bortezomib, SPARC

  12. The controversial origin of pericytes during angiogenesis - Implications for cell-based therapeutic angiogenesis and cell-based therapies.

    Blocki, Anna; Beyer, Sebastian; Jung, Friedrich; Raghunath, Michael

    2018-01-01

    Pericytes reside within the basement membrane of small vessels and are often in direct cellular contact with endothelial cells, fulfilling important functions during blood vessel formation and homeostasis. Recently, these pericytes have been also identified as mesenchymal stem cells. Mesenchymal stem cells, and especially their specialized subpopulation of pericytes, represent promising candidates for therapeutic angiogenesis applications, and have already been widely applied in pre-clinical and clinical trials. However, cell-based therapies of ischemic diseases (especially of myocardial infarction) have not resulted in significant long-term improvement. Interestingly, pericytes from a hematopoietic origin were observed in embryonic skin and a pericyte sub-population expressing leukocyte and monocyte markers was described during adult angiogenesis in vivo. Since mesenchymal stem cells do not express hematopoietic markers, the latter cell type might represent an alternative pericyte population relevant to angiogenesis. Therefore, we sourced blood-derived angiogenic cells (BDACs) from monocytes that closely resembled hematopoietic pericytes, which had only been observed in vivo thus far. BDACs displayed many pericytic features and exhibited enhanced revascularization and functional tissue regeneration in a pre-clinical model of critical limb ischemia. Comparison between BDACs and mesenchymal pericytes indicated that BDACs (while resembling hematopoietic pericytes) enhanced early stages of angiogenesis, such as endothelial cell sprouting. In contrast, mesenchymal pericytes were responsible for blood vessel maturation and homeostasis, while reducing endothelial sprouting.Since the formation of new blood vessels is crucial during therapeutic angiogenesis or during integration of implants into the host tissue, hematopoietic pericytes (and therefore BDACs) might offer an advantageous addition or even an alternative for cell-based therapies.

  13. Microfluidic cell culture systems for drug research.

    Wu, Min-Hsien; Huang, Song-Bin; Lee, Gwo-Bin

    2010-04-21

    In pharmaceutical research, an adequate cell-based assay scheme to efficiently screen and to validate potential drug candidates in the initial stage of drug discovery is crucial. In order to better predict the clinical response to drug compounds, a cell culture model that is faithful to in vivo behavior is required. With the recent advances in microfluidic technology, the utilization of a microfluidic-based cell culture has several advantages, making it a promising alternative to the conventional cell culture methods. This review starts with a comprehensive discussion on the general process for drug discovery and development, the role of cell culture in drug research, and the characteristics of the cell culture formats commonly used in current microfluidic-based, cell-culture practices. Due to the significant differences in several physical phenomena between microscale and macroscale devices, microfluidic technology provides unique functionality, which is not previously possible by using traditional techniques. In a subsequent section, the niches for using microfluidic-based cell culture systems for drug research are discussed. Moreover, some critical issues such as cell immobilization, medium pumping or gradient generation in microfluidic-based, cell-culture systems are also reviewed. Finally, some practical applications of microfluidic-based, cell-culture systems in drug research particularly those pertaining to drug toxicity testing and those with a high-throughput capability are highlighted.

  14. Radioresistant head and neck squamous cell carcinoma cells: Intracellular signaling, putative biomarkers for tumor recurrences and possible therapeutic targets

    Skvortsov, Sergej; Jimenez, Connie R.; Knol, Jaco C.; Eichberger, Paul; Schiestl, Bernhard; Debbage, Paul; Skvortsova, Ira; Lukas, Peter

    2011-01-01

    Purpose: Treatment of local and distant head and neck cancer recurrences after radiotherapy remains an unsolved problem. In order to identify potential targets for use in effective therapy of recurrent tumors, we have investigated protein patterns in radioresistant (FaDu-IRR and SCC25-IRR, “IRR cells”) as compared to parental (FaDu and SCC25) head and neck carcinoma cells. Methods and materials: Radiation resistant IRR cells were derived from parental cells after repeated exposure to ionizing radiation 10 times every two weeks at a single dose of 10 Gy, resulting in a total dose of 100 Gy. Protein profiling in parental and IRR cells was carried out using two-dimensional differential gel electrophoresis (2D-DIGE) followed by MALDI-TOF/TOF mass spectrometry. Cell viability, cell migration assays and Western blot analysis were used to confirm results obtained using the proteome approach. Results: Forty-five proteins that were similarly modulated in FaDu-IRR and SCC25-IRR cells compared to parental cells were selected to analyze their common targets. It was found that these either up- or down-regulated proteins are closely related to the enhancement of cell migration which is regulated by Rac1 protein. Further investigations confirmed that Rac1 is up-regulated in IRR cells, and inhibiting its action reduces the migratory abilities of these cells. Additionally, the Rac1 inhibitor exerts cytostatic effects in HNSCC cells, mostly in migratory cells. Conclusions: Based on these results, we conclude that radioresistant HNSCC cells possess enhanced metastatic abilities that are regulated by a network of migration-related proteins. Rac1 protein may be considered as a putative biomarker of HNSCC radiation resistance, and as a potential therapeutic target for treating local and distant HNSCC recurrences.

  15. Hormone Use for Therapeutic Amenorrhea and Contraception During Hematopoietic Cell Transplantation

    Chang, Katherine; Merideth, Melissa A.; Stratton, Pamela

    2015-01-01

    There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks and benefits of the hormonal options just prior, during and for the year after hematopoietic stem cell transplantation. PMID:26348182

  16. MESENCHYMAL STEM CELLS AS A THERAPEUTIC STRATEGY FOR MULTIPLE SCLEROSIS: ISSUES AND PERSPECTIVES

    M. M. Zafranskaya

    2017-01-01

    Full Text Available The ability of mesenchymal stem cells (MSC to influence the regulatory/suppressive effect in the autoimmune process and promote remyelination allows to consider them a new method of multiple sclerosis (MS therapy, by means of modifying the disease activity. Genetic stability, proliferative potential, ability to migrate into the damaged tissue areas and agreed protocols for isolation and culture are the main advantages for successful autologous, as well as allogeneic MSC therapy. Preliminary results from clinical studies using MSC application in MS patients show efficiency and safety of this therapeutic approach. Nevertheless, successful demonstration of the cell therapy in MS is only possible after detailed analysis and understanding of MSC biology and mechanisms of appropriate intercellular interactions. The article reviews general experience in usage of immunomodulatory and neuroprotective properties of MSС in MS, and highlights the issues of validity in cell-based therapy taking into account both in vitro и in vivo studies.

  17. Cell-derived microparticles: new targets in the therapeutic management of disease.

    Roseblade, Ariane; Luk, Frederick; Rawling, Tristan; Ung, Alison; Grau, Georges E R; Bebawy, Mary

    2013-01-01

    Intercellular communication is essential to maintain vital physiological activities and to regulate the organism's phenotype. There are a number of ways in which cells communicate with one another. This can occur via autocrine signaling, endocrine signaling or by the transfer of molecular mediators across gap junctions. More recently communication via microvesicular shedding has gained important recognition as a significant pathway by which cells can coordinate the spread and dominance of selective traits within a population. Through this communication apparatus, cells can now acquire and secure a survival advantage, particularly in the context of malignant disease. This review aims to highlight some of the functions and implications of microparticles in physiology of various disease states, and present a novel therapeutic strategy through the regulation of microparticle production.

  18. Interferon-gamma sensitizes colonic epithelial cell lines to physiological and therapeutic inducers of colonocyte apoptosis.

    O'Connell, J

    2012-02-03

    Homeostasis in the colonic epithelium is achieved by a continuous cycle of proliferation and apoptosis, in which imbalances are associated with disease. Inflammatory bowel disease (IBD) and colon cancer are associated with either excessive or insufficient apoptosis of colonic epithelial cells, respectively. By using two colonic epithelial cell lines, HT29 and SW620, we investigated how the epithelial cell\\'s sensitivity to apoptosis was regulated by the proinflammatory cytokine interferon-gamma (IFN-gamma). We found that IFN-gamma sensitized HT29 cells, and to a lesser extent SW620, to diverse inducers of apoptosis of physiologic or therapeutic relevance to the colon. These apoptosis inducers included Fas (CD95\\/APO-1) ligand (FasL), short-chain fatty acids, and chemotherapeutic drugs. The extent of IFN-gamma-mediated apoptosis sensitization in these two cell lines correlated well with the degree of IFN-gamma-mediated upregulation of the proapoptotic protease caspase-1. Although IFN-gamma alone effectively sensitized HT29 cells to apoptosis, inclusion of the protein synthesis inhibitor cyclohexamide (CHX) during apoptotic challenge was necessary for maximal sensitization of SW620. The requirement of CHX to sensitize SW620 cells to apoptosis implies a need to inhibit translation of antiapoptotic proteins absent from HT29. In particular, the antiapoptotic protein Bcl-2 was strongly expressed in SW620 cells but absent from HT29. Our results indicate that IFN-gamma increases the sensitivity of colonic epithelial cells to diverse apoptotic stimuli in concert, via upregulation of caspase-1. Our findings implicate caspase-1 and Bcl-2 as important central points of control determining the general sensitivity of colonic epithelial cells to apoptosis.

  19. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches

    Hira, Vashendriya V. V.; van Noorden, Cornelis J. F.; Carraway, Hetty E.; Maciejewski, Jaroslaw P.; Molenaar, Remco J.

    2017-01-01

    Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are

  20. Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications

    Ferro, Suellen; Azevedo-Silva, João; Casal, Margarida; Côrte-Real, Manuela; Baltazar, Fatima; Preto, Ana

    2016-01-01

    Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC. PMID:28874966

  1. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis.

    Bronckaers, Annelies; Hilkens, Petra; Martens, Wendy; Gervois, Pascal; Ratajczak, Jessica; Struys, Tom; Lambrichts, Ivo

    2014-08-01

    Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. The Role of Stem Cell Therapeutics in Wound Healing: Current Understanding and Future Directions.

    Sorice, Sarah; Rustad, Kristine C; Li, Alexander Y; Gurtner, Geoffrey C

    2016-09-01

    Chronic wounds present unique challenges for healthcare providers as they place patients at increased risk for various morbidities and mortality. Advances in wound care technology have expanded the treatment options available for wound management, but few products fully address the underlying core deficiencies responsible for the development of poorly healing wounds. In the future, addressing these derangements will undoubtedly play a key role in the treatment of these patients. Broad enthusiasm has surrounded the field of stem cell biology, which has shown great promise in repairing damaged tissues across numerous disease phenotypes. In this review, we provide a comprehensive review of the literature and evaluate the present landscape of wound therapeutics while discussing the rationales and allure behind stem cell-based products. We further propose 2 challenges that remain as new stem cell-based therapies are being developed and as this technology moves toward clinical translation. Given the relatively young age of this newer technology in wound healing, numerous challenges continue to surround its effective use including identifying the ideal population of stem cells to use and determining the optimal cell delivery method. However, significant forward progress has been made, with several clinical trials beginning to demonstrate reliable clinical benefit. The upward trajectory of stem cell technologies provides an exciting opportunity to positively impact patient outcomes through the controlled application of regenerative cell-based therapy.

  3. Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model.

    Xiujuan Zhang

    Full Text Available Multiple sclerosis (MS, characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE, a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression.

  4. CRISPR/Cas9 Genome Editing: A Promising Tool for Therapeutic Applications of Induced Pluripotent Stem Cells.

    Zhang, Yanli; Sastre, Danuta; Wang, Feng

    2018-01-01

    Induced pluripotent stem cells hold tremendous potential for biological and therapeutic applications. The development of efficient technologies for targeted genome alteration of stem cells in disease models is a prerequisite for utilizing stem cells to their full potential. The revolutionary technology for genome editing known as the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) system is recently recognized as a powerful tool for editing DNA at specific loci. The ease of use of the CRISPR-Cas9 technology will allow us to improve our understanding of genomic variation in disease processes via cellular and animal models. More recently, this system was modified to repress (CRISPR interference, CRISPRi) or activate (CRISPR activation, CRISPRa) gene expression without alterations in the DNA, which amplified the scope of applications of CRISPR systems for stem cell biology. Here, we highlight latest advances of CRISPR-associated applications in human pluripotent stem cells. The challenges and future prospects of CRISPR-based systems for human research are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

    Bathe, Oliver F; Dalyot-Herman, Nava; Malek, Thomas R

    2003-01-01

    Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several

  6. Amniotic fluid stem cells: a promising therapeutic resource for cell-based regenerative therapy.

    Antonucci, Ivana; Pantalone, Andrea; Tete, Stefano; Salini, Vincenzo; Borlongan, Cesar V; Hess, David; Stuppia, Liborio

    2012-01-01

    Stem cells have been proposed as a powerful tool in the treatment of several human diseases, both for their ability to represent a source of new cells to replace those lost due to tissue injuries or degenerative diseases, and for the ability of produce trophic molecules able to minimize damage and promote recovery in the injured tissue. Different cell types, such as embryonic, fetal or adult stem cells, human fetal tissues and genetically engineered cell lines, have been tested for their ability to replace damaged cells and to restore the tissue function after transplantation. Amniotic fluid -derived Stem cells (AFS) are considered a novel resource for cell transplantation therapy, due to their high renewal capacity, the "in vitro" expression of embryonic cell lineage markers, and the ability to differentiate in tissues derived from all the three embryonic layers. Moreover, AFS do not produce teratomas when transplanted into animals and are characterized by a low antigenicity, which could represent an advantage for cell transplantation or cell replacement therapy. The present review focuses on the biological features of AFS, and on their potential use in the treatment of pathological conditions such as ischemic brain injury and bone damages.

  7. A fully automated primary screening system for the discovery of therapeutic antibodies directly from B cells.

    Tickle, Simon; Howells, Louise; O'Dowd, Victoria; Starkie, Dale; Whale, Kevin; Saunders, Mark; Lee, David; Lightwood, Daniel

    2015-04-01

    For a therapeutic antibody to succeed, it must meet a range of potency, stability, and specificity criteria. Many of these characteristics are conferred by the amino acid sequence of the heavy and light chain variable regions and, for this reason, can be screened for during antibody selection. However, it is important to consider that antibodies satisfying all these criteria may be of low frequency in an immunized animal; for this reason, it is essential to have a mechanism that allows for efficient sampling of the immune repertoire. UCB's core antibody discovery platform combines high-throughput B cell culture screening and the identification and isolation of single, antigen-specific IgG-secreting B cells through a proprietary technique called the "fluorescent foci" method. Using state-of-the-art automation to facilitate primary screening, extremely efficient interrogation of the natural antibody repertoire is made possible; more than 1 billion immune B cells can now be screened to provide a useful starting point from which to identify the rare therapeutic antibody. This article will describe the design, construction, and commissioning of a bespoke automated screening platform and two examples of how it was used to screen for antibodies against two targets. © 2014 Society for Laboratory Automation and Screening.

  8. Therapeutic peptides for cancer therapy. Part II - cell cycle inhibitory peptides and apoptosis-inducing peptides.

    Raucher, Drazen; Moktan, Shama; Massodi, Iqbal; Bidwell, Gene L

    2009-10-01

    Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that arrest the cell cycle by mimicking CDK inhibitors or induce apoptosis directly are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Inhibition of cancer cell proliferation directly using peptides that arrest the cell cycle or induce apoptosis is a promising strategy. Peptides can be designed that interact very specifically with cyclins and/or cyclin-dependent kinases and with members of apoptotic cascades. Use of these peptides is not limited by their design, as a rational approach to peptide design is much less challenging than the design of small molecule inhibitors of specific protein-protein interactions. However, the limitations of peptide therapy lie in the poor pharmacokinetic properties of these large, often charged molecules. Therefore, overcoming the drug delivery hurdles could open the door for effective peptide therapy, thus making an entirely new class of molecules useful as anticancer drugs.

  9. Fake news portrayals of stem cells and stem cell research.

    Marcon, Alessandro R; Murdoch, Blake; Caulfield, Timothy

    2017-10-01

    This study examines how stem cells and stem cell research are portrayed on websites deemed to be purveyors of distorted and dubious information. Content analysis was conducted on 224 articles from 2015 to 2016, compiled by searching with the keywords 'stem cell(s)' on a list of websites flagged for containing either 'fake' or 'junk science' news. Articles contained various exaggerated positive and negative claims about stem cells and stem cell science, health and science related conspiracy theories, and statements promoting fear and mistrust of conventional medicine. Findings demonstrate the existence of organized misinformation networks, which may lead the public away from accurate information and facilitate a polarization of public discourse.

  10. WE-FG-BRA-04: A Portable Confocal Microscope to Image Live Cell Damage Response Induced by Therapeutic Radiation

    McFadden, C; Flint, D; Grosshans, D; Sawakuchi, G [The University of Texas MD Anderson Cancer Center, Houston, TX (United States); Sadetaporn, D [The University of Texas MD Anderson Cancer Center, Houston, TX (United States); Rice University, Houston, TX (United States); Asaithamby, A [UT Southwestern Medical Center, Dallas, TX (United States)

    2016-06-15

    Purpose: To construct a custom and portable fluorescence confocal laser-scanning microscope (FCLSM) that can be placed in the path of therapeutic radiation beams to study real-time radiation-induced damage response in live cells. Methods: We designed and constructed a portable FCLSM with three laser diodes for excitation (405, 488, and 635 nm). An objective lens focuses the excitation light and collects fluorescence from the sample. A pair of galvanometer mirrors scans/collects the laser beam/fluorescence along the focal plane (x/y-directions). A stepper motor stage scans in the axial direction and positions the x/y of the image field. Barrier filters and dichroic mirrors are used to route the spectral emission bands to the appropriate photodetector. An avalanche photodiode collects near-infrared fluorescence; a photodiode collects back-reflected 635 nm light; and a photomultiplier tube collects green fluorescence in the range of eGFP/eYFP. A 200-µm diameter pinhole was used to implement the confocal geometry for near-infrared and red channels and a 150-µm diameter pinhole for the green channel. Data acquisition and system control were achieved using a high-throughput data acquisition card. In-house software developed in LabVIEW was used to control the hardware, collect data from the photodetectors and reconstruct the confocal images. Results: 6 frames/s can be acquired for a 25 µm{sup 2} (128×128 pixels) field of view, visualizing the entire volume of the cell nucleus (∼10 µm depth) in <10 s. To demonstrate the usefulness of our FCLSM, we imaged gold nanoshells in live cells, radiation-induced damage in fibrosarcoma cells expressing eGFP tagged to a DNA repair protein, and neurons expressing eGFP. The system can also image particle tracks in fluorescent nuclear track detectors. Conclusion: We developed a versatile and portable FCLSM that allows radiobiology studies in live cells exposed to therapeutic radiation. The FCLSM can be placed in any vertical beam

  11. WE-FG-BRA-04: A Portable Confocal Microscope to Image Live Cell Damage Response Induced by Therapeutic Radiation

    McFadden, C; Flint, D; Grosshans, D; Sawakuchi, G; Sadetaporn, D; Asaithamby, A

    2016-01-01

    Purpose: To construct a custom and portable fluorescence confocal laser-scanning microscope (FCLSM) that can be placed in the path of therapeutic radiation beams to study real-time radiation-induced damage response in live cells. Methods: We designed and constructed a portable FCLSM with three laser diodes for excitation (405, 488, and 635 nm). An objective lens focuses the excitation light and collects fluorescence from the sample. A pair of galvanometer mirrors scans/collects the laser beam/fluorescence along the focal plane (x/y-directions). A stepper motor stage scans in the axial direction and positions the x/y of the image field. Barrier filters and dichroic mirrors are used to route the spectral emission bands to the appropriate photodetector. An avalanche photodiode collects near-infrared fluorescence; a photodiode collects back-reflected 635 nm light; and a photomultiplier tube collects green fluorescence in the range of eGFP/eYFP. A 200-µm diameter pinhole was used to implement the confocal geometry for near-infrared and red channels and a 150-µm diameter pinhole for the green channel. Data acquisition and system control were achieved using a high-throughput data acquisition card. In-house software developed in LabVIEW was used to control the hardware, collect data from the photodetectors and reconstruct the confocal images. Results: 6 frames/s can be acquired for a 25 µm 2 (128×128 pixels) field of view, visualizing the entire volume of the cell nucleus (∼10 µm depth) in <10 s. To demonstrate the usefulness of our FCLSM, we imaged gold nanoshells in live cells, radiation-induced damage in fibrosarcoma cells expressing eGFP tagged to a DNA repair protein, and neurons expressing eGFP. The system can also image particle tracks in fluorescent nuclear track detectors. Conclusion: We developed a versatile and portable FCLSM that allows radiobiology studies in live cells exposed to therapeutic radiation. The FCLSM can be placed in any vertical beam line

  12. How to optimize therapeutic ratio in brachytherapy of head and neck squamous cell carcinoma?

    Mazeron, J.J.; Simon, J.M.; Hardiman, C.; Gerbaulet, A.

    1998-01-01

    Considerable experience has been accumulated with low dose rate (LDR) brachytherapy in the treatment of squamous cell carcinoma of the oral cavity and oropharynx, 4 cm or less in diameter. Recent analysis of large clinical series provided data indicating that modalities of LDR brachytherapy should be optimized in treating these tumours for increasing therapeutic ratio. LDR brachytherapy is now challenged by high dose rate (HDR) brachytherapy and pulsed dose rate (PDR) brachytherapy. Preliminary results obtained with the last two modalities are discussed in comparison with those achieved with LDR brachytherapy. (orig.)

  13. New technology for ultrasensitive detection and isolation of rare cells for clinical diagnostics and therapeutics

    Leary, James F.; McLaughlin, Scott R.

    1995-04-01

    A high-speed, 11-parameter, 6-color fluorescence, laser flow cytometer/cell sorter with a number of special and unique features has been built for ultrasensitive detection and isolation of rare cells for clinical diagnostics and therapeutics. The software for real-time data acquisition and sort control, written as C++ programming language modules with a WindowsTM graphical user interface, runs on a 66-MHz 80486 computer joined by an extended bus to 23 sophisticated multi-layered boards of special data acquisition and sorting electronics. Special features include: high-speed (> 100,000 cells/sec) real-time data classification module (U.S. Patent 5,204,884 (1993)); real-time principal component cell sorting; multi-queue signal-processing system with multiple hardware and software event buffers to reduce instrument dead time, LUT charge-pulse definition, high-resolution `flexible' sorting for optimal yield/purity sort strategies (U.S. Patent 5,199,576); pre-focusing optical wavelength correction for a second laser beam; and two trains of three fluorescence detectors-- each adjustable for spatial separation to interrogate only one of two laser beams, syringe- driven or pressure-driven fluidics, and time-windowed parameters. The system has been built to be both expandable and versatile through the use of LUT's and a modular hardware and software design. The instrument is especially useful at detection and isolation of rare cell subpopulations for which our laboratory is well-known. Cell subpopulations at frequencies as small as 10-7 have been successfully studied with this system. Current applications in clinical diagnostics and therapeutics include detection and isolation of (1) fetal cells from material blood for prenatal diagnosis of birth defects, (2) hematopoietic stem and precursor cells for autologous bone marrow transplantation, (3) metastatic breast cancer cells for molecular characterization, and (4) HIV-infected maternal cells in newborn blood to study mother

  14. Human cloning, stem cell research. An Islamic perspective.

    Al-Aqeel, Aida I

    2009-12-01

    The rapidly changing technologies that involve human subjects raise complex ethical, legal, social, and religious issues. Recent advances in the field of cloning and stem cell research have introduced new hopes for the treatment of serious diseases. But this promise has raised many complex questions. This field causes debate and challenge, not only among scientists but also among ethicists, religious scholars, governments, and politicians. There is no consensus on the morality of human cloning, even within specific religious traditions. In countries in which religion has a strong influence on political decision making, the moral status of the human embryo is at the center of the debate. Because of the inevitable consequences of reproductive cloning, it is prohibited in Islam. However, stem cell research for therapeutic purposes is permissible with full consideration, and all possible precautions in the pre-ensoulment stages of early fetus development, if the source is legitimate.

  15. Regulatory T cell derived Exosomes: possible therapeutic and diagnostic tools in transplantation

    Akansha eAgarwal

    2014-11-01

    Full Text Available Exosomes are extracellular vesicles released by many cells of the body. These small vesicles play an important part in intercellular communication both in the local environment and systemically, facilitating in the transfer of proteins, cytokines as well as miRNA between cells. The observation that exosomes isolated from immune cells such as dendritic cells (DCs modulate the immune response has paved the way for these structures to be considered as potential immunotherapeutic reagents. Indeed clinical trials using DC derived exosomes to facilitate immune responses to specific cancer antigens are now underway. Exosomes can also have a negative effect on the immune response and exosomes isolated from regulatory T cells (Tregs and other subsets of T cells have been shown to have immune suppressive capacities. Here we review what is currently known about Treg derived exosomes and their contribution to immune regulation, as well as highlighting their possible therapeutic potential for preventing graft rejection, and their possible use as diagnostic tools to assess transplant outcome.

  16. Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells.

    Stephenson, Emma; Ogilvie, Caroline Mackie; Patel, Heema; Cornwell, Glenda; Jacquet, Laureen; Kadeva, Neli; Braude, Peter; Ilic, Dusko

    2010-12-06

    The use of stem cells for regenerative medicine has captured the imagination of the public, with media attention contributing to rising expectations of clinical benefits. Human embryonic stem cells (hESCs) are the best model for capital investment in stem cell therapy and there is a clear need for their robust genetic characterization before scaling-up cell expansion for that purpose. We have to be certain that the genome of the starting material is stable and normal, but the limited resolution of conventional karyotyping is unable to give us such assurance. Advanced molecular cytogenetic technologies such as array comparative genomic hybridization for identifying chromosomal imbalances, and single nucleotide polymorphism analysis for identifying ethnic background and loss of heterozygosity should be introduced as obligatory diagnostic tests for each newly derived hESC line before it is deposited in national stem cell banks. If this new quality standard becomes a requirement, as we are proposing here, it would facilitate and accelerate the banking process, since end-users would be able to select the most appropriate line for their particular application, thus improving efficiency and streamlining the route to manufacturing therapeutics. The pharmaceutical industry, which may use hESC-derived cells for drug screening, should not ignore their genomic profile as this may risk misinterpretation of results and significant waste of resources.

