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Sample records for adoptive cellular therapy

  1. Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy.

    PubMed

    Payne, Kyle K; Bear, Harry D; Manjili, Masoud H

    2014-08-01

    The mammalian immune system has evolved to produce multi-tiered responses consisting of both innate and adaptive immune cells collaborating to elicit a functional response to a pathogen or neoplasm. Immune cells possess a shared ancestry, suggestive of a degree of coevolution that has resulted in optimal functionality as an orchestrated and highly collaborative unit. Therefore, the development of therapeutic modalities that harness the immune system should consider the crosstalk between cells of the innate and adaptive immune systems in order to elicit the most effective response. In this review, the authors will discuss the success achieved using adoptive cellular therapy in the treatment of cancer, recent trends that focus on purified T cells, T cells with genetically modified T-cell receptors and T cells modified to express chimeric antigen receptors, as well as the use of unfractionated immune cell reprogramming to achieve optimal cellular crosstalk upon infusion for adoptive cellular therapy. PMID:25303057

  2. Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study

    PubMed Central

    Rikabi, Sarah; French, Anna; Pinedo-Villanueva, Rafael; Morrey, Mark E; Wartolowska, Karolina; Judge, Andrew; MacLaren, Robert E; Mathur, Anthony; Williams, David J; Wall, Ivan; Birchall, Martin; Reeve, Brock; Atala, Anthony; Barker, Richard W; Cui, Zhanfeng; Furniss, Dominic; Bure, Kim; Snyder, Evan Y; Karp, Jeffrey M; Price, Andrew; Carr, Andrew; Brindley, David A

    2014-01-01

    There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community. PMID:25383173

  3. Human Cytomegalovirus Antigens in Malignant Gliomas as Targets for Adoptive Cellular Therapy

    PubMed Central

    Landi, Daniel; Hegde, Meenakshi; Ahmed, Nabil

    2014-01-01

    Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year. Over the last decade, investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas, including glioblastoma (GBM). This discovery is significant because HCMV gene products can be targeted by immune-based therapies. In this review, we describe the current level of understanding regarding the presence and role in pathogenesis of HCMV in GBM. We describe our success detecting and expanding HCMV-specific cytotoxic T lymphocytes to kill GBM cells and explain how these cells can be used as a platform for enhanced cellular therapies. We discuss alternative approaches that capitalize on HCMV infection to treat patients with HCMV-positive tumors. Adoptive cellular therapy for HCMV-positive GBM has been tried in a small number of patients with some benefit, but we reason why, to date, these approaches generally fail to generate long-term remission or cure. We conjecture how cellular therapy for GBM can be improved and describe the barriers that must be overcome to cure these patients. PMID:25505736

  4. Modification of Expanded NK Cells with Chimeric Antigen Receptor mRNA for Adoptive Cellular Therapy.

    PubMed

    Chu, Yaya; Flower, Allyson; Cairo, Mitchell S

    2016-01-01

    NK cells are bone marrow-derived cytotoxic lymphocytes that play a major role in the rejection of tumors and cells infected by viruses. The regulation of NK activation vs inhibition is regulated by the expression of a variety of NK receptors (NKRs) and specific NKRs' ligands expressed on their targets. However, factors limiting NK therapy include small numbers of active NK cells in unexpanded peripheral blood and lack of specific tumor targeting. Chimeric antigen receptors (CAR) usually include a single-chain Fv variable fragment from a monoclonal antibody, a transmembrane hinge region, and a signaling domain such as CD28, CD3-zeta, 4-1BB (CD137), or 2B4 (CD244) endodimers. Redirecting NK cells with a CAR will circumvent the limitations of the lack of NK targeting specificity. This chapter focuses on the methods to expand human NK cells from peripheral blood by co-culturing with feeder cells and to modify the expanded NK cells efficiently with the in vitro transcribed CAR mRNA by electroporation and to test the functionality of the CAR-modified expanded NK cells for use in adoptive cellular immunotherapy. PMID:27177669

  5. Adoptive cell therapy for sarcoma

    PubMed Central

    Mata, Melinda; Gottschalk, Stephen

    2015-01-01

    Current therapy for sarcomas, though effective in treating local disease, is often ineffective for patients with recurrent or metastatic disease. To improve outcomes, novel approaches are needed and cell therapy has the potential to meet this need since it does not rely on the cytotoxic mechanisms of conventional therapies. The recent successes of T-cell therapies for hematological malignancies have led to renewed interest in exploring cell therapies for solid tumors such as sarcomas. In this review, we will discuss current cell therapies for sarcoma with special emphasis on genetic approaches to improve the effector function of adoptively transferred cells. PMID:25572477

  6. Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer.

    PubMed

    Paul, Sourav; Lal, Girdhari

    2016-09-01

    γδ T cells are an important innate immune component of the tumor microenvironment and are known to affect the immune response in a wide variety of tumors. Unlike αβ T cells, γδ T cells are capable of spontaneous secretion of IL-17A and IFN-γ without undergoing clonal expansion. Although γδ T cells do not require self-MHC-restricted priming, they can distinguish "foreign" or transformed cells from healthy self-cells by using activating and inhibitory killer Ig-like receptors. γδ T cells were used in several clinical trials to treat cancer patient due to their MHC-unrestricted cytotoxicity, ability to distinguish transformed cells from normal cells, the capacity to secrete inflammatory cytokines and also their ability to enhance the generation of antigen-specific CD8(+) and CD4(+) T cell response. In this review, we discuss the effector and regulatory function of γδ T cells in the tumor microenvironment with special emphasis on the potential for their use in adoptive cellular immunotherapy. PMID:27012367

  7. Adoptive Cell Therapies for Glioblastoma

    PubMed Central

    Bielamowicz, Kevin; Khawja, Shumaila; Ahmed, Nabil

    2013-01-01

    Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients (1). Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly “self,” it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer cells, natural killer cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts. PMID:24273748

  8. Cellular therapy for haematological malignancies.

    PubMed

    Roddie, P H; Turner, M L

    2002-11-01

    The aim of this review was to summarize the recent progress made in the field of cellular therapeutics in haematological malignancy. The review also examined the role that the National Transfusion Services might play in the manufacture of new cellular therapeutic agents, given both their expertise in the safe provision of blood products and their possession of accredited cell manipulation facilities. Cellular therapy is entering an era in which novel cellular products will find increasing clinical use, particularly in the areas of haematopoietic stem cell transplantation and immunotherapy. The production of novel cell-based therapies, both in Europe and North America, is now under strict regulatory control and therefore collaboration with the National Transfusion Services in the manufacture of these agents may well be beneficial if the production standards demanded by the regulatory authorities are to be fulfilled. PMID:12437515

  9. Predictors of Adopting Motivational Enhancement Therapy

    ERIC Educational Resources Information Center

    Ager, Richard; Roahen-Harrison, Stephanie; Toriello, Paul J.; Kissinger, Patricia; Morse, Patricia; Morse, Edward; Carney, Linton; Rice, Janet

    2011-01-01

    Substance abuse counselors have shown limited success in adopting evidence-based practices (EBPs). The purpose of this paper is to identify the barriers and facilitators of adopting an EBP called motivational enhancement therapy (MET). One hundred thirty-six predominantly female (60%) African American (68%) addiction counselors representing over…

  10. Adoptive T-cell therapy.

    PubMed

    Lokhorst, H M; Liebowitz, D

    1999-01-01

    Adoptive immunotherapy, or the transfer of immunocompetent cells, has been shown to be a promising new strategy for treatment of a variety of malignancies, including leukemia and non-Hodgkin's lymphoma. The possibility that it may likewise benefit patients with multiple myeloma is now being explored by researchers in Europe and the United States. Two alternatives, one using donor leukocyte infusions (DLIs) and the other using autologous T cells, are described. In the Netherlands, researchers studied the use of DLIs in 17 patients with multiple myeloma who relapsed after bone marrow transplant (BMT). Of 16 evaluable patients, 10 (62%) responded, with six (37%) achieving a complete response (CR). After a median follow-up duration of 28 months, five patients relapsed and five remained in remission. Graft-versus-host disease (GVHD) developed in nine patients. In the United States, adoptive immunotherapy is currently being tested in eight patients with chemotherapy-resistant lymphoma. Autologous T cells were obtained prior to BMT and expanded using an anti-CD3/CD28 culture system. After BMT, the cells were reinfused into the patient. At approximately day 14, granulocyte levels began to recover in the six evaluable patients, and levels remained relatively stable over the posttreatment course. Two patients developed severe autoimmune toxicity, which responded to treatment in one and resolved spontaneously in the other. PMID:9989486

  11. [Attachment and Adoption: Diagnostics, Psychopathology, and Therapy].

    PubMed

    Brisch, Karl-Heinz

    2015-01-01

    This presentation describes the development of attachment between adopted children and their adoptive parents with a focus on the particular issues seen in international adoptions. The questions of settling in, trauma in the country of origin, and the motivations of the adoptive parents will be discussed. Diagnosis and various psychopathological manifestations will be examined, as will outpatient and inpatient modes of therapy. The treatment of children of various ages will be covered along with the necessity for intensive counseling and psychotherapy for the adoptive parents. This will enable the parents to work through early trauma, which will give them and their adopted child the basis for developing healthy attachment patterns. This in turn will enable the child to mature and integrate into society. Possibilities of prevention are discussed. Many of the approaches discussed here regarding attachment and adoption may be applied to foster children and their foster parents. PMID:26645775

  12. Adoptive T-cell therapy for Leukemia.

    PubMed

    Garber, Haven R; Mirza, Asma; Mittendorf, Elizabeth A; Alatrash, Gheath

    2014-01-01

    Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high-affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We

  13. Cellular Therapy for Heart Failure.

    PubMed

    Psaltis, Peter J; Schwarz, Nisha; Toledo-Flores, Deborah; Nicholls, Stephen J

    2016-01-01

    The pathogenesis of cardiomyopathy and heart failure (HF) is underpinned by complex changes at subcellular, cellular and extracellular levels in the ventricular myocardium. For all of the gains that conventional treatments for HF have brought to mortality and morbidity, they do not adequately address the loss of cardiomyocyte numbers in the remodeling ventricle. Originally conceived to address this problem, cellular transplantation for HF has already gone through several stages of evolution over the past two decades. Various cell types and delivery routes have been implemented to positive effect in preclinical models of ischemic and nonischemic cardiomyopathy, with pleiotropic benefits observed in terms of myocardial remodeling, systolic and diastolic performance, perfusion, fibrosis, inflammation, metabolism and electrophysiology. To a large extent, these salubrious effects are now attributed to the indirect, paracrine capacity of transplanted stem cells to facilitate endogenous cardiac repair processes. Promising results have also followed in early phase human studies, although these have been relatively modest and somewhat inconsistent. This review details the preclinical and clinical evidence currently available regarding the use of pluripotent stem cells and adult-derived progenitor cells for cardiomyopathy and HF. It outlines the important lessons that have been learned to this point in time, and balances the promise of this exciting field against the key challenges and questions that still need to be addressed at all levels of research, to ensure that cell therapy realizes its full potential by adding to the armamentarium of HF management. PMID:27280304

  14. PET imaging of adoptive progenitor cell therapies.

    SciTech Connect

    Gelovani, Juri G.

    2008-05-13

    Objectives. The overall objective of this application is to develop novel technologies for non-invasive imaging of adoptive stem cell-based therapies with positron emission tomography (PET) that would be applicable to human patients. To achieve this objective, stem cells will be genetically labeled with a PET-reporter gene and repetitively imaged to assess their distribution, migration, differentiation, and persistence using a radiolabeled reporter probe. This new imaging technology will be tested in adoptive progenitor cell-based therapy models in animals, including: delivery pro-apoptotic genes to tumors, and T-cell reconstitution for immunostimulatory therapy during allogeneic bone marrow progenitor cell transplantation. Technical and Scientific Merits. Non-invasive whole body imaging would significantly aid in the development and clinical implementation of various adoptive progenitor cell-based therapies by providing the means for non-invasive monitoring of the fate of injected progenitor cells over a long period of observation. The proposed imaging approaches could help to address several questions related to stem cell migration and homing, their long-term viability, and their subsequent differentiation. The ability to image these processes non-invasively in 3D and repetitively over a long period of time is very important and will help the development and clinical application of various strategies to control and direct stem cell migration and differentiation. Approach to accomplish the work. Stem cells will be genetically with a reporter gene which will allow for repetitive non-invasive “tracking” of the migration and localization of genetically labeled stem cells and their progeny. This is a radically new approach that is being developed for future human applications and should allow for a long term (many years) repetitive imaging of the fate of tissues that develop from the transplanted stem cells. Why the approach is appropriate. The novel approach to

  15. Scientists adopt new strategy to find Huntington's disease therapies

    MedlinePlus

    ... 2017 President's Budget Calendar of Events Proceedings Funding Information Research Programs Training & Career Awards Enhancing Diversity Find People About NINDS Scientists adopt new strategy to find Huntington’s disease therapies Follow NINDSnews For ...

  16. Important cellular targets for antimicrobial photodynamic therapy.

    PubMed

    Awad, Mariam M; Tovmasyan, Artak; Craik, James D; Batinic-Haberle, Ines; Benov, Ludmil T

    2016-09-01

    The persistent problem of antibiotic resistance has created a strong demand for new methods for therapy and disinfection. Photodynamic inactivation (PDI) of microbes has demonstrated promising results for eradication of antibiotic-resistant strains. PDI is based on the use of a photosensitive compound (photosensitizer, PS), which upon illumination with visible light generates reactive species capable of damaging and killing microorganisms. Since photogenerated reactive species are short lived, damage is limited to close proximity of the PS. It is reasonable to expect that the larger the number of damaged targets is and the greater their variety is, the higher the efficiency of PDI is and the lower the chances for development of resistance are. Exact molecular mechanisms and specific targets whose damage is essential for microbial inactivation have not been unequivocally established. Two main cellular components, DNA and plasma membrane, are regarded as the most important PDI targets. Using Zn porphyrin-based PSs and Escherichia coli as a model Gram-negative microorganism, we demonstrate that efficient photoinactivation of bacteria can be achieved without detectable DNA modification. Among the cellular components which are modified early during illumination and constitute key PDI targets are cytosolic enzymes, membrane-bound protein complexes, and the plasma membrane. As a result, membrane barrier function is lost, and energy and reducing equivalent production is disrupted, which in turn compromises cell defense mechanisms, thus augmenting the photoinduced oxidative injury. In conclusion, high PDI antimicrobial effectiveness does not necessarily require impairment of a specific critical cellular component and can be achieved by inducing damage to multiple cellular targets. PMID:27221289

  17. Voluntary accreditation of cellular therapies: Foundation for the Accreditation of Cellular Therapy (FACT).

    PubMed

    Warkentin, P I

    2003-01-01

    Voluntary accreditation of cells, tissues, and cellular and tissue-based products intended for human transplantation is an important mechanism for improving quality in cellular therapy. The Foundation for the Accreditation of Cellular Therapy (FACT) has developed and implemented programs of voluntary inspection and accreditation for hematopoietic cellular therapy, and for cord blood banking. These programs are based on the standards of the clinical and laboratory professionals of the American Society of Blood and Marrow Transplantation (ASBMT), the International Society for Cellular Therapy (ISCT), and NETCORD. FACT has collaborated with European colleagues in the development of the Joint Accreditation Committee in Europe (jACIE). FACT has published standards documents, a guidance manual, accreditation checklists, and inspection documents; and has trained as inspectors over 300 professionals active in the field. All inspectors have a minimum of 5 years' experience in the area they inspect. Since the incorporation of FACT in 1996, 215 hematopoietic progenitor cell facilities have applied for FACT accreditation. Of these facilities, 113 are fully accredited; the others are in the process of document submission or inspection. Significant opportunities and challenges exist for FACT in the future, including keeping standards and guidance materials current and relevant, recruiting and retaining expert inspectors, and establishing collaborations to develop standards and accreditation systems for new cellular products. The continuing dialogue with the Food and Drug Administration (FDA) is also important to ensure that they are aware of the accomplishments of voluntary accreditation, and keep FACT membership alerted to FDA intentions for the future. Other potential avenues of communication and cooperation with FDA and other regulatory agencies are being investigated and evaluated. PMID:12944235

  18. Adoptive T cell therapy for cancer in the clinic

    PubMed Central

    June, Carl H.

    2007-01-01

    The transfusion of lymphocytes, referred to as adoptive T cell therapy, is being tested for the treatment of cancer and chronic infections. Adoptive T cell therapy has the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease. This form of personalized medicine is now in various early- and late-stage clinical trials. These trials are currently testing strategies to infuse tumor-infiltrating lymphocytes, CTLs, Th cells, and Tregs. Improved molecular biology techniques have also increased enthusiasm and feasibility for testing genetically engineered T cells. The current status of the field and prospects for clinical translation are reviewed herein. PMID:17549249

  19. Developing Cellular Therapies for Retinal Degenerative Diseases

    PubMed Central

    Bharti, Kapil; Rao, Mahendra; Hull, Sara Chandros; Stroncek, David; Brooks, Brian P.; Feigal, Ellen; van Meurs, Jan C.; Huang, Christene A.; Miller, Sheldon S.

    2014-01-01

    Biomedical advances in vision research have been greatly facilitated by the clinical accessibility of the visual system, its ease of experimental manipulation, and its ability to be functionally monitored in real time with noninvasive imaging techniques at the level of single cells and with quantitative end-point measures. A recent example is the development of stem cell–based therapies for degenerative eye diseases including AMD. Two phase I clinical trials using embryonic stem cell–derived RPE are already underway and several others using both pluripotent and multipotent adult stem cells are in earlier stages of development. These clinical trials will use a variety of cell types, including embryonic or induced pluripotent stem cell–derived RPE, bone marrow– or umbilical cord–derived mesenchymal stem cells, fetal neural or retinal progenitor cells, and adult RPE stem cells–derived RPE. Although quite distinct, these approaches, share common principles, concerns and issues across the clinical development pipeline. These considerations were a central part of the discussions at a recent National Eye Institute meeting on the development of cellular therapies for retinal degenerative disease. At this meeting, emphasis was placed on the general value of identifying and sharing information in the so-called “precompetitive space.” The utility of this behavior was described in terms of how it could allow us to remove road blocks in the clinical development pipeline, and more efficiently and economically move stem cell–based therapies for retinal degenerative diseases toward the clinic. Many of the ocular stem cell approaches we discuss are also being used more broadly, for nonocular conditions and therefore the model we develop here, using the precompetitive space, should benefit the entire scientific community. PMID:24573369

  20. The Media Adoption Stage Model of Technology for Art Therapy

    ERIC Educational Resources Information Center

    Peterson, Brent Christian

    2010-01-01

    This study examined survey data from professional credentialed members of the American Art Therapy Association and 8 follow up interviews to determine how art therapists adopt or reject technology and/or new digital media for therapeutic use with their clients. Using Rogers's (2003) "diffusion of innovation" model, the author identified a…

  1. Adoptive T Cell Therapy Targeting CD1 and MR1

    PubMed Central

    Guo, Tingxi; Chamoto, Kenji; Hirano, Naoto

    2015-01-01

    Adoptive T cell immunotherapy has demonstrated clinically relevant efficacy in treating malignant and infectious diseases. However, much of these therapies have been focused on enhancing, or generating de novo, effector functions of conventional T cells recognizing HLA molecules. Given the heterogeneity of HLA alleles, mismatched patients are ineligible for current HLA-restricted adoptive T cell therapies. CD1 and MR1 are class I-like monomorphic molecules and their restricted T cells possess unique T cell receptor specificity against entirely different classes of antigens. CD1 and MR1 molecules present lipid and vitamin B metabolite antigens, respectively, and offer a new front of targets for T cell therapies. This review will cover the recent progress in the basic research of CD1, MR1, and their restricted T cells that possess translational potential. PMID:26052329

  2. Cellular cardiac regenerative therapy in which patients?

    PubMed

    Chachques, Juan C

    2009-08-01

    Cell-based myocardial regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles owing to ischemic and nonischemic myocardial diseases. A variety of myogenic and angiogenic cell types have been proposed, such as skeletal myoblasts, mononuclear and mesenchymal bone marrow cells, circulating blood-derived progenitors, adipose-derived stromal cells, induced pluripotent stem cells, umbilical cord cells, endometrial mesenchymal stem cells, adult testis pluripotent stem cells and embryonic cells. Current indications for stem cell therapy concern patients who have had a left- or right-ventricular infarction or idiopathic dilated cardiomyopathies. Other indications and potential applications include patients with diabetic cardiomyopathy, Chagas heart disease (American trypanosomiasis), ischemic mitral regurgitation, left ventricular noncompacted myocardium and pediatric cardiomyopathy. Suitable sources of cells for cardiac implant will depend on the types of diseases to be treated. For acute myocardial infarction, a cell that reduces myocardial necrosis and augments vascular blood flow will be desirable. For heart failure, cells that replace or promote myogenesis, reverse apoptopic mechanisms and reactivate dormant cell processes will be useful. It is important to note that stem cells are not an alternative to heart transplantation; selected patients should be in an early stage of heart failure as the goal of this regenerative approach is to avoid or delay organ transplantation. Since the cell niche provides crucial support needed for stem cell maintenance, the most interesting and realistic perspectives include the association of intramyocardial cell transplantation with tissue-engineered scaffolds and multisite cardiac pacing in order to transform a passive regenerative approach into a 'dynamic cellular support', a promising method for the creation of

  3. Adoptive T-cell therapy for B-cell malignancies

    PubMed Central

    Hudecek, Michael; Anderson, Larry D; Nishida, Tetsuya; Riddell, Stanley R

    2011-01-01

    The success of allogeneic hematopoietic cell transplantation (HCT) for B-cell malignancies is evidence that these tumors can be eliminated by T lymphocytes. This has encouraged the development of specific adoptive T-cell therapy, both for augmenting the anti-tumor effect of HCT and for patients not undergoing HCT. T cells that are capable of recognizing antigens expressed on malignant B cells may be recruited from the endogenous repertoire or engineered to express tumor-targeting receptors. Critical insights into the qualities of T cells that enable their persistence and function in vivo have been derived, and obstacles to effective T-cell-mediated tumor eradication are being elucidated. These advances provide the tools to translate adoptive T-cell transfer into reliable clinical therapies. PMID:21083018

  4. Opportunities and limitations of NK cells as adoptive therapy for malignant disease

    PubMed Central

    Davies, James O. J.; Stringaris, Kate; Barrett, John A.; Rezvani, Katayoun

    2014-01-01

    While NK cells can be readily generated for adoptive therapy with current techniques, their optimal application to treat malignant diseases requires an appreciation of the dynamic balance between signals that either synergise with, or antagonise each other. Individuals display wide differences in NK function which determine their therapeutic efficacy. The ability of NK cells to kill target cells or produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. The selection of NK cells with a predominant activating profile is critical for delivering successful antitumor activity. This can be achieved through selection of KIR mismatched NK donors and by using blocking molecules against inhibitory pathways. Optimum NK cytotoxicity may require licensing or priming with tumor cells. Recent discoveries in the molecular and cellular biology of NK cells inform in the design of new strategies, including adjuvant therapies, to maximise the cytotoxic potential of NK cells for adoptive transfer to treat human malignancies. PMID:24856895

  5. Adoption

    MedlinePlus

    ... the birth nor adoptive parents know the others' identities. Other adoptions are handled more openly. Open adoptions, ... desire to seek out more information about the identity of the birth family. Most of us (whether ...

  6. Promoting transplantation tolerance; adoptive regulatory T cell therapy

    PubMed Central

    Safinia, N; Leech, J; Hernandez-Fuentes, M; Lechler, R; Lombardi, G

    2013-01-01

    Transplantation is a successful treatment for end-stage organ failure. Despite improvements in short-term outcome, long-term survival remains suboptimal because of the morbidity and mortality associated with long-term use of immunosuppression. There is, therefore, a pressing need to devise protocols that induce tolerance in order to minimize or completely withdraw immunosuppression in transplant recipients. In this review we will discuss how regulatory T cells (Tregs) came to be recognized as an attractive way to promote transplantation tolerance. We will summarize the preclinical data, supporting the importance of these cells in the induction and maintenance of immune tolerance and that provide the rationale for the isolation and expansion of these cells for cellular therapy. We will also describe the data from the first clinical trials, using Tregs to inhibit graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation and will address both the challenges and opportunities in human Treg cell therapy. PMID:23574313

  7. [Principles of adoptive cell therapy based on "Tumor Infiltrating Lymphocytes"].

    PubMed

    Martins, Filipe; Orcurto, Angela; Michielin, Olivier; Coukos, George

    2016-05-18

    Adoptive cell therapy consists in the use of T lymphocytes for therapeutic purposes. Up to now, of limited use in clinical practice for logistical reasons, technical progress and substantial level of evidence obtained in the last decade allow its arrival in universitary hospitals. We will principally discuss the administration of expanded tumor infiltrating T cells in the treatment of metastatic melanoma. This treatment modality exploits the natural specificity of these cells and aims to potentiate their effectiveness. This personalized immunotherapy detains a potential for expansion to many other advanced tumor types. PMID:27424426

  8. Orthopedic cellular therapy: An overview with focus on clinical trials

    PubMed Central

    Noh, Moon Jong; Lee, Kwan Hee

    2015-01-01

    In this editorial, the authors tried to evaluate the present state of cellular therapy in orthopedic field. The topics the authors try to cover include not only the clinical trials but the various research areas as well. Both the target diseases for cellular therapy and the target cells were reviewed. New methods to activate the cells were interesting to review. Most advanced clinical trials were also included because several of them have advanced to phase III clinical trials. In the orthopedic field, there are many diseases with a definite treatment gap at this time. Because cellular therapies can regenerate damaged tissues, there is a possibility for cellular therapies to become disease modifying drugs. It is not clear whether cellular therapies will become the standard of care in any of the orthopedic disorders, however the amount of research being performed and the number of clinical trials that are on-going make the authors believe that cellular therapies will become important treatment modalities within several years. PMID:26601056

  9. [Adoption].

    ERIC Educational Resources Information Center

    Pawl, Jeree, Ed.; And Others

    1990-01-01

    This newsletter theme issue addresses adoption and the young child's life. Contributors suggest ways in which practitioners in many professions and settings can better understand and support adoptive families. The first article, "Adoption, 1990" by Barbara F. Nordhaus and Albert J. Solnit, reviews the history of adoption and notes obstacles to…

  10. Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy

    PubMed Central

    Chen, Yamei

    2014-01-01

    As a result of the recent advances in molecular immunology, virology, genetics, and cell processing, chimeric antigen receptor (CAR)-directed cancer therapy has finally arrived for clinical application. CAR-directed adoptive immunotherapy represents a novel form of gene therapy, cellular therapy, and immunotherapy, a combination of three in one. Early phase clinical trial was reported in patients with refractory chronic lymphoid leukemia with 17p deletion. Accompanying the cytokine storm and tumor lysis syndrome was the shocking disappearance of the leukemia cells refractory to chemotherapy and monoclonal antibodies. CAR therapy was reproduced in both children and adults with refractory acute lymphoid leukemia. The CAR technology is being explored for solid tumor therapy, such as glioma. Close to 30 clinical trials are underway in the related fields (www.clinicaltrials.gov). Further improvement in gene targeting, cell expansion, delivery constructs (such as using Sleeping Beauty or Piggyback transposons) will undoubtedly enhance clinical utility. It is foreseeable that CAR-engineered T cell therapy will bring targeted cancer therapy into a new era.

  11. Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy.

    PubMed

    Figueroa, Jose A; Reidy, Adair; Mirandola, Leonardo; Trotter, Kayley; Suvorava, Natallia; Figueroa, Alejandro; Konala, Venu; Aulakh, Amardeep; Littlefield, Lauren; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Musgrove, Breeanna; Radhi, Saba; D'Cunha, Nicholas; D'Cunha, Luke N; Hermonat, Paul L; Cobos, Everardo; Chiriva-Internati, Maurizio

    2015-03-01

    Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer. PMID:25901860

  12. 77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-29

    ... Investigational Cellular and Gene Therapy Products; Availability AGENCY: Food and Drug Administration, HHS. ACTION... document entitled ``Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene... for Biologics Research and Evaluation (CBER), Office of Cellular, Tissue, and Gene Therapies...

  13. Cellular therapy to treat haematological and other malignancies: progress and pitfalls.

    PubMed

    Fromm, Phillip D; Gottlieb, David; Bradstock, Kenneth F; Hart, Derek N J

    2011-10-01

    The recent Food and Drug Administration (FDA) approval of a cellular therapy to treat castration resistant prostate cancer has reinforced the potential of cellular therapy to consolidate current pharmacological approaches to treating cancer. The emergence of the cell manufacturing facility to facilitate clinical translation of these new methodologies allows greater access to these novel therapies. Here we review different strategies currently being explored to treat haematological malignancies with a focus on adoptive allogeneic or autologous transfer of antigen specific T cells, NK cells or dendritic cells. These approaches all aim to generate immunological responses against overexpressed tissue antigens, mismatched minor histocompatability antigens or tumour associated antigens. Current successes and limitations of these different approaches will be discussed with an emphasis on challenges encountered in generating long term engraftment, antigen selection and implementation as well as therapeutic immune monitoring of clinical responses, with examples from recent clinical trials. PMID:21897329

  14. Regenerative cellular therapies for neurologic diseases.

    PubMed

    Levy, Michael; Boulis, Nicholas; Rao, Mahendra; Svendsen, Clive N

    2016-05-01

    The promise of stem cell regeneration has been the hope of many neurologic patients with permanent damage to the central nervous system. There are hundreds of stem cell trials worldwide intending to test the regenerative capacity of stem cells in various neurological conditions from Parkinson׳s disease to multiple sclerosis. Although no stem cell therapy is clinically approved for use in any human disease indication, patients are seeking out trials and asking clinicians for guidance. This review summarizes the current state of regenerative stem cell transplantation divided into seven conditions for which trials are currently active: demyelinating diseases/spinal cord injury, amyotrophic lateral sclerosis, stroke, Parkinson׳s disease, Huntington׳s disease, macular degeneration and peripheral nerve diseases. This article is part of a Special Issue entitled SI: PSC and the brain. PMID:26239912

  15. 78 FR 43889 - Synergizing Efforts in Standards Development for Cellular Therapies and Regenerative Medicine...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-22

    ...: Standardization efforts concerning the clinical development of cellular therapies and regenerative medicine... Therapies and Regenerative Medicine Products; Public Workshop AGENCY: Food and Drug Administration, HHS... Development for Cellular Therapies and Regenerative Medicine Products.'' The purpose of the public workshop...

  16. 75 FR 65640 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-26

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... and Gene Therapies Advisory Committee. General Function of the Committee: To provide advice and... Tumor Vaccines and Biotechnology Branch, Office of Cellular, Tissue and Gene Therapies, Center...

  17. Cellular therapy in bone-tendon interface regeneration

    PubMed Central

    Rothrauff, Benjamin B; Tuan, Rocky S

    2014-01-01

    The intrasynovial bone-tendon interface is a gradual transition from soft tissue to bone, with two intervening zones of uncalcified and calcified fibrocartilage. Following injury, the native anatomy is not restored, resulting in inferior mechanical properties and an increased risk of re-injury. Recent in vivo studies provide evidence of improved healing when surgical repair of the bone-tendon interface is augmented with cells capable of undergoing chondrogenesis. In particular, cellular therapy in bone-tendon healing can promote fibrocartilage formation and associated improvements in mechanical properties. Despite these promising results in animal models, cellular therapy in human patients remains largely unexplored. This review highlights the development and structure-function relationship of normal bone-tendon insertions. The natural healing response to injury is discussed, with subsequent review of recent research on cellular approaches for improved healing. Finally, opportunities for translating in vivo findings into clinical practice are identified. PMID:24326955

  18. Cellular Bioenergetics as a Target for Obesity Therapy

    PubMed Central

    Tseng, Yu-Hua; Cypess, Aaron M.; Kahn, C. Ronald

    2010-01-01

    Summary Obesity develops when energy intake exceeds energy expenditure. While most current obesity therapies are focused on reducing caloric intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach. This is especially true for adaptive thermogenesis - the physiological process whereby energy is dissipated in the form of heat in response to external stimuli. There have been significant recent advances in identifying factors that control the development and function of these tissues and in techniques to measure brown fat in human adults. In this review, we integrate these developments in relation to the classic understandings of cellular bioenergetics to explore the potential for developing novel anti-obesity therapies that target cellular energy expenditure. PMID:20514071

  19. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies

    PubMed Central

    Wang, X; Rivière, I

    2015-01-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical-grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic. PMID:25721207

  20. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies.

    PubMed

    Wang, X; Rivière, I

    2015-03-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical-grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic. PMID:25721207

  1. Metabolic modulation and cellular therapy of cardiac dysfunction and failure

    PubMed Central

    Revenco, Diana; Morgan, James P

    2009-01-01

    Abstract At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy. PMID:19382894

  2. [Cellular therapy and gene therapy: perspectives in neuromuscular pathology].

    PubMed

    Fardeau, M

    1993-10-01

    Identification of the gene coding for the protein (dystrophin) which is lacking or abnormal in Duchenne or Becker type human muscular dystrophies was a decisive turning point in neuro-muscular pathology. Since that time, a considerable number of gene abnormalities have been identified or at least localized. The severity of these diseases, their steady evolution and the absence of any efficient drug therapy, have lead to the development of new therapeutic approaches based on restoring the genetic capacities of the muscle cell. There are two possibilities for therapy. The first is based on the transfer of myogenic cells derived from the 'satellite' cells normally present at the periphery of muscle fibers. The results obtained from a murine model of Duchenne dystrophy ('mdx' mouse) were very promising. However, the results from application of the same techniques to the canine model (GRMDX) or to affected children are, at the present time, disappointing. A number of biological questions remain to be solved before this technique can be more extensively applied to humans. The second possibility is based on gene transfer, through a viral vector. The adenovirus is presently a possible vector. The first experimental results, on 'mdx' mice, are again very encouraging. Extension of these studies to the canine model is a necessary prerequisite for any human application. It should be noted that these two approaches are complementary. Their future applications may depend on the diffuse or selective nature of the skeletal muscle atrophy, and on whether cardiac and respiratory muscles are involved. PMID:8290312

  3. Is adoptive T-cell therapy for solid tumors coming of age?

    PubMed

    Pedrazzoli, P; Comoli, P; Montagna, D; Demirer, T; Bregni, M

    2012-08-01

    Among the novel biological therapeutics that will increase our ability to cure human cancer in years to come, adoptive cellular therapy is one of the most promising approaches. Although this is a complex and challenging field, there have been major advances in basic and translational research resulting in clinical trial activity that is now beginning to confirm this promise. The results obtained with tumor-infiltrating lymphocytes therapy for melanoma, and virus-specific CTLs for EBV-associated malignancies are encouraging in terms of both ability to obtain clinical benefit and limited toxicity profile. In both settings, objective responses were obtained in at least 50% of treated patients. However, improvements to the clinical protocols, in terms of better patient selection and timing of administration, as well as cell product quality and availability, are clearly necessary to further ameliorate outcome, and logistical solutions are warranted to extend T-cell therapy beyond academic centers. In particular, there is a need to simplify cell production, in order to decrease costs and ease preparation. Promising implementations are underway, including harnessing the therapeutic potential of T cells transduced with TCRs directed against shared tumor antigens, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells. PMID:21804611

  4. Integrative therapies in hospice and home health: introduction and adoption.

    PubMed

    Johnson, Esther L; O'Brien, Deborah

    2009-02-01

    Integrative therapies comprise a variety of nonpharmacologic methods that provide pain and symptom management. These therapies are increasingly gaining acceptance in the healthcare community as complementary to traditional treatments for pain. This article details the introduction, scope, and challenges healthcare organizations face when incorporating integrative therapies into their care plans. PMID:19212218

  5. 78 FR 44133 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... be open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee... on guidance documents issued from the Office of Cellular, Tissue and Gene Therapies, Center...

  6. Cellular Therapies Clinical Research Roadmap: Lessons learned on how to move a cellular therapy into a clinical trial

    PubMed Central

    Ouseph, Stacy; Tappitake, Darah; Armant, Myriam; Wesselschmidt, Robin; Derecho, Ivy; Draxler, Rebecca; Wood, Deborah; Centanni, John M.

    2014-01-01

    A clinical research roadmap has been developed as a resource for researchers to identify critical areas and potential pitfalls when transitioning a cellular therapy product from the research laboratory, via and Investigational New Drug (IND) application, into early phase clinical trials. The roadmap describes four key areas; basic and preclinical research, resource development, translational research and good manufacturing practice (GMP), and IND assembly and submission. Basic and preclinical research identifies a new therapeutic concept and demonstrates its potential value using a model of the relevant disease. During resource development the appropriate specialists and the required expertise to bring this product into the clinic are identified (e.g., researchers, regulatory specialists, GMP manufacturing staff, clinicians, and clinical trials staff, etc.). Additionally, the funds required to achieve this goal (or a plan to procure them) are identified. In the next phase the plan to translate the research product into a clinical grade therapeutic is developed. Finally regulatory approval to start the trial must be obtained. In the United States this is done by filing an IND application with the Food and Drug Administration. The NHLBI-funded Production Assistance for Cellular Therapies (PACT) program has facilitated the transition of a variety of cellular therapy products from the laboratory into Phase1/2 trials. The five PACT facilities have assisted investigators by performing translational studies and GMP manufacturing to ensure that cellular products met release specifications and were manufactured safely, reproducibly, and at the appropriate scale. The roadmap resulting from this experience is the focus of this article. PMID:25484311

  7. Child-Parent Relationship Therapy for Adoptive Families

    ERIC Educational Resources Information Center

    Carnes-Holt, Kara

    2012-01-01

    Adopted children may present with a wide range of disruptive behaviors making it difficult to implement holistic therapeutic interventions. The number of primary caregivers, disrupted placements, and repeated traumatic events contribute to the overall mental health of the adoptee and greater number of occurrences increases the risk of…

  8. Adoptive cell therapy: a highly successful individualized therapy for melanoma with great potential for other malignancies.

    PubMed

    Verdegaal, Els M E

    2016-04-01

    Adoptive cell therapy (ACT) by infusion of autologous or redirected tumor-specific T-cells has had a major impact on the treatment of several metastasized malignancies that were until now hardly treatable. Recent findings provide a more profound knowledge on the underlying mechanisms of success and allow the optimization of the ACT protocol with respect to (1) the treatment related side-effects, (2) the quality and specificity of infused T-cells, and (3) the immunosuppressive phenotype of the tumor environment. In this review, the results and insights in the success of ACT as well as the possibilities to improve ACT and its exploitation as treatment option for various metastatic cancer types, will be discussed. PMID:26829458

  9. Concise review: Nanoparticles and cellular carriers-allies in cancer imaging and cellular gene therapy?

    PubMed Central

    Tang, Catherine; Russell, Pamela J; Martiniello-Wilks, Rosetta; J Rasko, John E; Khatri, Aparajita

    2010-01-01

    Ineffective treatment and poor patient management continue to plague the arena of clinical oncology. The crucial issues include inadequate treatment efficacy due to ineffective targeting of cancer deposits, systemic toxicities, suboptimal cancer detection and disease monitoring. This has led to the quest for clinically relevant, innovative multifaceted solutions such as development of targeted and traceable therapies. Mesenchymal stem cells (MSCs) have the intrinsic ability to “home” to growing tumors and are hypoimmunogenic. Therefore, these can be used as (a) “Trojan Horses” to deliver gene therapy directly into the tumors and (b) carriers of nanoparticles to allow cell tracking and simultaneous cancer detection. The camouflage of MSC carriers can potentially tackle the issues of safety, vector, and/or transgene immunogenicity as well as nanoparticle clearance and toxicity. The versatility of the nanotechnology platform could allow cellular tracking using single or multimodal imaging modalities. Toward that end, noninvasive magnetic resonance imaging (MRI) is fast becoming a clinical favorite, though there is scope for improvement in its accuracy and sensitivity. In that, use of superparamagnetic iron-oxide nanoparticles (SPION) as MRI contrast enhancers may be the best option for tracking therapeutic MSC. The prospects and consequences of synergistic approaches using MSC carriers, gene therapy, and SPION in developing cancer diagnostics and therapeutics are discussed. STEM CELLS 2010; 28:1686–1702. PMID:20629172

  10. Acceptance and Commitment Therapy: Western adoption of Buddhist tenets?

    PubMed

    Fung, Kenneth

    2015-08-01

    Acceptance and Commitment Therapy (ACT) is a psychological intervention that has wide clinical applications with emerging empirical support. It is based on Functional Contextualism and is derived as a clinical application of the Relational Frame Theory, a behavioral account of the development of human thought and cognition. The six core ACT therapeutic processes include: Acceptance, Defusion, Present Moment, Self-as-Context, Values, and Committed Action. In addition to its explicit use of the concept of mindfulness, the therapeutic techniques of ACT implicitly incorporate other aspects of Buddhism. This article describes the basic principles and processes of ACT, explores the similarities and differences between ACT processes and some of the common tenets in Buddhism such as the Four Noble Truths and No-Self, and reports on the experience of running a pilot intervention ACT group for the Cambodian community in Toronto in partnership with the community's Buddhist Holy Monk. Based on this preliminary exploration in theory and the reflections of the group experience, ACT appears to be consistent with some of the core tenets of Buddhism in the approach towards alleviating suffering, with notable differences in scope reflecting their different aims and objectives. Further development of integrative therapies that can incorporate psychological and spiritual as well as diverse cultural perspectives may help the continued advancement and evolution of more effective psychotherapies that can benefit diverse populations. PMID:25085722

  11. 78 FR 79699 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-31

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue, and Gene Therapies Advisory Committee... be open to the public. Name of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee..., Tissue, and Gene Therapies, Center for Biologics Evaluation and Research (CBER), FDA. On February...

  12. 75 FR 66381 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-28

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... be open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee... Lentiviral Vector Based Gene Therapy Products. FDA intends to make background material available to...

  13. 76 FR 22405 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-21

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... be open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee... gene therapy products for the treatment of retinal disorders. Topics to be considered include...

  14. US Food and Drug Administration international collaborations for cellular therapy product regulation

    PubMed Central

    2012-01-01

    Cellular therapy products are an emerging medical product class undergoing rapid scientific and clinical innovation worldwide. These products pose unique regulatory challenges both for countries with existing regulatory frameworks and for countries where regulatory frameworks for cellular therapy products are under development. The United States Food and Drug Administration (US FDA) has a history of productive working relationships with international regulatory authorities, and seeks to extend this to the cellular therapy field. The US FDA and its global regulatory counterparts are engaged in collaborations focused on the convergence of scientific and regulatory approaches, and the education of scientists, clinicians, regulators, and the public at large on the development of cellular therapies. PMID:23021082

  15. Hyperthermia versus Oncothermia: Cellular Effects in Complementary Cancer Therapy

    PubMed Central

    Hegyi, Gabriella; Szigeti, Gyula P.; Szász, András

    2013-01-01

    Hyperthermia means overheating of the living object completely or partly. Hyperthermia, the procedure of raising the temperature of a part of or the whole body above normal for a defined period of time, is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. However, hyperthermia is not generally accepted as conventional therapy. The problem is its controversial performance. The controversy is originated from the complications of the deep heating and the focusing of the heat effect. The idea of oncothermia solves the selective deep action on nearly cellular resolution. We would like to demonstrate the force and perspectives of oncothermia, as a highly specialized hyperthermia in clinical oncology. Our aim is to prove the ability of oncothermia to be a candidate to become a widely accepted modality of the standard cancer care. We would like to show the proofs and the challenges of the hyperthermia and oncothermia applications to provide the presently available data and summarize the knowledge in the topic. Like many early stage therapies, oncothermia lacks adequate treatment experience and long-range, comprehensive statistics that can help us optimize its use for all indications. PMID:23662149

  16. Cellular unfolded protein response against viruses used in gene therapy

    PubMed Central

    Sen, Dwaipayan; Balakrishnan, Balaji; Jayandharan, Giridhara R.

    2014-01-01

    Viruses are excellent vehicles for gene therapy due to their natural ability to infect and deliver the cargo to specific tissues with high efficiency. Although such vectors are usually “gutted” and are replication defective, they are subjected to clearance by the host cells by immune recognition and destruction. Unfolded protein response (UPR) is a naturally evolved cyto-protective signaling pathway which is triggered due to endoplasmic reticulum (ER) stress caused by accumulation of unfolded/misfolded proteins in its lumen. The UPR signaling consists of three signaling pathways, namely PKR-like ER kinase, activating transcription factor 6, and inositol-requiring protein-1. Once activated, UPR triggers the production of ER molecular chaperones and stress response proteins to help reduce the protein load within the ER. This occurs by degradation of the misfolded proteins and ensues in the arrest of protein translation machinery. If the burden of protein load in ER is beyond its processing capacity, UPR can activate pro-apoptotic pathways or autophagy leading to cell death. Viruses are naturally evolved in hijacking the host cellular translation machinery to generate a large amount of proteins. This phenomenon disrupts ER homeostasis and leads to ER stress. Alternatively, in the case of gutted vectors used in gene therapy, the excess load of recombinant vectors administered and encountered by the cell can trigger UPR. Thus, in the context of gene therapy, UPR becomes a major roadblock that can potentially trigger inflammatory responses against the vectors and reduce the efficiency of gene transfer. PMID:24904562

  17. 77 FR 73472 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-10

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... and Gene Therapies Advisory Committee. General Function of the Committee: To provide advice...

  18. [Novel therapy for malignant lymphoma: adoptive immuno-gene therapy using chimeric antigen receptor(CAR)-expressing T lymphocytes].

    PubMed

    Ozawa, Keiya

    2014-03-01

    Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3 zeta receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in the clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In this review article, CD19-CAR-T gene therapy for refractory B-cell non-Hodgkin lymphoma is discussed. PMID:24724418

  19. 76 FR 64951 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-19

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... be open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory...

  20. 77 FR 65693 - Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ... Administration (FDA) is announcing an amendment to the notice of a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee. This meeting was announced in the Federal Register of October 17, 2012 (77 FR... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory...

  1. DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer.

    PubMed

    Terracina, Krista P; Graham, Laura J; Payne, Kyle K; Manjili, Masoud H; Baek, Annabel; Damle, Sheela R; Bear, Harry D

    2016-09-01

    Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer. PMID:27416831

  2. Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells.

    PubMed

    Ager, Ann; Watson, H Angharad; Wehenkel, Sophie C; Mohammed, Rebar N

    2016-04-15

    The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8(+)T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8(+)T-cell infiltration of tumours and increase the efficacy of adoptive CD8(+)T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy 'normalizes' (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients. PMID:27068943

  3. Learning, Misallocation, and Technology Adoption: Evidence from New Malaria Therapy in Tanzania

    PubMed Central

    Adhvaryu, Achyuta

    2014-01-01

    I study how the misallocation of new technology to individuals who have low ex post returns to its use affects learning and adoption behavior. I focus on antimalarial treatment, which is frequently over-prescribed in many low-income country contexts where diagnostic tests are inaccessible. I show that misdiagnosis reduces average therapeutic effectiveness, because only a fraction of adopters actually have malaria, and slows the rate of social learning due to increased noise. I use data on adoption choices, the timing and duration of fever episodes, and individual blood slide confirmations of malarial status from a pilot study for a new malaria therapy in Tanzania to show that individuals whose reference groups experienced fewer misdiagnoses exhibited stronger learning effects and were more likely to adopt. PMID:25729112

  4. 76 FR 81513 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-28

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue, and Gene Therapies Advisory Committee..., Tissue, and Gene Therapies Advisory Committee. General Function of the Committee: To provide advice and... Gene Therapies, Center for Biologics Evaluation and Research, FDA. FDA intends to make...

  5. Adoption of Motivational Interviewing and Motivational Enhancement Therapy Following Clinical Trials†

    PubMed Central

    Guydish, Joseph; Jessup, Martha; Tajima, Barbara; Manser, Sarah Turcotte

    2012-01-01

    The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) is designed to test drug abuse treatment interventions in multisite clinical trials and to support the translation of effective interventions into practice. In this study, qualitative methods were applied to examine adoption of motivational interviewing and motivational enhancement therapy (MI/MET) in five clinics where these interventions were tested. Participants were clinic staff (n = 17) who were interviewed about the MI/MET study, and about whether MI/MET was adopted after the study ended. Although clinics’ participation in a clinical trial includes many elements thought to be necessary for later adoption of the intervention, we found that there was “adoption” in one clinic, “partial adoption” in one clinic, “counselor adoption” in one clinic, and “no adoption” in two clinics. These findings highlight a distinction between adoption at the organizational and counselor levels, and suggest that a range of adoption outcomes may be observed in the field. Findings are relevant to clinical staff, program directors, administrators and policy makers concerned with improvement of drug abuse treatment systems through adoption of evidence-based practices. PMID:21138198

  6. Adoptive Therapy with Chimeric Antigen Receptor Modified T Cells of Defined Subset Composition

    PubMed Central

    Riddell, Stanley R.; Sommermeyer, Daniel; Berger, Carolina; Liu, Lingfeng (Steven); Balakrishnan, Ashwini; Salter, Alex; Hudecek, Michael; Maloney, David G.; Turtle, Cameron J.

    2014-01-01

    The ability to engineer T cells to recognize tumor cells through genetic modification with a synthetic chimeric antigen receptor has ushered in a new era in cancer immunotherapy. The most advanced clinical applications are in in targeting CD19 on B cell malignancies. The clinical trials of CD19 CAR therapy have thus far not attempted to select defined subsets prior to transduction or imposed uniformity of the CD4 and CD8 cell composition of the cell products. This review will discuss the rationale for and challenges to utilizing adoptive therapy with genetically modified T cells of defined subset and phenotypic composition. PMID:24667960

  7. Anti-CD137 monoclonal antibodies and adoptive T cell therapy: a perfect marriage?

    PubMed

    Weigelin, Bettina; Bolaños, Elixabet; Rodriguez-Ruiz, Maria E; Martinez-Forero, Ivan; Friedl, Peter; Melero, Ignacio

    2016-05-01

    CD137(4-1BB) costimulation and adoptive T cell therapy strongly synergize in terms of achieving maximal efficacy against experimental cancers. These costimulatory biological functions of CD137 have been exploited by means of introducing the CD137 signaling domain in clinically successful chimeric antigen receptors and to more efficiently expand T cells in culture. In addition, immunomagnetic sorting of CD137-positive T cells among tumor-infiltrating lymphocytes selects for the fittest antitumor T lymphocytes for subsequent cultures. In mouse models, co-infusion of both agonist antibodies and T cells attains marked synergistic effects that result from more focused and intense cytolytic activity visualized under in vivo microscopy and from more efficient entrance of T cells into the tumor through the vasculature. These several levels of dynamic interaction between adoptive T cell therapy and CD137 offer much opportunity to raise the efficacy of current cancer immunotherapies. PMID:26970765

  8. 76 FR 9028 - Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-16

    ..., 2008 (73 FR 59635), FDA announced the availability of the draft guidance of the same title. FDA... HUMAN SERVICES Food and Drug Administration Guidance for Industry: Potency Tests for Cellular and Gene... Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011. The guidance...

  9. 78 FR 15726 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-12

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... portion of the meeting will be closed to the public. Name of Committee: Cellular, Tissue and...

  10. 76 FR 18768 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-05

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Cellular, Tissue, and Gene Therapies Advisory Committee... portion of the meeting will be closed to the public. Name of Committee: Cellular, Tissue, and...

  11. 78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-25

    ... Federal Register of November 29, 2012 (77 FR 71194), FDA announced the availability of the draft guidance... Investigational Cellular and Gene Therapy Products; Availability AGENCY: Food and Drug Administration, HHS. ACTION... entitled ``Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene...

  12. 77 FR 63840 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-17

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee..., Tissue and Gene Therapies Advisory Committee. General Function of the Committee: To provide advice and... in open session to hear updates of research programs in the Gene Transfer and Immunogenicity...

  13. Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy.

    PubMed

    Riet, Tobias; Holzinger, Astrid; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Abken, Hinrich

    2013-01-01

    Redirecting T cells with a chimeric antigen receptor (CAR) of predefined specificity showed remarkable efficacy in the adoptive therapy trials of malignant diseases. The CAR consists of a single chain fragment of variable region (scFv) antibody targeting domain covalently linked to the CD3ζ signalling domain of the T cell receptor complex to mediate T cell activation upon antigen engagement. By using an antibody-derived targeting domain a CAR can potentially redirect T cells towards any target expressed on the cell surface as long as a binding domain is available. Antibody-mediated targeting moreover circumvents MHC restriction of the targeted antigen, thereby broadening the potential of applicability of adoptive T cell therapy. While T cells were so far genetically modified by viral transduction, transient modification with a CAR by RNA transfection gained increasing interest during the last years. This chapter focuses on methods to modify human T cells from peripheral blood with a CAR by electroporation of in vitro transcribed RNA and to test modified T cells for function for use in adoptive immunotherapy. PMID:23296935

  14. The impact of cellular senescence in cancer therapy: is it true or not?

    PubMed Central

    Zhang, Yi; Yang, Jin-ming

    2011-01-01

    Cellular senescence is defined as the physiological program of terminal growth arrest, which can be triggered by various endogenous or exogenous stress signals. Cellular senescence can be induced in response to oncogenic activation and acts as a barrier to tumorigenesis. Moreover, tumor cells can undergo senescence when exposed to chemotherapeutic agents. In addition to suppressing tumorigenesis, senescent cells remain metabolically active and may contribute to tumor formation and to therapy resistance. In the current review, we discuss the molecular regulation of cellular senescence, the potential implications of senescence in human cancers, and the possibility of exploiting cellular senescence for the treatment of cancers. PMID:21909124

  15. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement.

    PubMed

    Horwitz, E M; Le Blanc, K; Dominici, M; Mueller, I; Slaper-Cortenbach, I; Marini, F C; Deans, R J; Krause, D S; Keating, A

    2005-01-01

    The plastic-adherent cells isolated from BM and other sources have come to be widely known as mesenchymal stem cells (MSC). However, the recognized biologic properties of the unfractionated population of cells do not seem to meet generally accepted criteria for stem cell activity, rendering the name scientifically inaccurate and potentially misleading to the lay public. Nonetheless, a bona fide MSC most certainly exists. To address this inconsistency between nomenclature and biologic properties, and to clarify the terminology, we suggest that the fibroblast-like plastic-adherent cells, regardless of the tissue from which they are isolated, be termed multipotent mesenchymal stromal cells, while the term mesenchymal stem cells is used only for cells that meet specified stem cell criteria. The widely recognized acronym, MSC, may be used for both cell populations, as is the current practice; thus, investigators must clearly define the more scientifically correct designation in their reports. The International Society for Cellular Therapy (ISCT) encourages the scientific community to adopt this uniform nomenclature in all written and oral communications. PMID:16236628

  16. Reprogrammed quiescent B cells provide an effective cellular therapy against chronic experimental autoimmune encephalomyelitis

    PubMed Central

    Calderón-Gómez, Elisabeth; Lampropoulou, Vicky; Shen, Ping; Neves, Patricia; Roch, Toralf; Stervbo, Ulrik; Rutz, Sascha; Kühl, Anja A.; Heppner, Frank L.; Loddenkemper, Christoph; Anderton, Stephen M.; Kanellopoulos, Jean M.; Charneau, Pierre; Fillatreau, Simon

    2011-01-01

    Activated B cells can regulate immunity, and have been envisaged as potential cell-based therapy for treating autoimmune diseases. However, activated human B cells can also propagate immune responses, and the effects resulting from their infusion into patients cannot be predicted. This led us to consider resting B cells, which in contrast are poorly immunogenic, as an alternative cellular platform for the suppression of unwanted immunity. Here, we report that resting B cells can be directly engineered to express antigens in a remarkably simple, rapid, and effective way with lentiviral vectors. Notably, this neither required nor induced activation of the B cells. With that approach we were able to produce reprogrammed resting B cells that inhibited antigen-specific CD4+ T cells, CD8+ T cells, and B cells upon adoptive transfer in mice. Furthermore, resting B cells engineered to ectopically express myelin oligodendrocyte glycoprotein antigen protected recipient mice from severe disability and demyelination in experimental autoimmune encephalomyelitis, and even induced complete remission from disease in mice lacking functional natural regulatory T cells, which otherwise developed a chronic paralysis. In conclusion, our study introduces reprogrammed quiescent B cells as a novel tool for suppressing undesirable immunity. PMID:21469107

  17. Putting a price tag on novel autologous cellular therapies.

    PubMed

    Abou-El-Enein, Mohamed; Bauer, Gerhard; Medcalf, Nicholas; Volk, Hans-Dieter; Reinke, Petra

    2016-08-01

    Cell therapies, especially autologous therapies, pose significant challenges to researchers who wish to move from small, probably academic, methods of manufacture to full commercial scale. There is a dearth of reliable information about the costs of operation, and this makes it difficult to predict with confidence the investment needed to translate the innovations to the clinic, other than as small-scale, clinician-led prescriptions. Here, we provide an example of the results of a cost model that takes into account the fixed and variable costs of manufacture of one such therapy. We also highlight the different factors that influence the product final pricing strategy. Our findings illustrate the need for cooperative and collective action by the research community in pre-competitive research to generate the operational models that are much needed to increase confidence in process development for these advanced products. PMID:27288308

  18. Photonic cancer therapy: modulating cellular metabolism with light

    NASA Astrophysics Data System (ADS)

    Coutinho, Isabel; Correia, Manuel; Viruthachalam, Thiagarajan; Gajula, Gnana Prakash; Petersen, Steffen B.; Neves-Petersen, Maria Teresa

    2013-03-01

    The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases. EGFR activation upon binding of ligands (such as EGF and TGF-α) results in cell signaling cascades that promote cell proliferation, survival and apoptosis inhibition. As reported for many solid tumors, EGFR overactivation is associated with tumor development and progression, resistance to cancer therapies and poor prognosis. Therefore, inhibition of EGFR function is a rational cancer therapy approach. We have shown previously that 280 nm UV illumination of two cancer cell lines overexpressing EGFR could prevent phosphorylation of EGFR and of its downstream signalling molecules despite the presence of EGF. Our earlier studies demonstrated that UV illumination of aromatic residues in proteins leads to the disruption of nearby disulphide bridges. Since human EGFR is rich in disulphide bridges and aromatic residues, it is likely that structural changes can be induced upon UV excitation of its pool of aromatic residues (Trp, Tyr and Phe). Such changes may impair the correct binding of ligands to EGFR which will halt the process of tumor growth. In this paper we report structural changes induced by UV light on the extracellular domain of human EGFR. Steady state fluorescence spectroscopy and binding immunoassays were carried out. Our goal is to gain insight at the protein structure level that explains the way the new photonic cancer therapy works. This technology can be applicable to the treatment of various forms of cancer, alone or in combination with other therapies to improve treatment outcome.