  17. Do ABO blood group antigens hamper the therapeutic efficacy of mesenchymal stromal cells?

    Moll, Guido; Hult, Annika; von Bahr, Lena; Alm, Jessica J; Heldring, Nina; Hamad, Osama A; Stenbeck-Funke, Lillemor; Larsson, Stella; Teramura, Yuji; Roelofs, Helene; Nilsson, Bo; Fibbe, Willem E; Olsson, Martin L; Le Blanc, Katarina

    2014-01-01

    Investigation into predictors for treatment outcome is essential to improve the clinical efficacy of therapeutic multipotent mesenchymal stromal cells (MSCs). We therefore studied the possible harmful impact of immunogenic ABO blood groups antigens - genetically governed antigenic determinants - at all given steps of MSC-therapy, from cell isolation and preparation for clinical use, to final recipient outcome. We found that clinical MSCs do not inherently express or upregulate ABO blood group antigens after inflammatory challenge or in vitro differentiation. Although antigen adsorption from standard culture supplements was minimal, MSCs adsorbed small quantities of ABO antigen from fresh human AB plasma (ABP), dependent on antigen concentration and adsorption time. Compared to cells washed in non-immunogenic human serum albumin (HSA), MSCs washed with ABP elicited stronger blood responses after exposure to blood from healthy O donors in vitro, containing high titers of ABO antibodies. Clinical evaluation of hematopoietic stem cell transplant (HSCT) recipients found only very low titers of anti-A/B agglutination in these strongly immunocompromised patients at the time of MSC treatment. Patient analysis revealed a trend for lower clinical response in blood group O recipients treated with ABP-exposed MSC products, but not with HSA-exposed products. We conclude, that clinical grade MSCs are ABO-neutral, but the ABP used for washing and infusion of MSCs can contaminate the cells with immunogenic ABO substance and should therefore be substituted by non-immunogenic HSA, particularly when cells are given to immunocompentent individuals.

  18. Androgen-Forming Stem Leydig cells: Identification, Function and Therapeutic Potential

    Yunhui Zhang

    2008-01-01

    Full Text Available Leydig cells are the primary source of testosterone in the male, and differentiation of Leydig cells in the testes is one of the primary events in the development of the male body and fertility. Stem Leydig cells (SLCs exist in the testis throughout postnatal life, but a lack of cell surface markers previously hindered attempts to obtain purified SLC fractions. Once isolated, the properties of SLCs provide interesting clues for the ontogeny of these cells within the embryo. Moreover, the clinical potential of SLCs might be used to reverse age-related declines in testosterone levels in aging men, and stimulate reproductive function in hypogonadal males. This review focuses on the source, identification and outlook for therapeutic applications of SLCs. Separate pools of SLCs may give rise to fetal and adult generations of Leydig cell, which may account for their observed functional differences. These differences should in turn be taken into account when assessing the consequences of environmental pollutants such as the phthalate ester, diethylhexylphthalate (DEHP.

  19. Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.

    Aguisanda, Francis; Yeh, Charles D; Chen, Catherine Z; Li, Rong; Beers, Jeanette; Zou, Jizhong; Thorne, Natasha; Zheng, Wei

    2017-06-28

    Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development.

  20. Tumor cells and memory T cells converge at glycolysis: Therapeutic implications

    Karthikeyan, Swathi; Geschwind, Jean-Francois; Ganapathy-Kanniappan, Shanmugasundaram

    2014-01-01

    In the immune system, activation of naïve T (Tn) cells into effector T cells (Teff) involves a metabolic switch to glycolysis to promote rapid proliferation and differentiation. In the October issue of The Journal of Clinical Investigation, Sukumar et al. have demonstrated that in CD8+ memory T (Tems) cells glycolytic phenotype contributes to the shortened lifespan of Tems. Conversely, inhibition of glycolysis in Tems not only extended their viability but also augmented desirable properties. ...

  1. Enhancement of therapeutic drug and DNA delivery into cells by electroporation

    Rabussay, Dietmar [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Dev, Nagendu B [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Fewell, Jason [Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX (United States); Smith, Louis C [Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX (United States); Widera, Georg [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Zhang Lei [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States)

    2003-02-21

    The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm{sup -1} generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes

  2. Enhancement of therapeutic drug and DNA delivery into cells by electroporation

    Rabussay, Dietmar; Dev, Nagendu B; Fewell, Jason; Smith, Louis C; Widera, Georg; Zhang Lei

    2003-01-01

    The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm -1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

  3. Patents and innovation in cancer therapeutics: lessons from CellPro.

    Bar-Shalom, Avital; Cook-Deegan, Robert

    2002-01-01

    This article discusses the interaction between intellectual property and cancer treatment. CellPro developed a stem cell separation technology based on research at the Fred Hutchinson Cancer Center. A patent with broad claims to bone marrow stem cell antibodies had been awarded to Johns Hopkins University and licensed to Baxter Healthcare under the 1980 Bayh-Dole Act to promote commercial use of inventions from federally funded research. CellPro got FDA approval more than two years before Baxter but lost patent infringement litigation. NIH elected not to compel Hopkins to license its patents to CellPro. CellPro went out of business, selling its technology to its competitor. Decisions at both firms and university licensing offices, and policies at the Patent and Trademark Office, NIH, and the courts influenced the outcome.

  4. Self-Assembling Peptide Amphiphiles for Therapeutic Delivery of Proteins, Drugs, and Stem Cells

    Lee, Sungsoo Seth

    Biomaterials are used to help regenerate or replace the structure and function of damaged tissues. In order to elicit desired therapeutic responses in vivo, biomaterials are often functionalized with bioactive agents, such as growth factors, small molecule drugs, or even stem cells. Therefore, the strategies used to incorporate these bioactive agents in the microstructures and nanostructures of biomaterials can strongly influence the their therapeutic efficacy. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures with improved interaction with three types of therapeutic agents: bone morphogenetic protein 2 (BMP-2) which promotes osteogenic differentiation and bone growth, anti-inflammatory drug naproxen which is used to treat osteo- and rheumatoid arthritis, and neural stem cells that could differentiate into neurons to treat neurodegenerative diseases. For BMP-2 delivery, two specific systems were investigated with affinity for BMP-2: 1) heparin-binding nanofibers that display the natural ligand of the osteogenic protein, and 2) nanofibers that display a synthetic peptide ligand discovered in our laboratory through phage display to directly bind BMP-2. Both systems promoted enhanced osteoblast differentiation of pluripotent C2C12 cells and augmented bone regeneration in two in vivo models, a rat critical-size femur defect model and spinal arthrodesis model. The thesis also describes the use of PA nanofibers to improve the delivery of the anti-inflammatory drug naproxen. To promote a controlled release, naproxen was chemically conjugated to the nanofiber surface via an ester bond that would only be cleaved by esterases, which are enzymes found naturally in the body. In the absence of esterases, the naproxen remained conjugated to the nanofibers and was non-bioactive. On the other hand, in the presence of esterases, naproxen was slowly released and inhibited cyclooxygenase-2 (COX-2) activity, an enzyme responsible

  5. Schwann Cell Precursors from Human Pluripotent Stem Cells as a Potential Therapeutic Target for Myelin Repair.

    Kim, Han-Seop; Lee, Jungwoon; Lee, Da Yong; Kim, Young-Dae; Kim, Jae Yun; Lim, Hyung Jin; Lim, Sungmin; Cho, Yee Sook

    2017-06-06

    Schwann cells play a crucial role in successful nerve repair and regeneration by supporting both axonal growth and myelination. However, the sources of human Schwann cells are limited both for studies of Schwann cell development and biology and for the development of treatments for Schwann cell-associated diseases. Here, we provide a rapid and scalable method to produce self-renewing Schwann cell precursors (SCPs) from human pluripotent stem cells (hPSCs), using combined sequential treatment with inhibitors of the TGF-β and GSK-3 signaling pathways, and with neuregulin-1 for 18 days under chemically defined conditions. Within 1 week, hPSC-derived SCPs could be differentiated into immature Schwann cells that were functionally confirmed by their secretion of neurotrophic factors and their myelination capacity in vitro and in vivo. We propose that hPSC-derived SCPs are a promising, unlimited source of functional Schwann cells for treating demyelination disorders and injuries to the peripheral nervous system. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Fuel cell research: Towards efficient energy

    Rohwer, MB

    2008-11-01

    Full Text Available fuel cells by optimising the loading of catalyst (being expensive noble metals) and ionomer; 2) Improving conventional acidic direct alcohol fuel cells by developing more efficient catalysts and by investigating other fuels than methanol; 3... these components add significantly to the overall cost of a PEMFC. 1 We focused our research activities on: 1) The effect of the loading of catalytic ink on cell performance; 2) The effect of the ionomer content in the catalytic ink; 3) Testing...

  7. Stem Cell Research and Health Education

    Eve, David J.; Marty, Phillip J.; McDermott, Robert J.; Klasko, Stephen K.; Sanberg, Paul R.

    2008-01-01

    Stem cells are being touted as the greatest discovery for the potential treatment of a myriad of diseases in the new millennium, but there is still much research to be done before it will be known whether they can live up to this description. There is also an ethical debate over the production of one of the most valuable types of stem cell: the…

  8. Regulatory T cells, maternal-foetal immune tolerance and recurrent miscarriage: new therapeutic challenging opportunities.

    Alijotas-Reig, Jaume; Melnychuk, Taisiia; Gris, Josep Maria

    2015-03-15

    Because maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to play a key role in altering the maternal immune response. Peripheral T regulatory cells (pTregs) at the maternal-foetal interface are necessary in situ to prevent early abortion, but only those pTregs that have been previously exposed to paternal alloantigens. It has been showed that pregnancy selectively stimulates the accumulation of maternal Foxp3(+)CD4(+)CD25(+) (Foxp3Tregs) cells with foetal specificity. Interestingly, after delivery, foetal-specific pTregs persist at elevated levels, maintain tolerance to pre-existing foetal antigen, and rapidly re-accumulate during subsequent pregnancy. pTreg up-regulation could be hypothesized as a possible future therapeutic strategy in humans. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  9. Electrochemotherapy as a new therapeutic strategy in advanced Merkel cell carcinoma of head and neck region

    Scelsi, Daniele; Mevio, Niccolò; Bertino, Giulia; Occhini, Antonio; Brazzelli, Valeria; Morbini, Patrizia; Benazzo, Marco

    2013-01-01

    Merkel Cell Carcinoma (MCC) is a rare and aggressive tumour, arising from a cutaneous mechanoceptor cell located in the basal layer of epidermis, with poor prognosis. The treatment of choice for the initial stage of the disease is surgery and/or radiotherapy. The treatment of recurrent or advanced disease is still controversial. We report a case of 84 years old woman with a recurrent MCC of the chin treated with electrochemotherapy (ECT). During the period of 20 months, four sessions of ECT were employed, which resulted in an objective response of the tumour and good quality of residual life. Our case shows the effectiveness of ECT in the treatment of locally advanced MCC of the head and neck region in a patient not suitable for standard therapeutic options

  10. Therapeutic Effects of Myeloid Cell Leukemia-1 siRNA on Human Acute Myeloid Leukemia Cells

    Hadi Karami

    2014-05-01

    Full Text Available Purpose: Up-regulation of Mcl-1, a known anti-apoptotic protein, is associated with the survival and progression of various malignancies including leukemia. The aim of this study was to explore the effect of Mcl-1 small interference RNA (siRNA on the proliferation and apoptosis of HL-60 acute myeloid leukemia (AML cells. Methods: siRNA transfection was performed using Lipofectamine™2000 reagent. Relative mRNA and protein expressions were quantified by quantitative real-time PCR and Western blotting, respectively. Trypan blue assay was performed to assess tumor cell proliferation after siRNA transfection. The cytotoxic effect of Mcl-1 siRNA on leukemic cells was measured using MTT assay. Apoptosis was detected using ELISA cell death assay. Results: Mcl-1 siRNA clearly lowered both Mcl-1 mRNA and protein levels in a time-dependent manner, leading to marked inhibition of cell survival and proliferation. Furthermore, Mcl-1 down-regulation significantly enhanced the extent of HL-60 apoptotic cells. Conclusion: Our results suggest that the down-regulation of Mcl-1 by siRNA can effectively trigger apoptosis and inhibit the proliferation of leukemic cells. Therefore, Mcl-1 siRNA may be a potent adjuvant in AML therapy.

  11. Therapeutic potential of mesenchymal stem cells to treat Achilles tendon injuries.

    Vieira, M H C; Oliveira, R J; Eça, L P M; Pereira, I S O; Hermeto, L C; Matuo, R; Fernandes, W S; Silva, R A; Antoniolli, A C M B

    2014-12-12

    Rupture of the Achilles tendon diminishes quality of life. The gold-standard therapy is a surgical suture, but this presents complications, including wound formation and inflammation. These complications spurred evaluation of the therapeutic potential of mesenchymal stem cells (MSCs) from adipose tissue. New Zealand rabbits were divided into 6 groups (three treatments with two time points each) evaluated at either 14 or 28 days after surgery: cross section of the Achilles tendon (CSAT); CSAT + Suture; and CSAT + MSC. A comparison between all groups at both time points showed a statistically significant increase in capillaries and in the structural organization of collagen in the healed tendon in the CSAT + Suture and CSAT + MSC groups at the 14-day assessment. Comparison between the two time points within the same group showed a statistically significant decrease in the inflammatory process and an increase in the structural organization of collagen in the CSAT and CSAT + MSC groups. A study of the genomic integrity of the cells suggested a linear correlation between an increase of injuries and culture time. Thus, MSC transplantation is a good alternative for treatment of Achilles tendon ruptures because it may be conducted without surgery and tendon suture and, therefore, has no risk of adverse effects resulting from the surgical wound or inflammation caused by nonabsorbable sutures. Furthermore, this alternative treatment exhibits a better capacity for wound healing and maintaining the original tendon architecture, depending on the arrangement of the collagen fibers, and has important therapeutic potential.

  12. Recruiting endogenous stem cells: a novel therapeutic approach for erectile dysfunction

    Zhong-Cheng Xin

    2016-01-01

    Full Text Available Transplanted stem cells (SCs, owing to their regenerative capacity, represent one of the most promising methods to restore erectile dysfunction (ED. However, insufficient source, invasive procedures, ethical and regulatory issues hamper their use in clinical applications. The endogenous SCs/progenitor cells resident in organ and tissues play critical roles for organogenesis during development and for tissue homeostasis in adulthood. Even without any therapeutic intervention, human body has a robust self-healing capability to repair the damaged tissues or organs. Therefore, SCs-for-ED therapy should not be limited to a supply-side approach. The resident endogenous SCs existing in patients could also be a potential target for ED therapy. The aim of this review was to summarize contemporary evidence regarding: (1 SC niche and SC biological features in vitro; (2 localization and mobilization of endogenous SCs; (3 existing evidence of penile endogenous SCs and their possible mode of mobilization. We performed a search on PubMed for articles related to these aspects in a wide range of basic studies. Together, numerous evidences hold the promise that endogenous SCs would be a novel therapeutic approach for the therapy of ED.

  13. Mesenchymal stem cell-based gene therapy: A promising therapeutic strategy.

    Mohammadian, Mozhdeh; Abasi, Elham; Akbarzadeh, Abolfazl

    2016-08-01

    Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in bone marrow, fat, and so many other tissues, and can differentiate into a variety of cell types including osteoblasts, chondrocytes, and adipocytes, as well as myocytes and neurons. Moreover, they have great capacity for self-renewal while maintaining their multipotency. Their capacity for proliferation and differentiation, in addition to their immunomodulatory activity, makes them very promising candidates for cell-based regenerative medicine. Moreover, MSCs have the ability of mobilization to the site of damage; therefore, they can automatically migrate to the site of injury via their chemokine receptors following intravenous transplantation. In this respect, they can be applied for MSC-based gene therapy. In this new therapeutic method, genes of interest are introduced into MSCs via viral and non-viral-based methods that lead to transgene expression in them. Although stem cell-based gene therapy is a relatively new strategy, it lights a new hope for the treatment of a variety of genetic disorders. In the near future, MSCs can be of use in a vast number of clinical applications, because of their uncomplicated isolation, culture, and genetic manipulation. However, full consideration is still crucial before they are utilized for clinical trials, because the number of studies that signify the advantageous effects of MSC-based gene therapy are still limited.

  14. Biomaterials-based 3D cell printing for next-generation therapeutics and diagnostics.

    Jang, Jinah; Park, Ju Young; Gao, Ge; Cho, Dong-Woo

    2018-02-01

    Building human tissues via 3D cell printing technology has received particular attention due to its process flexibility and versatility. This technology enables the recapitulation of unique features of human tissues and the all-in-one manufacturing process through the design of smart and advanced biomaterials and proper polymerization techniques. For the optimal engineering of tissues, a higher-order assembly of physiological components, including cells, biomaterials, and biomolecules, should meet the critical requirements for tissue morphogenesis and vascularization. The convergence of 3D cell printing with a microfluidic approach has led to a significant leap in the vascularization of engineering tissues. In addition, recent cutting-edge technology in stem cells and genetic engineering can potentially be adapted to the 3D tissue fabrication technique, and it has great potential to shift the paradigm of disease modeling and the study of unknown disease mechanisms required for precision medicine. This review gives an overview of recent developments in 3D cell printing and bioinks and provides technical requirements for engineering human tissues. Finally, we propose suggestions on the development of next-generation therapeutics and diagnostics. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells on Laser-Induced Retinal Injury in Mice

    Yuanfeng Jiang

    2014-05-01

    Full Text Available Stem cell therapy has shown encouraging results for neurodegenerative diseases. The retina provides a convenient locus to investigate stem cell functions and distribution in the nervous system. In the current study, we investigated the therapeutic potential of bone marrow mesenchymal stem cells (MSCs by systemic transplantation in a laser-induced retinal injury model. MSCs from C57BL/6 mice labeled with green fluorescent protein (GFP were injected via the tail vein into mice after laser photocoagulation. We found that the average diameters of laser spots and retinal cell apoptosis were decreased in the MSC-treated group. Interestingly, GFP-MSCs did not migrate to the injured retina. Further examination revealed that the mRNA expression levels of glial fibrillary acidic protein and matrix metalloproteinase-2 were lower in the injured eyes after MSC transplantation. Our results suggest that intravenously injected MSCs have the ability to inhibit retinal cell apoptosis, reduce the inflammatory response and limit the spreading of damage in the laser-injured retina of mice. Systemic MSC therapy might play a role in neuroprotection, mainly by regulation of the intraocular microenvironment.

  16. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-06-03

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

  17. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo JA; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-01-01

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression. The online version of this article (doi:10.1186/s12885-015-1450-3) contains supplementary material, which is available to authorized users

  18. Therapeutic effect of adipose-derived mesenchymal stem cells on radiation enteritis

    Chang Pengyu; Cui Shuang; Luo Jinghua; Qu Chao; Jiang Xin; Qu Yaqin; Dong Lihua

    2014-01-01

    Objective: To evaluate the therapeutic effect of adipose-derived mesenchymal stem cells on radiation enteritis. Methods: A total of 52 male Sprague-Dawley rats were used in the present study. Herein, 46 rats were randomly selected and irradiated with a dose of 15 Gy at their abdomens. Two hours post-irradiation, 23 rats were randomly selected and infused intraperitoneally with adipose-derived mesenchymal stem cells in passage 6 from young-female donor. The other 23 rats were intraperitoneally infused with PBS. The rest 6 rats were set as normal control. During the first 10 days post-irradiation, peripheral blood-samples from irradiated rats were harvested for testing the levels of IL-10 in serum using ELISA assay. Additionally, after isolating the thymic cells and peripheral blood mononuclear cells, the percentages of CD4/CD25/Foxp(3)-positive regulatory T cells in thymus and peripheral blood were tested by flow-cytometry. Finally, infiltration of inflammatory cells and deposition of collagens within irradiated small intestine were analyzed by H&E staining and Masson Trichrome staining, respectively. Based on the MPO-immunohistochemistry staining, the type of infiltrated cells was identified. The Kaplan-Meier method was used for analyzing the survival rate of irradiated rats. Results: During a period of 30 days post-irradiation, the irradiated rats receiving adipose-derived mesenchymal stem cells survived longer than those receiving PBS (t = 4.53, P < 0.05). Compared to the irradiated rats with PBS-treatment, adipose-derived mesenchymal stem cells could elevate the level of IL-10 in serum (7 d: t = 13.93, P < 0.05) and increase the percentages of CD4/CD25/Foxp(3)-positive regulatory T cells in both peripheral blood (3.5 d: t = 7.72, 7 d: t = 11.11, 10 d: t = 6.99, P < 0.05) and thymus (7 d: t = 16.17, 10 d: t = 12.12, P < 0.05). Moreover, infiltration of inflammatory cells and deposition of collagens within irradiated small intestine were mitigated by adipose

  19. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

    Pooja Ghatalia

    Full Text Available Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR and mammalian target of rapamycin (mTOR improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC, but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T, matched normal kidney (N and metastatic tumor tissue (M may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79 compared to those that did not develop metastasis for at least 2 years (n = 187. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001. The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

  20. A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer

    Sanal, Madhusudana Girija

    2014-01-01

    Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence e...

  1. Tumor cells and memory T cells converge at glycolysis: therapeutic implications.

    Karthikeyan, Swathi; Geschwind, Jean-Francois; Ganapathy-Kanniappan, Shanmugasundaram

    2014-05-01

    In the immune system, activation of naïve T (Tn) cells into effector T cells (Teff) involves a metabolic switch to glycolysis to promote rapid proliferation and differentiation. In the October issue of The Journal of Clinical Investigation, Sukumar et al. have demonstrated that in CD8(+) memory T (Tems) cells glycolytic phenotype contributes to the shortened lifespan of Tems. Conversely, inhibition of glycolysis in Tems not only extended their viability but also augmented desirable properties. Notably, they also demonstrate that glycolytic inhibition during the ex vivo clonal expansion of tumor-specific Tems enhanced their antitumor function. Overall, the data suggest that an antiglycolytic strategy targeting the Tems could enhance antitumor immune response. On the other hand, cancer cells have long been known to exhibit metabolic reprogramming which involves a shift toward glycolysis (the conversion of glucose into lactate) to facilitate uninterrupted growth. Interestingly, antiglycolytic treatment of cancer cells has been known to trigger antitumor immune response as well. Taken together, it is probable that a strategy involving concurrent inhibition of glycolysis in tumor cells and Tems could promote a dual attack on cancer by inducing an effective antitumor immune response and an immunogenic chemotherapy.

  2. Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies.

    Abbasalizadeh, Saeed; Baharvand, Hossein

    2013-12-01

    Recent technological advances in the generation, characterization, and bioprocessing of human pluripotent stem cells (hPSCs) have created new hope for their use as a source for production of cell-based therapeutic products. To date, a few clinical trials that have used therapeutic cells derived from hESCs have been approved by the Food and Drug Administration (FDA), but numerous new hPSC-based cell therapy products are under various stages of development in cell therapy-specialized companies and their future market is estimated to be very promising. However, the multitude of critical challenges regarding different aspects of hPSC-based therapeutic product manufacturing and their therapies have made progress for the introduction of new products and clinical applications very slow. These challenges include scientific, technological, clinical, policy, and financial aspects. The technological aspects of manufacturing hPSC-based therapeutic products for allogeneic and autologous cell therapies according to good manufacturing practice (cGMP) quality requirements is one of the most important challenging and emerging topics in the development of new hPSCs for clinical use. In this review, we describe main critical challenges and highlight a series of technological advances in all aspects of hPSC-based therapeutic product manufacturing including clinical grade cell line development, large-scale banking, upstream processing, downstream processing, and quality assessment of final cell therapeutic products that have brought hPSCs closer to clinical application and commercial cGMP manufacturing. © 2013.

  3. B cells are multifunctional players in multiple sclerosis pathogenesis: insights from therapeutic interventions

    Nele eClaes

    2015-12-01

    Full Text Available Multiple sclerosis (MS is a severe disease of the central nervous system (CNS characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell depleting treatment rituximab in patients with relapsing-remitting (RR MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate and teriflunomide, second-line (fingolimod, natalizumab and even third-line (monoclonal antibody therapies treatments on B cell subtype distribution, expression of functional surface markers and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

  4. Enhancement of cell-based therapeutic angiogenesis using a novel type of injectable scaffolds of hydroxyapatite-polymer nanocomposite microspheres.