  19. Cellular chromophores and signaling in low level light therapy

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Demidova-Rice, Tatiana N.

    2007-02-01

    The use of low levels of visible or near infrared light (LLLT) for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing tissue damage by reducing cellular apoptosis has been known for almost forty years since the invention of lasers. Originally thought to be a peculiar property of laser light (soft or cold lasers), the subject has now broadened to include photobiomodulation and photobiostimulation using non-coherent light. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial. This likely is due to two main reasons; firstly the biochemical mechanisms underlying the positive effects are incompletely understood, and secondly the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. In recent years major advances have been made in understanding the mechanisms that operate at the cellular and tissue levels during LLLT. Mitochondria are thought to be the main site for the initial effects of light and specifically cytochrome c oxidase that has absorption peaks in the red and near infrared regions of the electromagnetic spectrum matches the action spectra of LLLT effects. The discovery that cells employ nitric oxide (NO) synthesized in the mitochondria by neuronal nitric oxide synthase, to regulate respiration by competitive binding to the oxygen binding of cytochrome c oxidase, now suggests how LLLT can affect cell metabolism. If LLLT photodissociates inhibitory NO from cytochrome c oxidase, this would explain increased ATP production, modulation of reactive oxygen species, reduction and prevention of apoptosis, stimulation of angiogenesis, increase of blood flow and induction of transcription factors. In

  20. Antitumor activity of photodynamic therapy, adoptive immunotherapy, and chemotherapy in experimental tumor

    NASA Astrophysics Data System (ADS)

    Canti, Gianfranco L.; Calastretti, Angela; Cubeddu, Rinaldo; Taroni, Paola; Valentini, Gianluca; Reddi, Elena; Palumbo, Giuseppe

    2004-07-01

    Since Photodynamic therapy(PDT) is able to increase the antitumor immunity, in our laboratory we examine the antitumor effect of combination of PDT,with photoactivated Aluminium disulfonated Phthalocianine(ALS2Pc),adoptive immunotherapy, with immune lymphocytes, and chemotherapy on aggressive murine tumor. Mice bearing L1210 tumor were treated at day +4 with PDT ( 5mg/Kg of AlS2Pc and 100mW/cm2 x 10" of exposure of laser light 24hrs. later),at day +6 with Adriamycin(ADR 2mg/Kg) and at day + 7 with immune lymphocytes(IL),collected from L1210 bearing mice pretreated with PDT(2x107 cells).The results show that the combination ADR + PDT + IL demonstrates a significant synergistic antitumor effect while the chemotherapy treatment with low dose of the drug and the adotive immunotherapy treatment are slightly effective. The same positive results were obtained with the combination of PDT,Cisplatin(CDDP 2mg/Kg) and IL,while the CDDP treatment alone and the Il treatment alone are slightly effective. In conclusion these results suggest that it is possible to completely cure animals bearing advanced tumors, with a combined therapy, PDT + adoptive immunotherapy + low dose chemotherapy.

  1. A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

    PubMed Central

    Chung, Dong-Sup; Shin, Hye-Jin; Hong, Yong-Kil

    2014-01-01

    Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expanded ex vivo rapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas. PMID:25009822

  2. Role of T Cell Receptor Affinity in the Efficacy and Specificity of Adoptive T Cell Therapies

    PubMed Central

    Stone, Jennifer D.; Kranz, David M.

    2013-01-01

    Over the last several years, there has been considerable progress in the treatment of cancer using gene modified adoptive T cell therapies. Two approaches have been used, one involving the introduction of a conventional αβ T cell receptor (TCR) against a pepMHC cancer antigen, and the second involving introduction of a chimeric antigen receptor (CAR) consisting of a single-chain antibody as an Fv fragment linked to transmembrane and signaling domains. In this review, we focus on one aspect of TCR-mediated adoptive T cell therapies, the impact of the affinity of the αβ TCR for the pepMHC cancer antigen on both efficacy and specificity. We discuss the advantages of higher-affinity TCRs in mediating potent activity of CD4 T cells. This is balanced with the potential disadvantage of higher-affinity TCRs in mediating greater self-reactivity against a wider range of structurally similar antigenic peptides, especially in synergy with the CD8 co-receptor. Both TCR affinity and target selection will influence potential safety issues. We suggest pre-clinical strategies that might be used to examine each TCR for possible on-target and off-target side effects due to self-reactivities, and to adjust TCR affinities accordingly. PMID:23970885

  3. Controversial attachments: the indirect treatment of fostered and adopted children via Parent Co-Therapy.

    PubMed

    Hart, A; Thomas, H

    2000-12-01

    Fostered and adopted children often show a large array of psychosocial problems and are conceptualized as having attachment disorders. It can be necessary to engage such children in direct mental health treatment, in addition to interventions set up to deal with their problems through agencies such as Education and Social Services. In order to protect children from a multitude of treating professionals, thereby potentially further weakening the emerging parental attachments, a model is proposed of indirect treatment of children, with the adoptive parents as co-therapists. This elevates the status of parents and is controversial in child mental health work as it challenges traditional hierarchies. We refer to this model, based on a single case study, as Parent Co-Therapy (PCT). It is proposed that this may be a suitable treatment model for fostered and adopted children, particularly in the early years of placement. The model has the potential to strengthen the children's attachments to the parents and vice versa, with a concomitant reduction in symptomatology. PMID:11708221

  4. Cellular models and therapies for age-related macular degeneration

    PubMed Central

    Forest, David L.; Johnson, Lincoln V.; Clegg, Dennis O.

    2015-01-01

    ABSTRACT Age-related macular degeneration (AMD) is a complex neurodegenerative visual disorder that causes profound physical and psychosocial effects. Visual impairment in AMD is caused by the loss of retinal pigmented epithelium (RPE) cells and the light-sensitive photoreceptor cells that they support. There is currently no effective treatment for the most common form of this disease (dry AMD). A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. Multiple clinical trials are being initiated using a variety of cell therapies. Although many animal models are available for AMD research, most do not recapitulate all aspects of the disease, hampering progress. However, the use of cultured RPE cells in AMD research is well established and, indeed, some of the more recently described RPE-based models show promise for investigating the molecular mechanisms of AMD and for screening drug candidates. Here, we discuss innovative cell-culture models of AMD and emerging stem-cell-based therapies for the treatment of this vision-robbing disease. PMID:26035859

  5. CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2

    PubMed Central

    Bedognetti, D; Spivey, T L; Zhao, Y; Uccellini, L; Tomei, S; Dudley, M E; Ascierto, M L; De Giorgi, V; Liu, Q; Delogu, L G; Sommariva, M; Sertoli, M R; Simon, R; Wang, E; Rosenberg, S A; Marincola, F M

    2013-01-01

    Background: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. Methods: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). Results: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. Conclusion: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response. PMID:24129241

  6. Cellular iron metabolism in prognosis and therapy of breast cancer.

    PubMed

    Torti, Suzy V; Torti, Frank M

    2013-01-01

    Despite many recent advances, breast cancer remains a clinical challenge. Current issues include improving prognostic evaluation and increasing therapeutic options for women whose tumors are refractory to current frontline therapies. Iron metabolism is frequently disrupted in breast cancer, and may offer an opportunity to address these challenges. Iron enhances breast tumor initiation, growth and metastases. Iron may contribute to breast tumor initiation by promoting redox cycling of estrogen metabolites. Up-regulation of iron import and down-regulation of iron export may enable breast cancer cells to acquire and retain excess iron. Alterations in iron metabolism in macrophages and other cells of the tumor microenvironment may also foster breast tumor growth. Expression of iron metabolic genes in breast tumors is predictive of breast cancer prognosis. Iron chelators and other strategies designed to limit iron may have therapeutic value in breast cancer. The dependence of breast cancer on iron presents rich opportunities for improved prognostic evaluation and therapeutic intervention. PMID:23879588

  7. Cytokines as Adjuvants for Vaccine and Cellular Therapies for Cancer

    PubMed Central

    Capitini, Christian M.; Fry, Terry J.; Mackall, Crystal L.

    2009-01-01

    Problem statement The development of a potent vaccine that can help treat tumors resistant to conventional cytotoxic therapies remains elusive. While part of the problem may be that trials have focused on patients with bulky residual disease, the desire to maximize responses to the vaccine remains. Approach The gamma(c) family of cytokines offer a unique opportunity to support the expansion and effector potential of vaccine-responding T-cells, as well as stimulate other effectors, such as natural killer (NK) cells, to become activated. Results Combining vaccines with cytokines seems logical but can bring unwanted toxicity, as has been observed with interleukin (IL)-2. In addition, the nonspecific activation or expansion of unwanted cell subsets, such as regulatory T-cells, can contribute to global immunosuppression and limit vaccine responses. The development of IL-7 and IL-21 for the clinic offers the promise of enhancing anti-tumor responses but with far less systemic toxicity and no expansion of regulatory T cells. Preclinical studies demonstrate that IL-15 could also improve T-cell, and especially NK-cell, responses as well. Conclusions/Recommendations Future work should expand the use of vaccines with IL-7, IL-21 and hopefully IL-15 in high-risk patients, and consider treatment while in a state of minimal residual disease to maximize benefit. Identifying tumors that can signal through gamma(c) cytokines will also be essential so that induction of relapse will be avoided. PMID:20182648

  8. Management of patients with non-Hodgkin’s lymphoma: focus on adoptive T-cell therapy

    PubMed Central

    Perna, Serena Kimi; Huye, Leslie E; Savoldo, Barbara

    2015-01-01

    Non-Hodgkin’s lymphoma (NHL) represents a heterogeneous group of malignancies with high diversity in terms of biology, clinical responses, and prognosis. Standard therapy regimens produce a 5-year relative survival rate of only 69%, with the critical need to increase the treatment-success rate of this patient population presenting at diagnosis with a median age of 66 years and many comorbidities. The evidence that an impaired immune system favors the development of NHL has opened the stage for new therapeutics, and specifically for the adoptive transfer of ex vivo-expanded antigen-specific T-cells. In this review, we discuss how T-cells specific for viral-associated antigens, nonviral-associated antigens expressed by the tumor, T-cells redirected through the expression of chimeric antigen receptors, and transgenic T-cell receptors against tumor cells have been developed and used in clinical trials for the treatment of patients with NHLs. PMID:27471712

  9. Cancer treatment by photodynamic therapy combined with NK-cell-line-based adoptive immunotherapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Sun, Jinghai

    1998-05-01

    Treatment of solid cancers by photodynamic therapy (PDT) triggers a strong acute inflammatory reaction localized to the illuminated malignant tissue. This event is regulated by a massive release of various potent mediators which have a profound effect not only on local host cell populations, but also attract different types of immune cells to the treated tumor. Phagocytosis of PDT-damaged cancerous cells by antigen presenting cells, such as activated tumor associated macrophages, enables the recognition of even poorly immunogenic tumors by specific immune effector cells and the generation of immune memory populations. Because of its inflammatory/immune character, PDT is exceptionally responsive to adjuvant treatments with various types of immunotherapy. Combining PDT with immuneactivators, such as cytokines or other specific or non-specific immune agents, rendered marked improvements in tumor cures with various cancer models. Another clinically attractive strategy is adoptive immunotherapy, and the prospects of its use in conjunction with PDT are outlined.

  10. Adoptive cell therapy and modulation of the tumour microenvironment: new insights from ASCO 2016

    PubMed Central

    Khoja, Leila; Gyawali, Bishal

    2016-01-01

    Abstract Immuno-oncology has changed the landscape of cancer treatment in recent years. Immune checkpoint inhibitors (ICI) have shown survival advantage with long term remissions in a variety of cancers. However, there is another approach to harnessing the power of the immune system in combating cancer: the adoptive cell therapy (ACT) strategy. Although ACT is restricted to small specialized centres and has yet to deliver as much success as ICI, some important results were presented at this year’s ASCO meeting. Important lessons have been learned from these studies, including the prospects and challenges ahead. In this editorial, we summarize the important studies on ACT presented at the ASCO 2016 meeting and discuss the way forward. PMID:27610200

  11. Adoptive cell therapy and modulation of the tumour microenvironment: new insights from ASCO 2016.

    PubMed

    Khoja, Leila; Gyawali, Bishal

    2016-01-01

    Immuno-oncology has changed the landscape of cancer treatment in recent years. Immune checkpoint inhibitors (ICI) have shown survival advantage with long term remissions in a variety of cancers. However, there is another approach to harnessing the power of the immune system in combating cancer: the adoptive cell therapy (ACT) strategy. Although ACT is restricted to small specialized centres and has yet to deliver as much success as ICI, some important results were presented at this year's ASCO meeting. Important lessons have been learned from these studies, including the prospects and challenges ahead. In this editorial, we summarize the important studies on ACT presented at the ASCO 2016 meeting and discuss the way forward. PMID:27610200

  12. Cellular Responses and Tissue Depots for Nanoformulated Antiretroviral Therapy

    PubMed Central

    Martinez-Skinner, Andrea L.; Araínga, Mariluz A.; Puligujja, Pavan; Palandri, Diana L.; Baldridge, Hannah M.; Edagwa, Benson J.; McMillan, JoEllyn M.; Mosley, R. Lee; Gendelman, Howard E.

    2015-01-01

    Long-acting nanoformulated antiretroviral therapy (nanoART) induces a range of innate immune migratory, phagocytic and secretory cell functions that perpetuate drug depots. While recycling endosomes serve as the macrophage subcellular depots, little is known of the dynamics of nanoART-cell interactions. To this end, we assessed temporal leukocyte responses, drug uptake and distribution following both intraperitoneal and intramuscular injection of nanoformulated atazanavir (nanoATV). Local inflammatory responses heralded drug distribution to peritoneal cell populations, regional lymph nodes, spleen and liver. This proceeded for three days in male Balb/c mice. NanoATV-induced changes in myeloid populations were assessed by fluorescence-activated cell sorting (FACS) with CD45, CD3, CD11b, F4/80, and GR-1 antibodies. The localization of nanoATV within leukocyte cell subsets was determined by confocal microscopy. Combined FACS and ultra-performance liquid chromatography tandem mass-spectrometry assays determined nanoATV carriages by cell-based vehicles. A robust granulocyte, but not peritoneal macrophage nanoATV response paralleled zymosan A treatment. ATV levels were highest at sites of injection in peritoneal or muscle macrophages, dependent on the injection site. The spleen and liver served as nanoATV tissue depots while drug levels in lymph nodes were higher than those recorded in plasma. Dual polymer and cell labeling demonstrated a nearly exclusive drug reservoir in macrophages within the liver and spleen. Overall, nanoART induces innate immune responses coincident with rapid tissue macrophage distribution. Taken together, these works provide avenues for therapeutic development designed towards chemical eradication of human immunodeficiency viral infection. PMID:26716700

  13. Adoption of Intensity Modulated Radiation Therapy For Early-Stage Breast Cancer From 2004 Through 2011

    SciTech Connect

    Wang, Elyn H.; Mougalian, Sarah S.; Soulos, Pamela R.; Smith, Benjamin D.; Haffty, Bruce G.; Gross, Cary P.; Yu, James B.

    2015-02-01

    Purpose: Intensity modulated radiation therapy (IMRT) is a newer method of radiation therapy (RT) that has been increasingly adopted as an adjuvant treatment after breast-conserving surgery (BCS). IMRT may result in improved cosmesis compared to standard RT, although at greater expense. To investigate the adoption of IMRT, we examined trends and factors associated with IMRT in women under the age of 65 with early stage breast cancer. Methods and Materials: We performed a retrospective study of early stage breast cancer patients treated with BCS followed by whole-breast irradiation (WBI) who were ≤65 years old in the National Cancer Data Base from 2004 to 2011. We used logistic regression to identify factors associated with receipt of IMRT (vs standard RT). Results: We identified 11,089 women with early breast cancer (9.6%) who were treated with IMRT and 104,448 (90.4%) who were treated with standard RT, after BCS. The proportion of WBI patients receiving IMRT increased yearly from 2004 to 2009, with 5.3% of WBI patients receiving IMRT in 2004 and 11.6% receiving IMRT in 2009. Further use of IMRT declined afterward, with the proportion remaining steady at 11.0% and 10.7% in 2010 and 2011, respectively. Patients treated in nonacademic community centers were more likely to receive IMRT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.30-1.43 for nonacademic vs academic center). Compared to privately insured patients, the uninsured patients (OR, 0.81; 95% CI, 0.70-0.95) and those with Medicaid insurance (OR, 0.87; 95% CI, 0.79-0.95) were less likely to receive IMRT. Conclusions: The use of IMRT rose from 2004 to 2009 and then stabilized. Important nonclinical factors associated with IMRT use included facility type and insurance status.

  14. Elimination of Metastatic Melanoma Using Gold Nanoshell-Enabled Photothermal Therapy and Adoptive T Cell Transfer

    PubMed Central

    Perna, Serena K.; Mattos Almeida, Joao Paulo; Lin, Adam Y.; Eckels, Phillip C.; Drezek, Rebekah A.; Foster, Aaron E.

    2013-01-01

    Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b+Ly-6G/C+ myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control. PMID:23935927

  15. Early efficacy of stereotactic body radiation therapy combined with adoptive immunotherapy for advanced malignancies

    PubMed Central

    WANG, YI-SHAN; YANG, GUIQING; WANG, YUAN-YUAN; YANG, JIA-LIN; YANG, KE

    2013-01-01

    Stereotactic body radiation therapy (SBRT) concentrates radiation to a predefined target, affecting all the cells within it. Adoptive immunotherapy is not restricted by the major histocompatibility complex (MHC) in recognizing and eliminating target cells. We investigated the effects of the combined modality of SBRT and adoptive immunotherapy on patients with advanced malignant tumors. The database of 316 patients with 845 tumors who underwent SBRT between April, 2010 and February, 2012 was retrospectively reviewed. Of the 316 patients, 145 received biological immunotherapy and were assigned into the observation group, whereas the remaining patients constituted the control group. Patients in the two groups were recorded on efficacy assessment, Karnofsky performance status (KPS), cell phenotype expression level in vitro and the percentages of lymphocyte subsets and ratio of CD4+/CD8+ lymphocytes in the peripheral blood. Following treatment, the total effectiveness [complete response (CR) + partial response (PR)], the KPS score, the percentages of lymphocyte subsets and the CD4+/CD8+ lymphocyte ratio in the observation group were higher compared to those in the control group, with a statistically significant difference (P<0.05). The expression of CD3+ and CD3+CD56+ cytokine-induced killer (CIK) cells were increased from 56.76±4.54% and 11.32±2.96% to 94.67±4.46% and 32.65±1.12%, respectively, when cultured in vitro (P<0.01). The percentages of lymphocyte subsets and the CD4+/CD8+ lymphocyte ratio were significantly increased compared to prior to treatment in the observation group (P<0.05). SBRT combined with adoptive immunotherapy may be a novel therapeutic option for patients with advanced malignant tumors. PMID:24649272

  16. Adoptive T-cell therapy for fungal infections in haematology patients

    PubMed Central

    Deo, Shivashni S; Gottlieb, David J

    2015-01-01

    The prolonged immune deficiency resulting from haematopoietic stem cell transplant and chemotherapy predisposes to a high risk of invasive fungal infections. Despite the recent advances in molecular diagnostic testing, early initiation of pre-emptive antifungal therapy and the use of combination pharmacotherapy, mortality from invasive mould infections remain high among recipients of allogeneic stem cell transplant. The increasing incidences of previously rare and drug-resistant strains of fungi present a further clinical challenge. Therefore, there is a need for novel strategies to combat fungal infections in the immunocompromised. Adoptive therapy using in vitro-expanded fungus-specific CD4 cells of the Th-1 type has shown clinical efficacy in murine studies and in a small human clinical study. Several techniques for the isolation and expansion of fungus-specific T cells have been successfully applied. Here we discuss the incidence and changing patterns of invasive fungal diseases, clinical evidence supporting the role of T cells in fungal immunity, methods to expand fungus-specific T cells in the laboratory and considerations surrounding the use of T cells for fungal immunotherapy. PMID:26366286

  17. [Translational/regulatory science researches of NIHS for regenerative medicine and cellular therapy products].

    PubMed

    Sato, Yoji

    2014-01-01

    In 2013, the Japanese Diet passed the Regenerative Medicine Promotion Act and the revisions to the Pharmaceutical Affairs Act, which was also renamed as the Therapeutic Products Act (TPA). One of the aims of the new/revised Acts is to promote the development and translation of and access to regenerative/cellular therapies. In the TPA, a product derived from processing cells is categorized as a subgroup of "regenerative medicine, cellular therapy and gene therapy products" (RCGPs), products distinct from pharmaceuticals and medical devices, allowing RCGPs to obtain a conditional and time- limited marketing authorization much earlier than that under the conventional system. To foster not only RCGPs, but also innovative pharmaceuticals and medical devices, the Ministry of Health, Labour and Welfare recently launched Translational Research Program for Innovative Pharmaceuticals, Medical Devices and RCGPs. This mini-review introduces contributions of the National Institute of Health Sciences (NIHS) to research projects on RCGPs in the Program. PMID:25707195

  18. Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction.

    PubMed

    Ménager, Jérémie; Gorin, Jean-Baptiste; Maurel, Catherine; Drujont, Lucile; Gouard, Sébastien; Louvet, Cédric; Chérel, Michel; Faivre-Chauvet, Alain; Morgenstern, Alfred; Bruchertseifer, Frank; Davodeau, François; Gaschet, Joëlle; Guilloux, Yannick

    2015-01-01

    Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established. PMID:26098691

  19. Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction

    PubMed Central

    Ménager, Jérémie; Gorin, Jean-Baptiste; Maurel, Catherine; Drujont, Lucile; Gouard, Sébastien; Louvet, Cédric; Chérel, Michel; Faivre-Chauvet, Alain; Morgenstern, Alfred; Bruchertseifer, Frank; Davodeau, François

    2015-01-01

    Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. α-Radioimmunotherapy (α-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. α-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of α-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining α-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with α-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining α-RIT and ACT in the MM model we established. PMID:26098691

  20. New Tools in Experimental Cellular Therapy for the Treatment of Liver Diseases

    PubMed Central

    Ferrer, Jennifer R.; Chokechanachaisakul, Attasit; Wertheim, Jason A.

    2015-01-01

    The current standard of care for end stage liver disease is orthotopic liver transplantation (OLT). Through improvement in surgical techniques, immunosuppression, and general medical care, liver transplantation has become an effective treatment over the course of the last half-century. Unfortunately, due to the limited availability of donor organs, there is a finite limit to the number of patients who will benefit from this therapy. This review will discuss current research in experimental cellular therapies for acute, chronic, and metabolic liver failure that may be appropriate when liver transplantation is not an immediate option. PMID:26317066

  1. Treatment as prevention: are Argentinean HIV care providers willing to adopt earlier antiretroviral therapy?

    PubMed

    Socías, María Eugenia; Sued, Omar; Pryluka, Daniel; Patterson, Patricia; Fink, Valeria; Cesar, Carina; Cahn, Pedro

    2014-01-01

    HIV guidelines increasingly recommend antiretroviral therapy (ART) initiation at a higher CD4 levels. The extent to which these evolving standards are translated into routine clinical care has not been evaluated in Argentina. During October 2012, we conducted an online survey among Argentinean HIV clinicians to assess their attitudes and practices toward ART initiation and its potential use for HIV prevention. Of the 280 physicians included, 61% would prescribe ART at CD4 ≤ 500 cells/µL for asymptomatic patients. Although, only 11% would recommend ART irrespective of CD4 cell count, 72% would do it for serodiscordant couples, and 75% for sex workers. Most participants agreed that they would consider earlier initiation of ART if transmission risk exists, and that expansion of ART could help decrease HIV incidence. These results suggest that a large proportion of Argentinean HIV care providers are willing to adopt the recently updated Argentinean guidelines recommending earlier ART, especially when high HIV transmission risk exists. PMID:24773142

  2. Redox Homeostasis and Cellular Antioxidant Systems: Crucial Players in Cancer Growth and Therapy

    PubMed Central

    Ciucis, Chiara De

    2016-01-01

    Reactive oxygen species (ROS) and their products are components of cell signaling pathways and play important roles in cellular physiology and pathophysiology. Under physiological conditions, cells control ROS levels by the use of scavenging systems such as superoxide dismutases, peroxiredoxins, and glutathione that balance ROS generation and elimination. Under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage that may contribute to carcinogenesis. Several studies have shown that cancer cells display an adaptive response to oxidative stress by increasing expression of antioxidant enzymes and molecules. As a double-edged sword, ROS influence signaling pathways determining beneficial or detrimental outcomes in cancer therapy. In this review, we address the role of redox homeostasis in cancer growth and therapy and examine the current literature regarding the redox regulatory systems that become upregulated in cancer and their role in promoting tumor progression and resistance to chemotherapy. PMID:27418953

  3. Planes, Trains, and Automobiles: Perspectives on CAR T Cells and Other Cellular Therapies for Hematologic Malignancies.

    PubMed

    Gill, Saar

    2016-08-01

    Hematologic oncologists now have at their disposal (or a referral away) a myriad of new options to get from point A (a patient with relapsed or poor-risk disease) to point B (potential tumor eradication and long-term disease-free survival). In this perspective piece, we discuss the putative mechanisms of action and the relative strengths and weaknesses of currently available cellular therapy approaches. Notably, while many of these approaches have been published in high impact journals, with the exception of allogeneic stem cell transplantation and of checkpoint inhibitors (PD1/PDL1 or CTLA4 blockade), the published clinical trials have mostly been early phase, uncontrolled studies. Therefore, many of the new cellular therapy approaches have yet to demonstrate incontrovertible evidence of enhanced overall survival compared with controls. Nonetheless, the science behind these is sure to advance our understanding of cancer immunology and ultimately to bring us closer to our goal of curing cancer. PMID:27136938

  4. Adoptive precursor cell therapy to enhance immune reconstitution after hematopoietic stem cell transplantation in mouse and man

    PubMed Central

    Holland, Amanda M.; Zakrzewski, Johannes L.; Goldberg, Gabrielle L.; Ghosh, Arnab

    2016-01-01

    Hematopoietic stem cell transplantation is a curative therapy for hematological malignancies. T cell deficiency following transplantation is a major cause of morbidity and mortality. In this review, we discuss adoptive transfer of committed precursor cells to enhance T cell reconstitution and improve overall prognosis after transplantation. PMID:19015856

  5. Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

    PubMed Central

    Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

    2013-01-01

    Introduction Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. Methods We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Results Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Conclusions Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung

  6. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses.