    Yohei Mima

    Full Text Available BACKGROUND: Clinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis in patients with severe ischemic diseases; however, their success remains limited. Maintaining transplanted cells in place are expected to augment the cell-based therapeutic angiogenesis. We have reported that nano-hydroxyapatite (HAp coating on medical devices shows marked cell adhesiveness. Using this nanotechnology, HAp-coated poly(l-lactic acid (PLLA microspheres, named nano-scaffold (NS, were generated as a non-biological, biodegradable and injectable cell scaffold. We investigate the effectiveness of NS on cell-based therapeutic angiogenesis. METHODS AND RESULTS: Bone marrow mononuclear cells (BMNC and NS or control PLLA microspheres (LA were intramuscularly co-implanted into mice ischemic hindlimbs. When BMNC derived from enhanced green fluorescent protein (EGFP-transgenic mice were injected into ischemic muscle, the muscle GFP level in NS+BMNC group was approximate fivefold higher than that in BMNC or LA+BMNC groups seven days after operation. Kaplan-Meier analysis demonstrated that NS+BMNC markedly prevented hindlimb necrosis (P<0.05 vs. BMNC or LA+BMNC. NS+BMNC revealed much higher induction of angiogenesis in ischemic tissues and collateral blood flow confirmed by three-dimensional computed tomography angiography than those of BMNC or LA+BMNC groups. NS-enhanced therapeutic angiogenesis and arteriogenesis showed good correlations with increased intramuscular levels of vascular endothelial growth factor and fibroblast growth factor-2. NS co-implantation also prevented apoptotic cell death of transplanted cells, resulting in prolonged cell retention. CONCLUSION: A novel and feasible injectable cell scaffold potentiates cell-based therapeutic angiogenesis, which could be extremely useful for the treatment of severe ischemic disorders.

  5. [The advance in the research and therapeutic trials of amyotrophic lateral sclerosis].

    Moriwaka, F; Tashiro, K

    2000-12-01

    The research concerning with the pathogenesis of amyotrophic lateral sclerosis (ALS) has been in steady progress in the last 10 years, including discovery of SOD mutation in familial ALS. Riluzole, by its inhibiting excitatory amino acid release, is the only drug, which has been demonstrated the neuroprotective activity in the randomised double-blind placebo-controlled clinical trials in patients with ALS, although many other clinical therapeutic trials for ALS patients has been carried out. We discussed the clinical trials being the under way, especially SR57746A, (1-[2-(naphth-2-yl)ethy]-4-(3-trifluoromethyl phenyl)-1, 2, 5, 6-tetrahydro-pyridine, hydrochloride), a non-peptide compound which has been shown to exhibit a wide range of neurotrophic effects both in vitro and in vivo, and its phase II study in Japan and two kinds of phase III studies ongoing in the United States, Canada and Europe. We also introduced the clinical guideline for practice and care of ALS patients proposed by American Academy of Neurology, expecting to establish clinical guideline to be applicable to Japanese cases.

  6. How children can be respected as 'ends' yet still be used as subjects in non-therapeutic research.

    Redmon, R B

    1986-06-01

    The question of whether or not children may be used as subjects in non-therapeutic research projects has generated a great deal of debate and received answers varying from 'no, never' to 'yes, if societal interests are served'. It has been claimed that a Kantian, deontological ethics would necessarily rule out such research, since valid consent would be impossible. The present paper gives a deontological argument for allowing children to be subjects in certain types of research.

  7. How children can be respected as 'ends' yet still be used as subjects in non-therapeutic research.

    Redmon, R B

    1986-01-01

    The question of whether or not children may be used as subjects in non-therapeutic research projects has generated a great deal of debate and received answers varying from 'no, never' to 'yes, if societal interests are served'. It has been claimed that a Kantian, deontological ethics would necessarily rule out such research, since valid consent would be impossible. The present paper gives a deontological argument for allowing children to be subjects in certain types of research.

  8. How children can be respected as 'ends' yet still be used as subjects in non-therapeutic research.

    Redmon, R B

    1986-01-01

    The question of whether or not children may be used as subjects in non-therapeutic research projects has generated a great deal of debate and received answers varying from 'no, never' to 'yes, if societal interests are served'. It has been claimed that a Kantian, deontological ethics would necessarily rule out such research, since valid consent would be impossible. The present paper gives a deontological argument for allowing children to be subjects in certain types of research. PMID:3735361

  9. Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model.

    Morrison, Juliet; Rathore, Abhay P S; Mantri, Chinmay K; Aman, Siti A B; Nishida, Andrew; St John, Ashley L

    2017-09-15

    There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8 + T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease. IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs

  10. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

    2013-02-18

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  11. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

    2013-01-01

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm 3 ) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  12. Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity

    Kato, Shingo; Berzofsky, Jay A.; Terabe, Masaki

    2018-01-01

    Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies. PMID:29520281

  13. Improvement in therapeutic ability of wharton's jelly derived mesenchymal stem cells with vitamin e in breast cancer

    Wajid, N.; Azam, M.; Khalid, S.; Qazi, M.H.

    2017-01-01

    To assess the role of Vitamin E to improve the survival of Wharton's jelly derived mesenchymal stem cells (WJMSCs) in breast cancer conditions. Study Design:An experimental study. Place and Duration of Study:Centre for Research in Molecular Medicine, University of Lahore, from November 2016 to March 2017. Methodology:WJMSCs were obtained from umbilical cord tissue with enzyme digestion method. Isolated cells were characterized for CD90 and CD45 by immunocytochemistry. Pretreatment and conjugation therapies of vitamin E in 50mM and 100mM concentration were used on WJMSCs and breast cancer plasma was provided to mimic the cancer conditions, while WJMSCs provided with normal plasma were considered control. Cells' viability, proliferation and death were evaluated by crystal violet staining, MTT assay and LDH assay, respectively. Oxidative stress was observed by activity of anti-oxidant enzymes (GSH, catalase, SOD) and reactive oxygen species (MDA). Results:The isolated cells expressed mesenchymal stem cells marker CD90 and lacked hematopoietic marker CD45. Vitamin E improved the viability and proliferation of WJMSCs in normal plasma, in conjugation with breast cancer plasma and in pretreatment groups but conjugation group showed even better results with concentration of 100mM as compared to the pretreatment group and opposite was observed for LDH assay for cells death analysis. Vitamin E also reduced the oxidative stress in 100mM more pronounced in conjugation group as compared to pretreatment group while left no harmful effects on WJMSCs in normal plasma. Conclusion:Vitamin E conjugation with breast cancer conditions significantly improved growth of WJMSCs. Thus vitamin E treated WJMSCs are better therapeutic options for breast cancer. (author)

  14. A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease.

    Westbroek, Wendy; Nguyen, Matthew; Siebert, Marina; Lindstrom, Taylor; Burnett, Robert A; Aflaki, Elma; Jung, Olive; Tamargo, Rafael; Rodriguez-Gil, Jorge L; Acosta, Walter; Hendrix, An; Behre, Bahafta; Tayebi, Nahid; Fujiwara, Hideji; Sidhu, Rohini; Renvoise, Benoit; Ginns, Edward I; Dutra, Amalia; Pak, Evgenia; Cramer, Carole; Ory, Daniel S; Pavan, William J; Sidransky, Ellen

    2016-07-01

    Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1 Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1 To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba(-/-) mice and the control littermate (gba(+/+)) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba(-/-) neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba(+/+) neurons. This null allele gba(-/-) mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies. © 2016. Published by The Company of Biologists Ltd.

  15. A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

    Wendy Westbroek

    2016-07-01

    Full Text Available Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+ by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies.

  16. Identifying and engineering promoters for high level and sustainable therapeutic recombinant protein production in cultured mammalian cells.

    Ho, Steven C L; Yang, Yuansheng

    2014-08-01

    Promoters are essential on plasmid vectors to initiate transcription of the transgenes when generating therapeutic recombinant proteins expressing mammalian cell lines. High and sustained levels of gene expression are desired during therapeutic protein production while gene expression is useful for cell engineering. As many finely controlled promoters exhibit cell and product specificity, new promoters need to be identified, optimized and carefully evaluated before use. Suitable promoters can be identified using techniques ranging from simple molecular biology methods to modern high-throughput omics screenings. Promoter engineering is often required after identification to either obtain high and sustained expression or to provide a wider range of gene expression. This review discusses some of the available methods to identify and engineer promoters for therapeutic recombinant protein expression in mammalian cells.

  17. Live-Cell Imaging of Protease Activity: Assays to Screen Therapeutic Approaches.

    Chalasani, Anita; Ji, Kyungmin; Sameni, Mansoureh; Mazumder, Samia H; Xu, Yong; Moin, Kamiar; Sloane, Bonnie F

    2017-01-01

    Methodologies to image and quantify the activity of proteolytic enzymes have been developed in an effort to identify protease-related druggable pathways that are involved in malignant progression of cancer. Our laboratory has pioneered techniques for functional live-cell imaging of protease activity in pathomimetic avatars for breast cancer. We analyze proteolysis in the context of proliferation and formation of structures by tumor cells in 3-D cultures over time (4D). In order to recapitulate the cellular composition and architecture of tumors in the pathomimetic avatars, we include other tumor-associated cells (e.g., fibroblasts, myoepithelial cells, microvascular endothelial cells). We also model noncellular aspects of the tumor microenvironment such as acidic pericellular pH. Use of pathomimetic avatars in concert with various types of imaging probes has allowed us to image, quantify, and follow the dynamics of proteolysis in the tumor microenvironment and to test interventions that impact directly or indirectly on proteolytic pathways. To facilitate use of the pathomimetic avatars for screening of therapeutic modalities, we have designed and fabricated custom 3D culture chambers with multiple wells that are either individual or connected by a channel to allow cells to migrate between wells. Optical glass microscope slides underneath an acrylic plate allow the cultures to be imaged with an inverted microscope. Fluid ports in the acrylic plate are at a level above the 3D cultures to allow introduction of culture media and test agents such as drugs into the wells and the harvesting of media conditioned by the cultures for immunochemical and biochemical analyses. We are using the pathomimetic avatars to identify druggable pathways, screen drug and natural product libraries and accelerate entry of validated drugs or natural products into clinical trials.

  18. Onconase responsive genes in human mesothelioma cells: implications for an RNA damaging therapeutic agent

    Altomare, Deborah A; Rybak, Susanna M; Pei, Jianming; Maizel, Jacob V; Cheung, Mitchell; Testa, Joseph R; Shogen, Kuslima

    2010-01-01

    Onconase represents a new class of RNA-damaging drugs. Mechanistically, Onconase is thought to internalize, where it degrades intracellular RNAs such as tRNA and double-stranded RNA, and thereby suppresses protein synthesis. However, there may be additional or alternative mechanism(s) of action. In this study, microarray analysis was used to compare gene expression profiles in untreated human malignant mesothelioma (MM) cell lines and cells exposed to 5 μg/ml Onconase for 24 h. A total of 155 genes were found to be regulated by Onconase that were common to both epithelial and biphasic MM cell lines. Some of these genes are known to significantly affect apoptosis (IL-24, TNFAIP3), transcription (ATF3, DDIT3, MAFF, HDAC9, SNAPC1) or inflammation and the immune response (IL-6, COX-2). RT-PCR analysis of selected up- or down-regulated genes treated with varying doses and times of Onconase generally confirmed the expression array findings in four MM cell lines. Onconase treatment consistently resulted in up-regulation of IL-24, previously shown to have tumor suppressive activity, as well as ATF3 and IL-6. Induction of ATF3 and the pro-apoptotic factor IL-24 by Onconase was highest in the two most responsive MM cell lines, as defined by DNA fragmentation analysis. In addition to apoptosis, gene ontology analysis indicated that pathways impacted by Onconase include MAPK signaling, cytokine-cytokine-receptor interactions, and Jak-STAT signaling. These results provide a broad picture of gene activity after treatment with a drug that targets small non-coding RNAs and contribute to our overall understanding of MM cell response to Onconase as a therapeutic strategy. The findings provide insights regarding mechanisms that may contribute to the efficacy of this novel drug in clinical trials of MM patients who have failed first line chemotherapy or radiation treatment

  19. Identification of cell surface targets for HIV-1 therapeutics using genetic screens

    Dunn, Stephen J.; Khan, Imran H.; Chan, Ursula A.; Scearce, Robin L.; Melara, Claudia L.; Paul, Amber M.; Sharma, Vikram; Bih, Fong-Yih; Holzmayer, Tanya A.; Luciw, Paul A.; Abo, Arie

    2004-01-01

    Human immunodeficiency virus (HIV) drugs designed to interfere with obligatory utilization of certain host cell factors by virus are less likely to encounter development of resistant strains than drugs directed against viral components. Several cellular genes required for productive infection by HIV were identified by the use of genetic suppressor element (GSE) technology as potential targets for anti-HIV drug development. Fragmented cDNA libraries from various pools of human peripheral blood mononuclear cells (PBMC) were expressed in vitro in human immunodeficiency virus type 1 (HIV-1)-susceptible cell lines and subjected to genetic screens to identify GSEs that interfered with viral replication. After three rounds of selection, more than 15 000 GSEs were sequenced, and the cognate genes were identified. The GSEs that inhibited the virus were derived from a diverse set of genes including cell surface receptors, cytokines, signaling proteins, transcription factors, as well as genes with unknown function. Approximately 2.5% of the identified genes were previously shown to play a role in the HIV-1 life cycle; this finding supports the biological relevance of the assay. GSEs were derived from the following 12 cell surface proteins: CXCR4, CCR4, CCR7, CD11C, CD44, CD47, CD68, CD69, CD74, CSF3R, GABBR1, and TNFR2. Requirement of some of these genes for viral infection was also investigated by using RNA interference (RNAi) technology; accordingly, 10 genes were implicated in early events of the viral life cycle, before viral DNA synthesis. Thus, these cell surface proteins represent novel targets for the development of therapeutics against HIV-1 infection and AIDS

  20. Preclinical evaluation of NF-kappa B-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination

    Gerer, Kerstin F.; Erdmann, Michael; Hadrup, Sine Reker

    2017-01-01

    Background: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor ...

  1. Multidisciplinary perspectives for Alzheimer's and Parkinson's diseases: hydrogels for protein delivery and cell-based drug delivery as therapeutic strategies.

    Giordano, Carmen; Albani, Diego; Gloria, Antonio; Tunesi, Marta; Batelli, Sara; Russo, Teresa; Forloni, Gianluigi; Ambrosio, Luigi; Cigada, Alberto

    2009-12-01

    This review presents two intriguing multidisciplinary strategies that might make the difference in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The first proposed strategy is based on the controlled delivery of recombinant proteins known to play a key role in these neurodegenerative disorders that are released in situ by optimized polymer-based systems. The second strategy is the use of engineered cells, encapsulated and delivered in situ by suitable polymer-based systems, that act as drug reservoirs and allow the delivery of selected molecules to be used in the treatment of Alzheimer's and Parkinson's diseases. In both these scenarios, the design and development of optimized polymer-based drug delivery and cell housing systems for central nervous system applications represent a key requirement. Materials science provides suitable hydrogel-based tools to be optimized together with suitably designed recombinant proteins or drug delivering-cells that, once in situ, can provide an effective treatment for these neurodegenerative disorders. In this scenario, only interdisciplinary research that fully integrates biology, biochemistry, medicine and materials science can provide a springboard for the development of suitable therapeutic tools, not only for the treatment of Alzheimer's and Parkinson's diseases but also, prospectively, for a wide range of severe neurodegenerative disorders.

  2. Dendritic Cells Primed with Paracoccidioides brasiliensis Peptide P10 Are Therapeutic in Immunosuppressed Mice with Paracoccidioidomycosis

    Leandro B. R. Silva

    2017-06-01

    Full Text Available Paracoccidioidomycosis (PCM is an endemic systemic mycosis in Latin America, with the highest prevalence in Brazil, Colombia, and Venezuela. Fungi of the Paracoccidioides genus are etiologic agents of the disease. The 15 amino acid peptide P10 is derived from gp43, the main diagnostic antigen of Paracoccidioides brasiliensis. We previously reported that P10-pulsed dendritic cells (DCs induce a protective response against P. brasiliensis. Presently, dexamethasone-treated BALB/c mice were intratracheally infected with P. brasiliensis Pb18 to establish the therapeutic efficacy of P10-pulsed DCs. Immunosuppressed and infected animals that received DCs had a reduction in their fungal burden, and this result was most pronounced in mice receiving DCs primed with P10. The efficacy of therapeutic DCs was significantly augmented by concomitant treatment with trimethoprim-sulfamethoxazole. Additionally, primed-DCs with or without the antifungal drug induced a beneficial Th1-biased immune response and significantly reduced tissue damage. In conclusion, these studies with immunocompromised mice demonstrate that P10-pulsed DCs with or without concomitant antifungal drugs are potently effective in combating invasive PCM. These findings support further translational studies to validate the use of P10-primed DCs for PCM in immunocompetent and immunosuppressed hosts.

  3. Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease.

    Dinca, Ana; Chien, Wei-Ming; Chin, Michael T

    2016-02-22

    Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects.

  4. Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives

    Tomokazu Ohishi

    2015-12-01

    Full Text Available Bladder cancer (BC, the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC and non-muscle-invasive bladder cancer (NMIBC. MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs, which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory.

  5. Extravascular red blood cells and hemoglobin promote tumor growth and therapeutic resistance as endogenous danger signals.

    Yin, Tao; He, Sisi; Liu, Xiaoling; Jiang, Wei; Ye, Tinghong; Lin, Ziqiang; Sang, Yaxiong; Su, Chao; Wan, Yang; Shen, Guobo; Ma, Xuelei; Yu, Min; Guo, Fuchun; Liu, Yanyang; Li, Ling; Hu, Qiancheng; Wang, Yongsheng; Wei, Yuquan

    2015-01-01

    Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-κB pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1β release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance. Copyright © 2014 by The American Association of Immunologists, Inc.

  6. Hematopoietic stem cells transplant in patients with common variable immunodeficiency. Is a therapeutic option?

    Julio César Cambray-Gutiérrez

    2017-02-01

    Full Text Available Background: Patients with common variable immunodeficiency show higher incidence of sinopulmonary and gastrointestinal infections, as well as lymphoproliferative and autoimmune diseases. The treatment of choice is replacement therapy with human gamma-globulin. Hematopoietic stem cell transplantation is a non-conventional therapeutic modality. Clinical case: Twenty-six-year old woman with no family or hereditary history of primary immune deficiencies or consanguinity, with repeated episodes of otitis, sinusitis, gastroenteritis and bronchitis since childhood. At adolescence, she was diagnosed with common variable immunodeficiency; she was prescribed intravenous gamma-globulin, broad-spectrum antimicrobials and macrolides. At 22 years of age, she underwent hematopoietic stem cell transplantation owing to continued severe infections. At 4 months, post-transplantation she was diagnosed with hypothyroidism and ovarian insufficiency. During the following 3 years, she had no infections, but at 25 years of age she had immune thrombocytopenic purpura diagnosed, which persists together with Raynaud’s disease and upper respiratory tract persistent infections. At the moment of this report she is being treated with intravenous gamma-globulin and receiving prophylaxis with clarithromycin, without steroids or danazol. Conclusions: Given the high rate of morbidity and mortality associated and immune reconstitution failure, hematopoietic stem cell transplantation should be carefully evaluated in patients with treatment-unresponsive infections or lymphoproliferative disorders.

  7. Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis.

    Dang, Shipeng; Xu, Huanbai; Xu, Congfeng; Cai, Wei; Li, Qian; Cheng, Yiji; Jin, Min; Wang, Ru-Xing; Peng, Yongde; Zhang, Yi; Wu, Changping; He, Xiaozhou; Wan, Bing; Zhang, Yanyun

    2014-07-01

    Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.

  8. Magnetic catechin-dextran conjugate as targeted therapeutic for pancreatic tumour cells.

    Vittorio, Orazio; Voliani, Valerio; Faraci, Paolo; Karmakar, Biswajit; Iemma, Francesca; Hampel, Silke; Kavallaris, Maria; Cirillo, Giuseppe

    2014-06-01

    Catechin-dextran conjugates have recently attracted a lot of attention due to their anticancer activity against a range of cancer cells. Magnetic nanoparticles have the ability to concentrate therapeutically important drugs due to their magnetic-spatial control and provide opportunities for targeted drug delivery. Enhancement of the anticancer efficiency of catechin-dextran conjugate by functionalisation with magnetic iron oxide nanoparticles. Modification of the coating shell of commercial magnetic nanoparticles (Endorem) composed of dextran with the catechin-dextran conjugate. Catechin-dextran conjugated with Endorem (Endo-Cat) increased the intracellular concentration of the drug and it induced apoptosis in 98% of pancreatic tumour cells placed under magnetic field. The conjugation of catechin-dextran with Endorem enhances the anticancer activity of this drug and provides a new strategy for targeted drug delivery on tumour cells driven by magnetic field. The ability to spatially control the delivery of the catechin-dextran by magnetic field makes it a promising agent for further application in cancer therapy.

  9. [Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

    Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

    2015-01-01

    Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  10. Therapeutic Vaccination Using Cationic Liposome-Adjuvanted HIV Type 1 Peptides Representing HLA-Supertype-Restricted Subdominant T Cell Epitopes

    Román, Victor Raúl Gómez; Jensen, Kristoffer Jarlov; Jensen, Sanne Skov

    2013-01-01

    We have designed a therapeutic HIV-1 vaccine concept based on peptides together with the adjuvant CAF01. Peptides represented 15 HLA-supertype-restricted subdominant and conserved CD8 T cell epitopes and three CD4 T-helper cell epitopes. In this phase I clinical trial, safety and immunogenicity...... were assessed in untreated HIV-1-infected individuals in Guinea-Bissau, West Africa. Twenty-three HIV-1-infected individuals were randomized to receive placebo (n=5) or vaccine (n=18). Safety was appraised by clinical follow-up combined with monitoring of biochemistry, hematology, CD4 T cell counts......, and HIV-1 viral loads. T cell immunogenicity was monitored longitudinally by interferon (IFN)-γ ELISpot. New vaccine-specific T cell responses were induced in 6/14 vaccinees for whom ELISpot data were valid. CD4 T cell counts and viral loads were stable. The study shows that therapeutic immunization...

  11. Antecedents and Consequences of Therapeutic Communication in Iranian Nursing Students: A Qualitative Research

    Mahbobeh Abdolrahimi

    2017-01-01

    Full Text Available In recent years, particular attention has been paid to nursing students’ therapeutic communication (TC with patients, due to a strong emphasis on patient-centered education in the Iranian healthcare reform. However, various studies have highlighted the poor communication of future nurses. Therefore, researchers have used qualitative methodology to shed light on the antecedents and consequences of nursing students’ TC and promote it. We carried out a conventional content analysis using semistructured interviews with a purposefully selected sample of 18 participants, including nursing instructors, students, and patients in hospitals affiliated to Tehran University of Medical Sciences. “Communication readiness,” “predisposing factors,” and “continuity of care” were identified as the three major themes. “Communication readiness” consisted of “physical readiness,” “academic readiness,” and “developmental readiness.” “Predisposing factors” included “contextual factors” and “educational condition.” “Continuity of care” included “patient satisfaction” and “improving nursing student’s motivation to communicate with patients.” “Communication readiness” and “predisposing factors” constitute the antecedents of nursing student’s TC with patients, and “continuity of care” is considered as its consequence. More attention needs to be paid by the regulators to TC instruction in both theoretical and clinical educational curriculum. Furthermore, all nurses must be informed about the importance of TC in promoting patient outcomes and quality of care.

  12. Stem Cell Research: Unlocking the Mystery of Disease

    ... Home Current Issue Past Issues From the Director: Stem Cell Research: Unlocking the Mystery of Disease Past Issues / ... Zerhouni, NIH Director, described the need for expanding stem cell research. Recently, he spoke about stem cell research ...

  13. Translational findings from cardiovascular stem cell research.

    Mazhari, Ramesh; Hare, Joshua M

    2012-01-01

    The possibility of using stem cells to regenerate damaged myocardium has been actively investigated since the late 1990s. Consistent with the traditional view that the heart is a "postmitotic" organ that possesses minimal capacity for self-repair, much of the preclinical and clinical work has focused exclusively on introducing stem cells into the heart, with the hope of differentiation of these cells into functioning cardiomyocytes. This approach is ongoing and retains promise but to date has yielded inconsistent successes. More recently, it has become widely appreciated that the heart possesses endogenous repair mechanisms that, if adequately stimulated, might regenerate damaged cardiac tissue from in situ cardiac stem cells. Accordingly, much recent work has focused on engaging and enhancing endogenous cardiac repair mechanisms. This article reviews the literature on stem cell-based myocardial regeneration, placing emphasis on the mutually enriching interaction between basic and clinical research. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.

    Layek, Buddhadev; Sadhukha, Tanmoy; Panyam, Jayanth; Prabha, Swayam

    2018-06-01

    Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUC lung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196-206. ©2018 AACR . ©2018 American Association for Cancer Research.

  15. Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications.

    Abou-Antoun, Tamara J; Hale, James S; Lathia, Justin D; Dombrowski, Stephen M

    2017-04-01

    Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.

  16. Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells.

    Kumar, S; Peng, X; Daley, J; Yang, L; Shen, J; Nguyen, N; Bae, G; Niu, H; Peng, Y; Hsieh, H-J; Wang, L; Rao, C; Stephan, C C; Sung, P; Ira, G; Peng, G

    2017-04-17

    Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity. Therefore, the key link between HR repair and cellular tolerance to replication-associated DSBs provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress. DNA2 nuclease is an evolutionarily conserved essential enzyme in replication and HR repair. Here we demonstrate that DNA2 is overexpressed in pancreatic cancers, one of the deadliest and more aggressive forms of human cancers, where mutations in the KRAS are present in 90-95% of cases. In addition, depletion of DNA2 significantly reduces pancreatic cancer cell survival and xenograft tumor growth, suggesting the therapeutic potential of DNA2 inhibition. Finally, we develop a robust high-throughput biochemistry assay to screen for inhibitors of the DNA2 nuclease activity. The top inhibitors were shown to be efficacious against both yeast Dna2 and human DNA2. Treatment of cancer cells with DNA2 inhibitors recapitulates phenotypes observed upon DNA2 depletion, including decreased DNA double strand break end resection and attenuation of HR repair. Similar to genetic ablation of DNA2, chemical inhibition of DNA2 selectively attenuates the growth of various cancer cells with oncogene-induced replication stress. Taken together, our findings open a new avenue to develop a new class of anticancer drugs by targeting druggable nuclease DNA2. We propose DNA2 inhibition as new strategy in cancer therapy by targeting

  17. Industrial Production of Therapeutic Proteins: Cell Lines, Cell Culture, and Purification

    Zhu, Marie M.; Mollet, Michael; Hubert, Rene S.