    PubMed Central

    Yang, Y; Li, Q; Ertl, H C; Wilson, J M

    1995-01-01

    Recombinant adenoviruses are an attractive vehicle for gene therapy to the lung in the treatment of cystic fibrosis (CF). First-generation viruses deleted of E1a and E1b transduce genes into airway epithelial cells in vivo; however, expression of the transgene is transient and associated with substantial inflammatory responses, and gene transfer is significantly reduced following a second administration of the virus. In this study, we have used mice deficient in immunological effector functions in combination with adoptive and passive transfer techniques to define antigen-specific cellular and humoral immune responses that underlie these important limitations. Our studies indicate that major histocompatibility complex class I-restricted CD8+ cytotoxic T lymphocytes are activated in response to newly synthesized antigens, leading to destruction of virus infected cells and loss of transgene expression. Major histocompatibility complex class II-associated presentation of exogenous viral antigens activates CD4+ T-helper (TH) cells of the TH1 subset and, to a lesser extent, of the TH2 subset. CD4+ cell-mediated responses are insufficient in the absence of cytotoxic T cells to completely eliminate transgene containing cells; however, they contribute to the formation of neutralizing antibodies in the airway which block subsequent adenovirus-mediated gene transfer. Definition of immunological barriers to gene therapy of cystic fibrosis should facilitate the design of rational strategies to overcome them. PMID:7884845

  7. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis.

    PubMed

    Wright, Graham P; Notley, Clare A; Xue, Shao-An; Bendle, Gavin M; Holler, Angelika; Schumacher, Ton N; Ehrenstein, Michael R; Stauss, Hans J

    2009-11-10

    Regulatory T cells (Tregs) can suppress a wide range of immune cells, making them an ideal candidate for the treatment of autoimmunity. The potential clinical translation of targeted therapy with antigen-specific Tregs is hampered by the difficulties of isolating rare specificities from the natural polyclonal T cell repertoire. Moreover, the initiating antigen is often unknown in autoimmune disease. Here we tested the ability of antigen-specific Tregs generated by retroviral gene transfer to ameliorate arthritis through linked suppression and therefore without cognate recognition of the disease-initiating antigen. We explored two distinct strategies: T cell receptor (TCR) gene transfer into purified CD4+CD25+ T cells was used to redirect the specificity of naturally occurring Tregs; and co-transfer of FoxP3 and TCR genes served to convert conventional CD4(+) T cells into antigen-specific regulators. Following adoptive transfer into recipient mice, the gene-modified T cells engrafted efficiently and retained TCR and FoxP3 expression. Using an established arthritis model, we demonstrate antigen-driven accumulation of the gene modified T cells at the site of joint inflammation, which resulted in a local reduction in the number of inflammatory Th17 cells and a significant decrease in arthritic bone destruction. Together, we describe a robust strategy to rapidly generate antigen-specific regulatory T cells capable of highly targeted inhibition of tissue damage in the absence of systemic immune suppression. This opens the possibility to target Tregs to tissue-specific antigens for the treatment of autoimmune tissue damage without the knowledge of the disease-causing autoantigens recognized by pathogenic T cells. PMID:19884493

  8. The Survey on Cellular and Engineered Tissue Therapies in Europe in 2011

    PubMed Central

    Baldomero, Helen; Bocelli-Tyndall, Chiara; Emmert, Maximilian Y.; Hoerstrup, Simon P.; Ireland, Hilary; Passweg, Jakob; Tyndall, Alan

    2014-01-01

    Following the coordinated efforts of five established scientific organizations, this report describes the “novel cellular therapy” activity (i.e., cellular treatments excluding hematopoietic stem cells [HSC] for the reconstitution of hematopoiesis) in Europe for the year 2011. Two hundred forty-six teams from 35 countries responded to the cellular therapy survey, 126 teams from 24 countries provided data on 1759 patients using a dedicated survey and 120 teams reported no activity. Indications were musculoskeletal/rheumatological disorders (46%; 99% autologous), cardiovascular disorders (22%; 100% autologous), hematology/oncology, predominantly including the prevention or treatment of graft-versus-host disease (18%; 2% autologous), neurological disorders (2%; 83% autologous), gastrointestinal (1%; 68% autologous), and other indications (12%; 77% autologous). Autologous cells were used predominantly for musculoskeletal/rheumatological (58%) and cardiovascular (27%) disorders, whereas allogeneic cells were used mainly for hematology/oncology (84%). The reported cell types were mesenchymal stem/stromal cells (56%), HSC (23%), chondrocytes (12%), dermal fibroblasts (3%), keratinocytes (2%), and others (4%). In 40% of the grafts, cells were delivered following ex vivo expansion, whereas cells were transduced or sorted, respectively, in 3% and 10% of the reported cases. Cells were delivered intraorgan (42%), intravenously (26%), on a membrane or gel (16%), or using 3D scaffolds (16%). Compared to last year, the number of teams participating in the dedicated survey doubled and, for the first time, all European Group for Blood and Marrow Transplantation teams reporting information on cellular therapies completed the extended questionnaire. The data are compared with those collected since 2008 to identify trends in the field. This year's edition specifically focuses on cardiac cell therapy. PMID:24090467

  9. Mechanisms in photodynamic therapy: part two—cellular signaling, cell metabolism and modes of cell death

    PubMed Central

    Castano, Ana P.; Demidova, Tatiana N.; Hamblin, Michael R.

    2013-01-01

    Summary Photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In the second of a series of three reviews, we will discuss the mechanisms that operate in PDT on a cellular level. In Part I [Castano AP, Demidova TN, Hamblin MR. Mechanism in photodynamic therapy: part one—photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther 2004;1:279–93] it was shown that one of the most important factors governing the outcome of PDT, is how the photosensitizer (PS) interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. PS can localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes. An explosion of investigation and explorations in the field of cell biology have elucidated many of the pathways that mammalian cells undergo when PS are delivered in tissue culture and subsequently illuminated. There is an acute stress response leading to changes in calcium and lipid metabolism and production of cytokines and stress proteins. Enzymes particularly, protein kinases, are activated and transcription factors are expressed. Many of the cellular responses are centered on mitochondria. These effects frequently lead to induction of apoptosis either by the mitochondrial pathway involving caspases and release of cytochrome c, or by pathways involving ceramide or death receptors. However, under certain circumstances cells subjected to PDT die by necrosis. Although there have been many reports of DNA damage caused by PDT, this is not thought to be an important cell-death pathway. This mechanistic research is expected to lead to optimization of PDT as a tumor treatment, and to rational selection of combination therapies that include PDT as a component. PMID:25048553

  10. Adoptive T-cell therapy for cancer in the United kingdom: a review of activity for the British Society of Gene and Cell Therapy annual meeting 2015.

    PubMed

    Gilham, David Edward; Anderson, John; Bridgeman, John Stephen; Hawkins, Robert Edward; Exley, Mark Adrian; Stauss, Hans; Maher, John; Pule, Martin; Sewell, Andrew Kelvin; Bendle, Gavin; Lee, Steven; Qasim, Waseem; Thrasher, Adrian; Morris, Emma

    2015-05-01

    Adoptive T-cell therapy is delivering objective clinical responses across a number of cancer indications in the early phase clinical setting. Much of this clinical activity is taking place at major clinical academic centers across the United States. This review focuses upon cancer-focused cell therapy activity within the United Kingdom as a contribution to the 2015 British Society of Gene and Cell Therapy annual general meeting. This overview reflects the diversity and expansion of clinical and preclinical studies within the United Kingdom while considering the background context of this work against new infrastructural developments and the requirements of nationalized healthcare delivery within the UK National Health Service. PMID:25860661

  11. Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

    PubMed Central

    Anderson, John; Bridgeman, John Stephen; Hawkins, Robert Edward; Exley, Mark Adrian; Stauss, Hans; Maher, John; Pule, Martin; Sewell, Andrew Kelvin; Bendle, Gavin; Lee, Steven; Qasim, Waseem; Thrasher, Adrian; Morris, Emma

    2015-01-01

    Abstract Adoptive T-cell therapy is delivering objective clinical responses across a number of cancer indications in the early phase clinical setting. Much of this clinical activity is taking place at major clinical academic centers across the United States. This review focuses upon cancer-focused cell therapy activity within the United Kingdom as a contribution to the 2015 British Society of Gene and Cell Therapy annual general meeting. This overview reflects the diversity and expansion of clinical and preclinical studies within the United Kingdom while considering the background context of this work against new infrastructural developments and the requirements of nationalized healthcare delivery within the UK National Health Service. PMID:25860661

  12. Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

    PubMed Central

    Hickey, Michelle J.; Malone, Colin C.; Erickson, Kate L.; Lin, Amy; Soto, Horacio; Ha, Edward T.; Kamijima, Shuichi; Inagaki, Akihito; Takahashi, Masamichi; Kato, Yuki; Kasahara, Noriyuki; Mueller, Barbara M.; Kruse, Carol A.

    2013-01-01

    Purpose Individual or combined strategies of cellular therapy with alloreactive cytotoxic T lymphocytes (alloCTL) and gene therapy employing retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain. Experimental Design AlloCTL, sensitized to the human leukocyte antigens of MDA-MB-231 breast cancer cells, were examined in vitro for anti-tumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant. Results AlloCTL preparations were cytotoxic, proliferated and produced interferon-gamma when coincubated with target cells displaying relevant HLA. In vivo, intratumorally-placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRV-CD had a median survival of 97.5 days compared with single modalities (50–83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles. Conclusion The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain. PMID:23780889

  13. Monocyte Activation in Immunopathology: Cellular Test for Development of Diagnostics and Therapy

    PubMed Central

    Ivanova, Ekaterina A.; Orekhov, Alexander N.

    2016-01-01

    Several highly prevalent human diseases are associated with immunopathology. Alterations in the immune system are found in such life-threatening disorders as cancer and atherosclerosis. Monocyte activation followed by macrophage polarization is an important step in normal immune response to pathogens and other relevant stimuli. Depending on the nature of the activation signal, macrophages can acquire pro- or anti-inflammatory phenotypes that are characterized by the expression of distinct patterns of secreted cytokines and surface antigens. This process is disturbed in immunopathologies resulting in abnormal monocyte activation and/or bias of macrophage polarization towards one or the other phenotype. Such alterations could be used as important diagnostic markers and also as possible targets for the development of immunomodulating therapy. Recently developed cellular tests are designed to analyze the phenotype and activity of living cells circulating in patient's bloodstream. Monocyte/macrophage activation test is a successful example of cellular test relevant for atherosclerosis and oncopathology. This test demonstrated changes in macrophage activation in subclinical atherosclerosis and breast cancer and could also be used for screening a panel of natural agents with immunomodulatory activity. Further development of cellular tests will allow broadening the scope of their clinical implication. Such tests may become useful tools for drug research and therapy optimization. PMID:26885534

  14. Adoptive T-cell therapies for refractory/relapsed leukemia and lymphoma: current strategies and recent advances

    PubMed Central

    McLaughlin, Lauren; Cruz, C. Russell; Bollard, Catherine M.

    2015-01-01

    Despite significant advancements in the treatment and outcome of hematologic malignancies, prognosis remains poor for patients who have relapsed or refractory disease. Adoptive T-cell immunotherapy offers novel therapeutics that attempt to utilize the noted graft versus leukemia effect. While CD19 chimeric antigen receptor (CAR)-modified T cells have thus far been the most clinically successful application of adoptive T immunotherapy, further work with antigen specific T cells and CARs that recognize other targets have helped diversify the field to treat a broad spectrum of hematologic malignancies. This article will focus primarily on therapies currently in the clinical trial phase as well as current downfalls or limitations. PMID:26622998

  15. Adoptive T-cell therapies for refractory/relapsed leukemia and lymphoma: current strategies and recent advances.

    PubMed

    McLaughlin, Lauren; Cruz, C Russell; Bollard, Catherine M

    2015-12-01

    Despite significant advancements in the treatment and outcome of hematologic malignancies, prognosis remains poor for patients who have relapsed or refractory disease. Adoptive T-cell immunotherapy offers novel therapeutics that attempt to utilize the noted graft versus leukemia effect. While CD19 chimeric antigen receptor (CAR)-modified T cells have thus far been the most clinically successful application of adoptive T immunotherapy, further work with antigen specific T cells and CARs that recognize other targets have helped diversify the field to treat a broad spectrum of hematologic malignancies. This article will focus primarily on therapies currently in the clinical trial phase as well as current downfalls or limitations. PMID:26622998

  16. HIV migration between blood plasma and cellular subsets before and after HIV therapy.

    PubMed

    Choi, Jun Yong; Chaillon, Antoine; Oh, Jin Ok; Ahn, Jin Young; Ann, Hae Won; Jung, In Young; Ahn, Mi-Young; Jeon, Yong Duk; Ku, Nam Su; Smith, Davey M; Kim, June Myung

    2016-04-01

    The cellular source of HIV RNA circulating in blood plasma remains unclear. Here, we investigated whether sequence analysis of HIV RNA populations circulating before combination antiretroviral therapy (cART) and HIV DNA populations in cellular subsets (CS) after cART could identify the cellular sources of circulating HIV RNA. Blood was collected from five subjects at cART initiation and again 6 months later. Naïve CD4+ T cells, resting central memory and effector memory CD4+ T cells, activated CD4+ T cells, monocytes, and natural killer cells were sorted using a fluorescence-activated cell sorter. HIV-1 env C2V3 sequences from HIV RNA in blood plasma and HIV DNA in CSs were generated using single genome sequencing. Sequences were evaluated for viral compartmentalization (Fst test) and migration events (MEs; Slatkin Maddison and cladistic measures) between blood plasma and each CS. Viral compartmentalization was observed in 88% of all cellular subset comparisons (range: 77-100% for each subject). Most observed MEs were directed from blood plasma to CSs (52 MEs, 85.2%). In particular, there was only viral movement from plasma to NK cells (15 MEs), monocytes (seven MEs), and naïve cells (five ME). We observed a total of nine MEs from activated CD4 cells (2/9 MEs), central memory T cells (3/9 MEs), and effector memory T cells (4/9 MEs) to blood plasma. Our results revealed that the HIV RNA population in blood plasma plays an important role in seeding various cellular reservoirs and that the cellular source of the HIV RNA population is activated central memory and effector memory T cells. J. Med. Virol. 88:606-613, 2016. © 2015 Wiley Periodicals, Inc. PMID:26348372

  17. Multimodal imaging of gliomas in the context of evolving cellular and molecular therapies.

    PubMed

    Keunen, Olivier; Taxt, Torfinn; Grüner, Renate; Lund-Johansen, Morten; Tonn, Joerg-Christian; Pavlin, Tina; Bjerkvig, Rolf; Niclou, Simone P; Thorsen, Frits

    2014-09-30

    The vast majority of malignant gliomas relapse after surgery and standard radio-chemotherapy. Novel molecular and cellular therapies are thus being developed, targeting specific aspects of tumor growth. While histopathology remains the gold standard for tumor classification, neuroimaging has over the years taken a central role in the diagnosis and treatment follow up of brain tumors. It is used to detect and localize lesions, define the target area for biopsies, plan surgical and radiation interventions and assess tumor progression and treatment outcome. In recent years the application of novel drugs including anti-angiogenic agents that affect the tumor vasculature, has drastically modulated the outcome of brain tumor imaging. To properly evaluate the effects of emerging experimental therapies and successfully support treatment decisions, neuroimaging will have to evolve. Multi-modal imaging systems with existing and new contrast agents, molecular tracers, technological advances and advanced data analysis can all contribute to the establishment of disease relevant biomarkers that will improve disease management and patient care. In this review, we address the challenges of glioma imaging in the context of novel molecular and cellular therapies, and take a prospective look at emerging experimental and pre-clinical imaging techniques that bear the promise of meeting these challenges. PMID:25078721

  18. Adoptive transfer of natural antibodies to non-immunized chickens affects subsequent antigen-specific humoral and cellular immune responses.

    PubMed

    Lammers, Aart; Klomp, Marcel E V; Nieuwland, Mike G B; Savelkoul, Huub F J; Parmentier, Henk K

    2004-01-01

    To determine a regulatory function of natural antibodies in the immune response of chickens, pooled plasma obtained from non-immunized (naïve) 15 months old hens was subjected to keyhole limpet hemocyanin (KLH) antigen-affinity chromatography. Purified KLH-binding antibodies were adoptively transferred intravenously to 5 weeks-old cocks that were subsequently immunized subcutaneously 24 h later with KLH. Control groups consisted of birds that were either adoptively transferred with KLH-binding antibodies purified from plasma of KLH-immunized chickens, or PBS, or a salt precipitated total immunoglobulin fraction obtained from the corresponding pooled nai;ve chicken plasma, respectively.Total, IgM and IgY antibody titers to KLH in the plasma of recipients adoptively transferred with KLH-NAb, but not in the plasma of the groups transferred with salt precipitate or KLH-binding specific antibodies, were significantly enhanced as compared to the non-treated, KLH immunized group. Titers of IgA antibodies binding KLH were decreased in the plasma of the group that received specific KLH-binding antibodies, but not in the plasma of the other groups. Proliferation from peripheral blood leucocytes in whole blood from the KLH-NAb treated group, the group treated with KLH-binding specific antibodies and the group treated with salt precipitate, respectively, to both concanavalin A and KLH were significantly decreased as compared to the group receiving PBS. Our data show that antigen-specific antibodies can be isolated from plasma obtained from non-immunized chickens. Such antibodies that resemble natural antibodies as described in mammals may perform an important role in the enhancement of subsequent antigen-specific antibody responses or the maturation of the immune system, which may differ from the role of specific antibodies. PMID:12962982

  19. Apples Don’t Fall Far From the Tree: Influences on Psychotherapists’ Adoption and Sustained Use of New Therapies

    PubMed Central

    Schnurr, Paula P.; Biyanova, Tatyana; Coyne, James C.

    2013-01-01

    Objective The purpose of this investigation was to identify influences on the current clinical practices of a broad range of mental health providers as well as influences on their adoption and sustained use of new practices. Methods U.S. and Canadian psychotherapists (N=2,607) completed a Web-based survey in which they rated factors that influence their clinical practice, including their adoption and sustained use of new treatments. Results Empirical evidence had little influence on the practice of mental health providers. Significant mentors, books, training in graduate school, and informal discussions with colleagues were the most highly endorsed influences on current practice. The greatest influences on psychotherapists’ willingness to learn a new treatment were its potential for integration with the therapy they were already providing and its endorsement by therapists they respected. Clinicians were more often willing to continue to use a new treatment when they were able to effectively and enjoyably conduct the therapy and when their clients liked the therapy and reported improvement. Conclusions Implications for dissemination and sustained use of new psychotherapies by community psychotherapists are discussed. For example, evidence-based treatments may best be promoted through therapy courses and workshops, beginning with graduate studies; to ensure future use of new therapies, developers of training workshops should emphasize ways to integrate their approaches into clinicians’ existing practices. PMID:19411356

  20. Adoption of Hypofractionated Radiation Therapy for Breast Cancer After Publication of Randomized Trials

    SciTech Connect

    Jagsi, Reshma; Falchook, Aaron D.; Hendrix, Laura H.; Curry, Heather; Chen, Ronald C.

    2014-12-01

    Purpose: Large randomized trials have established the noninferiority of shorter courses of “hypofractionated” radiation therapy (RT) to the whole breast compared to conventional courses using smaller daily doses in the adjuvant treatment of selected breast cancer patients undergoing lumpectomy. Hypofractionation is more convenient and less costly. Therefore, we sought to determine uptake of hypofractionated breast RT over time. Methods and Materials: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, we identified 16,096 women with node-negative breast cancer and 4269 with ductal carcinoma in situ (DCIS) who received lumpectomy followed by more than 12 fractions of RT between 2004 and 2010. Based on Medicare claims, we determined the number of RT treatments given and grouped patients into those receiving hypofractionation (13-24) or those receiving conventional fractionation (≥25). We also determined RT technique (intensity modulated RT or not) using Medicare claims. We evaluated patterns and correlates of hypofractionation receipt using bivariate and multivariable analyses. Results: Hypofractionation use was similar in patients with DCIS and those with invasive disease. Overall, the use of hypofractionation increased from 3.8% in 2006 to 5.4% in 2007, to 9.4% in 2008, and to 13.6% in 2009 and 2010. Multivariable analysis showed increased use of hypofractionation in recent years and in patients with older age, smaller tumors, increased comorbidity, higher regional education, and Western SEER regions. However, even in patients over the age of 80, the hypofractionation rate in 2009 to 2010 was only 25%. Use of intensity modulated RT (IMRT) also increased over time (from 9.4% in 2004 to 22.7% in 2009-2010) and did not vary significantly between patients receiving hypofractionation and those receiving traditional fractionation. Conclusions: Hypofractionation use increased among low-risk older US breast cancer patients with

  1. Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

    PubMed Central

    Chhabra, Preeti; Brayman, Kenneth L.

    2011-01-01

    Clinical islet transplantation is a β-cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the β-cells regenerative capacity of stem cells. PMID:22046502

  2. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors.

    PubMed

    García-Castro, Javier; Martínez-Palacio, Jesús; Lillo, Rosa; García-Sánchez, Félix; Alemany, Ramón; Madero, Luis; Bueren, Juan A; Ramírez, Manuel

    2005-04-01

    A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors. PMID:15650763

  3. Cellular senescence in aging and age-related disease: from mechanisms to therapy

    PubMed Central

    Childs, Bennett G; Durik, Matej; Baker, Darren J; van Deursen, Jan M

    2016-01-01

    Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy. PMID:26646499

  4. Dynamics of the HIV infection under antiretroviral therapy: A cellular automata approach

    NASA Astrophysics Data System (ADS)

    González, Ramón E. R.; Coutinho, Sérgio; Zorzenon dos Santos, Rita Maria; de Figueirêdo, Pedro Hugo

    2013-10-01

    The dynamics of human immunodeficiency virus infection under antiretroviral therapy is investigated using a cellular automata model where the effectiveness of each drug is self-adjusted by the concentration of CD4+ T infected cells present at each time step. The effectiveness of the drugs and the infected cell concentration at the beginning of treatment are the control parameters of the cell population’s dynamics during therapy. The model allows describing processes of mono and combined therapies. The dynamics that emerges from this model when considering combined antiretroviral therapies reproduces with fair qualitative agreement the phases and different time scales of the process. As observed in clinical data, the results reproduce the significant decrease in the population of infected cells and a concomitant increase of the population of healthy cells in a short timescale (weeks) after the initiation of treatment. Over long time scales, early treatment with potent drugs may lead to undetectable levels of infection. For late treatment or treatments starting with a low density of CD4+ T healthy cells it was observed that the treatment may lead to a steady state in which the T cell counts are above the threshold associated with the onset of AIDS. The results obtained are validated through comparison to available clinical trial data.

  5. A cellular automata model for avascular solid tumor growth under the effect of therapy

    NASA Astrophysics Data System (ADS)

    Reis, E. A.; Santos, L. B. L.; Pinho, S. T. R.

    2009-04-01

    Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.

  6. The Survey on Cellular and Engineered Tissue Therapies in Europe in 2012*

    PubMed Central

    Ireland, Hilary; Baldomero, Helen; Passweg, Jakob

    2015-01-01

    Following the coordinated efforts of five established scientific organizations, this report describes activity in Europe for the year 2012 in the area of cellular and engineered tissue therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis. Three hundred thirteen teams from 33 countries responded to the cellular and engineered tissue therapy survey: 138 teams from 27 countries provided data on 2157 patients, while a further 175 teams reported no activity. Indications were musculoskeletal/rheumatological disorders (36%; 80% autologous), cardiovascular disorders (25%; 95% autologous), hematology/oncology, predominantly prevention or treatment of graft versus host disease and HSC graft enhancement (19%; 1% autologous), neurological disorders (3%; 99% autologous), gastrointestinal disorders (1%; 71% autologous), and other indications (16%; 79% autologous). Autologous cells were predominantly used for musculoskeletal/rheumatological (42%) and cardiovascular (34%) disorders, whereas allogeneic cells were mainly used for hematology/oncology (60%). The reported cell types were mesenchymal stem/stromal cells (49%), HSC (28%), chondrocytes (11%), dermal fibroblasts (4%), keratinocytes (1%), and others (7%). In 51% of the grafts, cells were delivered after ex vivo expansion, whereas cells were transduced or sorted in 10% and 16%, respectively, of the reported cases. Cells were delivered intra-organ (35%), intravenously (31%), on a membrane or gel (15%), or using 3D scaffolds (19%). The data are compared with those collected since 2008 to identify trends in the field and discussed in the light of recent publications and ongoing clinical studies. PMID:25425342

  7. Multiple functional nanoprobe for contrast-enhanced bimodal cellular imaging and targeted therapy.

    PubMed

    Meng, Hong-Min; Lu, Limin; Zhao, Xu-Hua; Chen, Zhuo; Zhao, Zilong; Yang, Chan; Zhang, Xiao-Bing; Tan, Weihong

    2015-04-21

    Many one-photon fluorescence-based theranostic nanosystems have been developed for simultaneous therapeutic intervention/monitoring for various types of cancers. However, for early diagnosis of cancer, two-photon fluorescence microscopy (TPFM) can realize deep-tissue imaging with higher spatial resolution. In this study, we first report a multiple functional nanoprobe for contrast-enhanced bimodal cellular imaging and targeted therapy. Components of the nanoprobe include (1) two-photon dye-doped mesoporous silica nanoparticles (TPD-MSNs); (2) MnO2 nanosheets that act as a (i) gatekeeper for TPD-MSNs, (ii) quencher for TP fluorescence, and (iii) contrast agent for MRI; (3) cancer cell-targeting aptamers. Guided by aptamers, TPD-MSNs are rapidly internalized into the target cells. Next, intracellular glutathione reduces MnO2 to Mn(2+) ions, resulting in contrast-enhanced TP fluorescence and magnetic resonance signal for cellular imaging. Meanwhile, preloaded doxorubicin and Chlorin e6 are released for chemotherapy and photodynamic therapy, respectively, with a synergistic effect and significantly enhanced therapeutic efficacy. PMID:25791340

  8. A Current View of Functional Biomaterials for Wound Care, Molecular and Cellular Therapies

    PubMed Central

    Piraino, Francesco; Selimović, Šeila

    2015-01-01

    The intricate process of wound healing involves activation of biological pathways that work in concert to regenerate a tissue microenvironment consisting of cells and external cellular matrix (ECM) with enzymes, cytokines, and growth factors. Distinct stages characterize the mammalian response to tissue injury: hemostasis, inflammation, new tissue formation, and tissue remodeling. Hemostasis and inflammation start right after the injury, while the formation of new tissue, along with migration and proliferation of cells within the wound site, occurs during the first week to ten days after the injury. In this review paper, we discuss approaches in tissue engineering and regenerative medicine to address each of these processes through the application of biomaterials, either as support to the native microenvironment or as delivery vehicles for functional hemostatic, antibacterial, or anti-inflammatory agents. Molecular therapies are also discussed with particular attention to drug delivery methods and gene therapies. Finally, cellular treatments are reviewed, and an outlook on the future of drug delivery and wound care biomaterials is provided. PMID:26509154

  9. USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

    PubMed Central

    2013-01-01

    Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells. PMID:23937906

  10. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

    PubMed Central

    2012-01-01

    Background Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. Methods This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day. Results Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Conclusion Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy. PMID:22909342

  11. A changing time: the International Society for Cellular Therapy embraces its industry members.

    PubMed

    Deans, Robert; Gunter, Kurt C; Allsopp, Timothy; Bonyhadi, Mark; Burger, Scott R; Carpenter, Melissa; Clark, Tara; Cox, Charles S; Driscoll, Dawn; Field, Ed; Huss, Ralf; Lardenoije, René; Lodie, Tracey A; Mason, Chris; Neubiser, Richard; Rasko, John E J; Rowley, Jon; Maziarz, Richard T

    2010-11-01

    The last decade has seen a dramatic rise in the development of new cellular therapeutics in a wide range of indications. There have been acceptable safety profiles reported in early studies using blood-derived and adherent stem cell products, but also an inconsistent efficacy record. Further expansion has been hindered in part by a lack of capital (both private and public) and delayed entry into the cell therapy space by large healthcare and pharmaceutical companies, those members of the industry most reliably able to initiate and maintain advanced-phase clinical trials. With recognition that the International Society for Cellular Therapy (ISCT) is uniquely positioned to serve the global translational regenerative medicine research community as a network hub for scientific standards and policy, the ISCT commissioned the establishment of an Industry Task Force (ITF) to address current and future roles for industry. The objectives of the ITF were to gather information and prioritize efforts for a new Commercialization Committee (CC) and to construct innovative platforms that would foster constructive and synergistic collaborations between industry and ISCT. Recommendations and conclusions of the ITF included that the new CC: (1) foster new relationships with therapeutic and stem cell societies, (2) foster educational workshops and forums to cross-educate and standardize practices, (3) create industry subcommittees to address priority initiatives, with clear benchmarks and global implementation, and (4) establish a framework for a greater industry community within ISCT, opening doors for industry to share the new vision for commercialization of cell therapy, emphasizing the regenerative medicine space. PMID:20942603

  12. The Adoption of New Adjuvant Radiation Therapy Modalities Among Medicare Beneficiaries With Breast Cancer: Clinical Correlates and Cost Implications

    SciTech Connect

    Roberts, Kenneth B.; Soulos, Pamela R.; Herrin, Jeph; Yu, James B.; Long, Jessica B.; Dostaler, Edward; and others

    2013-04-01

    Purpose: New radiation therapy modalities have broadened treatment options for older women with breast cancer, but it is unclear how clinical factors, geographic region, and physician preference affect the choice of radiation therapy modality. Methods and Materials: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify women diagnosed with stage I-III breast cancer from 1998 to 2007 who underwent breast-conserving surgery. We assessed the temporal trends in, and costs of, the adoption of intensity modulated radiation therapy (IMRT) and brachytherapy. Using hierarchical logistic regression, we evaluated the relationship between the use of these new modalities and patient and regional characteristics. Results: Of 35,060 patients, 69.9% received conventional external beam radiation therapy (EBRT). Although overall radiation therapy use remained constant, the use of IMRT increased from 0.0% to 12.6% from 1998 to 2007, and brachytherapy increased from 0.7% to 9.0%. The statistical variation in brachytherapy use attributable to the radiation oncologist and geographic region was 41.4% and 9.5%, respectively (for IMRT: 23.8% and 22.1%, respectively). Women undergoing treatment at a free-standing radiation facility were significantly more likely to receive IMRT than were women treated at a hospital-based facility (odds ratio for IMRT vs EBRT: 3.89 [95% confidence interval, 2.78-5.45]). No such association was seen for brachytherapy. The median radiation therapy cost per treated patient increased from $5389 in 2001 to $8539 in 2007. Conclusions: IMRT and brachytherapy use increased substantially from 1998 to 2007; overall, radiation therapy costs increased by more than 50%. Radiation oncologists played an important role in treatment choice for both types of radiation therapy, whereas geographic region played a bigger role in the use of IMRT than brachytherapy.

  13. Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

    PubMed

    Dahl, Maria; Doyle, Alexander; Olsson, Karin; Månsson, Jan-Eric; Marques, André R A; Mirzaian, Mina; Aerts, Johannes M; Ehinger, Mats; Rothe, Michael; Modlich, Ute; Schambach, Axel; Karlsson, Stefan

    2015-05-01

    Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease. PMID:25655314

  14. Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice

    PubMed Central

    Dahl, Maria; Doyle, Alexander; Olsson, Karin; Månsson, Jan-Eric; Marques, André R A; Mirzaian, Mina; Aerts, Johannes M; Ehinger, Mats; Rothe, Michael; Modlich, Ute; Schambach, Axel; Karlsson, Stefan

    2015-01-01

    Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease. PMID:25655314

  15. Cellular Therapies in Trauma and Critical Care Medicine: Forging New Frontiers

    PubMed Central

    Pati, Shibani; Pilia, Marcello; Grimsley, Juanita M.; Karanikas, Alexia T.; Oyeniyi, Blessing; Holcomb, John B.; Cap, Andrew P.; Rasmussen, Todd E.

    2015-01-01

    ABSTRACT Trauma is a leading cause of death in both military and civilian populations worldwide. Although medical advances have improved the overall morbidity and mortality often associated with trauma, additional research and innovative advancements in therapeutic interventions are needed to optimize patient outcomes. Cell-based therapies present a novel opportunity to improve trauma and critical care at both the acute and chronic phases that often follow injury. Although this field is still in its infancy, animal and human studies suggest that stem cells may hold great promise for the treatment of brain and spinal cord injuries, organ injuries, and extremity injuries such as those caused by orthopedic trauma, burns, and critical limb ischemia. However, barriers in the translation of cell therapies that include regulatory obstacles, challenges in manufacturing and clinical trial design, and a lack of funding are critical areas in need of development. In 2015, the Department of Defense Combat Casualty Care Research Program held a joint military–civilian meeting as part of its effort to inform the research community about this field and allow for effective planning and programmatic decisions regarding research and development. The objective of this article is to provide a “state of the science” review regarding cellular therapies in trauma and critical care, and to provide a foundation from which the potential of this emerging field can be harnessed to mitigate outcomes in critically ill trauma patients. PMID:26428845

  16. Cellular Therapies in Trauma and Critical Care Medicine: Forging New Frontiers.

    PubMed

    Pati, Shibani; Pilia, Marcello; Grimsley, Juanita M; Karanikas, Alexia T; Oyeniyi, Blessing; Holcomb, John B; Cap, Andrew P; Rasmussen, Todd E

    2015-12-01

    Trauma is a leading cause of death in both military and civilian populations worldwide. Although medical advances have improved the overall morbidity and mortality often associated with trauma, additional research and innovative advancements in therapeutic interventions are needed to optimize patient outcomes. Cell-based therapies present a novel opportunity to improve trauma and critical care at both the acute and chronic phases that often follow injury. Although this field is still in its infancy, animal and human studies suggest that stem cells may hold great promise for the treatment of brain and spinal cord injuries, organ injuries, and extremity injuries such as those caused by orthopedic trauma, burns, and critical limb ischemia. However, barriers in the translation of cell therapies that include regulatory obstacles, challenges in manufacturing and clinical trial design, and a lack of funding are critical areas in need of development. In 2015, the Department of Defense Combat Casualty Care Research Program held a joint military-civilian meeting as part of its effort to inform the research community about this field and allow for effective planning and programmatic decisions regarding research and development. The objective of this article is to provide a "state of the science" review regarding cellular therapies in trauma and critical care, and to provide a foundation from which the potential of this emerging field can be harnessed to mitigate outcomes in critically ill trauma patients. PMID:26428845

  17. A model of cellular dosimetry for macroscopic tumors in radiopharmaceutical therapy

    PubMed Central

    Hobbs, Robert F.; Baechler, Sébastien; Fu, De-Xue; Esaias, Caroline; Pomper, Martin G.; Ambinder, Richard F.; Sgouros, George

    2011-01-01

    Purpose: In the radiopharmaceutical therapy approach to the fight against cancer, in particular when it comes to translating laboratory results to the clinical setting, modeling has served as an invaluable tool for guidance and for understanding the processes operating at the cellular level and how these relate to macroscopic observables. Tumor control probability (TCP) is the dosimetric end point quantity of choice which relates to experimental and clinical data: it requires knowledge of individual cellular absorbed doses since it depends on the assessment of the treatment’s ability to kill each and every cell. Macroscopic tumors, seen in both clinical and experimental studies, contain too many cells to be modeled individually in Monte Carlo simulation; yet, in particular for low ratios of decays to cells, a cell-based model that does not smooth away statistical considerations associated with low activity is a necessity. The authors present here an adaptation of the simple sphere-based model from which cellular level dosimetry for macroscopic tumors and their end point quantities, such as TCP, may be extrapolated more reliably. Methods: Ten homogenous spheres representing tumors of different sizes were constructed in GEANT4. The radionuclide 131I was randomly allowed to decay for each model size and for seven different ratios of number of decays to number of cells, Nr: 1000, 500, 200, 100, 50, 20, and 10 decays per cell. The deposited energy was collected in radial bins and divided by the bin mass to obtain the average bin absorbed dose. To simulate a cellular model, the number of cells present in each bin was calculated and an absorbed dose attributed to each cell equal to the bin average absorbed dose with a randomly determined adjustment based on a Gaussian probability distribution with a width equal to the statistical uncertainty consistent with the ratio of decays to cells, i.e., equal to Nr-1∕2. From dose volume histograms the surviving fraction of cells

  18. Conversation focused aphasia therapy: investigating the adoption of strategies by people with agrammatism

    PubMed Central

    Beeke, Suzanne; Beckley, Firle; Johnson, Fiona; Heilemann, Claudia; Edwards, Susan; Maxim, Jane; Best, Wendy

    2015-01-01

    Background: A recent review of interaction (or conversation)-focused therapy highlighted the potential of programmes targeting the person with aphasia (PWA) directly. However, it noted the key limitations of current work in this field to be a reliance on single case analyses and qualitative evidence of change, a situation that is not unusual when a complex behavioural intervention is in the early stages of development and evaluation. Aims: This article aims to evaluate an intervention that targeted a PWA and their conversation partner (CP), a dyad, as equals in a novel conversation therapy for agrammatic aphasia, using both quantitative and qualitative evidence of change. The intervention aimed to increase the insight of a dyad into facilitator and barrier conversation behaviours, to increase the understanding of the effect of agrammatism on communication, and to support each speaker to choose three strategies to work on in therapy to increase mutual understanding and enhance conversation. Methods & Procedures: Quantitative and qualitative methods are used to analyse multiple pre-therapy and follow up assessments of conversation for two dyads. Outcomes & Results: Results show that one person with severe and chronic agrammatic aphasia was able to select and practise strategies that led to qualitative and quantitative changes in his post-therapy conversations. The other PWA showed a numerical increase in one of his three strategies post therapy, but no significant quantitative change. Although both CPs significantly reduced barrier behaviours in their post-therapy conversations, neither showed a significant increase in the strategies they chose to work on. For one CP, there was qualitative evidence of the use of different turn types. Conclusions: Individually tailored input from a speech and language therapist can assist some people with chronic agrammatism to develop conversational strategies that enhance communication. Outcomes are influenced by the severity and

  19. Effect of Cellular Therapy in Progression of Becker’s Muscular Dystrophy: A Case Study

    PubMed Central

    Sharma, Alok; Sane, Hemangi; Gokulchandra, Nandini; Sharan, Rishabh; Paranjape, Amruta; Yadav, Jayanti; Badhe, Prerna

    2016-01-01

    Becker muscular dystrophy (BMD) is an inherited disorder due to deletions of the dystrophin gene that leads to muscle weakness. Effects of bone marrow mononuclear cell (BMMNC) transplantation in Muscular Dystrophy have shown to be safe and beneficial. We treated a 20-year-old male suffering from BMD with autologous BMMNC transplantation followed by multidisciplinary rehabilitation. He presented with muscle weakness and had difficulty in performing his activities. The BMMNCs were transplanted via intrathecal and intramuscular routes. The effects were measured on clinical and functional changes. Over 9 months, gradual improvement was noticed in muscle strength, respiratory functions and North Star Ambulatory Assessment Scale. Functional Independence Measure, Berg Balance Score, Brooke and Vignos Scale remained stable indicating halting of the progression. The case report suggests that cellular therapy combined with rehabilitation may have possibility of repairing and regenerating muscle fibers and decreasing the rate of progression of BMD. PMID:27054018

  20. Effect of Cellular Therapy in Progression of Becker's Muscular Dystrophy: A Case Study.

    PubMed

    Sharma, Alok; Sane, Hemangi; Gokulchandra, Nandini; Sharan, Rishabh; Paranjape, Amruta; Kulkarni, Pooja; Yadav, Jayanti; Badhe, Prerna

    2016-02-23

    Becker muscular dystrophy (BMD) is an inherited disorder due to deletions of the dystrophin gene that leads to muscle weakness. Effects of bone marrow mononuclear cell (BMMNC) transplantation in Muscular Dystrophy have shown to be safe and beneficial. We treated a 20-year-old male suffering from BMD with autologous BMMNC transplantation followed by multidisciplinary rehabilitation. He presented with muscle weakness and had difficulty in performing his activities. The BMMNCs were transplanted via intrathecal and intramuscular routes. The effects were measured on clinical and functional changes. Over 9 months, gradual improvement was noticed in muscle strength, respiratory functions and North Star Ambulatory Assessment Scale. Functional Independence Measure, Berg Balance Score, Brooke and Vignos Scale remained stable indicating halting of the progression. The case report suggests that cellular therapy combined with rehabilitation may have possibility of repairing and regenerating muscle fibers and decreasing the rate of progression of BMD. PMID:27054018

  1. Analyzing Reasons for Non-Adoption of Distance Delivery Formats in Occupational Therapy Assistant (OTA) Education

    ERIC Educational Resources Information Center

    Gergen, Theresa; Roblyer, M. D.

    2013-01-01

    Though distance education formats could help address an urgent need for growth in the occupational therapy assistant (OTA) workforce, distance methods are not as accepted in these programs as they are in other professional and clinical programs. This study investigated whether beliefs and levels of experience of OTA program directors shaped their…

  2. Enhanced cellular uptake of protoporphyrine IX/linolenic acid-conjugated spherical nanohybrids for photodynamic therapy.

    PubMed

    Lee, Hye-In; Kim, Young-Jin

    2016-06-01

    Protoporphyrin IX (PpIX) has wide applications in photodynamic diagnosis and photodynamic therapy (PDT) in many human diseases. However, poor water solubility and cancer cell localization limit its direct application for PDT. We improved the water-solubility and cellular internalization of PpIX to enhance PDT efficacy by developing biocompatible PpIX/linolenic acid-conjugated polyhedral oligomeric silsesquioxane (PPLA) nanohybrids. The resulting PPLA nanohybrids exhibited a quasi-spherical shape with a size of <200nm. (1)H NMR analysis confirmed the synthesis of PPLA. The singlet oxygen formation of PPLA nanohybrids on laser irradiation was detected by photoluminescence emission. Fluorescence-activated cell sorting (FACS) analysis displayed higher cellular internalization of PPLA compared with free PpIX. In addition, PPLA nanohybrids exhibited significantly reduced dark-toxicity and a high phototoxicity mostly because of apoptotic cell death against human gastric cancer cells. These results imply that the PPLA nanohybrid system may be applicable in PDT. PMID:26954084

  3. Does maggot therapy promote wound healing? The clinical and cellular evidence.

    PubMed

    Nigam, Y; Morgan, C

    2016-05-01

    The larvae of Lucillia sericata, or maggots of the green-bottle fly, are used worldwide to help debride chronic, necrotic and infected wounds. Whilst there is abundant clinical and scientific evidence to support the role of maggots for debriding and disinfecting wounds, not so much emphasis has been placed on their role in stimulating wound healing. However, there is accumulating evidence to suggest that maggots and their externalized secretions may also promote wound healing in stubborn, recalcitrant chronic ulcers. There are a growing number of clinical reports which support the observation that wounds which have been exposed to a course of maggot debridement therapy also show earlier healing and closure end-points. In addition, recent pre-clinical laboratory studies also indicate that maggot secretions can promote important cellular processes which explain this increased healing activity. Such processes include activation of fibroblast migration, angiogenesis (the formation of new blood vessels from pre-existing vessels) within the wound bed, and an enhanced production of growth factors within the wound environment. Thus, in this review, we summarize the clinical evidence which links maggots and improved wound healing, and we précis recent scientific studies which examine and identify the role of maggots, particularly individual components of maggot secretions, on specific cellular aspects of wound healing. PMID:26691053

  4. Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy.

    PubMed

    Maus, Marcela V; June, Carl H

    2016-04-15

    Chimeric antigen receptors (CAR) are engineered fusion proteins constructed from antigen recognition, signaling, and costimulatory domains that can be expressed in cytotoxic T cells with the purpose of reprograming the T cells to specifically target tumor cells. CAR T-cell therapy uses gene transfer technology to reprogram a patient's own T cells to stably express CARs, thereby combining the specificity of an antibody with the potent cytotoxic and memory functions of a T cell. In early-phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses within a population of otherwise refractory patients with B-cell malignancies and, more specifically, have shown complete response rates of approximately 90% in patients with relapsed or refractory acute lymphoblastic leukemia. Given this clinical efficacy, preclinical development of CAR T-cell therapy for a number of cancer indications has been actively investigated, and the future of the CAR T-cell field is extensive and dynamic. Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into the mechanisms regulating the persistence of CAR T cells. In addition, numerous early-phase clinical trials are now investigating CAR T-cell therapy beyond targeting CD19, especially in solid tumors. Trials investigating combinations of CAR T cells with immune checkpoint blockade therapies are now beginning and results are eagerly awaited. This review evaluates several of the ongoing and future directions of CAR T-cell therapy.Clin Cancer Res; 22(8); 1875-84. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "OPPORTUNITIES AND CHALLENGES IN CANCER IMMUNOTHERAPY". PMID:27084741

  5. Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care

    PubMed Central

    Riccione, Katherine; Suryadevara, Carter M.; Snyder, David; Cui, Xiuyu; Sampson, John H.; Sanchez-Perez, Luis

    2016-01-01

    Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care. PMID:25741761

  6. Pharmacological Therapy in the Heart as an Alternative to Cellular Therapy: A Place for the Brain Natriuretic Peptide?

    PubMed Central

    Rosenblatt-Velin, Nathalie; Badoux, Suzanne; Liaudet, Lucas

    2016-01-01

    The discovery that stem cells isolated from different organs have the ability to differentiate into mature beating cardiomyocytes has fostered considerable interest in developing cellular regenerative therapies to treat cardiac diseases associated with the loss of viable myocardium. Clinical studies evaluating the potential of stem cells (from heart, blood, bone marrow, skeletal muscle, and fat) to regenerate the myocardium and improve its functional status indicated that although the method appeared generally safe, its overall efficacy has remained modest. Several issues raised by these studies were notably related to the nature and number of injected cells, as well as the route and timing of their administration, to cite only a few. Besides the direct administration of cardiac precursor cells, a distinct approach to cardiac regeneration could be based upon the stimulation of the heart's natural ability to regenerate, using pharmacological approaches. Indeed, differentiation and/or proliferation of cardiac precursor cells is controlled by various endogenous mediators, such as growth factors and cytokines, which could thus be used as pharmacological agents to promote regeneration. To illustrate such approach, we present recent results showing that the exogenous administration of the natriuretic peptide BNP triggers “endogenous” cardiac regeneration, following experimental myocardial infarction. PMID:26880973

  7. B-cell Maturation Antigen is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma

    PubMed Central

    Carpenter, Robert O.; Evbuomwan, Moses O.; Pittaluga, Stefania; Rose, Jeremy J.; Raffeld, Mark; Yang, Shicheng; Gress, Ronald E.; Hakim, Frances T.; Kochenderfer, James N.

    2013-01-01

    Purpose Multiple myeloma (MM) is a usually incurable malignancy of plasma cells. New therapies are urgently needed for MM. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T cell therapies of MM has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B-lineage cells including MM cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells. Experimental Design We conducted an assessment of BCMA expression in normal human tissues and MM cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs. Results BCMA had a restricted RNA expression pattern. Except for expression on plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34+ hematopoietic cells. We detected uniform BCMA cell-surface expression on primary MM cells from 5 of 5 patients. We designed the first anti-BCMA CARs to be reported, and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary MM cells. Conclusions BCMA is a suitable target for CAR-expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating MM. PMID:23344265

  8. The Survey on Cellular and Engineered Tissue Therapies in Europe in 2009

    PubMed Central

    Baldomero, Helen; Bocelli-Tyndall, Chiara; Slaper-Cortenbach, Ineke; Passweg, Jakob; Tyndall, Alan

    2011-01-01

    Thanks to the coordinated efforts of four major scientific organizations, this report describes the “novel cellular therapy” activity in Europe for the year 2009. Fifty teams from 22 countries reported data on 814 patients using a dedicated survey, which were combined to additional 328 records reported by 55 teams to the standard European Blood and Marrow Transplantation (EBMT) database. Indications were cardiovascular (37%; 64% autologous), graft-vs.-host disease (27%; 7% autologous), musculoskeletal (17%; 98% autologous), epithelial/parenchymal (8%; 73% autologous), autoimmune (9%; 84% autologous), or neurological diseases (3%; 50% autologous). Autologous cells were used predominantly for cardiovascular (42%) and musculoskeletal (30%) disorders, whereas allogeneic cells were used mainly for graft-vs.-host disease (58%) and cardiovascular (30%) indications. Reported cell types were mesenchymal stem/stromal cells (MSC) (46%), hematopoietic stem cells (27%), chondrocytes (7%), keratinocytes (5%), dermal fibroblast (13%), and others (2%). In 59% of the grafts, cells were delivered after expansion; in 2% of the cases, cells were transduced. Cells were delivered intraorgan (46%), on a membrane or gel (29%), intravenously (16%) or using 3D scaffolds (8%). As compared to last year, the number of teams adopting the dedicated survey was 1.7-fold higher, and, with few exceptions, the collected data confirmed the captured trends. This year's edition specifically describes and discusses the use of MSC for the treatment of autoimmune diseases, due to the scientific, clinical, and economical implications of this topic. PMID:21542713

  9. Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model

    NASA Astrophysics Data System (ADS)

    Maytin, Edward; Anand, Sanjay; Sato, Nobuyuki; Mack, Judith; Ortel, Bernhard

    2005-04-01

    During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

  10. Thrombotic Microangiopathy In Metastatic Melanoma Patients Treated with Adoptive Cell Therapy and Total Body Irradiation

    PubMed Central

    Tseng, Jennifer; Citrin, Deborah E.; Waldman, Meryl; White, Donald E.; Rosenberg, Steven A.; Yang, James C.

    2014-01-01

    Background Thrombotic microangioapathy (TMA) is a complication that developed in some patients receiving 12 Gy total body irradiation in addition to lymphodepleting preparative chemotherapy prior to infusion of autologous tumor infiltrating lymphocytes (TIL) with high-dose aldesleukin (IL-2). This paper describes the incidence, presentation and course of radiation-associated TMA. Methods The data for patients with metastatic melanoma who received ACT with TIL plus aldesleukin following myeloablative chemotherapy and 12 Gy total body irradiation was examined, looking at patient characteristics and the natural history of TMA. Results The median time to presentation was approximately 8 months after completing TBI. The estimated cumulative incidence of TMA was 31.2% (median follow-up of 24 months). Noninvasive criteria for diagnosis included newly elevated creatinine levels, new-onset hypertension, new-onset anemia, microscopic hematuria, thrombocytopenia, low haptoglobin and elevated lactate dehydrogenase values. Once diagnosed, patients were managed with control of their hypertension with multiple agents and supportive red blood cell transfusions. TMA typically stabilized or improved and no patient progressed to dialysis. TMA was associated with a higher probability of an anti-tumor response. Conclusions Thrombotic microangiopathy occurs in approximately a third of patients treated with a lymphodepleting preparative chemotherapy regimen with total body irradiation prior to autologous T-cell therapy. The disease has a variable natural history, however no patient developed end-stage renal failure. Successful management with supportive care and aggressive hypertension control is vital to the safe application of a systemic therapy that has shown curative potential for patients with disseminated melanoma. PMID:24474396

  11. Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy

    PubMed Central

    Kodumudi, Krithika N.; Siegel, Jessica; Weber, Amy M.; Scott, Ellen; Sarnaik, Amod A.; Pilon-Thomas, Shari

    2016-01-01

    Tumor-infiltrating lymphocytes (TIL) has been associated with improved survival in cancer patients. Within the tumor microenvironment, regulatory cells and expression of co-inhibitory immune checkpoint molecules can lead to the inactivation of TIL. Hence, there is a need to develop strategies that disrupt these negative regulators to achieve robust anti-tumor immune responses. We evaluated the blockade of immune checkpoints and their effect on T cell infiltration and function. We examined the ability of TIL to induce tumor-specific immune responses in vitro and in vivo. TIL isolated from tumor bearing mice were tumor-specific and expressed co-inhibitory immune checkpoint molecules. Administration of monoclonal antibodies against immune checkpoints led to a significant delay in tumor growth. However, anti-PD-L1 antibody treated mice had a significant increase in T cell infiltration and IFN-γ production compared to other groups. Adoptive transfer of in vitro expanded TIL from tumors of anti-PD-L1 antibody treated mice led to a significant delay in tumor growth. Blockade of co-inhibitory immune checkpoints could be an effective strategy to improve TIL infiltration and function. PMID:27050669

  12. Mitochondria in mesenchymal stem cell biology and cell therapy: From cellular differentiation to mitochondrial transfer.

    PubMed

    Hsu, Yi-Chao; Wu, Yu-Ting; Yu, Ting-Hsien; Wei, Yau-Huei

    2016-04-01

    Mesenchymal stem cells (MSCs) are characterized to have the capacity of self-renewal and the potential to differentiate into mesoderm, ectoderm-like and endoderm-like cells. MSCs hold great promise for cell therapies due to their multipotency in vitro and therapeutic advantage of hypo-immunogenicity and lower tumorigenicity. Moreover, it has been shown that MSCs can serve as a vehicle to transfer mitochondria into cells after cell transplantation. Mitochondria produce most of the energy through oxidative phosphorylation in differentiated cells. It has been increasingly clear that the switch of energy supply from glycolysis to aerobic metabolism is essential for successful differentiation of MSCs. Post-translational modifications of proteins have been established to regulate mitochondrial function and metabolic shift during MSCs differentiation. In this article, we review and provide an integrated view on the roles of different protein kinases and sirtuins in the maintenance and differentiation of MSCs. Importantly, we provide evidence to suggest that alteration in the expression of Sirt3 and Sirt5 and relative changes in the acylation levels of mitochondrial proteins might be involved in the activation of mitochondrial function and adipogenic differentiation of adipose-derived MSCs. We summarize their roles in the regulation of mitochondrial biogenesis and metabolism, oxidative responses and differentiation of MSCs. On the other hand, we discuss recent advances in the study of mitochondrial dynamics and mitochondrial transfer as well as their roles in the differentiation and therapeutic application of MSCs to improve cell function in vitro and in animal models. Accumulating evidence has substantiated that the therapeutic potential of MSCs is conferred not only by cell replacement and paracrine effects but also by transferring mitochondria into injured tissues or cells to modulate the cellular metabolism in situ. Therefore, elucidation of the underlying mechanisms

  13. Regulatory aspects of cellular therapy product in Europe: JACIE accreditation in a processing facility.

    PubMed

    Caunday, Olivia; Bensoussan, Danièle; Decot, Véronique; Bordigoni, Pierre; Stoltz, Jean François

    2009-01-01

    In 1997, the Joint Accreditation Committee ISCT & EBMT (JACIE) was created. The following year, it approved the first edition of standards for haemopoietic progenitor cell collection, processing and transplantation. The purpose of the standards is to ensure a minimal level of quality, alertness and homogeneity in the implementation of autologous and allogeneic haemopoietic stem cell transplantation (HSCT) programme in onco-hematology. The acquisition of accreditation is based upon the system of examination by trained medical professionals according to countries endorsements with the national regulation obligations applicable to HSCT. In 2008, the fourth edition has been launched. The range of application of the standards comprises both donors and recipients, and all phases of collection, processing, storage and administration of haemopoietic progenitor cells. Among the accredited processing facilities, a few have been integrated JACIE standards into their existing management quality system which is inspected by national health authority. In France, the comparison between JACIE standards and the good manufacturing practices of cellular therapy product reveals some common points and some differences to apply. PMID:20042804

  14. Macrophages in gene therapy: cellular delivery vehicles and in vivo targets.

    PubMed

    Burke, B; Sumner, S; Maitland, N; Lewis, C E

    2002-09-01

    The appearance and activation of macrophages are thought to be rapid events in the development of many pathological lesions, including malignant tumors, atherosclerotic plaques, and arthritic joints. This has prompted recent attempts to use macrophages as novel cellular vehicles for gene therapy, in which macrophages are genetically modified ex vivo and then reintroduced into the body with the hope that a proportion will then home to the diseased site. Here, we critically review the efficacy of various gene transfer methods (viral, bacterial, protozoan, and various chemical and physical methods) in transfecting macrophages in vitro, and the results obtained when transfected macrophages are used as gene delivery vehicles. Finally, we discuss the use of various viral and nonviral methods to transfer genes to macrophages in vivo. As will be seen, definitive evidence for the use of macrophages as gene transfer vehicles has yet to be provided and awaits detailed trafficking studies in vivo. Moreover, although methods for transfecting macrophages have improved considerably in efficiency in recent years, targeting of gene transfer specifically to macrophages in vivo remains a problem. However, possible solutions to this include placing transgenes under the control of macrophage-specific promoters to limit expression to macrophages or stably transfecting CD34(+) precursors of monocytes/macrophages and then differentiating these cells into monocytes/macrophages ex vivo. The latter approach could conceivably lead to the bone marrow precursor cells of patients with inherited genetic disorders being permanently fortified or even replaced with genetically modified cells. PMID:12223508

  15. Cellular and molecular aspects of the pathomechanism and therapy of murine experimental allergic encephalomyelitis.

    PubMed

    Tabira, T

    1989-01-01

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS). Its immune mechanism is well understood at the cellular and molecular levels, which is herein reviewed. Susceptibility to EAE is under the control of the genes partially inside and partially outside the H-2 complex. There are two myelin constituents known to be encephalitogenic, myelin basic protein and proteolipid apoprotein. EAE is mediated by effector T cells sensitized to the encephalitogen. Effector T cells bear surface phenotypes of Lyt1+2-, L3T4+, and they are activated by the encephalitogen/self Ia complex or certain alloantigens and acquire encephalitogenic activity. By unknown homing mechanisms, the effector T cells invade the CNS and induce the target phase phenomena, which include Ia-antigen expression in the local tissue, activation of procoagulant activity, breakdown of the blood-brain barrier, and excretion of lymphokines which induce inflammation and demyelination, resulting in functional alteration. Possibility of specific immune therapy is postulated as a model for human autoimmune disease. PMID:2484301

  16. Combining vascular and cellular targeting regimens enhances the efficacy of photodynamic therapy

    SciTech Connect

    Chen Bin; Pogue, Brian W. . E-mail: pogue@dartmouth.edu; Hoopes, P. Jack; Hasan, Tayyaba

    2005-03-15

    Purpose: Photodynamic therapy (PDT) can be designed to target either tumor vasculature or tumor cells by varying the drug-light interval. Photodynamic therapy treatments with different drug-light intervals can be combined to increase tumor response by targeting both tumor vasculature and tumor cells. The sequence of photosensitizer and light delivery can influence the effect of combined treatments. Methods and materials: The R3327-MatLyLu rat prostate tumor model was used in this study. Photosensitizer verteporfin distribution was quantified by fluorescence microscopy. Tumor blood flow changes were monitored by laser-Doppler system and tumor hypoxia was quantified by the immunohistochemical staining for the hypoxic marker EF5. The therapeutic effects of PDT treatments were evaluated by the histologic examination and tumor regrowth assay. Results: Fluorescence microscopic studies indicated that tumor localization of verteporfin changed from predominantly within the tumor vasculature at 15 min after injection, to being throughout the tumor parenchyma at 3 h after injection. Light treatment (50 J/cm{sup 2}) at 15 min after verteporfin injection (0.25 mg/kg, i.v.) induced significant tumor vascular damage, as manifested by tumor blood flow reduction and increase in the tumor hypoxic fraction. In contrast, the vascular effect observed after the same light dose (50 J/cm{sup 2}) delivered 3 h after administration of verteporfin (1 mg/kg, i.v.) was an initial acute decrease in blood flow, followed by recovery to the level of control. The EF5 staining revealed no significant increase in hypoxic fraction at 1 h after PDT using 3 h drug-light interval. The combination of 3-h interval PDT and 15-min interval PDT was more effective in inhibiting tumor growth than each individual PDT treatment. However, it was found that the combined treatment with the sequence of 3-h interval PDT before 15-min interval PDT led to a superior antitumor effect than the other combinative PDT

  17. Cellular automata approach for the dynamics of HIV infection under antiretroviral therapies: The role of the virus diffusion

    NASA Astrophysics Data System (ADS)

    González, Ramón E. R.; de Figueirêdo, Pedro Hugo; Coutinho, Sérgio

    2013-10-01

    We study a cellular automata model to test the timing of antiretroviral therapy strategies for the dynamics of infection with human immunodeficiency virus (HIV). We focus on the role of virus diffusion when its population is included in previous cellular automata model that describes the dynamics of the lymphocytes cells population during infection. This inclusion allows us to consider the spread of infection by the virus-cell interaction, beyond that which occurs by cell-cell contagion. The results show an acceleration of the infectious process in the absence of treatment, but show better efficiency in reducing the risk of the onset of AIDS when combined antiretroviral therapies are used even with drugs of low effectiveness. Comparison of results with clinical data supports the conclusions of this study.