    The biotechnology and pharmaceutical industries have seen a recent surge in the development of biological drug products manufactured from engineered mammalian cell lines. Since the hugely successful launch of human tissue plasminogen activator in 1987 and erythropoietin in 1988, the biopharmaceutical market has grown immensely. Global sales in 2003 exceeded US 30 billion.1 Currently, a total of 108 biotherapeutics are approved and available to patients (Table 32.1). In addition, 324 medically related, biotechnology-derived medicines for nearly 150 diseases are in clinical trials or under review by the U.S. Food and Drug Administration.2 These biopharmaceutical candidates promise to bring more and better treatments to patients. Compared to small molecule drugs, biotherapeutics show exquisite specificity with fewer off-target interactions and improved safety profiles.

  18. Therapeutic Change in Group Therapy For Interpersonal Trauma: A Relational Framework for Research and Clinical Practice.

    Chouliara, Zoë; Karatzias, Thanos; Gullone, Angela; Ferguson, Sandra; Cosgrove, Katie; Burke Draucker, Claire

    2017-04-01

    Our understanding of therapeutic change processes in group therapy for complex interpersonal trauma has been limited. The present study aimed at addressing this gap by developing a framework of therapeutic change in this field from a survivor and therapist perspective. This is a qualitative study, which utilized semistructured individual interviews. Transcripts were analyzed using interpretative phenomenological analysis (IPA) to identify recurrent themes. A final sample of n = 16 patients and n = 5 facilitators completed the interview. Main change processes identified by survivors were as follows: self versus others, trust versus threat, confrontation versus avoidance, and "patching up" versus true healing. Therapeutic processes identified by therapist facilitators included managing group dynamics, unpredictability and uncertainty, and process versus content. The proposed framework explains therapeutic change in group therapy in relational terms, that is, therapeutic dissonance, the dynamic interaction of self and experience as well as building empathic trusting relations. The importance of managing dissonance to aid personally meaningful recovery was highlighted. These findings have implications for the usefulness of relational and person-centered approaches to clinical practice in the area of interpersonal and complex trauma, especially in the early identification, prevention, and management of dropouts.

  19. Stem cell research: applicability in dentistry.

    Mathur, Shivani; Chopra, Rahul; Pandit, I K; Srivastava, Nikhil; Gugnani, Neeraj

    2014-01-01

    In the face of extraordinary advances in the prevention, diagnosis, and treatment of human diseases, the inability of most tissues and organs to repair and regenerate after damage is a problem that needs to be solved. Stem cell research is being pursued in the hope of achieving major medical breakthroughs. Scientists are striving to create therapies that rebuild or replace damaged cells with tissues grown from stem cells that will offer hope to people suffering from various ailments. Regeneration of damaged periodontal tissue, bone, pulp, and dentin is a problem that dentists face today. Stem cells present in dental pulp, periodontal ligament, and alveolar bone marrow have the potential to repair and regenerate teeth and periodontal structures. These stem cells can be harvested from dental pulp, periodontal ligament, and/or alveolar bone marrow; expanded; embedded in an appropriate scaffold; and transplanted back into a defect to regenerate bone and tooth structures. These cells have the potential to regenerate dentin, periodontal ligament, and cementum and can also be used to restore bone defects. The kind of scaffold, the source of cells, the type of in vitro culturing, and the type of surgical procedure to be used all require careful consideration. The endeavor is clearly multidisciplinary in nature, and the practicing dental surgeon has a critical role in it. Playing this role in the most effective way requires awareness of the huge potential associated with the use of stem cells in a clinical setting, as well as a proper understanding of the related problems.

  20. Depletion of Treg cells augments the therapeutic effect of cancer vaccines

    Bubeník, Jan

    2006-01-01

    Roč. 52, č. 6 (2006), s. 202-204 ISSN 0015-5500 Grant - others:EU-FP6-Clinigene(XE) 018933 Institutional research plan: CEZ:AV0Z50520514 Keywords : Treg cells * cancer vaccines Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.387, year: 2006

  1. Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

    Aparna Jayachandran

    2016-08-01

    Full Text Available Abstract Hepatocellular carcinoma (HCC remains one of the most common and lethal malignancies worldwide despite the development of various therapeutic strategies. A better understanding of the mechanisms responsible for HCC initiation and progression is essential for the development of more effective therapies. The cancer stem cell (CSC model has provided new insights into the development and progression of HCC. CSCs are specialized tumor cells that are capable of self-renewal and have long-term repopulation potential. As they are important mediators of tumor proliferation, invasion, metastasis, therapy resistance, and cancer relapse, the selective targeting of this crucial population of cells has the potential to improve HCC patient outcomes and survival. In recent years, the role of epithelial-to-mesenchymal transition (EMT in the advancement of HCC has gained increasing attention. This multi-step reprograming process resulting in a phenotype switch from an epithelial to a mesenchymal cellular state has been closely associated with the acquisition of stem cell-like attributes in tumors. Moreover, CSC mediates tumor metastasis by maintaining plasticity to transition between epithelial or mesenchymal states. Therefore, understanding the molecular mechanisms of the reprograming switches that determine the progression through EMT and generation of CSC is essential for developing clinically relevant drug targets. This review provides an overview of the proposed roles of CSC in HCC and discusses recent results supporting the emerging role of EMT in facilitating hepatic CSC plasticity. In particular, we discuss how these important new insights may facilitate rational development of combining CSC- and EMT-targeted therapies in the future.

  2. Efficacy of a therapeutic vaccine using mutated β-amyloid sensitized dendritic cells in Alzheimer's mice.

    Luo, Zhongqiu; Li, Jialin; Nabar, Neel R; Lin, Xiaoyang; Bai, Ge; Cai, Jianfeng; Zhou, Shu-Feng; Cao, Chuanhai; Wang, Jinhuan

    2012-09-01

    Despite FDA suspension of Elan's AN-1792 amyloid beta (Aβ) vaccine in phase IIb clinical trials, the implications of this study are the guiding principles for contemporary anti-Aβ immunotherapy against Alzheimer's disease (AD). AN-1792 showed promising results with regards to Aβ clearance and cognitive function improvement, but also exhibited an increased risk of Th1 mediated meningoencephalitis. As such, vaccine development has continued with an emphasis on eliciting a notable anti-Aβ antibody titer, while avoiding the unwanted Th1 pro-inflammatory response. Previously, we published the first report of an Aβ sensitized dendritic cell vaccine as a therapeutic treatment for AD in BALB/c mice. Our vaccine elicited an anti-Aβ titer, with indications that a Th1 response was not present. This study is the first to investigate the efficacy and safety of our dendritic cell vaccine for the prevention of AD in transgenic mouse models (PDAPP) for AD. We also used Immunohistochemistry to characterize the involvement of LXR, ABCA1, and CD45 in order to gain insight into the potential mechanisms through which this vaccine may provide benefit. The results indicate that (1) the use of mutant Aβ1-42 sensitized dendritic cell vaccine results in durable antibody production, (2) the vaccine provides significant benefits with regards to cognitive function without the global (Th1) inflammation seen in prior Aβ vaccines, (3) histological studies showed an overall decrease in Aβ burden, with an increase in LXR, ABCA1, and CD45, and (4) the beneficial results of our DC vaccine may be due to the LXR/ABCA1 pathway. In the future, mutant Aβ sensitized dendritic cell vaccines could be an efficacious and safe method for the prevention or treatment of AD that circumvents problems associated with traditional anti-Aβ vaccines.

  3. Chromatin Configuration Determines Cell Responses to Hormone Stimuli | Center for Cancer Research

    Ever since selective gene expression was established as the central driver of cell behavior, researchers have been working to understand the forces that control gene transcription. Aberrant gene expression can cause or promote many diseases, including cancer, and alterations in gene expression are the goal of many therapeutic agents. Recent work has focused on the potential

  4. Research progresses in treating diabetic foot with autologous stem cell transplantation

    Qin Hanlin; Gao Bin

    2010-01-01

    Because the distal arteries of lower extremities become narrowed or even occluded in diabetic foot, the clinical therapeutic results for diabetic foot have been unsatisfactory so far. Autologous stem cell transplantation that has emerged in recent years is a new, safe and effective therapy for diabetic foot, which achieves its excellent clinical success in restoring the blood supply of ischemic limb by way of therapeutic angiogenesis. Now autologous stem cell transplantation has become one of the hot points in medical research both at home and abroad, moreover, it has brought a new hope of cure to the patients with diabetic foot. (authors)

  5. Therapeutic Alliance in Telephone-Administered Cognitive-Behavioral Therapy for Hematopoietic Stem Cell Transplant Survivors

    Applebaum, Allison J.; DuHamel, Katherine N.; Winkel, Gary; Rini, Christine; Greene, Paul B.; Mosher, Catherine E.; Redd, William H.

    2012-01-01

    Objective: A strong therapeutic alliance has been found to predict psychotherapeutic treatment success across a variety of therapeutic modalities and patient populations. However, only a few studies have examined therapeutic alliance as a predictor of psychotherapy outcome among cancer survivors, and none have examined this relation in…

  6. What Undergraduates Misunderstand about Stem Cell Research

    Halverson, Kristy Lynn; Freyermuth, Sharyn K.; Siegel, Marcelle A.; Clark, Catharine G.

    2010-01-01

    As biotechnology-related scientific advances, such as stem cell research (SCR), are increasingly permeating the popular media, it has become ever more important to understand students' ideas about this issue. Very few studies have investigated learners' ideas about biotechnology. Our study was designed to understand the types of alternative…

  7. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

    Diez Cabezas, B.

    2015-01-01

    targeting efficiency, due to the toxicity associated with the nucleofection of cells treated with these nanoparticles. In our next step, we moved from healthy donor HSCs to FA hematopoietic cells. Using a therapeutic donor vector carrying the FANCA gene, we demonstrated that gene targeting can correct the phenotype in a FA-A LCL. This was deduced from the restoration of FANCD2 foci formation and the reversion of the sensitivity of FA-A cells to interstrand cross linkers, such as mitomycin C (MMC). To improve the gene targeting efficiency in FA-A hematopoietic cells, we also investigated the effects mediated by the transient inhibition of anti-recombinase PARI. Although the inhibition of PARI increased RAD51 foci, no significant increase of homology directed repair efficiency was observed. In a final set of experiments we demonstrated that our gene targeting approach has also taken place in hematopoietic progenitor cells from FA-A patients, leading to a partial reversion in their hyper-sensitivity to MMC. Our study demonstrates for the first time that gene targeting in the AAVS1 safe harbor locus is feasible in hematopoietic cells from Fanconi anemia-A patients, opening up new perspectives for the future gene therapy of this and other monogenic diseases of the hematopoietic system.(Author)

  8. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

    Diez Cabezas, B.

    2015-07-01

    targeting efficiency, due to the toxicity associated with the nucleofection of cells treated with these nanoparticles. In our next step, we moved from healthy donor HSCs to FA hematopoietic cells. Using a therapeutic donor vector carrying the FANCA gene, we demonstrated that gene targeting can correct the phenotype in a FA-A LCL. This was deduced from the restoration of FANCD2 foci formation and the reversion of the sensitivity of FA-A cells to interstrand cross linkers, such as mitomycin C (MMC). To improve the gene targeting efficiency in FA-A hematopoietic cells, we also investigated the effects mediated by the transient inhibition of anti-recombinase PARI. Although the inhibition of PARI increased RAD51 foci, no significant increase of homology directed repair efficiency was observed. In a final set of experiments we demonstrated that our gene targeting approach has also taken place in hematopoietic progenitor cells from FA-A patients, leading to a partial reversion in their hyper-sensitivity to MMC. Our study demonstrates for the first time that gene targeting in the AAVS1 safe harbor locus is feasible in hematopoietic cells from Fanconi anemia-A patients, opening up new perspectives for the future gene therapy of this and other monogenic diseases of the hematopoietic system.(Author)

  9. Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma

    Paola Savoia

    2015-09-01

    Full Text Available Basal cell carcinoma (BCC is the most common cancer in individuals with fair skin type (I–II and steadily increasing in incidence (70% of skin malignancy. It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%–0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC.

  10. Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma

    Savoia, Paola; Deboli, Tommaso; Previgliano, Alberto; Broganelli, Paolo

    2015-01-01

    Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I–II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%–0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC. PMID:26426005

  11. Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models

    Soledad eMac Keon

    2015-05-01

    Full Text Available Dendritic cells (DCs play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel T there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts towards an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment.

  12. Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

    Anja Geiselhart

    2012-01-01

    Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.

  13. Gene Editing and CRISPR Therapeutics: Strategies Taught by Cell and Gene Therapy.

    Ramirez, Juan C

    2017-01-01

    A few years ago, we assisted in the demonstration for the first time of the revolutionary idea of a type of adaptive-immune system in the bacteria kingdom. This system, named CRISPR, and variants engineered in the lab, have been demonstrated as functional with extremely high frequency and fidelity in almost all eukaryotic cells studied to date. The capabilities of this RNA-guided nuclease have added to the interest that was announced with the advent of previous technologies for genome editing tools, such as ZFN and TALEN. The capabilities exhibited by these gene editors, opens up a novel scenario that indicates the promise of a next-generation medicine based on precision and personalized objectives, mostly due to the change in the paradigm regarding gene-surgery. This has certainly attracted, like never before, the attention of the biotech business and investor community. This chapter offers a brief overview of some of the factors that have contributed to a rapid entry into the biotech and pharmaceutical company's pipeline, focusing on how cell and gene therapies (CGT), collectively known as advanced therapies, have become the driving forces toward the therapeutic uses of gene editing technology. The sum of all those efforts for more than 30years has contributed to the new paradigm of considering genes as medicines. Copyright © 2017. Published by Elsevier Inc.

  14. The Role of Bioactive Lipids in Stem Cell Mobilization and Homing: Novel Therapeutics for Myocardial Ischemia

    Yuri M. Klyachkin

    2014-01-01

    Full Text Available Despite significant advances in medical therapy and interventional strategies, the prognosis of millions of patients with acute myocardial infarction (AMI and ischemic heart disease (IHD remains poor. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infarcted myocardium. It is now well established that cardiomyocytes undergo continuous renewal, with contribution from bone marrow (BM-derived stem/progenitor cells (SPCs. This phenomenon is upregulated during AMI by initiating multiple innate reparatory mechanisms through which BMSPCs are mobilized towards the ischemic myocardium and contribute to myocardial regeneration. While a role for the SDF-1/CXCR4 axis in retention of BMSPCs in bone marrow is undisputed, its exclusive role in their mobilization and homing to a highly proteolytic microenvironment, such as the ischemic/infarcted myocardium, is currently being challenged. Recent evidence suggests a pivotal role for bioactive lipids in the mobilization of BMSPCs at the early stages following AMI and their homing towards ischemic myocardium. This review highlights the recent advances in our understanding of the mechanisms of stem cell mobilization, provides newer evidence implicating bioactive lipids in BMSPC mobilization and differentiation, and discusses their potential as therapeutic agents in the treatment of IHD.

  15. Cell Science and Cell Biology Research at MSFC: Summary

    2003-01-01

    The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

  16. The Paradox of Equipoise: The Principle That Drives and Limits Therapeutic Discoveries in Clinical Research

    Djulbegovic, Benjamin

    2009-01-01

    Background Progress in clinical medicine relies on the willingness of patients to take part in experimental clinical trials, particularly randomized controlled trials (RCTs). Before agreeing to enroll in clinical trials, patients require guarantees that they will not knowingly be harmed and will have the best possible chances of receiving the most favorable treatments. This guarantee is provided by the acknowledgment of uncertainty (equipoise), which removes ethical dilemmas and makes it easier for patients to enroll in clinical trials. Methods Since the design of clinical trials is mostly affected by clinical equipoise, the “clinical equipoise hypothesis” has been postulated. If the uncertainty requirement holds, this means that investigators cannot predict what they are going to discover in any individual trial that they undertake. In some instances, new treatments will be superior to standard treatments, while in others, standard treatments will be superior to experimental treatments, and in still others, no difference will be detected between new and standard treatments. It is hypothesized that there must be a relationship between the overall pattern of treatment successes and the uncertainties that RCTs are designed to address. Results An analysis of published trials shows that the results cannot be predicted at the level of individual trials. However, the results also indicate that the overall pattern of discovery of treatment success across a series of trials is predictable and is consistent with clinical equipoise hypothesis. The analysis shows that we can discover no more than 25% to 50% of successful treatments when they are tested in RCTs. The analysis also indicates that this discovery rate is optimal in helping to preserve the clinical trial system; a high discovery rate (eg, a 90% to 100% probability of success) is neither feasible nor desirable since under these circumstances, neither the patient nor the researcher has an interest in

  17. Therapeutic value of lymph node dissection for right middle lobe non-small-cell lung cancer

    Kuroda, Hiroaki; Mun, Mingyon; Motoi, Noriko; Ishikawa, Yuichi; Nakagawa, Ken; Yatabe, Yasushi; Okumura, Sakae

    2016-01-01

    Background Superior mediastinal and #11i lymph node (LN) metastases are adverse prognostic factors in patients with middle lobe lung cancer. We aimed to clarify the benefit of thorough lymphadenectomy by LN station or zone in middle lobe non-small-cell lung cancer (NSCLC). Methods Among 295 patients who underwent pulmonary resection and thorough lymphadenectomy for primary right middle lobe (RML) NSCLC at two institutions, we enrolled 68 patients (33 men, 35 women) and retrospectively studied their data. We divided each N1 location (i.e., #10, #11s and #11i) into N1(−)N2(+) and N1(+)N2(+) and divided the #12m location into N1(+)N2(−), N1(−)N2(+) and N1(+)N2(+). Results Interlobar node involvement was rare in pN1 NSCLC when compared with that in other N1 nodes. Lymph node dissection (LND) was beneficial when the hilar zone (HZ)/interlobar zone (IZ) LNs were located at the intermediate point of the upper zones (UZs) and subcarinal zones (SCZs), with the therapeutic benefit at the SCZ being 2.8-fold higher than that at the UZ and 9.7-fold higher than that at the lower zone (LZ). Furthermore, LND evidently had greater therapeutic value for the SCZ than the UZ, which was compatible with skip N2 metastases. Conclusions For middle lobe NSCLC, mediastinal LND should be considered a priority in the SCZ than in the UZ. Moreover, the HZ/IZ is central to unfavourable prognoses in patients with pN2 middle lobe NSCLC. PMID:27162652

  18. 3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

    Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

    2016-06-01

    The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.

  19. Targeting tissue factor as a novel therapeutic oncotarget for eradication of cancer stem cells isolated from tumor cell lines, tumor xenografts and patients of breast, lung and ovarian cancer.

    Hu, Zhiwei; Xu, Jie; Cheng, Jijun; McMichael, Elizabeth; Yu, Lianbo; Carson, William E

    2017-01-03

    Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.

  20. Systemic Administration of Interleukin 2 Enhances the Therapeutic Efficacy of Dendritic Cell-Based Tumor Vaccines

    Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.

    1999-03-01

    We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

  1. Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

    Tayra Judith

    2010-04-01

    Full Text Available Abstract Background Mesenchymal stem cells (MSCs are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL staining. Results Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. Conclusions Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

  2. Translating Research into Clinical Scale Manufacturing of Mesenchymal Stromal Cells

    Karen Bieback

    2010-01-01

    Full Text Available It sounds simple to obtain sufficient numbers of cells derived from fetal or adult human tissues, isolate and/or expand the stem cells, and then transplant an appropriate number of these cells into the patient at the correct location. However, translating basic research into routine therapies is a complex multistep process which necessitates product regulation. The challenge relates to managing the expected therapeutic benefits with the potential risks and to balance the fast move to clinical trials with time-consuming cautious risk assessment. This paper will focus on the definition of mesenchymal stromal cells (MSCs, and challenges and achievements in the manufacturing process enabling their use in clinical studies. It will allude to different cellular sources, special capacities of MSCs, but also to current regulations, with a special focus on accessory material of human or animal origin, like media supplements. As cellular integrity and purity, formulation and lot release testing of the final product, validation of all procedures, and quality assurance are of utmost necessity, these topics will be addressed.

  3. Recent Perspectives on Genome, Transmission, Clinical Manifestation, Diagnosis, Therapeutic Strategies, Vaccine Developments, and Challenges of Zika Virus Research

    Apoorva Shankar

    2017-09-01

    Full Text Available One of the potential threats to public health microbiology in 21st century is the increased mortality rate caused by Zika virus (ZIKV, a mosquito-borne flavivirus. The severity of ZIKV infection urged World Health Organization (WHO to declare this virus as a global concern. The limited knowledge on the structure, virulent factors, and replication mechanism of the virus posed as hindrance for vaccine development. Several vector and non-vector-borne mode of transmission are observed for spreading the disease. The similarities of the virus with other flaviviruses such as dengue and West Nile virus are worrisome; hence, there is high scope to undertake ZIKV research that probably provide insight for novel therapeutic intervention. Thus, this review focuses on the recent aspect of ZIKV research which includes the outbreak, genome structure, multiplication and propagation of the virus, current animal models, clinical manifestations, available treatment options (probable vaccines and therapeutics, and the recent advancements in computational drug discovery pipelines, challenges and limitation to undertake ZIKV research. The review suggests that the infection due to ZIKV became one of the universal concerns and an interdisciplinary environment of in vitro cellular assays, genomics, proteomics, and computational biology approaches probably contribute insights for screening of novel molecular targets for drug design. The review tried to provide cutting edge knowledge in ZIKV research with future insights required for the development of novel therapeutic remedies to curtail ZIKV infection.

  4. Clinical Tolerogenic Dendritic Cells: Exploring Therapeutic Impact on Human Autoimmune Disease

    Brett Eugene Phillips

    2017-10-01

    Full Text Available Tolerogenic dendritic cell (tDC-based clinical trials for the treatment of autoimmune diseases are now a reality. Clinical trials are currently exploring the effectiveness of tDC to treat autoimmune diseases of type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis (MS, and Crohn’s disease. This review will address tDC employed in current clinical trials, focusing on cell characteristics, mechanisms of action, and clinical findings. To date, the publicly reported human trials using tDC indicate that regulatory lymphocytes (largely Foxp3+ T-regulatory cell and, in one trial, B-regulatory cells are, for the most part, increased in frequency in the circulation. Other than this observation, there are significant differences in the major phenotypes of the tDC. These differences may affect the outcome in efficacy of recently launched and impending phase II trials. Recent efforts to establish a catalog listing where tDC converge and diverge in phenotype and functional outcome are an important first step toward understanding core mechanisms of action and critical “musts” for tDC to be therapeutically successful. In our view, the most critical parameter to efficacy is in vivo stability of the tolerogenic activity over phenotype. As such, methods that generate tDC that can induce and stably maintain immune hyporesponsiveness to allo- or disease-specific autoantigens in the presence of powerful pro-inflammatory signals are those that will fare better in primary endpoints in phase II clinical trials (e.g., disease improvement, preservation of autoimmunity-targeted tissue, allograft survival. We propose that pre-treatment phenotypes of tDC in the absence of functional stability are of secondary value especially as such phenotypes can dramatically change following administration, especially under dynamic changes in the inflammatory state of the patient. Furthermore, understanding the outcomes of different methods of cell delivery and sites

  5. 3 CFR - Guidelines for Human Stem Cell Research

    2010-01-01

    ... 3 The President 1 2010-01-01 2010-01-01 false Guidelines for Human Stem Cell Research Presidential Documents Other Presidential Documents Memorandum of July 30, 2009 Guidelines for Human Stem Cell Research..., scientifically worthy human stem cell research, including human embryonic stem cell research, to the extent...

  6. Assessing the risks of genotoxicity in the therapeutic development of induced pluripotent stem cells.

    Hong, So Gun; Dunbar, Cynthia E; Winkler, Thomas

    2013-02-01

    Induced pluripotent stem cells (iPSCs) have great potential for regenerative medicine as well as for basic and translational research. However, following the initial excitement over the enormous prospects of this technology, several reports uncovered serious concerns regarding its safety for clinical applications and reproducibility for laboratory applications such as disease modeling or drug screening. In particular, the genomic integrity of iPSCs is the focus of extensive research. Epigenetic remodeling, aberrant expression of reprogramming factors, clonal selection, and prolonged in vitro culture are potential pathways for acquiring genomic alterations. In this review, we will critically discuss current reprogramming technologies particularly in the context of genotoxicity, and the consequences of these alternations for the potential applications of reprogrammed cells. In addition, current strategies of genetic modification of iPSCs, as well as applicable suicide strategies to control the risk of iPSC-based therapies will be introduced.

  7. Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.

    Cathcart, Mary-Clare

    2011-03-01

    Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease.

  8. Recent developments in blood cell labeling research

    Srivastava, S.C.; Straub, R.F.; Meinken, G.E.

    1988-09-07

    A number of recent developments in research on blood cell labeling techniques are presented. The discussion relates to three specific areas: (1) a new in vitro method for red blood cell labeling with /sup 99m/Tc; (2) a method for labeling leukocytes and platelets with /sup 99m/Tc; and (3) the use of monoclonal antibody technique for platelet labeling. The advantages and the pitfalls of these techniques are examined in the light of available mechanistic information. Problems that remain to be resolved are reviewed. An assessment is made of the progress as well as prospects in blood cell labeling methodology including that using the monoclonal antibody approach. 37 refs., 4 figs.

  9. Recent developments in blood cell labeling research

    Srivastava, S.C.; Straub, R.F.; Meinken, G.E.

    1988-01-01

    A number of recent developments in research on blood cell labeling techniques are presented. The discussion relates to three specific areas: (1) a new in vitro method for red blood cell labeling with /sup 99m/Tc; (2) a method for labeling leukocytes and platelets with /sup 99m/Tc; and (3) the use of monoclonal antibody technique for platelet labeling. The advantages and the pitfalls of these techniques are examined in the light of available mechanistic information. Problems that remain to be resolved are reviewed. An assessment is made of the progress as well as prospects in blood cell labeling methodology including that using the monoclonal antibody approach. 37 refs., 4 figs

  10. Translational research: cells, tissues and organisms

    Chang, P.Y.

    2003-01-01

    Exposure to the complex space radiation environment poses an important health hazard for astronauts in long-term space missions. The central theme of NASA's space radiation health research effort is to acquire scientific knowledge to understand the mechanisms of particle radiation effects in biological systems and to use this knowledge to set exposure limits and to design countermeasures that will protect the astronauts. During the past few decades, a rich body of data has been developed to characterize HZE-induced biological responses both in vitro and in vivo using ground-based accelerator facilities available in a number of facilities around the world. Although much is known about particle-radiation-induced DNA damage and cell killing in cultured cell lines, recent evidence suggest that numerous other factors, such as membrane effects, altered gene expression, bystander effects and specific cell-type dependent features also play critical roles in cellular responses. Dose- and particle-dependent studies are also available for multicellular tissues and animal model systems where emerging information demonstrates complex interactions between cells including intercellular communications, activation of proteins, alterations in the microenvironment, tissue-specificity, and genetic status and these contribute in determining the consequences of HZE radiation. Due to the lack of human data, risk estimates depend on the extrapolation of experimental results in animals and cultured cell systems to man. In this presentation, selected topics reviewing particle radiation effects in cells, tissues and animal will be used to illustrate the importance of translational research and some of the limitations of such approaches

  11. Mechanisms and Therapeutic Implications of Cell Death Induction by Indole Compounds

    Ahmad, Aamir; Sakr, Wael A.; Rahman, KM Wahidur

    2011-01-01

    Indole compounds, obtained from cruciferous vegetables, are well-known for their anti-cancer properties. In particular, indole-3-carbinol (I3C) and its dimeric product, 3,3′-diindolylmethane (DIM), have been widely investigated for their effectiveness against a number of human cancers in vitro as well as in vivo. These compounds are effective inducers of apoptosis and the accumulating evidence documenting their ability to modulate multiple cellular signaling pathways is a testimony to their pleiotropic behavior. Here we attempt to update current understanding on the various mechanisms that are responsible for the apoptosis-inducing effects by these compounds. The significance of apoptosis-induction as a desirable attribute of anti-cancer agents such as indole compounds cannot be overstated. However, an equally intriguing property of these compounds is their ability to sensitize cancer cells to standard chemotherapeutic agents. Such chemosensitizing effects of indole compounds can potentially have major clinical implications because these non-toxic compounds can reduce the toxicity and drug-resistance associated with available chemotherapies. Combinational therapy is increasingly being realized to be better than single agent therapy and, through this review article, we aim to provide a rationale behind combination of natural compounds such as indoles with conventional therapeutics

  12. Therapeutic Outcome of Extranodal NK/T-Cell Lymphoma Initially Treated with Chemotherapy

    Kim, Byung Su; Kim, Tae-you; Kim, Chul Woo; Kim, Ji Yeun; Heo, Dae Seog; Bang, Yung-jue; Kim, Noe Kyeong

    2003-01-01

    The therapeutic outcome of chemotherapy in NK/T cell lymphoma (NTCL) has not been well documented until now. The aims of this study were to investigate the outcome of chemotherapy and to evaluate the clinical factors influencing the responsiveness to chemotherapy. Between 1995 and 2000, 59 patients received anthracycline-based chemotherapy as an initial treatment. Forty-five patients had nasal NTCL, whereas 14 had extranasal NTCL. Forty-one patients had stage I/II and 18 had stage III/IV disease. Epstein-Barr virus status was positive in 67.6% of cases. The results of initial chemotherapy were complete remission in 35.6% of the patients, 2-year disease-free survival in 22.9% and 2-year overall survival in 44.2%. Adjuvant radiotherapy after chemotherapy did not improve outcome in stage I/II nasal NTCL. The International Prognostic Index was a significant prognostic factor of complete remission rate, and stage was also significant for disease-free survival

  13. Therapeutic Outcome of Extranodal NK/T-Cell Lymphoma Initially Treated with Chemotherapy

    Kim, Byung Su; Kim, Tae-you; Kim, Chul Woo; Kim, Ji Yeun; Heo, Dae Seog; Bang, Yung-jue; Kim, Noe Kyeong [Seoul National Univ. College of Medicine (Korea, Republic of). Cancer Research Inst.

    2003-11-01

    The therapeutic outcome of chemotherapy in NK/T cell lymphoma (NTCL) has not been well documented until now. The aims of this study were to investigate the outcome of chemotherapy and to evaluate the clinical factors influencing the responsiveness to chemotherapy. Between 1995 and 2000, 59 patients received anthracycline-based chemotherapy as an initial treatment. Forty-five patients had nasal NTCL, whereas 14 had extranasal NTCL. Forty-one patients had stage I/II and 18 had stage III/IV disease. Epstein-Barr virus status was positive in 67.6% of cases. The results of initial chemotherapy were complete remission in 35.6% of the patients, 2-year disease-free survival in 22.9% and 2-year overall survival in 44.2%. Adjuvant radiotherapy after chemotherapy did not improve outcome in stage I/II nasal NTCL. The International Prognostic Index was a significant prognostic factor of complete remission rate, and stage was also significant for disease-free survival.

  14. An Aggressive Form of Langerhan Cell Histiocytosis in an Adult: Therapeutic Challenges

    Karan Seegobin

    2017-01-01

    Full Text Available Langerhans cell histiocytosis (LCH is rare in adults. Regular follow-up is mandatory due to reoccurrence. A 35-year-old male with an incidental left iliac bone lesion was diagnosed with LCH. He later became symptomatic with hip pain and spread of the disease. Despite excision of the symptomatic iliac lesion, he had progression while on cytarabine and nivolumab, evidenced by increased bone pain and involvement of other bones on imaging. He underwent excision of the jaw lesion followed by vinblastine; he was pain free and had stable disease on PET imaging after 3 months. LCH is an uncommon neoplasia. Treatment is reserved for symptomatic patients while asymptomatic patients are observed. Follow-up is imperative due to the risk of reoccurrence. Despite surgical treatment together with one of the front-line agents for refractory disease, in this case cytarabine, he still had progression of the disease. Furthermore, the trial of nivolumab was of no benefit. This case highlights good response to vinblastine which is previously reported to have good success. No trials are published, and the optimal strategy has yet to be defined. LCH with multiple bony involvement can be aggressive and therapeutically challenging.

  15. Clinical and Therapeutic Aspects of Squamous Cell Carcinoma of Oral Tongue

    Lee, Chang Gul; Suh, Chang Ok; Kim, Gwi Eon; Loh, John J. K.; Ryu, Samuel; Park, In Kyu

    1987-01-01

    Forty nine patients with squamous cell carcinoma of oral tongue were reviewed retrospectively for the evaluation of clinical manifestation and for the comparison between therapeutic modalities. The gross shape of the tumor was infiltrative in 22, ulcerative in 12, and ulceroinfiltrative type in 10 patients. Direct extension of the tumor was most commonly to the floor of the mouth. The incidence of nodal metastasis generally increased with tumor stage. 55% of the patients showed neck nodal metastasis at the time of diagnosis. Ipsilateral subdigastric node were most commonly involved, followed by submandibular nodes. The 5-year survival rate of patients treated with surgery and radiotherapy was 58.7% in contrast to 21.6% in radiation alone group. Overall 5-year survival rate was 31%. In radiation alone group, half of the patients in stage I, II were locally controlled. But the local control in stage III, IV was much inferior to early lesions. Especially, of 4 patients combined with implantation technique, 3 were completely controlled. 5-year survival rate of these implanted patients was 50%, 49.4% of patients treated over 7,000 cGy survived 5 years. This was significant in contrast to 6.4% of the group treated below 7,000 cGy. The most common sites of failures were primary sites. In early lesions primary radiotherapy with implantation would be an appropriate treatment in cancer of oral tongue, operation reserved for radiation failure. Operation and adjuvant radiotherapy is recommended in cases of advanced disease

  16. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity.

    Shuch, Brian; Amin, Ali; Armstrong, Andrew J; Eble, John N; Ficarra, Vincenzo; Lopez-Beltran, Antonio; Martignoni, Guido; Rini, Brian I; Kutikov, Alexander

    2015-01-01

    Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron. To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes. A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies. Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space. Kidney cancer can be subdivided into related but different cancers that arise from the kidney's tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtype's clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  17. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258 and its Therapeutic Implications

    Shalini S. Yadav

    2017-06-01

    Full Text Available Prostate cancer (PCa remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT; however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC. With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258 is a pan receptor tyrosine kinase (RTK inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

  18. Platelet lysate enhances synovial fluid multipotential stromal cells functions: Implications for therapeutic use.

    Altaie, Ala; Baboolal, Thomas G; Wall, Owen; Jones, Elena; McGonagle, Dennis

    2018-03-01

    Although intra-articular injection of platelet products is increasingly used for joint regenerative approaches, there are few data on their biological effects on joint-resident multipotential stromal cells (MSCs), which are directly exposed to the effects of these therapeutic strategies. Therefore, this study investigated the effect of platelet lysate (PL) on synovial fluid-derived MSCs (SF-MSCs), which in vivo have direct access to sites of cartilage injury. SF-MSCs were obtained during knee arthroscopic procedures (N = 7). Colony forming unit-fibroblast (CFU-F), flow-cytometric phenotyping, carboxyfluorescein succinimidyl ester-based immunomodulation for T-cell and trilineage differentiation assays were performed using PL and compared with standard conditions. PL-enhanced SF-MSC (PL-MSC) proliferation as CFU-F colonies was 1.4-fold larger, and growing cultures had shorter population-doubling times. PL-MSCs and fetal calf serum (FCS)-MSCs had the same immunophenotype and similar immunomodulation activities. In chondrogenic and osteogenic differentiation assays, PL-MSCs produced 10% more sulfated-glycosaminoglycan (sGAG) and 45% less Ca ++ compared with FCS-MSCs, respectively. Replacing chondrogenic medium transforming growth factor-β3 with 20% or 50% PL further increased sGAG production of PL-MSCs by 69% and 95%, respectively, compared with complete chondrogenic medium. Also, Dulbecco's Modified Eagle's Medium high glucose (HG-DMEM) plus 50% PL induced more chondrogenesis compared with HG-DMEM plus 10% FCS and was comparable to complete chondrogenic medium. This is the first study to assess SF-MSC responses to PL and provides biological support to the hypothesis that PL may be capable of modulating multiple functional aspects of joint resident MSCs with direct access to injured cartilage. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  19. Endothelial progenitor cells from human dental pulp-derived iPS cells as a therapeutic target for ischemic vascular diseases.

    Yoo, Chae Hwa; Na, Hee-Jun; Lee, Dong-Seol; Heo, Soon Chul; An, Yuri; Cha, Junghwa; Choi, Chulhee; Kim, Jae Ho; Park, Joo-Cheol; Cho, Yee Sook

    2013-11-01

    Human dental pulp cells (hDPCs) are a valuable source for the generation of patient-specific human induced pluripotent stem cells (hiPSCs). An advanced strategy for the safe and efficient reprogramming of hDPCs and subsequent lineage-specific differentiation is a critical step toward clinical application. In present research, we successfully generated hDPC-iPSCs using only two non-oncogenic factors: Oct4 and Sox2 (2F hDPC-hiPSCs) and evaluated the feasibility of hDPC-iPSCs as substrates for endothelial progenitor cells (EPCs), contributing to EPC-based therapies. Under conventional differentiation conditions, 2F hDPC-hiPSCs showed higher differentiation efficiency, compared to hiPSCs from other cell types, into multipotent CD34(+) EPCs (2F-hEPCs) capable to differentiate into functional endothelial and smooth muscle cells. The angiogenic and neovasculogenic activities of 2F-hEPCs were confirmed using a Matrigel plug assay in mice. In addition, the therapeutic effects of 2F-hEPC transplantation were confirmed in mouse models of hind-limb ischemia and myocardial infarction. Importantly, 2F-EPCs effectively integrated into newly formed vascular structures and enhanced neovascularization via likely both direct and indirect paracrine mechanisms. 2F hDPC-hiPSCs have a robust capability for the generation of angiogenic and vasculogenic EPCs, representing a strategy for patient-specific EPC therapies and disease modeling, particularly for ischemic vascular diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. MIS416 Enhances Therapeutic Functions of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Against Experimental Colitis by Modulating Systemic Immune Milieu

    Byung-Chul Lee

    2018-05-01

    Full Text Available Human adult stem cells, including umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs, have recently been considered a promising alternative treatment for inflammatory bowel disease (IBD due to their unique immunomodulatory properties and ability to promote tissue regeneration. However, despite many years of research and pre-clinical studies, results from clinical trials using these cells have been diverse and conflicting. This discrepancy is caused by several factors, such as poor engraftment, low survival rate, and donor-dependent variation of the cells. Enhancement of consistency and efficacy of MSCs remains a challenge for the feasibility of cell-based therapy. In this study, we investigated whether administration of MIS416, a novel microparticle that activates NOD2 and TLR9 signaling, could enhance the therapeutic efficacy of hUCB-MSCs against Crohn’s disease, using dextran sulfate sodium (DSS-induced colitis model. Colitis was experimentally induced in mice by using 3% DSS, and mice were administered a retro-orbital injection of MIS416 and subsequent intraperitoneal injection of hUCB-MSCs. Mice were examined grossly, and blood, spleen, and colon tissues were subsequently collected for further ex vivo analyses. To explore the effects of MIS416 on the therapeutic process, hUCB-MSCs and primary isolated immune cells were cultured with MIS416, and in vitro assays were performed. Compared to the single administration of hUCB-MSCs, co-administration with MIS416 improved the therapeutic efficiency of the stem cells by significantly alleviating the symptoms of IBD. Interestingly, MIS416 did not exert any direct effect on the immunomodulatory capacity of hUCB-MSCs. Instead, systemically injected MIS416 altered the immune milieu in the colon which caused hUCB-MSCs to be more readily recruited toward the lesion site and to suppress inflammation more efficiently. In addition, considerable numbers of regulatory immune cells were stimulated

  1. IL17/IL17RA as a Novel Signaling Axis Driving Mesenchymal Stem Cell Therapeutic Function in Experimental Autoimmune Encephalomyelitis

    Mónica Kurte

    2018-04-01

    Full Text Available The therapeutic effect of mesenchymal stem cells (MSCs in multiple sclerosis (MS and the experimental autoimmune encephalomyelitis (EAE model has been well described. This effect is, in part, mediated through the inhibition of IL17-producing cells and the generation of regulatory T cells. While proinflammatory cytokines such as IFNγ, TNFα, and IL1β have been shown to enhance MSCs immunosuppressive function, the role of IL17 remains poorly elucidated. The aim of this study was, therefore, to investigate the role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing on Th17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro, we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation and differentiation is partially dependent on IL17RA expression. This was associated with a reduced expression level of MSCs immunosuppressive mediators such as VCAM1, ICAM1, and PD-L1 in IL17RA−/− MSCs as compared to wild-type (WT MSCs. In the EAE model, we demonstrated that while WT MSCs significantly reduced the clinical scores of the disease, IL17RA−/− MSCs injected mice exhibited a clinical worsening of the disease. The disability of IL17RA−/− MSCs to reduce the progression of the disease paralleled the inability of these cells to reduce the frequency of Th17 cells in the draining lymph node of the mice as compared to WT MSCs. Moreover, we showed that the therapeutic effect of MSCs was correlated with the generation of classical Treg bearing the CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveal a novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAE and suggest that the modulation of IL17RA in MSCs could represent a novel method to enhance their therapeutic effect in MS.

  2. Current and future regenerative medicine - principles, concepts, and therapeutic use of stem cell therapy and tissue engineering in equine medicine

    Koch, Thomas Gadegaard; Berg, Lise Charlotte; Betts, Dean H.

    2009-01-01

    This paper provides a bird's-eye perspective of the general principles of stem-cell therapy and tissue engineering; it relates comparative knowledge in this area to the current and future status of equine regenerative medicine.The understanding of equine stem cell biology, biofactors, and scaffolds...... mesenchymal stromal cells, unless there is proof that they exhibit the fundamental in vivo characteristics of pluripotency and the ability to self-renew. That said, these cells from various tissues hold great promise for therapeutic use in horses. The 3 components of tissue engineering - cells, biological...... factors, and biomaterials - are increasingly being applied in equine medicine, fuelled by better scaffolds and increased understanding of individual biofactors and cell sources.The effectiveness of stem cell-based therapies and most tissue engineering concepts has not been demonstrated sufficiently...

  3. The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis.

    Heijman, Jordi; Algalarrondo, Vincent; Voigt, Niels; Melka, Jonathan; Wehrens, Xander H T; Dobrev, Dobromir; Nattel, Stanley

    2016-04-01

    Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation, and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal, and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and re-entrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodelling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients are enormously heterogeneous. An understanding of arrhythmia mechanisms is widely assumed to be the basis of therapeutic innovation, but while this assumption seems self-evident, we are not aware of any papers that have critically examined the practical contributions of basic research into AF mechanisms to arrhythmia management. Here, we review recent insights into the basic mechanisms of AF, critically analyse the role of basic research insights in the development of presently used anti-AF therapeutic options and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  4. TRANSPARENT COATINGS FOR SOLAR CELLS RESEARCH

    Glatkowski, P. J.; Landis, D. A.

    2013-04-16

    Todays solar cells are fabricated using metal oxide based transparent conductive coatings (TCC) or metal wires with optoelectronic performance exceeding that currently possible with Carbon Nanotube (CNT) based TCCs. The motivation for replacing current TCC is their inherent brittleness, high deposition cost, and high deposition temperatures; leading to reduced performance on thin substrates. With improved processing, application and characterization techniques Nanofiber and/or CNT based TCCs can overcome these shortcomings while offering the ability to be applied in atmospheric conditions using low cost coating processes At todays level of development, CNT based TCC are nearing commercial use in touch screens, some types of information displays (i.e. electronic paper), and certain military applications. However, the resistivity and transparency requirements for use in current commercial solar cells are more stringent than in many of these applications. Therefore, significant research on fundamental nanotube composition, dispersion and deposition are required to reach the required performance commanded by photovoltaic devices. The objective of this project was to research and develop transparent conductive coatings based on novel nanomaterial composite coatings, which comprise nanotubes, nanofibers, and other nanostructured materials along with binder materials. One objective was to show that these new nanomaterials perform at an electrical resistivity and optical transparency suitable for use in solar cells and other energy-related applications. A second objective was to generate new structures and chemistries with improved resistivity and transparency performance. The materials also included the binders and surface treatments that facilitate the utility of the electrically conductive portion of these composites in solar photovoltaic devices. Performance enhancement venues included: CNT purification and metallic tube separation techniques, chemical doping, CNT

  5. New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells.

    Sherley, James L

    2013-11-01

    A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.

  6. Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma

    Jing Lin

    2017-12-01

    Full Text Available Self-renewing tumor-initiating cells (TICs are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC. GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3.5–7 nM, disrupt the open reading frame (ORF of GLDC transcript (predisposing it for nonsense-mediated decay, halt cell proliferation, and prevent colony formation in both A549 cells and TIC-enriched NSCLC tumor sphere cells (TS32. One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications.

  7. Hsp40 gene therapy exerts therapeutic effects on polyglutamine disease mice via a non-cell autonomous mechanism.

    H Akiko Popiel

    Full Text Available The polyglutamine (polyQ diseases such as Huntington's disease (HD, are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1 and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5 expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.

  8. Prophylactic and therapeutic adenoviral vector-based multivirus-specific T-cell immunotherapy for transplant patients

    Vijayendra Dasari

    2016-01-01

    Full Text Available Viral infections including cytomegalovirus, Epstein-Barr virus, adenovirus, and BK virus are a common and predictable problem in transplant recipients. While cellular immune therapies have been successfully used to tackle infectious complications in transplant recipients, manufacturing immunotherapies to address the multitude of possible pathogens can be technically challenging and labor-intensive. Here we describe a novel adenoviral antigen presentation platform (Ad-MvP as a tool for rapid generation of multivirus-specific T-cells in a single step. Ad-MvP encodes 32 CD8+ T-cell epitopes from cytomegalovirus, Epstein-Barr virus, adenovirus, and BK virus as a contiguous polyepitope. We demonstrate that Ad-MvP vector can be successfully used for rapid in vitro expansion of multivirus-specific T-cells from transplant recipients and in vivo priming of antiviral T-cell immunity. Most importantly, using an in vivo murine model of Epstein-Barr virus-induced lymphoma, we also show that adoptive immunotherapy with Ad-MvP expanded autologous and allogeneic multivirus-specific T-cells is highly effective in controlling Epstein-Barr virus tumor outgrowth and improving overall survival. We propose that Ad-MvP has wide ranging therapeutic applications in greatly facilitating in vivo priming of antiviral T-cells, the generation of third-party T-cell banks as “off-the-shelf” therapeutics as well as autologous T-cell therapies for transplant patients.

  9. Macromolecular therapeutics.

    Yang, Jiyuan; Kopeček, Jindřich

    2014-09-28

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig

    Bjarkam, Carsten R; GLUD, AN; Margolin, Lee

    2010-01-01

    Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig......Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig...

  11. Autologous stem-cell transplantation in Hodgkin’s lymphoma: analysis of a therapeutic option

    Adriano de Moraes Arantes

    2011-06-01

    Full Text Available Objective: To report the clinical progress of patients with Hodgkin’slymphoma treated with autologous transplantation after failure orrelapse of first-line treatment with chemotherapy and/or radiationtherapy. Methods: The results of a retrospective analysis of 31patients submitted to autologous transplantation as second-linetreatment, between April 2000 and December 2008, were analyzed.Fourteen men and seventeen women, with a median age of 27 years,were submitted to autologous transplantation for relapsed (n = 21or refractory (n = 10 Hodgkin’s lymphoma. Results: Mortalityrelated to treatment in the first 100 days after transplant was 3.2%.With a mean follow-up period of 18 months (range: 1 to 88 months,the probability of global survival and progression-free survival in18 months was 84 and 80%, respectively. The probability of globalsurvival and progression-free survival at 18 months for patients withchemosensitive relapses (n = 21 was 95 and 90%, respectively,versus 60 and 45% for patients with relapses resistant to chemotherapy(n = 10 (p = 0.001 for global survival; p = 0.003 for progressionfreesurvival. In the multivariate analysis, absence of disease or pretransplant disease < 5 cm were favorable factors for global survival (p= 0.02; RR: 0.072; 95%CI: 0.01-0.85 and progression-free survival (p= 0.01; RR: 0.040; 95%CI: 0.007-0.78. Conclusion: Autologous transplantation of stem-cells is a therapeutic option for Hodgkin’s lymphoma patients after the first relapse. Promising results were observed in patients with a low tumor burden at transplant.

  12. Dual-energy CT in assessing therapeutic response to radiofrequency ablation of renal cell carcinomas

    Park, Sung Yoon; Kim, Chan Kyo, E-mail: chankyokim@skku.edu; Park, Byung Kwan

    2014-02-15

    Purpose: To investigate the utility of dual-energy (DE) CT using virtual noncontrast (VNC) and iodine overlay (IO) images to assess therapeutic response to radiofrequency ablation (RFA) for renal cell carcinomas (RCCs). Materials and methods: In this institutional review board-approved study (with waiver of informed consent), 47 patients with RCCs that underwent DECT after RFA were enrolled in this study. DECT protocols included true noncontrast (TNC), linearly blended DE corticomedullary and late nephrographic phase imaging. Two types of VNC and IO images were derived from corticomedullary and late nephrographic phases, respectively. To predict local tumor progression at RFA site, linearly blended and IO images were analyzed both qualitatively and quantitatively. Contrast-to-noise ratios (CNR) of renal cortex-to-RFA zones were calculated. The overall imaging quality of VNC images was compared with TNC images. Results: The IO images from corticomedullary and late nephrographic phases showed excellent diagnostic performance (each sensitivity 100% and each specificity 91.5%) for predicting local tumor progression. The degree of enhancement of local tumor progression was not significantly different between linearly blended and IO images (P > 0.05). The mean CT numbers were not significantly different between TNC and VNC images (P > 0.05). In renal cortex-to-RFA site, CNR between linearly blended and IO images was not significantly different (P > 0.05). The VNC imaging quality from the two phases was given a good rating. Conclusion: VNC and IO images from DECT may allow acceptable diagnostic performance with less radiation exposure as a follow-up imaging tool after RFA for RCC, compared to the linearly blended CT images.