  18. Administrative and research policies required to bring cellular therapies from the research laboratory to the patient's bedside.

    PubMed

    Yim, Robyn

    2005-10-01

    The research process is a balance between the inherent risks of new discoveries and the risks of research participant safety. Conflicts of interest, inherent to the research process, as well as those introduced by emerging cellular therapies, have the potential to compromise safety. The relationship of trust between the researcher and the clinical trial participant facilitates objective decision making, in the best interest of both parties. In the setup of each clinical trial, investigators incorporate ethical, political, legal, financial, and regulatory considerations as protocols are established. Responsibility to abide by these decisions ensures a systematic process and safeguards participants in this process. The integrity of the research process is strengthened by identifying potential conflicting issues with the guiding principles established in the protocols, which may threaten the objectivity of involved parties and jeopardize safety of the participants. The rapid pace and changing paradigms of new discoveries in cellular therapies exaggerate existing conflicts and introduce new ones. Ethical issues raised by emerging cellular therapies include the division of opinions regarding the use of embryonic and fetal tissue to develop stem cell lines for research, the individual versus professional conscience of a researcher, overselling of outcomes as a result of the researcher's desire to be the first to discover a cellular therapy, and therapeutic misconception resulting from a participant's desire for a miracle cure. The basic ethical issue of whether stem cells should be utilized as a cellular therapy raises heated debates because some believe that it is not acceptable to use fetal material as a source of research material for future cures and others feel equally as strong that inaction is unethical because it results in needless suffering and death owing to the absence of this research. Political issues include the divergent position statements of

  19. Cord blood-derived cytokine-induced killer cellular therapy plus radiation therapy for esophageal cancer: a case report.

    PubMed

    Wang, Liming; Huang, Shigao; Dang, Yazheng; Li, Ming; Bai, Wen; Zhong, Zhanqiang; Zhao, Hongliang; Li, Yang; Liu, Yongjun; Wu, Mingyuan

    2014-12-01

    Esophageal cancer is a serious malignancy with regards to mortality and prognosis. Current treatment options include multimodality therapy mainstays of current treatment including surgery, radiation, and chemotherapy. Cell therapy for esophageal cancer is an advancing area of research. We report a case of esophageal cancer following cord blood-derived cytokine-induced killer cell infusion and adjuvant radiotherapy. Initially, she presented with poor spirit, full liquid diets, and upper abdominal pain. Through cell therapy plus adjuvant radiotherapy, the patient remitted and was self-reliant. Recognition of this curative effect of sequent therapy for esophageal cancer is important to enable appropriate treatment. This case highlights cord blood-derived cytokine-induced killer cell therapy significantly alleviates the adverse reaction of radiation and improves the curative effect. Cell therapy plus adjuvant radiotherapy can be a safe and effective treatment for esophageal cancer. PMID:25526496

  20. Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients.

    PubMed

    Casati, Anna; Varghaei-Nahvi, Azam; Feldman, Steven Alexander; Assenmacher, Mario; Rosenberg, Steven Aaron; Dudley, Mark Edward; Scheffold, Alexander

    2013-10-01

    The adoptive transfer of lymphocytes genetically engineered to express tumor-specific antigen receptors is a potent strategy to treat cancer patients. T lymphocyte subsets, such as naïve or central memory T cells, selected in vitro prior to genetic engineering have been extensively investigated in preclinical mouse models, where they demonstrated improved therapeutic efficacy. However, so far, this is challenging to realize in the clinical setting, since good manufacturing practices (GMP) procedures for complex cell sorting and genetic manipulation are limited. To be able to directly compare the immunological attributes and therapeutic efficacy of naïve (T(N)) and central memory (T(CM)) CD8(+) T cells, we investigated clinical-scale procedures for their parallel selection and in vitro manipulation. We also evaluated currently available GMP-grade reagents for stimulation of T cell subsets, including a new type of anti-CD3/anti-CD28 nanomatrix. An optimized protocol was established for the isolation of both CD8(+) T(N) cells (CD4(-)CD62L(+)CD45RA(+)) and CD8(+) T(CM) (CD4(-)CD62L(+)CD45RA(-)) from a single patient. The highly enriched T cell subsets can be efficiently transduced and expanded to large cell numbers, sufficient for clinical applications and equivalent to or better than current cell and gene therapy approaches with unselected lymphocyte populations. The GMP protocols for selection of T(N) and T(CM) we reported here will be the basis for clinical trials analyzing safety, in vivo persistence and clinical efficacy in cancer patients and will help to generate a more reliable and efficacious cellular product. PMID:23903715

  1. Modulation of tumor response to photodynamic therapy in severe combined immunodeficient (SCID) mice by adoptively transferred lymphoid cells

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd; Krosl, Jana; Dougherty, Graeme J.

    1996-04-01

    Photodynamic treatment, consisting of intravenous injection of PhotofrinR (10 mg/kg) followed by exposure to 110 J/cm2 of 630 plus or minus 10 nm light 24 hours later, cured 100% of EMT6 tumors (murine mammary sarcoma) growing in syngeneic immunocompetent BALB/C mice. In contrast, the same treatment produced no cures of EMT6 tumors growing in either nude or SCID mice (immunodeficient strains). EMT6 tumors growing in BALB/C and SCID mice showed no difference in either the level of PhotofrinR accumulated per gram of tumor tissue, or the extent of tumor cell killing during the first 24 hours post photodynamic therapy (PDT). In an attempt to improve the sensitivity to PDT of EMT6 tumors growing in SCID mice, these hosts were given either splenic T lymphocytes or whole bone marrow from BALB/C mice. The adoptive transfer of lymphocytes 9 days before PDT was successful in delaying tumor recurrence but produced no cures. A better improvement in PDT response was obtained with tumors growing in SCID mice reconstituted with BALB/C bone marrow (tumor cure rate of 63%). The results of this study demonstrate that, at least with the EMT6 tumor model, antitumor immune activity mediated by lymphoid cell populations makes an important contribution to the curative effect of PDT.

  2. Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.

    PubMed

    McGinley, Lisa M; Sims, Erika; Lunn, J Simon; Kashlan, Osama N; Chen, Kevin S; Bruno, Elizabeth S; Pacut, Crystal M; Hazel, Tom; Johe, Karl; Sakowski, Stacey A; Feldman, Eva L

    2016-03-01

    Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD. PMID:26744412

  3. 75 FR 67987 - Guidance for Industry: Cellular Therapy for Cardiac Disease; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-04

    ... regarding cellular delivery systems. In the Federal Register of April 2, 2009 (74 FR 14992), FDA announced... preclinical and clinical studies and on the chemistry, manufacturing and controls (CMC) information...

  4. Cellular uptake behaviour, photothermal therapy performance, and cytotoxicity of gold nanorods with various coatings

    NASA Astrophysics Data System (ADS)

    Zhu, Xiao-Ming; Fang, Caihong; Jia, Henglei; Huang, Yu; Cheng, Christopher H. K.; Ko, Chun-Hay; Chen, Zhiyi; Wang, Jianfang; Wang, Yi-Xiang J.

    2014-09-01

    With the development of Au nanorods for a number of biomedical applications, understanding their cellular responses has become increasingly important. In this study, we systematically evaluated the cellular uptake behaviour and cytotoxicity of Au nanorods with various surface coatings, including organic cetyltrimethylammonium bromide (CTAB), poly(sodium 4-styrenesulfonate) (PSS), and poly(ethylene glycol) (PEG), and inorganic mesoporous silica (mSiO2), dense silica (dSiO2), and titanium dioxide (TiO2). The cellular behaviour of Au nanorods was found to be highly dependent on both the surface coating and the cell type. CTAB-, PSS-, and mSiO2-coated Au nanorods exhibit notable cytotoxicity, while PEG-, dSiO2-, and TiO2-coated Au nanorods do not induce cell injury. Optical imaging studies indicated that the cell type plays a preferential role in Au nanorod cellular uptake. Higher cellular uptake of Au nanorods was seen in U-87 MG, PC-3, MDA-MB-231, and RAW 264.7 cells, as opposed to HepG2 and HT-29 cells. In addition, Au nanorod cellular uptake is also highly affected by serum protein binding to the surface coating. mSiO2-, dSiO2-, and TiO2-coated Au nanorods show significantly higher cellular uptake than PSS- and PEG-coated ones, which results in a better photothermal ablation effect for Au nanorods with the inorganic surface coatings. Our study provides valuable insights into the effects of the surface modification on the biocompatibility, cellular uptake, as well as biomedical functions of Au nanorods.With the development of Au nanorods for a number of biomedical applications, understanding their cellular responses has become increasingly important. In this study, we systematically evaluated the cellular uptake behaviour and cytotoxicity of Au nanorods with various surface coatings, including organic cetyltrimethylammonium bromide (CTAB), poly(sodium 4-styrenesulfonate) (PSS), and poly(ethylene glycol) (PEG), and inorganic mesoporous silica (mSiO2), dense silica (d

  5. Rapid generation of NY-ESO-1-specific CD4+ THELPER1 cells for adoptive T-cell therapy

    PubMed Central

    Kayser, Simone; Boβ, Cristina; Feucht, Judith; Witte, Kai-Erik; Scheu, Alexander; Bülow, Hans-Jörg; Joachim, Stefanie; Stevanović, Stefan; Schumm, Michael; Rittig, Susanne M; Lang, Peter; Röcken, Martin; Handgretinger, Rupert; Feuchtinger, Tobias

    2015-01-01

    Tumor-associated antigens such as NY-ESO-1 are expressed in a variety of solid tumors but absent in mature healthy tissues with the exception of germline cells. The immune system anti-cancer attack is mediated by cell lysis or induction of growth arrest through paralysis of tumor cells, the latter of which can be achieved by tumor-specific CD4+, IFNγ-producing THelper type 1 (TH1) cells. Translation of these immune-mediated mechanisms into clinical application has been limited by availability of immune effectors, as well as the need for complex in vitro protocols and regulatory hurdles. Here, we report a procedure to generate cancer-testis antigen NY-ESO-1-targeting CD4+ TH1 cells in vitro for cancer immunotherapy in the clinic. After in vitro sensitization by stimulating T cells with protein-spanning, overlapping peptide pools of NY-ESO-1 in combination with IL-7 and low dose IL-2, antigen-specific T cells were isolated using IFNγ capture technique and subsequently expanded with IL-2, IL-7 and IL-15. Large numbers of NY-ESO-1-specific CD4+ T cells with a TH1 cytokine profile and lower numbers of cytokine-secreting CD8+ T cells could be generated from healthy donors with a high specificity and expansion potential. Manufactured CD4+ T cells showed strong specific TH1-responses with IFNγ+, TNFα+, IL-2+ and induced cell cycle arrest and apoptosis in tumor cells. The protocol is GMP-grade and approved by the regulatory authorities. The tumor-antigen specific CD4+ TH1 lymphocytes can be adoptively transferred as a T-cell therapy to boost anticancer immunity and this novel cancer treatment approach is applicable to both T cells from healthy allogeneic donors as well as to autologous T cells derived from cancer patients. PMID:26155389

  6. Current perspectives on the use of ancillary materials for the manufacture of cellular therapies.

    PubMed

    Solomon, Jennifer; Csontos, Lynn; Clarke, Dominic; Bonyhadi, Mark; Zylberberg, Claudia; McNiece, Ian; Kurtzberg, Joanne; Bell, Rosemarie; Deans, Robert

    2016-01-01

    Continued growth in the cell therapy industry and commercialization of cell therapies that successfully advance through clinical trials has led to increased awareness around the need for specialized and complex materials utilized in their manufacture. Ancillary materials (AMs) are components or reagents used during the manufacture of cell therapy products but are not intended to be part of the final products. Commonly, there are limitations in the availability of clinical-grade reagents used as AMs. Furthermore, AMs may affect the efficacy of the cell product and subsequent safety of the cell therapy for the patient. As such, AMs must be carefully selected and appropriately qualified during the cell therapy development process. However, the ongoing evolution of cell therapy research, limited number of clinical trials and registered cell therapy products results in the current absence of specific regulations governing the composition, compliance, and qualification of AMs often leads to confusion by suppliers and users in this field. Here we provide an overview and interpretation of the existing global framework surrounding AM use and investigate some common misunderstandings within the industry, with the aim of facilitating the appropriate selection and qualification of AMs. The key message we wish to emphasize is that in order to most effectively mitigate risk around cell therapy development and patient safety, users must work with their suppliers and regulators to qualify each AM to assess source, purity, identity, safety, and suitability in a given application. PMID:26596503

  7. Immunological characterization of multipotent mesenchymal stromal cells--The International Society for Cellular Therapy (ISCT) working proposal.

    PubMed

    Krampera, Mauro; Galipeau, Jacques; Shi, Yufang; Tarte, Karin; Sensebe, Luc

    2013-09-01

    Cultured mesenchymal stromal cells (MSCs) possess immune regulatory properties and are already used for clinical purposes, although preclinical data (both in vitro and in vivo in animal models) are not always homogeneous and unequivocal. However, the various MSC-based clinical approaches to treat immunological diseases would be significantly validated and strengthened by using standardized immune assays aimed at obtaining shared, reproducible and consistent data. Thus, the MSC Committee of the International Society for Cellular Therapy has decided to put forward for general discussion a working proposal for a standardized approach based on a critical view of literature data. PMID:23602578

  8. ESC Working Group Cellular Biology of the Heart: Position Paper: improving the preclinical assessment of novel cardioprotective therapies

    PubMed Central

    Lecour, Sandrine; Bøtker, Hans E.; Condorelli, Gianluigi; Davidson, Sean M.; Garcia-Dorado, David; Engel, Felix B.; Ferdinandy, Peter; Heusch, Gerd; Madonna, Rosalinda; Ovize, Michel; Ruiz-Meana, Marisol; Schulz, Rainer; Sluijter, Joost P.G.; Van Laake, Linda W.; Yellon, Derek M.; Hausenloy, Derek J.

    2014-01-01

    Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia–reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes. PMID:25344369

  9. Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry.

    PubMed

    Bravery, Christopher A; Carmen, Jessica; Fong, Timothy; Oprea, Wanda; Hoogendoorn, Karin H; Woda, Juliana; Burger, Scott R; Rowley, Jon A; Bonyhadi, Mark L; Van't Hof, Wouter

    2013-01-01

    The evaluation of potency plays a key role in defining the quality of cellular therapy products (CTPs). Potency can be defined as a quantitative measure of relevant biologic function based on the attributes that are linked to relevant biologic properties. To achieve an adequate assessment of CTP potency, appropriate in vitro or in vivo laboratory assays and properly controlled clinical data need to be created. The primary objective of a potency assay is to provide a mechanism by which the manufacturing process and the final product for batch release are scrutinized for quality, consistency and stability. A potency assay also provides the basis for comparability assessment after process changes, such as scale-up, site transfer and new starting materials (e.g., a new donor). Potency assays should be in place for early clinical development, and validated assays are required for pivotal clinical trials. Potency is based on the individual characteristics of each individual CTP, and the adequacy of potency assays will be evaluated on a case-by-case basis by regulatory agencies. We provide an overview of the expectations and challenges in development of potency assays specific for CTPs; several real-life experiences from the cellular therapy industry are presented as illustrations. The key observation and message is that aggressive early investment in a solid potency evaluation strategy can greatly enhance eventual CTP deployment because it can mitigate the risk of costly product failure in late-stage development. PMID:23260082

  10. miR-23a blockade enhances adoptive T cell transfer therapy by preserving immune-competence in the tumor microenvironment

    PubMed Central

    Lin, Regina; Sampson, John H; Li, Qi-Jing; Zhu, Bo

    2015-01-01

    In adoptive T cell transfer therapy (ACT), the antitumor efficacy of cytotoxic CD8+ T lymphocytes (CTLs) has been limited by tumor-induced immunosuppression. We have demonstrated that miR-23a blockade in tumor-specific CTLs conferred resilience to TGFβ-mediated immunosuppression, resulting in superior tumor control. Our studies highlight miR-23a in tumor-specific CTLs as a clinically relevant target to enhance ACT. PMID:25949909

  11. Cardiac regeneration and cellular therapy: is there a benefit of exercise?

    PubMed

    Figueiredo, P A; Appell Coriolano, H-J; Duarte, J A

    2014-03-01

    Cardiovascular diseases (CVD) are a global epidemic in developed countries. Cumulative evidence suggests that myocyte formation is preserved during postnatal life, in adulthood or senescence, suggesting the existence of a growth reserve of the heart throughout lifespan. Several medical therapeutic approaches to CVD have considerably improved the clinical outcome for patients. Intense interest has been focused on regenerative medicine as an emerging strategy for CVD. Cellular therapeutic approaches have been proposed for enhancing survival and propagation of stem cells in myocardium, leading to cardiac cellular repair. Strong epidemiological and clinical data exists concerning the impact of regular physical exercise on cardiovascular health. Several mechanisms of acute and chronic exercise-induced cardiovascular adaptations to exercise have been presented, considering primary and secondary prevention of CVD. In this context, exercise-related improvements in the function and regeneration of the cardiovascular system may be associated with the exercise-induced activation, mobilization, differentiation, and homing of stem and progenitor cells. In this review several topics will be addressed concerning the relation between exercise, recruitment and biological activity of blood-circulating progenitor cells and resident cardiac stem cells. We hypothesize that exercise-induced stem cell activation may enhance overall heart function and improve the efficacy of cardiac cellular therapeutic protocols. PMID:23900898

  12. Recent Advances in Superparamagnetic Iron Oxide Nanoparticles for Cellular Imaging and Targeted Therapy Research

    PubMed Central

    Wang, Yi-Xiang J.; Xuan, Shouhu; Port, Marc; Idee, Jean-Marc

    2013-01-01

    Advances of nanotechnology have led to the development of nanomaterials with both potential diagnostic and therapeutic applications. Among them, superparamagnetic iron oxide (SPIO) nanoparticles have received particular attention. Over the past decade, various SPIOs with unique physicochemical and biological properties have been designed by modifying the particle structure, size and coating. This article reviews the recent advances in preparing SPIOs with novel properties, the way these physicochemical properties of SPIOs influence their interaction with cells, and the development of SPIOs in liver and lymph nodes magnetic resonance imaging (MRI) contrast. Cellular uptake of SPIO can be exploited in a variety of potential clinical applications, including stem cell and inflammation cell tracking and intra-cellular drug delivery to cancerous cells which offers higher intra-cellular concentration. When SPIOs are used as carrier vehicle, additional advantages can be achieved including magnetic targeting and hyperthermia options, as well as monitoring with MRI. Other potential applications of SPIO include magnetofection and gene delivery, targeted retention of labeled stem cells, sentinel lymph nodes mapping, and magnetic force targeting and cell orientation for tissue engineering. PMID:23621536

  13. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis

    PubMed Central

    Auletta, Jeffery J; Bartholomew, Amelia M; Maziarz, Richard T; Deans, Robert J; Miller, Robert H; Lazarus, Hillard M; Cohen, Jeffrey A

    2012-01-01

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS for which only partially effective therapies exist. Intense research defining the underlying immune pathophysiology is advancing both the understanding of MS as well as revealing potential targets for disease intervention. Mesenchymal stromal cell (MSC) therapy has the potential to modulate aberrant immune responses causing demyelination and axonal injury associated with MS, as well as to repair and restore damaged CNS tissue and cells. This article reviews the pathophysiology underlying MS, as well as providing a cutting-edge perspective into the field of MSC therapy based upon the experience of authors intrinsically involved in MS and MSC basic and translational science research. PMID:22642335

  14. Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives

    PubMed Central

    Berezin, Alexander E

    2014-01-01

    Diabetes mellitus (DM) is the most prevailing disease with progressive incidence worldwide. Despite contemporary treatment type one DM and type two DM are frequently associated with long-term major microvascular and macrovascular complications. Currently restoration of failing β-cell function, regulation of metabolic processes with stem cell transplantation is discussed as complements to contemporary DM therapy regimens. The present review is considered paradigm of the regenerative care and the possibly effects of cell therapy in DM. Reprogramming stem cells, bone marrow-derived mononuclear cells; lineage-specified progenitor cells are considered for regenerative strategy in DM. Finally, perspective component of stem cell replacement in DM is discussed. PMID:25512780

  15. Cellular HIV-1 DNA quantitation in patients during simplification therapy with protease inhibitor-sparing regimens.

    PubMed

    Sarmati, Loredana; Parisi, Saverio Giuseppe; Nicastri, Emanuele; d'Ettorre, Gabriella; Andreoni, Carolina; Dori, Luca; Gatti, Francesca; Montano, Marco; Buonomini, Anna Rita; Boldrin, Caterina; Palù, Giorgio; Vullo, Vincenzo; Andreoni, Massimo

    2007-07-01

    Simplified regimens containing protease-inhibitors (PI)-sparing combinations were used in patients with virological suppression after prolonged highly active antiretroviral therapy. This study evaluated the total HIV-1 DNA quantitation as a predictor of long-term success for PI-sparing simplified therapy. Sixty-two patients were enrolled in a prospective non-randomized cohort. All patients have been receiving a triple-therapy regimen, two nucleoside reverse transcriptase inhibitors (NRTIs) plus one PI, for at least 9 months and were characterized by undetectable plasma HIV-1 RNA levels (<50 cp/ml) for at least 6 months. Patients were changed to a simplified PI-sparing regimen to overcome PI-associated adverse effects. HIV-DNA levels in peripheral blood mononuclear cells (PBMCs) were evaluated at baseline and at the end of follow-up. Patients with proviral DNA levels below the median value (226 copies/10(6) PBMCs) had a significant higher CD4 cell count at nadir (P = 0.003) and at enrolment (P = 0.001) with respect to patients with HIV-DNA levels above the median value. At month 18, 53 out of 62 (85%) patients on simplified regimen showed virological success, 4 (6.4%) patients experienced virological failure and 5 (8%) patients showed viral blip. At logistic regression analysis, HIV-DNA levels below 226 copies/10(6) PBMCs at baseline were associated independently to a reduced risk of virological failure or viral blip during simplified therapy (OR 0.002, 95% CI 0.001-0.46, P = 0.025). The substitution of PI with NRTI or non-NRTIs may represent an effective treatment option. Indeed, treatment failure or viral blip were experienced by 6% and 8% of the patients on simplified therapy, respectively. In addition, sustained suppression of the plasma viral load was significantly correlated with low levels of proviral DNA before treatment simplification. PMID:17516532

  16. Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?

    PubMed

    Wislet-Gendebien, Sabine; Laudet, Emerence; Neirinckx, Virginie; Rogister, Bernard

    2012-01-01

    The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy. PMID:22319243

  17. Adult Bone Marrow: Which Stem Cells for Cellular Therapy Protocols in Neurodegenerative Disorders?

    PubMed Central

    Wislet-Gendebien, Sabine; Laudet, Emerence; Neirinckx, Virginie; Rogister, Bernard

    2012-01-01

    The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy. PMID:22319243

  18. PAA-derived gold nanorods for cellular targeting and photothermal therapy.

    PubMed

    Kirui, Dickson K; Krishnan, Sushmitha; Strickland, Aaron D; Batt, Carl A

    2011-06-14

    A single-step LbL procedure to functionalize CTAB-capped GNRs via electrostatic self-assembly is reported. This approach allows for consistent biomolecule/GNR coupling using standard carboxyl-amine conjugation chemistry. The focus is on cancer-targeting biomolecule/GNR conjugates and selective photothermal destruction of cancer cells by GNR-mediated hyperthermia and NIR light. GNRs were conjugated to a single-chain antibody selective for colorectal carcinoma cells and used as probes to demonstrate photothermal therapy. Selective targeting and GNR uptake in antigen-expressing SW 1222 cells were observed using fluorescence microscopy. Selective photothermal therapy is demonstrated using SW 1222 cells, where >62% cell death was observed after cells are treated with targeted A33scFv-GNRs. PMID:21438153

  19. Lymphocytes as cellular vehicles for gene therapy in mouse and man

    SciTech Connect

    Culver, K.; Cornetta, K.; Morgan, R.; Morecki, S.; Aebersold, P.; Kasid, A.; Lotze, M.; Rosenberg, S.A.; Anderson, W.F.; Blaese, R.M. )

    1991-04-15

    The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. The authors that retroviral vectors can stably introduce genes into antigen-specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. They studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.

  20. Evaluating the Role of Cellular Immune Responses in the Emergence of HCV NS3 Resistance Mutations During Protease Inhibitor Therapy.

    PubMed

    Abdel-Hameed, Enass A; Rouster, Susan D; Ji, Hong; Ulm, Ashley; Hetta, Helal F; Anwar, Nadeem; Sherman, Kenneth E; Shata, Mohamed Tarek M

    2016-05-01

    The efficacy of protease inhibitor drugs in hepatitis C virus (HCV) treatment is limited by the selection and expansion of drug-resistant mutations. HCV replication is error-prone and genetic variability within the dominant epitopes ensures its persistence. The aims of this study are to evaluate the role of cellular immune response in the emergence of HCV protease resistance mutations and its effects on treatment outcome. Ten chronically HCV-infected subjects were treated with boceprevir (BOC)-based triple therapy. HCV-RNA was tested for BOC resistance-associated viral variants. HCV protease resistance mutations were investigated pretreatment and 24 weeks post-treatment. Synthetic peptides representing the wild-type and the potential nonstructural (NS)3 variants were used to evaluate T cell responses and human leukocyte antigen binding. Sustained viral response was achieved in 70% of patients, two patients were treatment nonresponders (NRs) and one was classified as a relapse. Pretreatment, the proportion of drug-resistant variants within individuals was higher in sustained viral responders (SVRs) than in NR patients. However, resistance-associated variants increased in NRs after BOC combined triple therapy. In contrast to NR patients, significant stronger cell-mediated immune responses were observed at the baseline among those who achieved sustained viral response for all T cell epitopes tested. Despite the increase in cell-mediated immune responses at week 24 in NRs, they failed to control the virus replication, leading to development of overt drug-resistant variants. Our data suggest that strong NS3-specific T cell immune responses at the baseline may predict a positive outcome of directly acting antiviral-based therapy, and the presence of pre-existent resistance mutations does not play a significant role in the outcome of anti-HCV combined therapy. PMID:26885675

  1. Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy.

    PubMed

    Nair, Nitya; Mei, Henrik E; Chen, Shih-Yu; Hale, Matthew; Nolan, Garry P; Maecker, Holden T; Genovese, Mark; Fathman, C Garrison; Whiting, Chan C

    2015-01-01

    The development of biomarkers for autoimmune diseases has been hampered by a lack of understanding of disease etiopathogenesis and of the mechanisms underlying the induction and maintenance of inflammation, which involves complex activation dynamics of diverse cell types. The heterogeneous nature and suboptimal clinical response to treatment observed in many autoimmune syndromes highlight the need to develop improved strategies to predict patient outcome to therapy and personalize patient care. Mass cytometry, using CyTOF®, is an advanced technology that facilitates multiparametric, phenotypic analysis of immune cells at single-cell resolution. In this review, we outline the capabilities of mass cytometry and illustrate the potential of this technology to enhance the discovery of cellular biomarkers for rheumatoid arthritis, a prototypical autoimmune disease. PMID:25981462

  2. Minimum information about tolerogenic antigen-presenting cells (MITAP): a first step towards reproducibility and standardisation of cellular therapies

    PubMed Central

    Spiering, Rachel; Aguillon, Juan C.; Anderson, Amy E.; Appel, Silke; Benitez-Ribas, Daniel; ten Brinke, Anja; Broere, Femke; Cools, Nathalie; Cuturi, Maria Cristina; Diboll, Julie; Geissler, Edward K.; Giannoukakis, Nick; Gregori, Silvia; van Ham, S. Marieke; Lattimer, Staci; Marshall, Lindsay; Harry, Rachel A.; Hutchinson, James A.; Isaacs, John D.; Joosten, Irma; van Kooten, Cees; Lopez Diaz de Cerio, Ascension; Nikolic, Tatjana; Oral, Haluk Barbaros; Sofronic-Milosavljevic, Ljiljana; Ritter, Thomas; Riquelme, Paloma; Thomson, Angus W.; Trucco, Massimo; Vives-Pi, Marta; Martinez-Caceres, Eva M.

    2016-01-01

    Cellular therapies with tolerogenic antigen-presenting cells (tolAPC) show great promise for the treatment of autoimmune diseases and for the prevention of destructive immune responses after transplantation. The methodologies for generating tolAPC vary greatly between different laboratories, making it difficult to compare data from different studies; thus constituting a major hurdle for the development of standardised tolAPC therapeutic products. Here we describe an initiative by members of the tolAPC field to generate a minimum information model for tolAPC (MITAP), providing a reporting framework that will make differences and similarities between tolAPC products transparent. In this way, MITAP constitutes a first but important step towards the production of standardised and reproducible tolAPC for clinical application.

  3. Achieving Informed Consent for Cellular Therapies: A Preclinical Translational Research Perspective on Regulations versus a Dose of Reality.

    PubMed

    Anderson, Aileen J; Cummings, Brian J

    2016-09-01

    A central principle of bioethics is "subject autonomy," the acknowledgement of the primacy of the informed consent of the subject of research. Autonomy requires informed consent - the assurance that the research participant is informed about the possible risks and benefits of the research. In fact, informed consent is difficult when a single drug is being tested, although subjects have a baseline understanding of the testing of a pharmacological agent and the understanding that they can stop taking the drug if there were an adverse event. However, informed consent is even less easily achieved in the modern arena of complex new molecular and cellular therapies. In this article, we argue that as science confronts new issues such as transplantation of stem cell products, which may live within the participant for the rest of their lives, researchers must carefully consider and constantly re-examine how they properly inform subjects considering participation trials of these novel therapeutic strategies.For example, the manufacture of a vial of a cell product that consists of a collection of growing cells is very different than the production of a vial of identical pills, which can be presumed to be identical. The scientific concepts on which these cellular approaches are based may seem alien and incomprehensible to a research subject, who thinks of a clinical trial as simply the selection and testing of the most efficacious pharmaceutical agent already proven to work in preclinical animal studies. The research subject would be wrong. PMID:27587445

  4. Multi-functionality Redefined with Colloidal Carotene Carbon Nanoparticles for Synchronized Chemical Imaging, Enriched Cellular Uptake and Therapy.

    PubMed

    Misra, Santosh K; Mukherjee, Prabuddha; Chang, Huei-Huei; Tiwari, Saumya; Gryka, Mark; Bhargava, Rohit; Pan, Dipanjan

    2016-01-01

    Typically, multiplexing high nanoparticle uptake, imaging, and therapy requires careful integration of three different functions of a multiscale molecular-particle assembly. Here, we present a simpler approach to multiplexing by utilizing one component of the system for multiple functions. Specifically, we successfully synthesized and characterized colloidal carotene carbon nanoparticle (C(3)-NP), in which a single functional molecule served a threefold purpose. First, the presence of carotene moieties promoted the passage of the particle through the cell membrane and into the cells. Second, the ligand acted as a potent detrimental moiety for cancer cells and, finally, the ligands produced optical contrast for robust microscopic detection in complex cellular environments. In comparative tests, C(3)-NP were found to provide effective intracellular delivery that enables both robust detection at cellular and tissue level and presents significant therapeutic potential without altering the mechanism of intracellular action of β-carotene. Surface coating of C(3) with phospholipid was used to generate C(3)-Lipocoat nanoparticles with further improved function and biocompatibility, paving the path to eventual in vivo studies. PMID:27405011

  5. Multi-functionality Redefined with Colloidal Carotene Carbon Nanoparticles for Synchronized Chemical Imaging, Enriched Cellular Uptake and Therapy

    NASA Astrophysics Data System (ADS)

    Misra, Santosh K.; Mukherjee, Prabuddha; Chang, Huei-Huei; Tiwari, Saumya; Gryka, Mark; Bhargava, Rohit; Pan, Dipanjan

    2016-07-01

    Typically, multiplexing high nanoparticle uptake, imaging, and therapy requires careful integration of three different functions of a multiscale molecular-particle assembly. Here, we present a simpler approach to multiplexing by utilizing one component of the system for multiple functions. Specifically, we successfully synthesized and characterized colloidal carotene carbon nanoparticle (C3-NP), in which a single functional molecule served a threefold purpose. First, the presence of carotene moieties promoted the passage of the particle through the cell membrane and into the cells. Second, the ligand acted as a potent detrimental moiety for cancer cells and, finally, the ligands produced optical contrast for robust microscopic detection in complex cellular environments. In comparative tests, C3-NP were found to provide effective intracellular delivery that enables both robust detection at cellular and tissue level and presents significant therapeutic potential without altering the mechanism of intracellular action of β-carotene. Surface coating of C3 with phospholipid was used to generate C3-Lipocoat nanoparticles with further improved function and biocompatibility, paving the path to eventual in vivo studies.

  6. Multi-functionality Redefined with Colloidal Carotene Carbon Nanoparticles for Synchronized Chemical Imaging, Enriched Cellular Uptake and Therapy

    PubMed Central

    Misra, Santosh K.; Mukherjee, Prabuddha; Chang, Huei-Huei; Tiwari, Saumya; Gryka, Mark; Bhargava, Rohit; Pan, Dipanjan

    2016-01-01

    Typically, multiplexing high nanoparticle uptake, imaging, and therapy requires careful integration of three different functions of a multiscale molecular-particle assembly. Here, we present a simpler approach to multiplexing by utilizing one component of the system for multiple functions. Specifically, we successfully synthesized and characterized colloidal carotene carbon nanoparticle (C3-NP), in which a single functional molecule served a threefold purpose. First, the presence of carotene moieties promoted the passage of the particle through the cell membrane and into the cells. Second, the ligand acted as a potent detrimental moiety for cancer cells and, finally, the ligands produced optical contrast for robust microscopic detection in complex cellular environments. In comparative tests, C3-NP were found to provide effective intracellular delivery that enables both robust detection at cellular and tissue level and presents significant therapeutic potential without altering the mechanism of intracellular action of β-carotene. Surface coating of C3 with phospholipid was used to generate C3-Lipocoat nanoparticles with further improved function and biocompatibility, paving the path to eventual in vivo studies. PMID:27405011

  7. Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.

    PubMed

    Sandri, Sara; Bobisse, Sara; Moxley, Kelly; Lamolinara, Alessia; De Sanctis, Francesco; Boschi, Federico; Sbarbati, Andrea; Fracasso, Giulio; Ferrarini, Giovanna; Hendriks, Rudi W; Cavallini, Chiara; Scupoli, Maria Teresa; Sartoris, Silvia; Iezzi, Manuela; Nishimura, Michael I; Bronte, Vincenzo; Ugel, Stefano

    2016-05-01

    Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR. PMID:27197263

  8. Delivery of nucleic acids for cancer gene therapy: overcoming extra- and intra-cellular barriers.

    PubMed

    McErlean, Emma M; McCrudden, Cian M; McCarthy, Helen O

    2016-09-01

    The therapeutic potential of cancer gene therapy has been limited by the difficulty of delivering genetic material to target sites. Various biological and molecular barriers exist which need to be overcome before effective nonviral delivery systems can be applied successfully in oncology. Herein, various barriers are described and strategies to circumvent such obstacles are discussed, considering both the extracellular and intracellular setting. Development of multifunctional delivery systems holds much promise for the progression of gene delivery, and a growing body of evidence supports this approach involving rational design of vectors, with a unique molecular architecture. In addition, the potential application of composite gene delivery platforms is highlighted which may provide an alternative delivery strategy to traditional systemic administration. PMID:27582234

  9. Mechanisms in photodynamic therapy: part one—-photosensitizers, photochemistry and cellular localization

    PubMed Central

    Castano, Ana P.; Demidova, Tatiana N.; Hamblin, Michael R.

    2013-01-01

    Summary The use of non-toxic dyes or photosensitizers (PS) in combination with harmless visible light that is known as photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In a series of three reviews we will discuss the mechanisms that operate in the field of PDT. Part one discusses the recent explosion in discovery and chemical synthesis of new PS. Some guidelines on how to choose an ideal PS for a particular application are presented. The photochemistry and photophysics of PS and the two pathways known as Type I (radicals and reactive oxygen species) and Type II (singlet oxygen) photochemical processes are discussed. To carry out PDT effectively in vivo, it is necessary to ensure sufficient light reaches all the diseased tissue. This involves understanding how light travels within various tissues and the relative effects of absorption and scattering. The fact that most of the PS are also fluorescent allows various optical imaging and monitoring strategies to be combined with PDT. The most important factor governing the outcome of PDT is how the PS interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. Examples of PS that localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes are given. Finally the use of 5-aminolevulinic acid as a natural precursor of the heme biosynthetic pathway, stimulates accumulation of the PS protoporphyrin IX is described. PMID:25048432

  10. Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor.

    PubMed

    Tähtinen, Siri; Grönberg-Vähä-Koskela, Susanna; Lumen, Dave; Merisalo-Soikkeli, Maiju; Siurala, Mikko; Airaksinen, Anu J; Vähä-Koskela, Markus; Hemminki, Akseli

    2015-08-01

    Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8(+) T-cell (OT-I) therapy. Following intraperitoneal transfer of polyclonally activated OT-I lymphocytes, control of tumor growth was superior in mice given intratumoral adenovirus compared with control mice, even in the absence of oncolytic virus replication. Preexisting antiviral immunity against serotype 5 did not hinder the therapeutic efficacy of the combination treatment. Intratumoral adenovirus injection was associated with an increase in proinflammatory cytokines, CD45(+) leukocytes, CD8(+) lymphocytes, and F4/80(+) macrophages, suggesting enhanced tumor immunogenicity. The proinflammatory effects of adenovirus on the tumor microenvironment led to expression of costimulatory signals on CD11c(+) antigen-presenting cells and subsequent activation of T cells, thus breaking the tumor-induced peripheral tolerance. An increased number of CD8(+) T cells specific for endogenous tumor antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell-treated mice rejected the challenge of parental B16.F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer. PMID:25977260

  11. Training and Utilization of the Physical Therapy Assistant; Policy Statement Adopted by the 1967 House of Delegates.

    ERIC Educational Resources Information Center

    American Physical Therapy Association, New York, NY.

    The physical therapy assistant is defined as a skilled technical worker who assists the professional physical therapist in patient related activities and carries out designated tasks within a service administered by a professional physical therapist. Training standards require a 2-year college level program administered by a qualified physical…

  12. Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy

    PubMed Central

    Gill, Harinder; Leung, Anskar Y. H.; Kwong, Yok-Lam

    2016-01-01

    Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. PMID:27023522

  13. Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level

    NASA Astrophysics Data System (ADS)

    Gholami, Y.; Zhu, X.; Fulton, R.; Meikle, S.; El-Fakhri, G.; Kuncic, Z.

    2015-08-01

    Radium-223 dichloride (223Ra) is an alpha particle emitter and a natural bone-seeking radionuclide that is currently used for treating osteoblastic bone metastases associated with prostate cancer. The stochastic nature of alpha emission, hits and energy deposition poses some challenges for estimating radiation damage. In this paper we investigate the distribution of hits to cells by multiple alpha particles corresponding to a typical clinically delivered dose using a Monte Carlo model to simulate the stochastic effects. The number of hits and dose deposition were recorded in the cytoplasm and nucleus of each cell. Alpha particle tracks were also visualized. We found that the stochastic variation in dose deposited in cell nuclei (≃ 40%) can be attributed in part to the variation in LET with pathlength. We also found that ≃ 18% of cell nuclei receive less than one sigma below the average dose per cell (≃ 15.4 Gy). One possible implication of this is that the efficacy of cell kill in alpha particle therapy need not rely solely on ionization clustering on DNA but possibly also on indirect DNA damage through the production of free radicals and ensuing intracellular signaling.

  14. Effects of strength training on muscle cellular outcomes in prostate cancer patients on androgen deprivation therapy.

    PubMed

    Nilsen, T S; Thorsen, L; Fosså, S D; Wiig, M; Kirkegaard, C; Skovlund, E; Benestad, H B; Raastad, T

    2016-09-01

    Androgen deprivation therapy (ADT) improves life expectancy in prostate cancer (PCa) patients, but is associated with adverse effects on muscle mass. Here, we investigated the effects of strength training during ADT on muscle fiber cross-sectional area (CSA) and regulators of muscle mass. PCa patients on ADT were randomized to 16 weeks of strength training (STG) (n = 12) or a control group (CG; n = 11). Muscle biopsies were obtained from m. vastus lateralis and analyzed by immunohistochemistry and western blot. Muscle fiber CSA increased with strength training (898 μm(2) , P = 0.04), with the only significant increase observed in type II fibers (1076 μm(2) , P = 0.03). There was a trend toward a difference in mean change between groups myonuclei number (0.33 nuclei/fiber, P = 0.06), with the only significant increase observed in type I fibers, which decreased the myonuclear domain size of type I fibers (P = 0.05). Satellite cell numbers and the content of androgen receptor and myostatin remained unchanged. Sixteen weeks of strength training during ADT increased type II fiber CSA and reduced myonuclear domain in type I fibers in PCa patients. The increased number of satellite cells normally seen following strength training was not observed. PMID:26282343

  15. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane.

    PubMed

    Macdonald, James B; Macdonald, Brooke; Golitz, Loren E; LoRusso, Patricia; Sekulic, Aleksandar

    2015-02-01

    There has been a rapid emergence of numerous targeted agents in the oncology community in the last decade. This exciting paradigm shift in drug development lends promise for the future of individualized medicine. Given the pace of development and clinical deployment of targeted agents with novel mechanisms of action, dermatology providers may not be familiar with the full spectrum of associated skin-related toxicities. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents, and their intensity can be dose-limiting or lead to therapy discontinuation. In light of the often life-saving nature of emerging oncotherapeutics, it is critical that dermatologists both understand the mechanisms and recognize clinical signs and symptoms of such toxicities in order to provide effective clinical management. Part I of this continuing medical education article will review in detail the potential skin-related adverse sequelae, the frequency of occurrence, and the implications associated with on- and off-target cutaneous toxicities of inhibitors acting at the cell membrane level, chiefly inhibitors of epidermal growth factor receptor, KIT, and BCR-ABL, angiogenesis, and multikinase inhibitors. PMID:25592338

  16. Imaging of boron in tissue at the cellular level for boron neutron capture therapy.

    PubMed

    Arlinghaus, H F; Spaar, M T; Switzer, R C; Kabalka, G W

    1997-08-15

    Glioblastoma multiforme, and other tumors involving the brain, are undergoing experimental treatment with a promising new technique: boron neutron capture therapy (BNCT). BNCT relies on the capture of thermal neutrons by boron deposited biochemically in the tumor and the subsequent fission of the boron into energetic lithium ions and alpha particles. An important requirement for improved BNCT is the development of more selective boron delivery mechanisms. The ability to image the boron concentration in tissue sections and even inside individual cells would be an important aid in the development of these delivery mechanisms. We have compared both sputter-initiated resonance ionization microprobe (SIRIMP), which combines resonance ionization with a high-energy pulsed focused sputter ion beam and mass spectrometric detection of ions, with laser atomization resonance ionization microprobe (LARIMP), which uses a laser pulse instead of an ion pulse for the atomization process, to determine their characteristics in locating and quantifying boron concentrations as a function of position in tissues obtained from a rat which had been infused with a BNCT drug. The data show that the SIRIMP/LARIMP techniques are well suited for quantitative and ultrasensitive imaging of boron trace element concentrations in biological tissue sections. The LARIMP mode could be used to quickly determine the spatial boron concentration with intercellular resolution over large areas down to the low nanograms-per-gram level, while the SIRIMP mode could be used to determine the spatial boron concentration and its variability in intracellular areas. PMID:9271061

  17. Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level.

    PubMed

    Gholami, Y; Zhu, X; Fulton, R; Meikle, S; El-Fakhri, G; Kuncic, Z

    2015-08-01

    Radium-223 dichloride ((223)Ra) is an alpha particle emitter and a natural bone-seeking radionuclide that is currently used for treating osteoblastic bone metastases associated with prostate cancer. The stochastic nature of alpha emission, hits and energy deposition poses some challenges for estimating radiation damage. In this paper we investigate the distribution of hits to cells by multiple alpha particles corresponding to a typical clinically delivered dose using a Monte Carlo model to simulate the stochastic effects. The number of hits and dose deposition were recorded in the cytoplasm and nucleus of each cell. Alpha particle tracks were also visualized. We found that the stochastic variation in dose deposited in cell nuclei ([Formula: see text]40%) can be attributed in part to the variation in LET with pathlength. We also found that [Formula: see text]18% of cell nuclei receive less than one sigma below the average dose per cell ([Formula: see text]15.4 Gy). One possible implication of this is that the efficacy of cell kill in alpha particle therapy need not rely solely on ionization clustering on DNA but possibly also on indirect DNA damage through the production of free radicals and ensuing intracellular signaling. PMID:26216391

  18. Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

    PubMed Central

    Nguyen, Van T. M.; Barozzi, Iros; Faronato, Monica; Lombardo, Ylenia; Steel, Jennifer H.; Patel, Naina; Darbre, Philippa; Castellano, Leandro; Győrffy, Balázs; Woodley, Laura; Meira, Alba; Patten, Darren K.; Vircillo, Valentina; Periyasamy, Manikandan; Ali, Simak; Frige, Gianmaria; Minucci, Saverio; Coombes, R. Charles; Magnani, Luca

    2015-01-01

    Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients. PMID:26610607

  19. Chinese Medicines Induce Cell Death: The Molecular and Cellular Mechanisms for Cancer Therapy

    PubMed Central

    Wang, Xuanbin; Tan, Hor Yue; Zhong, Sen

    2014-01-01

    Chinese medicines have long history in treating cancer. With the growing scientific evidence of biomedical researches and clinical trials in cancer therapy, they are increasingly accepted as a complementary and alternative treatment. One of the mechanisms is to induce cancer cell death. Aim. To comprehensively review the publications concerning cancer cell death induced by Chinese medicines in recent years and provide insights on anticancer drug discovery from Chinese medicines. Materials and Methods. Chinese medicines (including Chinese medicinal herbs, animal parts, and minerals) were used in the study. The key words including “cancer”, “cell death”, “apoptosis”, “autophagy,” “necrosis,” and “Chinese medicine” were used in retrieval of related information from PubMed and other databases. Results. The cell death induced by Chinese medicines is described as apoptotic, autophagic, or necrotic cell death and other types with an emphasis on their mechanisms of anticancer action. The relationship among different types of cell death induced by Chinese medicines is critically reviewed and discussed. Conclusions. This review summarizes that CMs treatment could induce multiple pathways leading to cancer cell death, in which apoptosis is the dominant type. To apply these preclinical researches to clinic application will be a key issue in the future. PMID:25379508

  20. Targeted 25-hydroxyvitamin D3 1α-hydroxylase adoptive gene therapy ameliorates dss-induced colitis without causing hypercalcemia in mice.

    PubMed

    Li, Bo; Baylink, David J; Walter, Michael H; Lau, Kin-Hing William; Meng, Xianmei; Wang, Jun; Cherkas, Andriy; Tang, Xiaolei; Qin, Xuezhong

    2015-02-01

    Systemic 1,25(OH)2D3 treatment ameliorating murine inflammatory bowel diseases (IBD) could not be applied to patients because of hypercalcemia. We tested the hypothesis that increasing 1,25(OH)2D3 synthesis locally by targeting delivery of the 1α-hydroxylase gene (CYP27B1) to the inflamed bowel would ameliorate IBD without causing hypercalcemia. Our targeting strategy is the use of CD11b(+)/Gr1(+) monocytes as the cell vehicle and a macrophage-specific promoter (Mac1) to control CYP27B1 expression. The CD11b(+)/Gr1(+) monocytes migrated initially to inflamed colon and some healthy tissues in dextran sulfate sodium (DSS) colitis mice; however, only the migration of monocytes to the inflamed colon was sustained. Adoptive transfer of Gr1(+) monocytes did not cause hepatic injury. Infusion of Mac1-CYP27B1-modified monocytes increased body weight gain, survival, and colon length, and expedited mucosal regeneration. Expression of pathogenic Th17 and Th1 cytokines (interleukin (IL)-17a and interferon (IFN)-α) was decreased, while expression of protective Th2 cytokines (IL-5 and IL-13) was increased, by the treatment. This therapy also enhanced tight junction gene expression in the colon. No hypercalcemia occurred following this therapy. In conclusion, we have for the first time obtained proof-of-principle evidence for a novel monocyte-based adoptive CYP27B1 gene therapy using a mouse IBD model. This strategy could be developed into a novel therapy for IBD and other autoimmune diseases. PMID:25327179

  1. Preparation, characterization, and cellular studies of photosensitizer-loaded lipid nanoparticles for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Navarro, Fabrice P.; Bechet, Denise; Delmas, Thomas; Couleaud, Pierre; Frochot, Céline; Verhille, Marc; Kamarulzaman, Ezatul; Vanderesse, Régis; Boisseau, Patrick; Texier, Isabelle; Gravier, Julien; Vinet, Françoise; Barberi-Heyob, Muriel; Couffin, Anne Claude

    2011-02-01

    PhotoDynamic Therapy (PDT) has been established as a potent and less invasive treatment for different kinds of cancer. Among various attempts to enhance the therapeutics efficacy of PDT, the specific delivery of the PhotoSensitizer (PS) in the tumor is expected to increase its clinical applications, since unwanted accumulation, especially in the skin, impairs the patients' quality of life (prolonged cutaneous photosensitivity). The aim of this study was to engineer Lipid Nanoparticles (LNP) with different sizes and various PS contents, using simple, solvent-free and easily scale up manufacturing processes. Meso-tetra (hydroxyphenyl) chlorin (mTHPC) is one of the most potent photoactive compounds for clinical use and it has been successfully applied in the treatment of various indications, such as the head and neck, prostate and pancreatic cancers. Here, a derivative of mTHPC was efficiently incorporated into the lipid core of LNP, leading to a large range of stable and reproducible mTHPC-loaded LNP with narrow size distribution. The photophysical and photochemical properties of mTHPC-loaded LNP were studied by measuring absorbance and fluorescence spectra, colloidal stability, particle size and zeta potential, as well as singlet oxygen luminescence. The photocytotoxicity of three selected mTHPC-loaded LNP (25 nm, 45 nm and 95 nm of diameter, respectively) was evaluated on MCF-7 cells, in comparison to free mTHPC, under irradiation at 652 nm with a range of light fluence from 1 to 5 J/cm2. All the physico-chemical, photophysical and biological measurements allow us to conclude that LNP is a promising nano-drug delivery system for PDT.

  2. A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

    PubMed Central

    Okon, Elena B.; Karimi-Abdolrezaee, Soheila; Hill, Caitlin E.; Sparling, Joseph S.; Plemel, Jason R.; Plunet, Ward T.; Tsai, Eve C.; Baptiste, Darryl; Smithson, Laura J.; Kawaja, Michael D.; Fehlings, Michael G.; Kwon, Brian K.

    2011-01-01

    Abstract Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same “type” exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits. PMID:20146557

  3. Cellular and tissue effects induced by photogem® and red LED in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Ribeiro, A. P. D.; Pavarina, A. C.; Trindade, F. Z.; Bagnato, V. S.; Kurachi, C.; de Souza Costa, C. A.

    2011-01-01

    In order to consider the photodynamic therapy (PDT) as a clinical treatment for candidosis, it is necessary to know its cytotoxic effect on normal cells and tissues. Therefore, this study evaluated the toxicity of PDT with Photogem® associated with red light-emitting diode (LED) on L929 and MDPC-23 cell cultures and healthy rat palatal mucosa. In the in vitro experiment, the cells (30000 cells/cm2) were seeded in 24-well plates for 48 h, incubated with Photogem® (50, 100, or 150 mg/l) and either irradiated or not with a red LED source (630 ± 3 nm; 75 or 100 J/cm2; 22 mW/cm2). Cell metabolism was evaluated by the MTT assay (ANOVA and Dunnet's post hoc tests; p < 0.05) and cell morphology was examined by scanning electron microscopy. In the in vivo evaluation, Photogem® (500 mg/l) was applied to the palatal mucosa of Wistar rats during 30 min and exposed to red LED (630 nm) during 20 min (306 J/cm2). The palatal mucosa was photographed for macroscopic analysis at 0, 1, 3, and 7 days posttreatment and subjected to histological analysis after sacrifice of the rats. For both cell lines, there was a statistically significant decrease of the mitochondrial activity (90-97%) for all Photogem® concentrations associated with red LED regardless of the energy density. However, in the in vivo evaluation, the PDT-treated groups presented intact mucosa with normal characteristics both macroscopically and histologically. From these results, it may be concluded that the association of Photogem® and red LED caused severe toxic effects on normal cell cultures, characterized by the reduction of mitochondrial activity and morphological alterations, but did not cause damage to the rat palatal mucosa in vivo.