  13. Dual-energy CT in assessing therapeutic response to radiofrequency ablation of renal cell carcinomas

    Park, Sung Yoon; Kim, Chan Kyo; Park, Byung Kwan

    2014-01-01

    Purpose: To investigate the utility of dual-energy (DE) CT using virtual noncontrast (VNC) and iodine overlay (IO) images to assess therapeutic response to radiofrequency ablation (RFA) for renal cell carcinomas (RCCs). Materials and methods: In this institutional review board-approved study (with waiver of informed consent), 47 patients with RCCs that underwent DECT after RFA were enrolled in this study. DECT protocols included true noncontrast (TNC), linearly blended DE corticomedullary and late nephrographic phase imaging. Two types of VNC and IO images were derived from corticomedullary and late nephrographic phases, respectively. To predict local tumor progression at RFA site, linearly blended and IO images were analyzed both qualitatively and quantitatively. Contrast-to-noise ratios (CNR) of renal cortex-to-RFA zones were calculated. The overall imaging quality of VNC images was compared with TNC images. Results: The IO images from corticomedullary and late nephrographic phases showed excellent diagnostic performance (each sensitivity 100% and each specificity 91.5%) for predicting local tumor progression. The degree of enhancement of local tumor progression was not significantly different between linearly blended and IO images (P > 0.05). The mean CT numbers were not significantly different between TNC and VNC images (P > 0.05). In renal cortex-to-RFA site, CNR between linearly blended and IO images was not significantly different (P > 0.05). The VNC imaging quality from the two phases was given a good rating. Conclusion: VNC and IO images from DECT may allow acceptable diagnostic performance with less radiation exposure as a follow-up imaging tool after RFA for RCC, compared to the linearly blended CT images

  14. Dual-energy CT in assessing therapeutic response to radiofrequency ablation of renal cell carcinomas.

    Park, Sung Yoon; Kim, Chan Kyo; Park, Byung Kwan

    2014-02-01

    To investigate the utility of dual-energy (DE) CT using virtual noncontrast (VNC) and iodine overlay (IO) images to assess therapeutic response to radiofrequency ablation (RFA) for renal cell carcinomas (RCCs). In this institutional review board-approved study (with waiver of informed consent), 47 patients with RCCs that underwent DECT after RFA were enrolled in this study. DECT protocols included true noncontrast (TNC), linearly blended DE corticomedullary and late nephrographic phase imaging. Two types of VNC and IO images were derived from corticomedullary and late nephrographic phases, respectively. To predict local tumor progression at RFA site, linearly blended and IO images were analyzed both qualitatively and quantitatively. Contrast-to-noise ratios (CNR) of renal cortex-to-RFA zones were calculated. The overall imaging quality of VNC images was compared with TNC images. The IO images from corticomedullary and late nephrographic phases showed excellent diagnostic performance (each sensitivity 100% and each specificity 91.5%) for predicting local tumor progression. The degree of enhancement of local tumor progression was not significantly different between linearly blended and IO images (P>0.05). The mean CT numbers were not significantly different between TNC and VNC images (P>0.05). In renal cortex-to-RFA site, CNR between linearly blended and IO images was not significantly different (P>0.05). The VNC imaging quality from the two phases was given a good rating. VNC and IO images from DECT may allow acceptable diagnostic performance with less radiation exposure as a follow-up imaging tool after RFA for RCC, compared to the linearly blended CT images. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

  15. Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies?

    Malik, Shabana T; Birch, Brian R; Voegeli, David; Fader, Mandy; Foria, Vipul; Cooper, Alan J; Walls, Andrew F; Lwaleed, Bashir A

    2018-05-15

    To identify the presence and geographical distribution of mast cell (MC) subtypes: MC T (tryptase positive-chymase negative) and MC TC (tryptase positive-chymase positive) in bladder tissue. Bladder tissue was obtained from patients with painful bladder syndrome/interstitial cystitis (n=14) and normal histology from University Hospital Southampton tissue bank. Sequential tissue slices were immunohistochemically stained for MC subtypes using anti-MC tryptase (for MC T and MC TC ) and anti-MC chymase (for MC TC ). Stained sections were photographed, and positively stained MCs were quantified using ImageJ. Data were analysed using descriptive statistics and individual paired t-tests. There was a significant difference in the density of MCs between each layer of the disease bladder, with the greatest accumulation within the detrusor (p<0.001). There was a significant increase in MC TC subtype in the lamina (p=0.009) in painful bladder syndrome/interstitial cystitis. Our results suggest that mastocytosis is present within all layers of disease bladder, especially the muscle layer. The varying increase in MC subtypes in the lamina and mucosa may explain the variability in painful bladder syndrome/interstitial cystitis symptoms. A high influx of MC TC in the mucosa of individuals who also had ulceration noted within their diagnostic notes may be of the Hunner's ulcer subclassification. These findings suggest a relationship between the pathogenesis of MC subtypes and the clinical presentation of painful bladder syndrome/interstitial cystitis. A cohort study would further elucidate the diagnostic and/or therapeutic potential of MCs in patients with painful bladder syndrome/interstitial cystitis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  16. [Research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration].

    Liang, Hang; Deng, Xiangyu; Shao, Zengwu

    2017-10-01

    To summarize the research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration and deduce the therapeutic potential of endogenous repair for intervertebral disc degeneration. The original articles about intervertebral disc endogenous stem cells for intervertebral disc regeneration were extensively reviewed; the reparative potential in vivo and the extraction and identification in vitro of intervertebral disc endogenous stem cells were analyzed; the prospect of endogenous stem cells for intervertebral disc regeneration was predicted. Stem cell niche present in the intervertebral discs, from which stem cells migrate to injured tissues and contribute to tissues regeneration under certain specific microenvironment. Moreover, the migration of stem cells is regulated by chemokines system. Tissue specific progenitor cells have been identified and successfully extracted and isolated. The findings provide the basis for biological therapy of intervertebral disc endogenous stem cells. Intervertebral disc endogenous stem cells play a crucial role in intervertebral disc regeneration. Therapeutic strategy of intervertebral disc endogenous stem cells is proven to be a promising biological approach for intervertebral disc regeneration.

  17. Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling

    Li, Hui; Jiao, Shun [Department of Obstetrics and Gynaecology, JingZhou Hospital Affiliated to Huazhong University of Science and Technology, Jingzhou (China); Li, Xin [Department of Obstetrics and Gynaecology, RenMin Hospital of Wuhan University, Wuhan (China); Banu, Hasina; Hamal, Shreejana [Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou (China); Wang, Xianrong, E-mail: Dr.XianRong.Wang@hotmail.com [Department of Obstetrics and Gynaecology, JingZhou Hospital Affiliated to Huazhong University of Science and Technology, Jingzhou (China)

    2015-11-06

    Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. - Highlights: • We repurposed the antibiotic drug tigecycline for cervical cancer treatment. • Tigecycline is effectively against cervical cancer cells in vitro and in vivo. • Combination of tigecycline and paclitaxel is synergistic in targeting Hela cells. • Tigecycline acts on Hela cells through inhibiting Wnt/β-catenin signaling.

  18. Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling

    Li, Hui; Jiao, Shun; Li, Xin; Banu, Hasina; Hamal, Shreejana; Wang, Xianrong

    2015-01-01

    Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. - Highlights: • We repurposed the antibiotic drug tigecycline for cervical cancer treatment. • Tigecycline is effectively against cervical cancer cells in vitro and in vivo. • Combination of tigecycline and paclitaxel is synergistic in targeting Hela cells. • Tigecycline acts on Hela cells through inhibiting Wnt/β-catenin signaling.

  19. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

    Martirosyan, Anna; Clendening, James W; Goard, Carolyn A; Penn, Linda Z

    2010-01-01

    Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism. Moreover, we also show lovastatin synergizes

  20. Report of the 2. research coordination meeting on development of generator technologies for therapeutic radionuclides

    2006-01-01

    The objectives of this CRP are to evaluate various generator and concentration technologies for 188 W- 188 Re, 99 Mo- 99 mTc and 90 Sr- 90 Y generators, to optimize generator fabrication and use, to standardize quality control techniques for the eluted radionuclides and to provide standardized procedures to participating laboratories. The following issues will be addressed during the CRP. - Development of reproducible methodologies for the preparation of 188 W- 188 Re, 99 Mo- 99 mTc and 90 Sr- 90 Y generators. - Development and evaluation of chromatography adsorbents (Zr/Ti composites) having higher binding capacities and demonstration of their utility in the preparation of column generators for 188 Re and 99 mTc. - Comparison and optimization of technologies for post elution concentration of 188 Re and 99 mTc in order to improve the radioactive concentration. - Development of quality control techniques and specifications for generator eluted therapeutic radionuclides

  1. Diagnostic significance and therapeutic consequences of computed tomography (patient outcome research). Pt. 1. Diagnosis in traumatology

    Schroeder, R.J.; Hidajat, N.; Vogl, T.; Haas, N.; Suedkamp, N.; Schedel, H.; Felix, R.

    1995-01-01

    During 1993, 201 primary traumatologic patients underwent 230 computed tomography examinations. 87% of the CT's were performed completely without contrast media, 2.6% exclusively supported by intravenously given contrast media, 9.1% in both ways, and 1.3% after intra-articular contrast media administration. 97.4% served for primary diagnostic purposes and 2.6% for the control of therapeutic results. In 47.8% of the CT's, the principle diagnosis was known before CT. In 52.2%, the diagnosis without CT was impossible by other methods. The CT diagnoses were correctly positive in 58.7% and correctly negative in 41.3%. 60.9% of CT's demonstrated a missing indication for operation in the examined body region; in 39.1% the operation followed. (orig.) [de

  2. Cancer Stem Cells and Molecular Biology Test in Colorectal Cancer: Therapeutic Implications.

    Effendi-Ys, Rustam

    2017-10-01

    Colorectal cancer (CRC) is the third most frequent cancer in males, the second in females, and is the second leading cause of cancer related death worldwide. Within Indonesia's 250 million population, the incidence rates for CRC per 100,000 population were 15.2 for males and 10.2 for females, and estimated 63,500 cases per year.  More than 50% of colorectal cancer patients will develop metastasis. CRC is still the main cause of tumor-related death, and although most CRC patients are treated with surgery to remove the tumor tissue, some of the CRC patients recurred. Chemotherapy used as adjuvant or neoadjuvant therapy also has several problems, in which these treatments are useless in tumor cells with chemo-resistance. Molecular testing of CRC from tumor tissues has important implications for the selection of treatment. Biomarkers can be used as prognostic value, molecular predictive factors, and targeted therapy. Recent research reported that, cancer stem cells (CSCs) are considered as the origin of tumorigenesis, development, metastasis and recurrence. At present, it has been shown that CSCs existed in many tumors including CRC. This review aims to summarize the issue on CSCs, and the future development of drugs that target colorectal cancer stem cells.

  3. Therapeutic effects of human multilineage-differentiating stress enduring (MUSE cell transplantation into infarct brain of mice.

    Tomohiro Yamauchi

    Full Text Available Bone marrow stromal cells (BMSCs are heterogeneous and their therapeutic effect is pleiotropic. Multilineage-differentiating stress enduring (Muse cells are recently identified to comprise several percentages of BMSCs, being able to differentiate into triploblastic lineages including neuronal cells and act as tissue repair cells. This study was aimed to clarify how Muse and non-Muse cells in BMSCs contribute to functional recovery after ischemic stroke.Human BMSCs were separated into stage specific embryonic antigen-3-positive Muse cells and -negative non-Muse cells. Immunodeficient mice were subjected to permanent middle cerebral artery occlusion and received transplantation of vehicle, Muse, non-Muse or BMSCs (2.5×104 cells into the ipsilateral striatum 7 days later.Motor function recovery in BMSC and non-Muse groups became apparent at 21 days after transplantation, but reached the plateau thereafter. In Muse group, functional recovery was not observed for up to 28 days post-transplantation, but became apparent at 35 days post-transplantation. On immunohistochemistry, only Muse cells were integrated into peri-infarct cortex and differentiate into Tuj-1- and NeuN-expressing cells, while negligible number of BMSCs and non-Muse cells remained in the peri-infarct area at 42 days post-transplantation.These findings strongly suggest that Muse cells and non-Muse cells may contribute differently to tissue regeneration and functional recovery. Muse cells may be more responsible for replacement of the lost neurons through their integration into the peri-infarct cortex and spontaneous differentiation into neuronal marker-positive cells. Non-Muse cells do not remain in the host brain and may exhibit trophic effects rather than cell replacement.

  4. Splenectomy enhances the therapeutic effect of adipose tissue-derived mesenchymal stem cell infusion on cirrhosis rats.

    Tang, Wei-Ping; Akahoshi, Tomohiko; Piao, Jing-Shu; Narahara, Sayoko; Murata, Masaharu; Kawano, Takahito; Hamano, Nobuhito; Ikeda, Tetsuo; Hashizume, Makoto

    2016-08-01

    Clinical studies suggest that splenectomy improves liver function in cirrhotic patients, but the influence of splenectomy on stem cell transplantation is poorly understood. This study investigated the effect of splenectomy on stem cell infusion and elucidated its mechanism. Rat adipose tissue-derived mesenchymal stem cells were infused into cirrhosis rats with or without splenectomy, followed by the assessment of the in vivo distribution of stem cells and pathological changes. Stromal cell-derived factor-1 and hepatocyte growth factor expression were also investigated in splenectomized cirrhosis patients and rats. Splenectomy, prior to cell infusion, improved liver function and suppressed fibrosis progression more efficiently than cell infusion alone in the experimental cirrhosis model. Stromal cell-derived factor-1 and hepatocyte growth factor levels after splenectomy were increased in patients and rats. These upregulated cytokines significantly facilitated stem cell motility, migration and proliferation in vitro. C-X-C chemokine receptor type 4 neutralization weakened the promotion of cell migration by these cytokines. The infused cells integrated into liver fibrosis septa and participated in regeneration more efficiently in splenectomized rats. Direct coculture with stem cells led to inhibition of hepatic stellate cell proliferation. In addition, hepatocyte growth factor induced hepatic stellate cell apoptosis via the c-jun N-terminal kinase-p53 pathway. Splenectomy prior to cell infusion enhanced the therapeutic effect of stem cells on cirrhosis, which involved upregulation of stromal cell-derived factor-1 and hepatocyte growth factor after splenectomy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer.

    Sanal, Madhusudana Girija

    2014-01-01

    Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient's somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT) combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system) this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is the question of

  6. Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma.

    Kung-Chao Chang

    Full Text Available Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL showed differential expression of Ran GTPase-activating protein 1 (RanGAP1 between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50 were RanGAP1(+, while reactive lymphoid hyperplasia (n = 12 was RanGAP1(+ predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180 with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95% or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin's lymphoma 91%. Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62 than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52 and healthy controls (0.55 ± 1.58 ng/mL, n = 75 (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test. In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035 and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030 along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon, a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.

  7. Targeting the Immune System’s Natural Response to Cell Death to Improve Therapeutic Response in Breast Cancers

    2016-09-01

    pharmacological MerTK inhibition, measuring intra-tumoral leukocytes and tumor epithelial cell signaling in the post-therapeutic setting using flow...7Department of Pediatrics, National Jewish Health, Denver, Colorado, USA. 8Departments of Pharmacology and Medicine and UNC Lineberger Comprehensive...tail vein injection into lethally irradiated 6-week-old female MMTV-PyVmT recipients. (B) Average tumor volume ± SEM measured in live mice by MRI at

  8. Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson's Disease.

    Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Hsu, Ching-Ju; Lin, Shinn-Zong; Tu, Chi-Tang; Chang, Li-Hsun; Wu, Ping-An; Liu, Shih-Ping

    2018-03-01

    Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.

  9. PRX1 knockdown potentiates vitamin K3 toxicity in cancer cells: a potential new therapeutic perspective for an old drug.

    He, Tiantian; Hatem, Elie; Vernis, Laurence; Lei, Ming; Huang, Meng-Er

    2015-12-21

    Many promising anticancer molecules are abandoned during the course from bench to bedside due to lack of clear-cut efficiency and/or severe side effects. Vitamin K3 (vitK3) is a synthetic naphthoquinone exhibiting significant in vitro and in vivo anticancer activity against multiple human cancers, and has therapeutic potential when combined with other anticancer molecules. The major mechanism for the anticancer activity of vitK3 is the generation of cytotoxic reactive oxygen species (ROS). We thus reasoned that a rational redox modulation of cancer cells could enhance vitK3 anticancer efficiency. Cancer cell lines with peroxiredoxin 1 (PRX1) gene transiently or stably knocked-down and corresponding controls were exposed to vitK3 as well as a set of anticancer molecules, including vinblastine, taxol, doxorubicin, daunorubicin, actinomycin D and 5-fluorouracil. Cytotoxic effects and cell death events were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based assay, cell clonogenic assay, measurement of mitochondrial membrane potential and annexin V/propidium iodide double staining. Global ROS accumulation and compartment-specific H2O2 generation were determined respectively by a redox-sensitive chemical probe and H2O2-sensitive sensor HyPer. Oxidation of endogenous antioxidant proteins including TRX1, TRX2 and PRX3 was monitored by redox western blot. We observed that the PRX1 knockdown in HeLa and A549 cells conferred enhanced sensitivity to vitK3, reducing substantially the necessary doses to kill cancer cells. The same conditions (combination of vitK3 and PRX1 knockdown) caused little cytotoxicity in non-cancerous cells, suggesting a cancer-cell-selective property. Increased ROS accumulation had a crucial role in vitK3-induced cell death in PRX1 knockdown cells. The use of H2O2-specific sensors HyPer revealed that vitK3 lead to immediate accumulation of H2O2 in the cytosol, nucleus, and mitochondrial matrix. PRX1 silencing

  10. Spectral matching research for light-emitting diode-based neonatal jaundice therapeutic device light source

    Gan, Ruting; Guo, Zhenning; Lin, Jieben

    2015-09-01

    To decrease the risk of bilirubin encephalopathy and minimize the need for exchange transfusions, we report a novel design for light source of light-emitting diode (LED)-based neonatal jaundice therapeutic device (NJTD). The bilirubin absorption spectrum in vivo was regarded as target. Based on spectral constructing theory, we used commercially available LEDs with different peak wavelengths and full width at half maximum as matching light sources. Simple genetic algorithm was first proposed as the spectral matching method. The required LEDs number at each peak wavelength was calculated, and then, the commercial light source sample model of the device was fabricated to confirm the spectral matching technology. In addition, the corresponding spectrum was measured and the effect was analyzed finally. The results showed that fitted spectrum was very similar to the target spectrum with 98.86 % matching degree, and the actual device model has a spectrum close to the target with 96.02 % matching degree. With higher fitting degree and efficiency, this matching algorithm is very suitable for light source matching technology of LED-based spectral distribution, and bilirubin absorption spectrum in vivo will be auspicious candidate for the target spectrum of new LED-based NJTD light source.

  11. Therapeutic Value of Medical Marijuana in New Jersey Patients: A Community Partnership Research Endeavor.

    Crowell, Tara L

    2017-01-01

    The Public Health Program at Stockton University partnered with the Compassionate Care Foundation to ascertain the impact of medical marijuana on patients in New Jersey. Patients volunteered to complete a survey once a month for 8 months. The survey explored their use, form, and strain of medical marijuana and its influence on pain and 12 other physical and mental health variables. Also, an increase or decrease in other medication taken and any unexpected outcomes were recorded. From a total of 955 patients, patients responding to the surveys varied from 501 for visit 1, 290 for visit 2, to 179 for visit 3. Results provide insight into the diagnoses for which patients used medical marijuana. Results indicate increased mood, general overall condition, and energy as the highest consequences; level of pain in the middle range; and most frequent usage as 3 to 4 times a day. Repeated measures done after visit 2 showed eight statistically significant differences for patients after using medical marijuana: an increase in general quality of life, mobility, and mood, with a decrease in inflammation, intraocular pressure, spasms, seizures, and pain. Results after visit 3 indicated seven significant differences compared to visit 1: decreased seizures, intraocular pressure, spasms, nausea, and pain, along with increased energy and mobility. No differences were found by patient diagnosis or age, but sex-related differences occurred in inflammation, mood, and energy. Results support positive therapeutic benefits of medical marijuana, and despite methodological limitations, our study contributes to the growing body of literature.

  12. Cynaropicrin: a comprehensive research review and therapeutic potential as an anti- hepatitis C virus agent

    Mahmoud Fahmi Elsebai

    2016-12-01

    Full Text Available The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV. Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway. These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV.

  13. Autophagy‑mediated adaptation of hepatocellular carcinoma cells to hypoxia‑mimicking conditions constitutes an attractive therapeutic target.

    Owada, Satoshi; Endo, Hitoshi; Shida, Yukari; Okada, Chisa; Ito, Kanako; Nezu, Takahiro; Tatemichi, Masayuki

    2018-04-01

    Hepatocellular carcinoma has extremely poor prognosis. In cancerous liver tissues, aberrant proliferation of cancer cells leads to the creation of an area where an immature vascular network is formed. Since oxygen is supplied to cancer tissues through the bloodstream, a part of the tumor is exposed to hypoxic conditions. As hypoxia is known to severely reduce the effectiveness of existing anticancer agents, novel valid therapeutic targets must be identified for the treatment of hepatocellular carcinoma. Generally, autophagy has been reported to play an important role in the adaptation of cancer cells to hypoxia. However, the exact role and significance of this process vary depending on the cancer type, requiring detailed analysis in individual primary tumors and cell lines. In the present study, we examined autophagy induced by cobalt chloride, a hypoxia‑mimicking agent, in hepatocellular carcinoma cells with the aim to evaluate the validity of this process as a potential therapeutic target. We observed that treatment with cobalt chloride induced autophagy, including the intracellular quality control mechanism, in an AMPK‑dependent manner. Furthermore, treatment with autophagy inhibitors (bafilomycin and LY294002) resulted in significant, highly‑selective cytotoxicity and apoptosis activation under hypoxia‑mimicking conditions. The knockdown of AMPK also revealed significant cytotoxicity in hypoxia‑mimicking conditions. These results clearly demonstrated that autophagy, especially mitophagy, was induced by the AMPK pathway when hepatocellular carcinoma cells were subjected to hypoxic conditions and played an important role in the adaptation of these cells to such conditions. Thus, autophagy may constitute an attractive therapeutic target for the treatment of hepatocellular carcinoma.

  14. Inhibition of miR-155, a therapeutic target for breast cancer, prevented in cancer stem cell formation.

    Zuo, Jiangcheng; Yu, Yalan; Zhu, Man; Jing, Wei; Yu, Mingxia; Chai, Hongyan; Liang, Chunzi; Tu, Jiancheng

    2018-02-06

    Breast cancer is a common cancer in women of worldwide. Cancer cells with stem-like properties played important roles in breast cancer, such as relapse, metastasis and treatment resistance. Micro-RNA-155 (miR-155) is a well-known oncogenic miRNA overexpressed in many human cancers. The expression levels of miR-155 in 38 pairs of cancer tissues and adjacent normal tissues from breast cancer patients were detected using quantitative real-time PCR. The invasive cell line MDA-MB-231 was used to quantify the expression of miR-155 by tumor-sphere forming experiment. Soft agar colony formation assay and tumor xenografts was used to explore whether the inhibition of miR-155 could reduce proliferation of cancer cells in vivo and vitro. In the study, we found miR-155 was upregulated in BC. Soft agar colony formation assay and tumor xenografts showed inhibition of miR-155 could significantly reduce proliferation of cancer cells in vivo and vitro, which confirmed that miR-155 is an effective therapeutic target of breast cancer. Sphere-forming experiment showed that overexpression of miR-155 significantly correlated with stem-like properties. Expressions of ABCG2, CD44 and CD90 were repressed by inhibition of miR-155, but CD24 was promoted. Interestingly, inhibition of miR-155 rendered MDA-MB-231 cells more sensitive to Doxorubicinol, which resulted in an increase of inhibition rate from 20.23% to 68.72%. Expression of miR-155 not only was a therapeutic target but also was associated with cancer stem cell formation and Doxorubicinol sensitivity. Our results underscore the importance of miR-155 as a therapeutic target and combination of Doxorubicinol and miR-155-silencing would be a potential way to cure breast cancer.

  15. Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma.

    Vig, Navin; Mackenzie, Ian C; Biddle, Adrian

    2015-10-01

    It is increasingly recognised that phenotypic plasticity, apparently driven by epigenetic mechanisms, plays a key role in tumour behaviour and markedly influences the important processes of therapeutic survival and metastasis. An important source of plasticity in malignancy is epithelial-to-mesenchymal transition (EMT), a common epigenetically controlled event that results in transition of malignant cells between different phenotypic states that confer motility and enhance survival. In this review, we discuss the importance of phenotypic plasticity and its contribution to cellular heterogeneity in oral squamous cell carcinoma with emphasis on aspects of drug resistance and EMT. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

    Wagner, Florence F; Lundh, Morten; Kaya, Taner

    2016-01-01

    Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series...... of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology...... pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes....

  17. Ground Zero in the Debate over Stem-Cell Research.

    Southwick, Ron

    2001-01-01

    Describes how political, legal, and ethical battles over embryonic stem-cell research are focused on the University of Wisconsin at Madison, where the cells were first isolated. Addresses the issue of access to the university's stem cells and a recent presidential decision regarding funding for stem-cell research.(EV)

  18. Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities.

    Xiong, Ye; Mahmood, Asim; Chopp, Michael

    2018-04-24

    Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI. Copyright © 2018 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  19. Musings on genome medicine: is there hope for ethical and safe stem cell therapeutics?

    Rao, Mahendra; Condic, Maureen L

    2009-01-01

    Although most stem cell therapy has been non-controversial, therapy based on pluripotent stem cells has raised both ethical and safety concerns. Despite these concerns, the use of cells derived from pluripotent stem cells has recently been approved for clinical trials. We suggest that recent advances in the field have provided avenues to develop pluripotent cells that raise far fewer ethical concerns. Moreover, advances in cell sorting, gene modification and screening have allowed the develop...

  20. Receptor tyrosine kinase (c-Kit inhibitors: a potential therapeutic target in cancer cells

    Abbaspour Babaei M

    2016-08-01

    Full Text Available Maryam Abbaspour Babaei,1 Behnam Kamalidehghan,2,3 Mohammad Saleem,4–6 Hasniza Zaman Huri,1,7 Fatemeh Ahmadipour1 1Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB, Shahrak-e Pajoohesh, 3Medical Genetics Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Department of Urology, 5Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, 6Section of Molecular Therapeutics & Cancer Health Disparity, The Hormel Institute, Austin, MN, USA; 7Clinical Investigation Centre, University Malaya Medical Centre, Lembah Pantai, Kuala Lumpur, Malaysia Abstract: c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c

  1. Ethical, legal and practical issues of establishing an adipose stem cell bank for research.

    West, C C; Murray, I R; González, Z N; Hindle, P; Hay, D C; Stewart, K J; Péault, B

    2014-06-01

    Access to human tissue is critical to medical research, however the laws and regulations surrounding gaining ethical and legal access to tissue are often poorly understood. Recently, there has been a huge increase in the interest surrounding the therapeutic application of adipose tissue, and adipose-derived stem cells. To facilitate our own research interests and possibly assist our local colleagues and collaborators, we established a Research Tissue Bank (RTB) to collect, store and distribute human adipose tissue derived cells with all the appropriate ethical approval for subsequent downstream research. Here we examine the legal, ethical and practical issues relating to the banking of adipose tissue for research in the UK, and discuss relevant international guidelines and policies. We also share our experiences of establishing an RTB including the necessary infrastructure and the submission of an application to a Research Ethics Committee (REC). Copyright © 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  2. Potential therapeutic applications of biosurfactants.

    Gudiña, Eduardo J; Rangarajan, Vivek; Sen, Ramkrishna; Rodrigues, Lígia R

    2013-12-01

    Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface activity, these molecules interact with cell membranes of several organisms and/or with the surrounding environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for therapeutic purposes, providing new directions towards the discovery and development of molecules with novel structures and diverse functions for advanced applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. A Survey of Italian Physicians' Opinion about Stem Cells Research: What Doctors Prefer and What the Law Requires

    Frati, Paola; Gulino, Matteo; Pacchiarotti, Arianna; D'Errico, Stefano; Sicuro, Lorella; Fineschi, Vittorio

    2014-01-01

    To evaluate the Italian physicians' knowledge/information level about the therapeutic potential of stem cells, the research choice between embryonic and cordonal stem cells, and the preference between autologous and heterologous storage of cordonal stem cells, we performed a national survey. The questionnaire—distributed to 3361 physicians—involved physicians of different religious orientations and of different medical specialities. Most of the physicians involved (67%) were Catholics, and th...

  4. Generation, characterization and potential therapeutic applications of mature and functional hepatocytes from stem cells.

    Zhang, Zhenzhen; Liu, Jianfang; Liu, Yang; Li, Zheng; Gao, Wei-Qiang; He, Zuping

    2013-02-01

    Liver cancer is the sixth most common tumor in the world and the majority of patients with this disease usually die within 1 year. The effective treatment for end-stage liver disease (also known as liver failure), including liver cancer or cirrhosis, is liver transplantation. However, there is a severe shortage of liver donors worldwide, which is the major handicap for the treatment of patients with liver failure. Scarcity of liver donors underscores the urgent need of using stem cell therapy to the end-stage liver disease. Notably, hepatocytes have recently been generated from hepatic and extra-hepatic stem cells. We have obtained mature and functional hepatocytes from rat hepatic stem cells. Here, we review the advancements on hepatic differentiation from various stem cells, including hepatic stem cells, embryonic stem cells, the induced pluripotent stem cells, hematopoietic stem cells, mesenchymal stem cells, and probably spermatogonial stem cells. The advantages, disadvantages, and concerns on differentiation of these stem cells into hepatic cells are highlighted. We further address the methodologies, phenotypes, and functional characterization on the differentiation of numerous stem cells into hepatic cells. Differentiation of stem cells into mature and functional hepatocytes, especially from an extra-hepatic stem cell source, would circumvent the scarcity of liver donors and human hepatocytes, and most importantly it would offer an ideal and promising source of hepatocytes for cell therapy and tissue engineering in treating liver disease. Copyright © 2012 Wiley Periodicals, Inc.

  5. Current research into brain barriers and the delivery of therapeutics for neurological diseases

    Greenwood, John; Hammarlund-Udenaes, Margareta; Jones, Hazel C

    2017-01-01

    This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consi...

  6. Computerized clinical decision support systems for therapeutic drug monitoring and dosing: A decision-maker-researcher partnership systematic review

    Weise-Kelly Lorraine

    2011-08-01

    Full Text Available Abstract Background Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing. Methods We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (i.e., CCDSS showed improvement if at least 50% of the relevant study outcomes were statistically significantly positive. Results Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14, insulin (6, theophylline/aminophylline (4, aminoglycosides (3, digoxin (2, lidocaine (1, or as part of a multifaceted approach (3. Cluster randomization was rarely used (18% and CCDSSs were usually stand-alone systems (76% primarily used by physicians (85%. Overall, 18 of 30 studies (60% showed an improvement in the process of care and 4 of 19 (21% an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range. Conclusions CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing

  7. Improving the Post-Stroke Therapeutic Potency of Mesenchymal Multipotent Stromal Cells by Cocultivation With Cortical Neurons: The Role of Crosstalk Between Cells.

    Babenko, Valentina A; Silachev, Denis N; Zorova, Ljubava D; Pevzner, Irina B; Khutornenko, Anastasia A; Plotnikov, Egor Y; Sukhikh, Gennady T; Zorov, Dmitry B

    2015-09-01

    The goal of the present study was to maximally alleviate the negative impact of stroke by increasing the therapeutic potency of injected mesenchymal multipotent stromal cells (MMSCs). To pursue this goal, the intercellular communications of MMSCs and neuronal cells were studied in vitro. As a result of cocultivation of MMSCs and rat cortical neurons, we proved the existence of intercellular contacts providing transfer of cellular contents from one cell to another. We present evidence of intercellular exchange with fluorescent probes specifically occupied by cytosol with preferential transfer from neurons toward MMSCs. In contrast, we observed a reversed transfer of mitochondria (from MMSCs to neural cells). Intravenous injection of MMSCs in a postischemic period alleviated the pathological indexes of a stroke, expressed as a lower infarct volume in the brain and partial restoration of neurological status. Also, MMSCs after cocultivation with neurons demonstrated more profound neuroprotective effects than did unprimed MMSCs. The production of the brain-derived neurotrophic factor was slightly increased in MMSCs, and the factor itself was redistributed in these cells after cocultivation. The level of Miro1 responsible for intercellular traffic of mitochondria was increased in MMSCs after cocultivation. We conclude that the exchange by cellular compartments between neural and stem cells improves MMSCs' protective abilities for better rehabilitation after stroke. This could be used as an approach to enhance the therapeutic benefits of stem cell therapy to the damaged brain. The idea of priming stem cells before practical use for clinical purposes was applied. Thus, cells were preconditioned by coculturing them with the targeted cells (i.e., neurons for the treatment of brain pathological features) before the transfusion of stem cells to the organism. Such priming improved the capacity of stem cells to treat stroke. Some additional minimal study will be required to

  8. An Official American Thoracic Society Research Statement : Current Challenges Facing Research and Therapeutic Advances in Airway Remodeling

    Prakash, Y S; Halayko, Andrew J; Gosens, Reinoud; Panettieri Jr., Reynold A; Camoretti-Mercado, Blanca; Penn, Raymond B; Burgess, Janette K

    2017-01-01

    BACKGROUND: Airway remodeling (AR) is a prominent feature of asthma and other obstructive lung diseases that is minimally affected by current treatments. The goals of this Official American Thoracic Society (ATS) Research Statement are to discuss the scientific, technological, economic, and

  9. Therapeutic immunization strategies against cervical cancer : induction of cell-mediated immunity in murine models

    Bungener, Laura Barbara

    2004-01-01

    The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high

  10. TRPV2 activation induces apoptotic cell death in human T24 bladder cancer cells: a potential therapeutic target for bladder cancer.

    Yamada, Takahiro; Ueda, Takashi; Shibata, Yasuhiro; Ikegami, Yosuke; Saito, Masaki; Ishida, Yusuke; Ugawa, Shinya; Kohri, Kenjiro; Shimada, Shoichi

    2010-08-01

    To investigate the functional expression of the transient receptor potential vanilloid 2 (TRPV2) channel protein in human urothelial carcinoma (UC) cells and to determine whether calcium influx into UC cells through TRPV2 is involved in apoptotic cell death. The expression of TRPV2 mRNA in bladder cancer cell lines (T24, a poorly differentiated UC cell line and RT4, a well-differentiated UC cell line) was analyzed using reverse transcriptase-polymerase chain reaction. The calcium permeability of TRPV2 channels in T24 cells was investigated using a calcium imaging assay that used cannabidiol (CBD), a relatively selective TRPV2 agonist, and ruthenium red (RuR), a nonselective TRPV channel antagonist. The death of T24 or RT4 cells in the presence of CBD was evaluated using a cellular viability assay. Apoptosis of T24 cells caused by CBD was confirmed using an annexin-V assay and small interfering RNA (siRNA) silencing of TRPV2. TRPV2 mRNA was abundantly expressed in T24 cells. The expression level in UC cells was correlated with high-grade disease. The administration of CBD increased intracellular calcium concentrations in T24 cells. In addition, the viability of T24 cells progressively decreased with increasing concentrations of CBD, whereas RT4 cells were mostly unaffected. Cell death occurred via apoptosis caused by continuous influx of calcium through TRPV2. TRPV2 channels in UC cells are calcium-permeable and the regulation of calcium influx through these channels leads directly to the death of UC cells. TRPV2 channels in UC cells may be a potential new therapeutic target, especially in higher-grade UC cells. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Drug-releasing nano-engineered titanium implants: therapeutic efficacy in 3D cell culture model, controlled release and stability

    Gulati, Karan [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia); Kogawa, Masakazu; Prideaux, Matthew; Findlay, David M. [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Atkins, Gerald J., E-mail: gerald.atkins@adelaide.edu.au [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Losic, Dusan, E-mail: dusan.losic@adelaide.edu.au [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia)

    2016-12-01

    There is an ongoing demand for new approaches for treating localized bone pathologies. Here we propose a new strategy for treatment of such conditions, via local delivery of hormones/drugs to the trauma site using drug releasing nano-engineered implants. The proposed implants were prepared in the form of small Ti wires/needles with a nano-engineered oxide layer composed of array of titania nanotubes (TNTs). TNTs implants were inserted into a 3D collagen gel matrix containing human osteoblast-like, and the results confirmed cell migration onto the implants and their attachment and spread. To investigate therapeutic efficacy, TNTs/Ti wires loaded with parathyroid hormone (PTH), an approved anabolic therapeutic for the treatment of severe bone fractures, were inserted into 3D gels containing osteoblast-like cells. Gene expression studies revealed a suppression of SOST (sclerostin) and an increase in RANKL (receptor activator of nuclear factor kappa-B ligand) mRNA expression, confirming the release of PTH from TNTs at concentrations sufficient to alter cell function. The performance of the TNTs wire implants using an example of a drug needed at relatively higher concentrations, the anti-inflammatory drug indomethacin, is also demonstrated. Finally, the mechanical stability of the prepared implants was tested by their insertion into bovine trabecular bone cores ex vivo followed by retrieval, which confirmed the robustness of the TNT structures. This study provides proof of principle for the suitability of the TNT/Ti wire implants for localized bone therapy, which can be customized to cater for specific therapeutic requirements. - Highlights: • Ti wire with titania nanotubes (TNTs) are proposed as ‘in-bone’ therapeutic implants. • 3D cell culture model is used to confirm therapeutic efficacy of drug releasing implants. Osteoblasts migrated and firmly attached to the TNTs and the micro-scale cracks. • Tailorable drug loading from few nanograms to several hundred

  12. Cure therapeutics and strategic prevention: raising the bar for mental health research.

    Insel, T R; Scolnick, E M

    2006-01-01

    Mental disorders cause more disability than any other class of medical illness in Americans between ages 15 and 44 years. The suicide rate is higher than the annual mortality from homicide, AIDS, and most forms of cancer. In contrast to nearly all communicable and most non-communicable diseases, there is little evidence that the morbidity and mortality from mental disorders have changed in the past several decades. Mental health advocates, including psychiatric researchers, have pointed to stigma as one of the reasons for the lack of progress with mental illnesses relative to other medical illnesses. This review considers how the expectations and goals of the research community have contributed to this relative lack of progress. In contrast to researchers in cancer and heart disease who have sought cures and preventions, biological psychiatrists in both academia and industry have set their sights on incremental and marketable advances, such as drugs with fewer adverse effects. This essay argues for approaches that can lead to cures and strategies for prevention of schizophrenia and mood disorders.

  13. Targeting of tolerogenic dendritic cells towards heat-shock proteins: a novel therapeutic strategy for autoimmune diseases?

    Jansen, Manon A A; Spiering, Rachel; Broere, Femke; van Laar, Jacob M; Isaacs, John D; van Eden, Willem; Hilkens, Catharien M U

    2018-01-01

    Tolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens. © 2017 John Wiley & Sons Ltd.

  14. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via fcg receptor-mediated cross-linking

    Overdijk, Marije B.; Jansen, J. H. Marco; Nederend, Maaike

    2016-01-01

    RIIb as well as activating FcgRs induce DARA cross-linking-mediated PCD. In conclusion, our in vitro and in vivo data show that FcgRmediated cross-linking of DARA induces PCD of CD38-expressing multiple myeloma tumor cells, which potentially contributes to the depth of response observed in DARA......Emerging evidence suggests that FcgR-mediated cross-linking of tumor-bound mAbs may induce signaling in tumor cells that contributes to their therapeutic activity. In this study, we show that daratumumab (DARA), a therapeutic human CD38 mAb with a broad-spectrum killing activity, is able to induce...... programmed cell death (PCD) of CD38+ multiple myeloma tumor cell lines when cross-linked in vitro by secondary Abs or via an FcgR. By comparing DARA efficacy in a syngeneic in vivo tumor model using FcRg-chain knockout or NOTAM mice carrying a signaling-inactive FcRg-chain, we found that the inhibitory Fcg...

  15. Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy.

    Weiss, Glen J; Beck, Julia; Braun, Donald P; Bornemann-Kolatzki, Kristen; Barilla, Heather; Cubello, Rhiannon; Quan, Walter; Sangal, Ashish; Khemka, Vivek; Waypa, Jordan; Mitchell, William M; Urnovitz, Howard; Schütz, Ekkehard

    2017-09-01

    Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum-derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers. Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed. Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs. Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074-81. ©2017 AACR . ©2017 American Association for Cancer Research.

  16. Deciphering the therapeutic stem cell strategies of large and midsize pharmaceutical firms.

    Vertès, Alain A

    2014-01-01

    The slow adoption of cytotherapeutics remains a vexing hurdle given clinical progress achieved to date with a variety of stem cell lineages. Big and midsize pharmaceutical companies as an asset class still delay large-scale investments in this arena until technological and market risks will have been further reduced. Nonetheless, a handful of stem cell strategic alliance and licensing transactions have already been implemented, indicating that progress is actively monitored, although most of these involve midsize firms. The greatest difficulty is, perhaps, that the regenerative medicine industry is currently only approaching the point of inflexion of the technology development S-curve, as many more clinical trials read out. A path to accelerating technology adoption is to focus on innovation outliers among healthcare actors. These can be identified by analyzing systemic factors (e.g., national science policies and industry fragmentation) and intrinsic factors (corporate culture, e.g., nimble decision-making structures; corporate finance, e.g., opportunity costs and ownership structure; and operations, e.g., portfolio management strategies, threats on existing businesses and patent expirations). Another path is to accelerate the full clinical translation and commercialization of an allogeneic cytotherapeutic product in any indication to demonstrate the disease-modifying potential of the new products for treatment and prophylaxis, ideally for a large unmet medical need such as dry age-related macular degeneration, or for an orphan disease such as biologics-refractory acute graft-versus-host disease. In times of decreased industry average research productivities, regenerative medicine products provide important prospects for creating new franchises with a market potential that could very well mirror that achieved with the technology of monoclonal antibodies.

  17. Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.

    Hisamatsu, Takeshi; Mabuchi, Seiji; Matsumoto, Yuri; Kawano, Mahiru; Sasano, Tomoyuki; Takahashi, Ryoko; Sawada, Kenjiro; Ito, Kimihiko; Kurachi, Hirohisa; Schilder, Russell J; Testa, Joseph R; Kimura, Tadashi

    2013-07-01

    The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

  18. Comparison of different options for harvest of a therapeutic protein product from high cell density yeast fermentation broth.

    Wang, Alice; Lewus, Rachael; Rathore, Anurag S

    2006-05-05

    Recovery of therapeutic protein from high cell density yeast fermentations at commercial scale is a challenging task. In this study, we investigate and compare three different harvest approaches, namely centrifugation followed by depth filtration, centrifugation followed by filter-aid enhanced depth filtration, and microfiltration. This is achieved by presenting a case study involving recovery of a therapeutic protein from Pichia pastoris fermentation broth. The focus of this study is on performance of the depth filtration and the microfiltration steps. The experimental data has been fitted to the conventional models for cake filtration to evaluate specific cake resistance and cake compressibility. In the case of microfiltration, the experimental data agrees well with flux predicted by shear induced diffusion model. It is shown that, under optimal conditions, all three options can deliver the desired product recovery ( >80%), harvest time ( making a final decision on a harvesting approach.

  19. Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension

    Lim, Jisun; Kim, YongHwan; Heo, Jinbeom; Kim, Kang-Hyun; Lee, Seungun; Lee, Sei Won; Kim, Kyunggon; Kim, In-Gyu; Shin, Dong-Myung

    2016-01-01

    Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called “priming” factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK p42/44 and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients. - Highlights: • Human BM-derived MSCs primed with C1P have enhanced migratory activity. • C1P primed MSCs increase proliferation, self-renewal, and anti-inflammatory capacity. • C1P priming enhances the therapeutic capacity of MSCs in a PAH animal model.

  20. Priming with ceramide-1 phosphate promotes the therapeutic effect of mesenchymal stem/stromal cells on pulmonary artery hypertension

    Lim, Jisun [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Physiology, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505 (Korea, Republic of); Kim, YongHwan; Heo, Jinbeom; Kim, Kang-Hyun; Lee, Seungun [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Physiology, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Lee, Sei Won [Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Kyunggon [Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Clinical Proteomics Core Lab, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, In-Gyu, E-mail: igkim@plaza.snu.ac.kr [Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505 (Korea, Republic of); Shin, Dong-Myung, E-mail: d0shin03@amc.seoul.kr [Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Physiology, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2016-04-22

    Some molecules enriched in damaged organs can contribute to tissue repair by stimulating the mobilization of stem cells. These so-called “priming” factors include bioactive lipids, complement components, and cationic peptides. However, their therapeutic significance remains to be determined. Here, we show that priming of mesenchymal stromal/stem cells (MSCs) with ceramide-1 phosphate (C1P), a bioactive lipid, enhances their therapeutic efficacy in pulmonary artery hypertension (PAH). Human bone marrow (BM)-derived MSCs treated with 100 or 200 μM C1P showed improved migration activity in Transwell assays compared with non-primed MSCs and concomitantly activated MAPK{sup p42/44} and AKT signaling cascades. Although C1P priming had little effect on cell surface marker phenotypes and the multipotency of MSCs, it potentiated their proliferative, colony-forming unit-fibroblast, and anti-inflammatory activities. In a monocrotaline-induced PAH animal model, a single administration of human MSCs primed with C1P significantly attenuated the PAH-related increase in right ventricular systolic pressure, right ventricular hypertrophy, and thickness of α-smooth muscle actin-positive cells around the vessel wall. Thus, this study shows that C1P priming increases the effects of MSC therapy by enhancing the migratory, self-renewal, and anti-inflammatory activity of MSCs and that MSC therapy optimized with priming protocols might be a promising option for the treatment of PAH patients. - Highlights: • Human BM-derived MSCs primed with C1P have enhanced migratory activity. • C1P primed MSCs increase proliferation, self-renewal, and anti-inflammatory capacity. • C1P priming enhances the therapeutic capacity of MSCs in a PAH animal model.

  1. Yoga as a Therapeutic Intervention: A Bibliometric Analysis of Published Research Studies from 1967 to 2013

    Slutsky, Jeremiah; Singh, Nilkamal; Khalsa, Sat Bir S.

    2015-01-01

    Abstract Objective: A comprehensive bibliometric analysis was conducted on publications for yoga therapy research in clinical populations. Methods: Major electronic databases were searched for articles in all languages published between 1967 and 2013. Databases included PubMed, PsychInfo, MEDLINE, IndMed, Indian Citation Index, Index Medicus for South-East Asia Region, Web of Knowledge, Embase, EBSCO, and Google Scholar. Nonindexed journals were searched manually. Key search words included yoga, yoga therapy, pranayama, asana. All studies met the definition of a clinical trial. All styles of yoga were included. The authors extracted the data. Results: A total of 486 articles met the inclusion criteria and were published in 217 different peer-reviewed journals from 29 different countries on 28,080 study participants. The primary result observed is the three-fold increase in number of publications seen in the last 10 years, inclusive of all study designs. Overall, 45% of the studies published were randomized controlled trials, 18% were controlled studies, and 37% were uncontrolled studies. Most publications originated from India (n=258), followed by the United States (n=122) and Canada (n=13). The top three disorders addressed by yoga interventions were mental health, cardiovascular disease, and respiratory disease. Conclusion: A surge in publications on yoga to mitigate disease-related symptoms in clinical populations has occurred despite challenges facing the field of yoga research, which include standardization and limitations in funding, time, and resources. The population at large has observed a parallel surge in the use of yoga outside of clinical practice. The use of yoga as a complementary therapy in clinical practice may lead to health benefits beyond traditional treatment alone; however, to effect changes in health care policy, more high-quality, evidence-based research is needed. PMID:26196166

  2. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions

    Catherine Tomaro-Duchesneau

    2013-01-01

    Full Text Available Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed.

  3. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions

    Saha, Shyamali; Malhotra, Meenakshi; Kahouli, Imen; Prakash, Satya

    2013-01-01

    Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed. PMID:26555963

  4. Nanovectors for Targeting and Delivery of Therapeutics to HER-2 NEU Positive Breast Cancer Cells

    Serda, Rita E

    2008-01-01

    Nanofabricated devices designed to carry drug and contrast agents to breast cancer cells are surface modified with targeting moieties that recognize unique or abundantly expressed molecules on the surface of tumor cells...

  5. College Students' Conceptions of Stem Cells, Stem Cell Research, and Cloning

    Concannon, James P.; Siegel, Marcelle A.; Halverson, Kristy; Freyermuth, Sharyn

    2010-01-01

    In this study, we examined 96 undergraduate non-science majors' conceptions of stem cells, stem cell research, and cloning. This study was performed at a large, Midwest, research extensive university. Participants in the study were asked to answer 23 questions relating to stem cells, stem cell research, and cloning in an on-line assessment before…

  6. [Max Weber's disease. Research on the disease and therapeutic management at the turn of the century].

    Frommer, J; Frommer, S

    1998-05-01

    This article on the German economist and sociologist Max Weber (1864-1920) continues our pathographic and psychohistoric studies on the interrelations between his life, his illness, and his work on "Protestantic Ethics and the Spirit of Capitalism". In a former paper (Frommer u. Frommer, 1993) we focussed on Weber's definition of modern society as an "iron cage" determined by Western rationalism. His theory, which shows that this cultural background demands a great amount of role conformity from the individual, converges with current psychopathological approaches on the personality of depressed patients. In the second article we report on results of our research on further personal documents, and some medical certificates by Weber's physicians. These documents demonstrate the diagnosis of a severe depression in a narcisstic and hypernomic personality.

  7. Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm.

    Philippe, Laure; Ceroi, Adam; Bôle-Richard, Elodie; Jenvrin, Alizée; Biichle, Sabeha; Perrin, Sophie; Limat, Samuel; Bonnefoy, Francis; Deconinck, Eric; Saas, Philippe; Garnache-Ottou, Francine; Angelot-Delettre, Fanny

    2017-11-01

    Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals' survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged. Copyright© Ferrata Storti Foundation.

  8. ?Mesenchymal stem cells?: fact or fiction, and implications in their therapeutic use

    Robey, Pamela

    2017-01-01

    The concept of a post-natal “mesenchymal stem cell” (“MSC”) originated from studies focused on bone marrow stromal cells (BMSCs), which are non-hematopoietic adherent cells, a subset of which are skeletal stem cells (SSCs), able to form cartilage, bone, hematopoiesis-supportive stroma, and marrow adipocytes based on rigorous clonal and differentiation assays. Subsequently, it was speculated that BMSCs could form other mesodermal derivatives and even cell types from other germ layers. Based on...

  9. Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis*

    Dun, Matthew D.; Chalkley, Robert J.; Faulkner, Sam; Keene, Sheridan; Avery-Kiejda, Kelly A.; Scott, Rodney J.; Falkenby, Lasse G.; Cairns, Murray J.; Larsen, Martin R.; Bradshaw, Ralph A.; Hondermarck, Hubert

    2015-01-01

    Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and l-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation. PMID:26041846

  10. Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

    Cathcart, Mary-Clare

    2011-03-09

    Abstract Background Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease. Methods TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation\\/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.

  11. Immunophenotyping of Waldenstroms macroglobulinemia cell lines reveals distinct patterns of surface antigen expression: potential biological and therapeutic implications.

    Aneel Paulus

    Full Text Available Waldenströms macroglobulinemia (WM is a subtype of Non-Hodgkin's lymphoma in which the tumor cell population is markedly heterogeneous, consisting of immunoglobulin-M secreting B-lymphocytes, plasmacytoid lymphocytes and plasma cells. Due to rarity of disease and scarcity of reliable preclinical models, many facets of WM molecular and phenotypic architecture remain incompletely understood. Currently, there are 3 human WM cell lines that are routinely used in experimental studies, namely, BCWM.1, MWCL-1 and RPCI-WM1. During establishment of RPCI-WM1, we observed loss of the CD19 and CD20 antigens, which are typically present on WM cells. Intrigued by this observation and in an effort to better define the immunophenotypic makeup of this cell line, we conducted a more comprehensive analysis for the presence or absence of other cell surface antigens that are present on the RPCI-WM1 model, as well as those on the two other WM cell lines, BCWM.1 and MWCL-1. We examined expression of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers by flow cytometry analysis. RPCI-WM1 cells demonstrated decreased expression of CD19, CD20, and CD23 with enhanced expression of CD28, CD38 and CD184, antigens that were differentially expressed on BCWM.1 and MWCL-1 cells. Due to increased expression of CD184/CXCR4 and CD38, RPCI-WM1 represents a valuable model in which to study the effects anti-CXCR4 or anti-CD38 targeted therapies that are actively being developed for treatment of hematologic cancers. Overall, differences in surface antigen expression across the 3 cell lines may reflect the tumor clone population predominant in the index patients, from whom the cell lines were developed. Our analysis defines the utility of the most commonly employed WM cell lines as based on their immunophenotype profiles, highlighting unique differences that can be further studied for

  12. Targeting Midbodies in Ovarian Cancer Stem Cells as a Therapeutic Strategy

    2014-12-01

    Cell Biology 2013. 1Depto Genetica e Biologia Evolutiva, University of São Paulo, São Paulo, Brazil, 2Department of Cell and Developmental Biology...prevention, diagnosis, prognosis, treatment and /or rehabilitation of a disease, injury or condition , or to improve the quality of life. This list...Under these conditions , MKLP1-GFP+ MBds were degraded in MBd-rich HeLa cells but not in MBd-poor hRPE-1 cells indicating that MBd-poor cells

  13. Functional Genomics to Identify Therapeutic Targets in Cancer Stem Cells Using a Novel Murine CRPC Model

    2015-11-01

    age, serial CyTOF analyses using an expanded antibody panel of 17 surface markers (Supplementary Table S1) were performed on single cells from...CD19 + ), natural killer (NK) cells (CD45 + NK1.1 + ), dendritic cells (CD45 + CD11c + ), putative MDSCs (CD45 + CD11b + Gr1 + ), and macrophages...Fig.  S3C). This MDSC depletion was accompanied by an increase of CD8 + T cells (so-called killer T cells; Fig. 4A ), consistent with elimination

  14. Benefiting from 'evil': an incipient moral problem in human stem cell research.

    Green, Ronald M

    2002-11-01

    When does benefiting from others' wrongdoing effectively make one a moral accomplice in their evil deeds? If stem cell research lives up to its therapeutic promise, this question (which has previously cropped up in debates over fetal tissue research or the use of Nazi research data) is likely to become a central one for opponents of embryo destruction. I argue that benefiting from wrongdoing is prima facie morally wrong under any of three conditions: (1) when the wrongdoing is one's agent; (2) when acceptance of benefit directly encourages the repetition of the wrongful deed (even though no agency relationship is involved); and (3) when acceptance of a benefit legitimates a wrongful practice. I conclude by showing that, because of the ways in which most embryonic stem cell lines come into being, people who oppose embryo destruction may use human embryonic stem cells without incurring moral blame.

  15. Attitude of A Sample of Iranian Researchers toward The Future of Stem Cell Research.

    Lotfipanah, Mahdi; Azadeh, Fereydoon; Totonchi, Mehdi; Omani-Samani, Reza

    2018-10-01

    Stem cells that have unlimited proliferation potential as well as differentiation potency are considered to be a promising future treatment method for incurable diseases. The aim of the present study is to evaluate the future trend of stem cell researches from researchers' viewpoints. This was a cross-sectional descriptive study on researchers involved in stem cell research at Royan Institute. We designed a questionnaire using a qualitative study based on expert opinion and a literature review. Content validity was performed using three rounds of the Delphi method with experts. Face validity was undertaken by a Persian literature expert and a graphics designer. The questionnaire was distributed among 150 researchers involved in stem cell studies in Royan Institute biology laboratories. We collected 138 completed questionnaires. The mean age of participants was 31.13 ± 5.8 years; most (60.9%) were females. Participants (76.1%) considered the budget to be the most important issue in stem cell research, 79.7% needed financial support from the government, and 77.5% felt that charities could contribute substantially to stem cell research. A total of 90.6% of participants stated that stem cells should lead to commercial usage which could support future researches (86.2%). The aim of stem cell research was stipulated as increasing health status of the society according to 92.8% of the participants. At present, among cell types, importance was attached to cord blood and adult stem cells. Researchers emphasized the importance of mesenchymal stem cells (MSCs) rather than hematopoietic stem cells (HSCs, 57.73%). The prime priorities were given to cancer so that stem cell research could be directed to sphere stem cell research whereas the least preference was given to skin research. Regenerative medicine is considered the future of stem cell research with emphasis on application of these cells, especially in cancer treatment. Copyright© by Royan Institute. All rights

  16. Potential Therapeutic Roles of Tanshinone IIA in Human Bladder Cancer Cells

    Sheng-Chun Chiu

    2014-09-01

    Full Text Available Tanshinone IIA (Tan-IIA, one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer.

  17. Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

    Nigel G. Kooreman

    2017-08-01

    Full Text Available There is growing interest in using embryonic stem cell (ESC and induced pluripotent stem cell (iPSC derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an “allogenized” mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.

  18. Proliferation differentiation and therapeutic effect of short-term cultured murine bone marrow cells

    Zhao Zekun; Cong Jianbo

    1986-01-01

    Murine bone marrow cells were cultured in conditioned medium of muscle. After 24 hours of culture, both adherent and suspended cells appeared in the culture. The adherent cells mainly consisted of macrophages and the suspended cells were predominantly granulocytes. After 6 days, the total number of nucleated cells and CFU-C in the culture increased about 400% and 600% respectively, but CFU-S reduced to 21% approximately. Lymphocytes persisted only for 4 days. The stem cells (CFU-S) from 6-day culture were injected into the lethally irradiated syngenic mice. The 30 day survival rate of the treated mice was 89% whereas that of the controls was only 7%. The bone marrow cells in 2/8 of recipients sacrificed at 30 or 60 days were of donor type and 6/8 of the recipients were chimeras

  19. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

    2011-01-01

    Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent. PMID:21299897

  20. Therapeutic Effect of CD4+CD25+ Regulatory T Cells Amplified In Vitro on Experimental Autoimmune Neuritis in Rats

    Feng-Jie Wang

    2018-05-01

    Full Text Available Background/Aims: This study aimed to explore whether the adoptive transfusion of autologous CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs has a therapeutic effect on Experimental autoimmune neuritis (EAN model rats, and it provides new experimental and theoretical bases for the immunotherapy of Guillain-Barre syndrome (GBS. Methods: CD4+CD25+ Tregs were sorted from the spleens of rats using immunomagnetic bead separation techniques combined with flow cytometry. Their in vitro inhibitory function was determined using a lymphocyte proliferation inhibition test, and their purity was confirmed by flow cytometry. Cells were stimulated using CD3/CD28 monoclonal antibodies and were cultured in culture medium containing interleukin 2 (IL-2, transforming growth factor-β (TGF-β and rapamycin. After 15 days of amplification, CD4+CD25+ Tregs were collected and transfused into EAN model rats. Changes in the pathology and electron microscopical morphology of rat sciatic nerves in the normal group, untreated group, low-dose group (2 × 107 and high-dose group (4 × 107 were observed, and the expression of CD4+CD25+FOXP3 in peripheral blood in the four groups of rats was detected by flow cytometry. Results: Compared with rats in the untreated group, rats in the treatment groups had significantly reduced infiltration of inflammatory cells in the sciatic nerve, as well as myelin and axonal damage. Additionally, the CD4+CD25+ Tregs levels in peripheral blood were significantly higher than those in the untreated group (P< 0. 05. Moreover, the therapeutic effect became more significant with an increase in the dose of adoptive transfusion. Conclusion: Adoptive transfusion of CD4+CD25+ Tregs into EAN model rats has significant therapeutic effects.

  1. Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases.

    Moral, Mario E G; Siahaan, Teruna J

    2017-01-01

    Overexpressed cell-surface receptors are hallmarks of many disease states and are often used as markers for targeting diseased cells over healthy counterparts. Cell adhesion peptides, which are often derived from interacting regions of these receptor-ligand proteins, mimic surfaces of intact proteins and, thus, have been studied as targeting agents for various payloads to certain cell targets for cancers and autoimmune diseases. Because many cytotoxic agents in the free form are often harmful to healthy cells, the use of cell adhesion peptides in targeting their delivery to diseased cells has been studied to potentially reduce required effective doses and associated harmful side-effects. In this review, multiple cell adhesion peptides from extracellular matrix and ICAM proteins were used to selectively direct drug payloads, signal-inhibitor peptides, and diagnostic molecules, to diseased cells over normal counterparts. RGD constructs have been used to improve the selectivity and efficacy of diagnostic and drug-peptide conjugates against cancer cells. From this precedent, novel conjugates of antigenic and cell adhesion peptides, called Bifunctional Peptide Inhibitors (BPIs), have been designed to selectively regulate immune cells and suppress harmful inflammatory responses in autoimmune diseases. Similar peptide conjugations with imaging agents have delivered promising diagnostic methods in animal models of rheumatoid arthritis. BPIs have also been shown to generate immune tolerance and suppress autoimmune diseases in animal models of type-1 diabetes, rheumatoid arthritis, and multiple sclerosis. Collectively, these studies show the potential of cell adhesion peptides in improving the delivery of drugs and diagnostic agents to diseased cells in clinical settings. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Mitochondrial protection impairs BET bromodomain inhibitor-mediated cell death and provides rationale for combination therapeutic strategies.

    Lasorsa, E; Smonksey, M; Kirk, J S; Rosario, S; Hernandez-Ilizaliturri, F J; Ellis, L

    2015-12-10

    Inhibitors of the bromodomain and extraterminal domain family (BETI) have recently entered phase I clinical trials. In patients with advanced leukemia's, potent antileukemia activity was displayed with minimum dose-limiting toxicity. In preclinical models of hematological malignancies, including aggressive B-cell lymphomas, BETI induced cell-cycle arrest and apoptosis. However, the underlying cell death mechanisms are still not well understood. Dissecting the mechanisms required by BETI to mediate cell death would provide strong direction on how to best utilize BETI to treat patients with aggressive hematological malignancies. Herein, we provide understanding of the molecular mechanisms underlying BETI-mediated cell death using I-BET762. Induction of cell death occurred in primary murine and human B-cell lymphomas through apoptosis. Genetic dissection using Eμ-myc B-cell lymphoma compound mutants demonstrated that I-BET762-induced apoptosis does not require the p53 pathway. Furthermore, deletion of Apaf1, and thus the absence of a functional apoptosome, is associated with a delayed drug response but do not provide long-term resistance. Prolonged treatment of this model in fact fails to suppress the therapeutic efficacy of the drug and is associated with biochemical features of autophagy. However, lack of mitochondrial permeability completely inhibited I-BET762-mediated tumor cell death, indicating mitochondrial damage as key events for its activity. Combination of I-BET762 with BH3-only mimetics ABT-263 or obatoclax, restored sensitivity to I-BET762 lymphoma killing; however, success was determined by expression of Bcl-2 family antiapoptotic proteins. Our study provides critical insight for clinical decisions regarding the appropriate strategy for using BETI as a single agent or in combination to treat patients with aggressive B-cell lymphomas.

  3. Determination of hemispheric emotional valence in individual subjects: A new approach with research and therapeutic implications

    Polcari Ann

    2007-03-01

    Full Text Available Abstract Background Much has been theorized about the emotional properties of the hemispheres. Our review of the dominant hypotheses put forth by Schore, Joseph, Davidson, and Harmon-Jones on hemispheric emotional valences (HEV shows that none are supported by robust data. Instead, we propose that individual's hemispheres are organized to have differing HEVs that can be lateralized in either direction. Methods Probe auditory evoked potentials (AEP recorded during a neutral and an upsetting memory were used to assess HEV in 28 (20 F right-handed subjects who were either victims of childhood maltreatment (N = 12 or healthy controls. In a sub-population, we determined HEV by emotional response to lateral visual field stimulation (LVFS, in which vision is limited to one, then the other hemifield. We compare a number of morphometric and functional brain measures between individuals who have right-negative versus left-negative HEV. Results Using AEPs to determine HEV, we found 62% of controls and 67% of maltreated subjects had right negative HEV. There was a strong interaction between HEV-laterality and gender, which together accounted for 60% of individual variability in total grey matter volume (GMV. HEV-laterality was associated with differences in hippocampal volume, amygdala/hippocampal ratios, and measures of verbal, visual and global memory. HEV-laterality was associated also with different constellations of symptoms comparing maltreated subjects to controls. Emotional response to LVFS provided a convenient and complementary measure of HEV-laterality that correlated significantly with the HEVs determined by AEPs. Conclusion Our findings suggest that HEV-laterality, like handedness or gender, is an important individual difference with significant implications for brain and behavioral research, and for guiding lateralized treatments such as rTMS.

  4. Determination of hemispheric emotional valence in individual subjects: a new approach with research and therapeutic implications.

    Schiffer, Fredric; Teicher, Martin H; Anderson, Carl; Tomoda, Akemi; Polcari, Ann; Navalta, Carryl P; Andersen, Susan L

    2007-03-06

    Much has been theorized about the emotional properties of the hemispheres. Our review of the dominant hypotheses put forth by Schore, Joseph, Davidson, and Harmon-Jones on hemispheric emotional valences (HEV) shows that none are supported by robust data. Instead, we propose that individual's hemispheres are organized to have differing HEVs that can be lateralized in either direction. Probe auditory evoked potentials (AEP) recorded during a neutral and an upsetting memory were used to assess HEV in 28 (20 F) right-handed subjects who were either victims of childhood maltreatment (N = 12) or healthy controls. In a sub-population, we determined HEV by emotional response to lateral visual field stimulation (LVFS), in which vision is limited to one, then the other hemifield. We compare a number of morphometric and functional brain measures between individuals who have right-negative versus left-negative HEV. Using AEPs to determine HEV, we found 62% of controls and 67% of maltreated subjects had right negative HEV. There was a strong interaction between HEV-laterality and gender, which together accounted for 60% of individual variability in total grey matter volume (GMV). HEV-laterality was associated with differences in hippocampal volume, amygdala/hippocampal ratios, and measures of verbal, visual and global memory. HEV-laterality was associated also with different constellations of symptoms comparing maltreated subjects to controls. Emotional response to LVFS provided a convenient and complementary measure of HEV-laterality that correlated significantly with the HEVs determined by AEPs. Our findings suggest that HEV-laterality, like handedness or gender, is an important individual difference with significant implications for brain and behavioral research, and for guiding lateralized treatments such as rTMS.

  5. A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer

    Madhusudana Girija Sanal

    2014-09-01

    Full Text Available Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC, we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient’s somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is

  6. Cryopreservation of human insulin expressing cells macro-encapsulated in a durable therapeutic immunoisolating device theracyte.

    Yakhnenko, Ilya; Wong, Wallace K; Katkov, Igor I; Itkin-Ansari, Pamela

    2012-01-01

    Encapsulating insulin producing cells (INPCs) in an immunoisolation device have been shown to cure diabetes in rodents without the need for immunosuppression. However, micro-encapsulation in semi-solid gels raises longevity and safety concerns for future use of stem cell derived INPCs. We have focused on a durable and retrievable macro-encapsulation (> 10(6) cells) device (TheraCyte). Cryopreservation (CP) of cells preloaded into the device is highly desirable but may require prolonged exposure to cryoprotectants during loading and post-thaw manipulations. Here, we are reporting survival and function of a human islet cell line frozen as single cells or as islet-like cell clusters. The non-clusterized cells exhibited high cryosurvival after prolonged pre-freeze or post-thaw exposure to 10 percent DMSO. However, both clusterization and especially loading INPCs into the device reduced viable yield even without CP. The survived cryopreserved macro-encapsulated INPCs remained fully functional suggesting that CP of macro-encapsulated cells is a promising tool for cell based therapies.

  7. Minimally invasive and targeted therapeutic cell delivery to the skin using microneedle devices.

    Gualeni, B; Coulman, S A; Shah, D; Eng, P F; Ashraf, H; Vescovo, P; Blayney, G J; Piveteau, L-D; Guy, O J; Birchall, J C

    2018-03-01

    Translation of cell therapies to the clinic is accompanied by numerous challenges, including controlled and targeted delivery of the cells to their site of action, without compromising cell viability and functionality. To explore the use of hollow microneedle devices (to date only used for the delivery of drugs and vaccines into the skin and for the extraction of biological fluids) to deliver cells into skin in a minimally invasive, user-friendly and targeted fashion. Melanocyte, keratinocyte and mixed epidermal cell suspensions were passed through various types of microneedles and subsequently delivered into the skin. Cell viability and functionality are maintained after injection through hollow microneedles with a bore size ≥ 75 μm. Healthy cells are delivered into the skin at clinically relevant depths. Hollow microneedles provide an innovative and minimally invasive method for delivering functional cells into the skin. Microneedle cell delivery represents a potential new treatment option for cell therapy approaches including skin repigmentation, wound repair, scar and burn remodelling, immune therapies and cancer vaccines. © 2017 British Association of Dermatologists.

  8. Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

    Xiong, J; Bian, J; Wang, L; Zhou, J-Y; Wang, Y; Zhao, Y; Wu, L-L; Hu, J-J; Li, B; Chen, S-J; Yan, C; Zhao, W-L

    2015-01-01

    Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways

  9. Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease

    Gu Qing

    2009-06-01

    Full Text Available Abstract Background New strategies for the treatment of Parkinson's disease (PD are shifted from dopamine (DA replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE cells as substitution for degenerated dopaminergic (DAergic neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA. Methods We evaluated the protective effects of conditioned medium (CM from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF and brain derived neurotrophic factor (BDNF released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR. Results We report here: (1 CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2 cultured RPE cells express L-dopa decarboxylase (DDC and synthesize DA; (3 RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4 GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues. Conclusion These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.

  10. Long-Term Therapeutic Effects of Mesenchymal Stem Cells Compared to Dexamethasone on Recurrent Experimental Autoimmune Uveitis of Rats

    Zhang, Lingjun; Zheng, Hui; Shao, Hui; Nian, Hong; Zhang, Yan; Bai, Lingling; Su, Chang; Liu, Xun; Dong, Lijie; Li, Xiaorong; Zhang, Xiaomin

    2014-01-01

    Purpose. We tested the long-term effects of different regimens of mesenchymal stem cell (MSC) administration in a recurrent experimental autoimmune uveitis (rEAU) model in rats, and compared the efficacy of MSC to that of dexamethasone (DEX). Methods. One or two courses of MSC treatments were applied to R16-specific T cell–induced rEAU rats before or after disease onsets. The DEX injections were given for 7 or 50 days continuously after disease onsets. Clinical appearances were observed until the 50th day after transfer. On the 10th day, T cells from control and MSC groups were analyzed by flow cytometry. Supernatants from the proliferation assay and aqueous humor were collected for cytokine detection. Functions of T cells and APCs in spleens also were studied by lymphocyte proliferation assays. Results. One course of MSC therapy, administered after disease onset, led to a lasting therapeutic effect, with a decreased incidence, reduced mean clinical score, and reduced retinal impairment after 50 days of observation, while multiple courses of treatment did not improve the therapeutic benefit. Although DEX and MSCs equally reduced the severity of the first episode of rEAU, the effect of DEX was shorter lasting, and DEX therapy failed to control the disease even with long periods of treatment. The MSCs significantly decreased T helper 1 (Th1) and Th17 responses, suppressed the function of antigen-presenting cells, and upregulated T regulatory cells. Conclusions. These results suggested that MSCs might be new corticosteroid spring agents, while providing fewer side effects and longer lasting suppressive effects for recurrent uveitis. PMID:25125599

  11. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

    Congcong Zhang

    2017-05-01

    Full Text Available Significant progress has been made in recent years toward realizing the potential of natural killer (NK cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future

  12. Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders

    Jensen, Bettina Margrethe; Akin, C; Gilfillan, A M

    2008-01-01

    within these tissues, mast cell activation by antigen may also be amplified by SCF. Thus, KIT inhibitors may have potential application in multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast...... cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders....

  13. Chemical Library Screening for Potential Therapeutics Using Novel Cell Based Models of ALS

    2017-06-01

    indicative of the parental cell lines. Upon isolation and qPCR we identified a few clonal populations that grow similarly to the parental nH9 cells... grow and maintain. The only additional step of note is that cell culture dishes must be coated with a biological matrix, such as Geltrex or...associated tremor/ataxia syndrome (FXTAS), spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, and C9ORF72-associated frontotemporal dementia

  14. Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

    2015-10-01

    cellularity of the bone marrow of the treated and control mice. The smears demonstrated the presence of heterogeneous cell types including the larger...were supplemented with IL-3, rhTPO (Kirin brewery ), and FLT3-L (Peprotech) cytokines. Cells were suspended at 3 x 103 concentration in one ml of...flushed with a 23G (0.45 × 10 mm) syringe needle to collect single- cell suspensions. Bone marrow sections and blood May-Grünwald-Giemsa–stained

  15. Current and Emerging Therapeutics for Cutaneous T-Cell Lymphoma: Histone Deacetylase Inhibitors

    Annabelle L. Rodd; Katherine Ververis; Tom C. Karagiannis

    2012-01-01

    Cutaneous T-cell lymphoma is a term that encompasses a spectrum of non-Hodgkin’s T-cell lymphomas with primary manifestations in the skin. It describes a heterogeneous group of neoplasms that are characterised by an accumulation of malignant T cells of the CD4 phenotype that have the propensity to home and accumulate in the skin, lymph nodes, and peripheral blood. The two most common variants of cutaneous T-cell lymphoma include mycosis fungoides and the leukemic variant, the Sézary syndrome....

  16. Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B

    Ndeboko, Bénédicte; Lemamy, Guy Joseph; Nielsen, Peter E

    2015-01-01

    , such as chitosan (CS), appear of particular interest as nonviral vectors due to their capacity to facilitate cellular delivery of bioactive cargoes including peptide nucleic acids (PNAs) or DNA vaccines. We have investigated the ability of a PNA conjugated to different CPPs to inhibit the replication of duck......-modified CS and cationic nanoparticles. The results showed that these nonviral vectors considerably increased plasmid DNA uptake and expression. Collectively promising results obtained in preclinical studies suggest the usefulness of these safe delivery systems for the development of novel therapeutics...

  17. A Survey of Italian Physicians' Opinion about Stem Cells Research: What Doctors Prefer and What the Law Requires

    Paola Frati

    2014-01-01

    Full Text Available To evaluate the Italian physicians' knowledge/information level about the therapeutic potential of stem cells, the research choice between embryonic and cordonal stem cells, and the preference between autologous and heterologous storage of cordonal stem cells, we performed a national survey. The questionnaire—distributed to 3361 physicians—involved physicians of different religious orientations and of different medical specialities. Most of the physicians involved (67% were Catholics, and the majority were gynaecologists and paediatricians (43% who are mainly in charge to inform future mothers about the possibility of cordonal stem cells conservation. The majority of the physicians interviewed do not have specific knowledge about stem cells (59%, most of them having only generic information (92%. The largest part of physicians prefer to use umbilical cord blood cells rather than embryonic stem cells. Nevertheless, a large percentage of physicians were in favour of embryo research, especially when embryos are supernumerary (44% versus 34%. Eighty-seven % of the physicians interviewed proved to have a general knowledge about stem cells and believe in their therapeutic potential. They prefer research on cordonal stem cells rather than on embryo stem cells. Although they are in favour of heterologous stem cells donation, they still prefer cryopreservation for personal use.

  18. A Novel Technique to Follow Consequences of Exogenous Factors, Including Therapeutic Drugs, on Living Human Breast Epithelial Cells

    1999-07-01

    and lipid vectors, are being tested. Concurrent with the development of procedures for live - cell imaging , we are examining the distribution of proteins...dimensional matrix. These studies have not yet begun. There are a number of procedures that must be developed and perfected in the live - cell imaging , as...components of the Wnt signaling pathway are too preliminary and require additional research prior to publication. (9) CONCLUSIONS Live cell imaging of

  19. Therapeutic potential of dental pulp stem cells in regenerative medicine: An overview

    Kavita Verma

    2014-01-01

    Full Text Available The purpose of this review is to gain an overview of the applications of the dental pulp stem cells (DPSCs in the treatment of various medical diseases. Stem cells have the capacity to differentiate and regenerate into various tissues. DPSCs are the adult stem cells that reside in the cell rich zone of the dental pulp. These are the multipotent cells that can be explained by their embryonic origin from the neural crest. Owing to this multipotency, these DPSCs can be used in both dental and medical applications. A review of literature has been performed using electronic and hand-searching methods for the medical applications of DPSCs. On the basis of the available information, DPSCs appear to be a promising alternative for the regeneration of tissues and treatment of various diseases, although, long-term clinical trials and studies are needed to confirm their efficacy.

  20. Aggressive NK-cell leukemia: A rare entity with diagnostic and therapeutic challenge

    Alia Nazarullah

    2016-06-01

    Full Text Available Aggressive natural killer cell leukemia (ANKL is a rare neoplasm of mature natural killer cells, with an extremely poor overall survival, which is almost always EBV related, with majority of cases reported in East Asia. Here we report the case of an ANKL presenting in a young Hispanic male with secondary hemophagocytosis. Aggressive clinical course, high EBV DNA levels and leukemic presentation, often with associated hemophagocytosis, should raise suspicion of an NK/T-cell neoplasm like ANKL. Due to significant diagnostic overlap with extranodal NK/T-cell lymphoma, nasal type (ENKL, accurate diagnostic classification is crucial due to differing treatment and prognosis. L-asparaginase including chemotherapy followed by allogeneic stem cell transplantation appears to slightly prolong overall survival, but relapse is almost inevitable. Clinical