  4. Nuclear transcription factors: a new approach to enhancing cellular responses to ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay; Sato, Nobuyuki; Moore, Brian; Mack, Judith; Gasbarre, Christopher; Keevey, Samantha; Ortel, Bernhard; Sinha, Alok; Khachemoune, Amor

    2006-02-01

    Photodynamic therapy (PDT) using aminolevulinic acid (ALA) relies upon the uptake of ALA into cancer cells, where it is converted into a porphyrin intermediate, protoporphyrin IX (PpIX) that is highly photosensitizing. For large or resistant tumors, however, ALA/PDT is often not completely effective due to inadequate PpIX levels. Therefore, new approaches to enhance the intracellular production of PpIX are sought. Here, we describe a general approach to improve intracellular PpIX accumulation via manipulations that increase the expression of an enzyme, coproporphyrinogen oxidase (CPO), that is rate-determining for PpIX production. We show that nuclear hormones that promote terminal differentiation, e.g. vitamin D or androgens, can also increase the accumulation of PpIX and the amount of killing of the target cells upon exposure to light. These hormones bind to intracellular hormone receptors that translocate to the nucleus, where they act as transcription factors to increase the expression of target genes. We have found that several other transcription factors associated with terminal differentiation, including members of the CCAAT enhancer binding (C/EBP) family, and a homeobox protein named Hoxb13, are also capable of enhancing PpIX accumulation. These latter transcription factors appear to interact directly with the CPO gene promoter, resulting in enhanced CPO transcriptional activity. Our data in several different cell systems, including epithelial cells of the skin and prostate cancer cells, indicate that enhancement of CPO expression and PpIX accumulation represents a viable new approach toward improving the efficacy of ALA/PDT.

  5. An optical system adopting liquid crystals with electrical tunability of wavelength and energy density for low level light therapy

    NASA Astrophysics Data System (ADS)

    Chang, Chia-Ming; Wang, Yu-Jen; Chen, Hung-Shan; Lin, Yi-Hsin; Srivastava, Abhishek K.; Chigrinov, Vladimir G.

    2015-09-01

    We have developed a bistable negative lens by integrating a polarization switch of ferroelectric liquid crystals (FLCs) with a passively anisotropic focusing element. The proposed lens not only exhibits electrically tunable bistability but also fast response time of sub-milliseconds, which leads to good candidate of optical component in optical system for medical applications. In this paper, we demonstrate an optical system consisting of two FLC phase retarders and one LC lenses that exhibits both of electrically tunable wavelength and size of exposure area. The operating principles and the experimental results are discussed. The tunable spectrum, exposure area size and tunable irradiance are illustrated. Compared to conventional lenses with mechanical movements in the medical light therapy system, our electrically switchable optical system is more practical in the portable applications of light therapy (LLLT).

  6. Characterization and comparison of two novel nanosystems associated with siRNA for cellular therapy.

    PubMed

    André, E M; Pensado, A; Resnier, P; Braz, L; Rosa da Costa, A M; Passirani, C; Sanchez, A; Montero-Menei, C N

    2016-01-30

    To direct stem cell fate, a delicate control of gene expression through small interference RNA (siRNA) is emerging as a new and safe promising strategy. In this way, the expression of proteins hindering neuronal commitment may be transiently inhibited thus driving differentiation. Mesenchymal stem cells (MSC), which secrete tissue repair factors, possess immunomodulatory properties and may differentiate towards the neuronal lineage, are a promising cell source for cell therapy studies in the central nervous system. To better drive their neuronal commitment the repressor Element-1 silencing transcription (REST) factor, may be inhibited by siRNA technology. The design of novel nanoparticles (NP) capable of safely delivering nucleic acids is crucial in order to successfully develop this strategy. In this study we developed and characterized two different siRNA NP. On one hand, sorbitan monooleate (Span(®)80) based NP incorporating the cationic components poly-l-arginine or cationized pullulan, thus allowing the association of siRNA were designed. These NP presented a small size (205 nm) and a negative surface charge (-38 mV). On the other hand, lipid nanocapsules (LNC) associating polymers with lipids and allowing encapsulation of siRNA complexed with lipoplexes were also developed. Their size was of 82 nm with a positive surface charge of +7 mV. Both NP could be frozen with appropriate cryoprotectors. Cytotoxicity and transfection efficiency at different siRNA doses were monitored by evaluating REST expression. An inhibition of around 60% of REST expression was observed with both NP when associating 250 ng/mL of siRNA-REST, as recommended for commercial reagents. Span NP were less toxic for human MSCs than LNCs, but although both NP showed a similar inhibition of REST over time and the induction of neuronal commitment, LNC-siREST induced a higher expression of neuronal markers. Therefore, two different tailored siRNA NP offering great potential for human stem cell

  7. T-cell Depleted Allogeneic Hematopoietic Cell Transplants As A Platform For Adoptive Therapy With Leukemia Selective Or Virus-Specific T-cells

    PubMed Central

    O'Reilly, Richard J.; Koehne, Gunther; Hasan, Aisha N; Doubrovina, Ekaterina; Prockop, Susan

    2016-01-01

    Allogeneic hematopoietic cell transplants adequately depleted of T-cells can reduce or prevent acute and chronic GVHD in both HLA matched and haplotype disparate hosts, without post-transplant prophylaxis with immunosuppressive drugs. Recent trials indicate that high doses of CD34+ progenitors from G-CSF mobilized peripheral blood leukocytes isolated and T-cell depleted by immunoadsorption to paramagnetic beads, when administered after myeloablative conditioning with TBI and chemotherapy or chemotherapy alone can secure consistent engraftment and abrogate GVHD in patients with acute leukemia without incurring an increased risk of a recurrent leukemia. Early clinical trials also indicate that high doses of in vitro generated leukemia reactive donor T-cells can be adoptively transferred and can induce remissions of leukemia relapse without GVHD. Similarly, virus-specific T-cells generated from the transplant donor or an HLA partially matched third party, have induced remissions of Rituxan-refractory EBV lymphomas and can clear CMV disease or viremia persisting despite antiviral therapy in a high proportion of cases. Analyses of treatment responses and failures illustrate both the advantages and limitations of donor or banked, third party derived T-cells, but underscore the potential of adoptive T-cell therapy in the absence of ongoing immunosuppression. PMID:26039207

  8. Determination of safety distance limits for a human near a cellular base station antenna, adopting the IEEE standard or ICNIRP guidelines.

    PubMed

    Cooper, Justin; Marx, Bernd; Buhl, Johannes; Hombach, Volker

    2002-09-01

    This paper investigates the minimum distance for a human body in the near field of a cellular telephone base station antenna for which there is compliance with the IEEE or ICNIRP threshold values for radio frequency electromagnetic energy absorption in the human body. First, local maximum specific absorption rates (SARs), measured and averaged over volumes equivalent to 1 and to 10 g tissue within the trunk region of a physical, liquid filled shell phantom facing and irradiated by a typical GSM 900 base station antenna, were compared to corresponding calculated SAR values. The calculation used a homogeneous Visible Human body model in front of a simulated base station antenna of the same type. Both real and simulated base station antennas operated at 935 MHz. Antenna-body distances were between 1 and 65 cm. The agreement between measurements and calculations was excellent. This gave confidence in the subsequent calculated SAR values for the heterogeneous Visible Human model, for which each tissue was assigned the currently accepted values for permittivity and conductivity at 935 MHz. Calculated SAR values within the trunk of the body were found to be about double those for the homogeneous case. When the IEEE standard and the ICNIRP guidelines are both to be complied with, the local SAR averaged over 1 g tissue was found to be the determining parameter. Emitted power values from the antenna that produced the maximum SAR value over 1 g specified in the IEEE standard at the base station are less than those needed to reach the ICNIRP threshold specified for the local SAR averaged over 10 g. For the GSM base station antenna investigated here operating at 935 MHz with 40 W emitted power, the model indicates that the human body should not be closer to the antenna than 18 cm for controlled environment exposure, or about 95 cm for uncontrolled environment exposure. These safe distance limits are for SARs averaged over 1 g tissue. The corresponding safety distance limits

  9. Syngeneic syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting.

    PubMed

    Siurala, Mikko; Vähä-Koskela, Markus; Havunen, Riikka; Tähtinen, Siri; Bramante, Simona; Parviainen, Suvi; Mathis, J Michael; Kanerva, Anna; Hemminki, Akseli

    2016-05-01

    Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 d were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target (E/T) assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8(+) T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic antitumor immunity was induced. For the first time, TIL of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors. PMID:27467954

  10. Purification of melanoma reactive T cell by using a monocyte-based solid phase T-cell selection system for adoptive therapy.

    PubMed

    Li, Jongming; Mookerjee, Bijoyesh; Wagner, John

    2008-01-01

    The generation of melanoma-reactive T cells with the characteristics necessary for in vivo effectiveness remains a considerable obstacle to the application of adoptive cell therapy. Recent clinical success with adoptive cell therapy for melanoma is motivating additional investigation to improve the technology of generating such tumor reactive lymphocytes. Here we describe a novel solid phase T-cell selection system, in which monocytes are immobilized on solid support for antigen-specific T-cell purification. We hypothesized and proved that antigen-specific T cells recognize their cognate antigens and bind to them faster than nonantigen-specific T cells and are concentrated on the surface after removing the nonadherent cells by washing. Moreover, activated antigen-specific T cells proliferated more rapidly than nonspecific T cells, further increasing the frequency and purity of antigen-specific T cells. Optimal selection times for Melan-A-specific T cells are studied. Our data demonstrated that T-cell selection can usually increase the frequency of tumor antigen-specific T cells by >10-fold, whereas T-cell expansion after the selection boost the frequency of tumor antigen-specific T cells by another approximately 10-fold. More importantly, these T cells are generated under more physiologic conditions. This new T-cell selection system is superior to traditional repeated stimulation methods in generating tumor antigen-specific T cells for adoptive cell immunotherapy. This inexpensive and simple T-cell selection system can produce large quantity of highly purified Melan-A-specific T cells within 2 weeks after T-cell activation. PMID:18157015

  11. Targeting of Mutant p53 and the Cellular Redox Balance by APR-246 as a Strategy for Efficient Cancer Therapy

    PubMed Central

    Bykov, Vladimir J. N.; Zhang, Qiang; Zhang, Meiqiongzi; Ceder, Sophia; Abrahmsen, Lars; Wiman, Klas G.

    2016-01-01

    TP53 is the most frequently mutated gene in cancer. The p53 protein activates transcription of genes that promote cell cycle arrest or apoptosis, or regulate cell metabolism, and other processes. Missense mutations in TP53 abolish specific DNA binding of p53 and allow evasion of apoptosis and accelerated tumor progression. Mutant p53 often accumulates at high levels in tumor cells. Pharmacological reactivation of mutant p53 has emerged as a promising strategy for improved cancer therapy. Small molecules that restore wild type activity of mutant p53 have been identified using various approaches. One of these molecules, APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. This dual mechanism of action may account for the striking synergy between APR-246 and platinum compounds. APR-246 is the only mutant p53-targeting compound in clinical development. A phase I/IIa clinical trial in hematological malignancies and prostate cancer showed good safety profile and clinical effects in some patients. APR-246 is currently tested in a phase Ib/II trial in patients with high-grade serous ovarian cancer. PMID:26870698

  12. The conjugates of carbon nanodots and chlorin e6 for enhancing cellular internalization and photodynamic therapy of cancers

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Wang, Xiongwei; Wang, Shimiao; Huang, Zheng; Liu, Jun

    2016-09-01

    Chlorin e6 (Ce6), a large heterocyclic aromatic molecule, is a promising photosensitizer for photodynamic therapy (PDT). We propose an efficient nano-photosensitizer delivery system based on covalent interactions between Ce6 and polyethylenimine (PEI) coated carbon nanodots (CDots). We observed  >50% Ce6 drug loading content for PEI, due to this compound’s unique ‘proton sponge effect.’ We found that the covalently incorporated Ce6 molecules retained their functional properties for near-infrared (NIR) fluorescence imaging and PDT. The chemical characteristics of CDot-PEI-Ce6 and Ce6 were evaluated using different analytical methods, including transmission electron microscopy and UV–Visible absorption spectra. Time-correlated single photon counting (TCSPC) and fluorescence spectra were used to demonstrate that Ce6 successfully conjugated to the CDots. The high cellular uptake of CDots-PEI-Ce6 was confirmed using flow cytometry and confocal laser scanning microscopy. According to the MTT assay, the CDots-PEI-Ce6 exhibited low dark toxicity and efficient PDT efficacy to HeLa cancer cells. These results indicate that CDot-PEI-Ce6 conjugates are potential photosensitizer delivery systems for PDT.

  13. Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

    PubMed

    Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2015-04-01

    Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug. PMID:25637067

  14. Immunomodulatory Effects of Different Cellular Therapies of Bone Marrow Origin on Chimerism Induction and Maintenance Across MHC Barriers in a Face Allotransplantation Model.

    PubMed

    Hivelin, Mikael; Klimczak, Aleksandra; Cwykiel, Joanna; Sonmez, Erhan; Nasir, Serdar; Gatherwright, James; Siemionow, Maria

    2016-08-01

    Many more patients would benefit from vascularized composite allotransplantation if less toxic and safer immunosuppressive protocols will become available. Tolerance induction protocols with donor cells co-transplantation are one of the promising pathways to reduce maintenance immunosupressive regimens. We investigated the role of donor bone marrow cells (BMC), mesenchymal stromal cells (MSC) and in vivo created chimeric cells (CC) used as supportive therapies in a fully MHC-mismatched rat face transplantation model. Twenty-four fully MHC-mismatched hemiface transplantations were performed between ACI (RT1(a)) donors and Lewis (RT1(l)) recipients under combined seven-day immunosuppressive regimen of anti-αβ-T-cell receptor (TCR) monoclonal antibody and cyclosporin A. We studied four experimental groups-group 1: no cellular therapy; group 2: supportive therapy with BMC; group 3: supportive therapy with MSC; group 4: supportive therapy with CC generated in a primary chimera. We evaluated clinical and histological rejection grades, transplanted cells migration, donor-specific chimerism in the peripheral blood and bone marrow compartments, and CD4(+)/CD25(+) T-cell levels. Face allograft rejection was observed at 26.8 ± 0.6 days post-transplant (PT) in the absence of cellular therapy, at 34.5 ± 1.1 days for group 2, 29.3 ± 0.8 days for group 3, and 30.3 ± 1.38 PT for group 4. The longest survival was observed in allografts supported by co-transplantation of BMC. All support in cellular therapies delayed face allograft rejection by chimerism induction and/or immunomodulatory properties of co-transplanted cells. Survival time was comparable between groups, however, further studies, with different cell dosages, delivery routes and delivery times are required. PMID:26708158

  15. Adjuvant Therapy for Resected Gastric Cancer-Rapid, Yet Incomplete Adoption Following Results of Intergroup 0116 Trial

    SciTech Connect

    Coburn, Natalie G. Guller, Ulrich; Baxter, Nancy N.; Kiss, Alex; Ringash, Jolie; Swallow, Carol J.; Law, Calvin H.L.

    2008-03-15

    Purpose: The Southwest Oncology Group/Intergroup 0116 (INT-0116) trial showed that adjuvant chemoradiotherapy improves survival in high-risk gastric adenocarcinoma patients. This study examined the adoption of adjuvant treatment following the trial results and the factors associated with its use. Methods and Materials: Between 1996 and 2003, patients aged 18-85 years with resected gastric adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results (SEER) database and classified as diagnosed before (January 1996 to April 2000) or after (May 2000 to December 2003) presentation of the INT-0116 trial findings. Univariate and multivariable models were used to determine the factors associated with use of adjuvant radiotherapy (RT). Results: Of 10,230 patients studied, 14.6% were given adjuvant RT before the INT-0116 trial, increasing to 30.4% afterward (p < 0.001). Significant increases in adjuvant RT from before to after INT-0116 were seen in all demographic categories. Younger patients were significantly more likely to receive adjuvant RT (44.5%, 18-59 years; 31.0%, 60-74 years; and 12.6%, 75-85 years, p < 0.0001). Married patients were significantly more likely to receive adjuvant RT (30.9%) than were unmarried patients (23.6%, p < 0.001). A greater depth of tumor invasion, worse nodal status, and more lymph nodes assessed were associated with adjuvant RT (p < 0.0001). The rate of adjuvant RT varied from 22.9-44.2% across SEER regions. On multiple logistic regression analysis, age, SEER region, marital status, assessed lymph nodes, tumor depth, and nodal status were all significant independent predictors of the use of adjuvant RT. Conclusion: Use of adjuvant RT doubled after the INT-0116 trial results became public; however, the fraction of patients receiving adjuvant RT is still low. Additional examination of the statistically significant and clinically relevant variability between different SEER regions, tumor characteristics, and patient

  16. [Continuous renal replacement therapies (CRRT) will remain the most widely adopted dialysis modality in the critically ill].

    PubMed

    Morabito, S; Pistolesi, V; Cibelli, L; Pierucci, A

    2009-01-01

    In the last 10-15 years, user-friendly continuous renal replacement therapy (CRRT) machines have played a major role in increasing the popularity of these techniques in intensive care settings. At present it is not clear which modality of renal replacement therapy (RRT) is optimal for critically ill patients with acute kidney injury (AKI). The choice between different modalities should therefore not be based on unproven ''outcome'' advantages but on evaluation of the clinical picture and logistical circumstances. In hypercatabolic patients, CRRT and sustained low-efficiency dialysis (SLED) have been shown to provide similar metabolic control, but uncontrolled studies suggested a better hemodynamic stability during CRRT, intended as a higher mean arterial pressure and/or less frequent need to increase inotropic or vasoactive drugs. The incidence of hemorrhagic complications is higher with CRRT; however, in particular conditions, such as in patients at high risk of bleeding, CRRT can be performed without anticoagulation or with the use of alternative anticoagulation protocols. Among the different modalities, regional anticoagulation with citrate appears to be the most promising, and the continuous development of simplified protocols for citrate CRRT might facilitate the more extensive use of this technique in the near future. The presence of a mismatch between prescribed and delivered dialysis dose is frequently reported as an important drawback of CRRT. However, data from a recent study designed to evaluate the prognostic impact of the intensity of renal support in critically ill patients with AKI showed that the target Kt/V was obtained in only 67-69% of intermittent hemodialysis (IHD) sessions. Data from several studies comparing the costs of different RRT modalities showed that CRRT is more expensive than IHD or SLED. However, the costs related to SLED can fluctuate within a wide range and in particular settings the higher costs of CRRT could be partially

  17. Theoretical aspects and modelling of cellular decision making, cell killing and information-processing in photodynamic therapy of cancer

    PubMed Central

    2013-01-01

    Background The aim of this report is to provide a mathematical model of the mechanism for making binary fate decisions about cell death or survival, during and after Photodynamic Therapy (PDT) treatment, and to supply the logical design for this decision mechanism as an application of rate distortion theory to the biochemical processing of information by the physical system of a cell. Methods Based on system biology models of the molecular interactions involved in the PDT processes previously established, and regarding a cellular decision-making system as a noisy communication channel, we use rate distortion theory to design a time dependent Blahut-Arimoto algorithm where the input is a stimulus vector composed of the time dependent concentrations of three PDT related cell death signaling molecules and the output is a cell fate decision. The molecular concentrations are determined by a group of rate equations. The basic steps are: initialize the probability of the cell fate decision, compute the conditional probability distribution that minimizes the mutual information between input and output, compute the cell probability of cell fate decision that minimizes the mutual information and repeat the last two steps until the probabilities converge. Advance to the next discrete time point and repeat the process. Results Based on the model from communication theory described in this work, and assuming that the activation of the death signal processing occurs when any of the molecular stimulants increases higher than a predefined threshold (50% of the maximum concentrations), for 1800s of treatment, the cell undergoes necrosis within the first 30 minutes with probability range 90.0%-99.99% and in the case of repair/survival, it goes through apoptosis within 3-4 hours with probability range 90.00%-99.00%. Although, there is no experimental validation of the model at this moment, it reproduces some patterns of survival ratios of predicted experimental data. Conclusions

  18. A Bayesian adaptive phase 1 design to determine the optimal dose and schedule of an adoptive T-cell therapy in a mixed patient population.

    PubMed

    Quintana, Melanie; Li, Daniel H; Albertson, Tina M; Connor, Jason T

    2016-05-01

    We present a novel Bayesian adaptive phase 1 design to determine the optimal dosing regimen for an adoptive T-cell therapy in a mixed patient population. Our design is motivated by a B-cell Non-Hodgkin Lymphoma trial evaluating multiple dosing regimens within multiple disease subtypes. A utility score is calculated from both safety and efficacy utility functions and used to guide dose-escalation decisions. We pool safety data across disease subtypes and use a single dose-toxicity model while sharing efficacy information between disease subtypes using a hierarchical dose-response model. In addition, an adaptive randomization approach is applied to dynamically assign patients to a regimen when more than one regimen is open for enrollment. We illustrate this study design through a simulated trial example, and we investigate the operating characteristics using simulation studies. PMID:27109037

  19. Near-Infrared Imaging of Adoptive Immune Cell Therapy in Breast Cancer Model Using Cell Membrane Labeling

    PubMed Central

    Youniss, Fatma M.; Sundaresan, Gobalakrishnan; Graham, Laura J.; Wang, Li; Berry, Collin R.; Dewkar, Gajanan K.; Jose, Purnima; Bear, Harry D.; Zweit, Jamal

    2014-01-01

    The overall objective of this study is to non-invasively image and assess tumor targeting and retention of directly labeled T-lymphocytes following their adoptive transfer in mice. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in-vitro with Bryostatin/Ionomycin for 18 hours, and were grown in the presence of Interleukin-2 for 6 days. T-lymphocytes were then directly labeled with 1,1-dioctadecyltetramethyl indotricarbocyanine Iodide (DiR), a lipophilic near infrared fluorescent dye that labels the cell membrane. Assays for viability, proliferation, and function of labeled T-lymphocytes showed that they were unaffected by DiR labeling. The DiR labeled cells were injected via tail vein in mice bearing 4T1 tumors in the flank. In some cases labeled 4T1 specific T-lymphocytes were injected a week before 4T1 tumor cell implantation. Multi-spectral in vivo fluorescence imaging was done to subtract the autofluorescence and isolate the near infrared signal carried by the T-lymphocytes. In recipient mice with established 4T1 tumors, labeled 4T1 specific T-lymphocytes showed marked tumor retention, which peaked 6 days post infusion and persisted at the tumor site for up to 3 weeks. When 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes, T-lymphocytes responded to the immunologic challenge and accumulated at the site of 4T1 cell implantation within two hours and the signal persisted for 2 more weeks. Tumor accumulation of labeled 4T1 specific T-lymphocytes was absent in mice bearing Meth A sarcoma tumors. When lysate of 4T1 specific labeled T-lymphocytes was injected into 4T1 tumor bearing mice the near infrared signal was not detected at the tumor site. In conclusion, our validated results confirm that the near infrared signal detected at the tumor site represents the DiR labeled 4T1 specific viable T-lymphocytes and their response to immunologic challenge can be imaged in

  20. Intra-operative preparation of autologous bone marrow-derived CD34-enriched cellular products for cardiac therapy

    PubMed Central

    DONNENBERG, ALBERT D.; DONNENBERG, VERA S.; GRIFFIN, DEBORAH L.; MOORE, LINDA R.; TEKINTURHAN, FERDA; KORMOS, ROBERT L.

    2014-01-01

    Background and Aims With the advent of regenerative therapy, there is renewed interest in the use of bone marrow as a source of adult stem and progenitor cells, including cell subsets prepared by immunomagnetic selection. Cell selection must be rapid, efficient and performed according to current good manufacturing practices. In this report we present a methodology for intra-operative preparation of CD34+ selected autologous bone marrow for autologous use in patients receiving coronary artery bypass grafts or left ventricular assist devices. Methods and Results We developed a rapid erythrocyte depletion method using hydroxyethyl starch and low-speed centrifugation to prepare large-scale (mean 359 mL) bone marrow aspirates for separation on a Baxter Isolex 300i immunomagnetic cell separation device. CD34 recovery after erythrocyte depletion was 68.3 ± 20.2%, with an average depletion of 91.2 ± 2.8% and an average CD34 content of 0.58 ± 0.27%. After separation, CD34 purity was 64.1 ± 17.2%, with 44.3 ± 26.1% recovery and an average dose of 5.0 ± 2.7 × 10 6 CD34+ cells/product. In uncomplicated cases CD34-enriched cellular products could be accessioned, prepared, tested for release and administered within 6 h. Further analysis of CD34+ bone marrow cells revealed a significant proportion of CD45– CD34+ cells. Conclusions Intra-operative immunomagnetic separation of CD34-enriched bone marrow is feasible using rapid low-speed Hetastarch sedimentation for erythrocyte depletion. The resulting CD34-enriched product contains CD45– cells that may represent non-hematopoietic or very early hematopoietic stem cells that participate in tissue regeneration. PMID:21062114

  1. Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases.

    PubMed

    Ciccocioppo, Rachele; Cangemi, Giuseppina Cristina; Kruzliak, Peter; Corazza, Gino Roberto

    2016-06-01

    Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. Stem Cells 2016;34:1474-1486. PMID:27016400

  2. Dose point kernel for boron-11 decay and the cellular S values in boron neutron capture therapy

    SciTech Connect

    Ma Yunzhi; Geng Jinpeng; Gao Song; Bao Shanglian

    2006-12-15

    The study of the radiobiology of boron neutron capture therapy is based on the cellular level dosimetry of boron-10's thermal neutron capture reaction {sup 10}B(n,{alpha}){sup 7}Li, in which one 1.47 MeV helium-4 ion and one 0.84 MeV lithium-7 ion are spawned. Because of the chemical preference of boron-10 carrier molecules, the dose is heterogeneously distributed in cells. In the present work, the (scaled) dose point kernel of boron-11 decay, called {sup 11}B-DPK, was calculated by GEANT4 Monte Carlo simulation code. The DPK curve drops suddenly at the radius of 4.26 {mu}m, the continuous slowing down approximation (CSDA) range of a lithium-7 ion. Then, after a slight ascending, the curve decreases to near zero when the radius goes beyond 8.20 {mu}m, which is the CSDA range of a 1.47 MeV helium-4 ion. With the DPK data, S values for nuclei and cells with the boron-10 on the cell surface are calculated for different combinations of cell and nucleus sizes. The S value for a cell radius of 10 {mu}m and a nucleus radius of 5 {mu}m is slightly larger than the value published by Tung et al. [Appl. Radiat. Isot. 61, 739-743 (2004)]. This result is potentially more accurate than the published value since it includes the contribution of a lithium-7 ion as well as the alpha particle.

  3. Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer’s Disease

    PubMed Central

    McGinley, Lisa M.; Sims, Erika; Lunn, J. Simon; Kashlan, Osama N.; Chen, Kevin S.; Bruno, Elizabeth S.; Pacut, Crystal M.; Hazel, Tom; Johe, Karl; Sakowski, Stacey A.

    2016-01-01

    Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar “best in class” cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD. Significance There is no cure for Alzheimer’s disease (AD) and

  4. Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors

    PubMed Central

    Eom, Hyeon-Seok; Choi, Beom K.; Lee, Youngjoo; Lee, Hyewon; Yun, Tak; Kim, Young H.; Lee, Je-Jung

    2016-01-01

    Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8+ T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8+ T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8+ T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4–8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy. PMID:26938947

  5. Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors.

    PubMed

    Eom, Hyeon-Seok; Choi, Beom K; Lee, Youngjoo; Lee, Hyewon; Yun, Tak; Kim, Young H; Lee, Je-Jung; Kwon, Byoung S

    2016-04-01

    Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy. PMID:26938947

  6. Psychological Ramifications of Adoption and Implications for Counseling.

    ERIC Educational Resources Information Center

    Helwig, Andrew A.; Ruthven, Dorothy H.

    1990-01-01

    Examines adoption issues including family member loss, infertility, transracial adoptions, special-needs adoptions, older child adoption, inherited traits, adoptive family, biological parents, and open adoption. Suggests specific therapeutic interventions including redefinition, use of paradox, family therapy approaches, group therapy, and…

  7. Raising the standard: changes to the Australian Code of Good Manufacturing Practice (cGMP) for human blood and blood components, human tissues and human cellular therapy products.

    PubMed

    Wright, Craig; Velickovic, Zlatibor; Brown, Ross; Larsen, Stephen; Macpherson, Janet L; Gibson, John; Rasko, John E J

    2014-04-01

    In Australia, manufacture of blood, tissues and biologicals must comply with the federal laws and meet the requirements of the Therapeutic Goods Administration (TGA) Manufacturing Principles as outlined in the current Code of Good Manufacturing Practice (cGMP). The Therapeutic Goods Order (TGO) No. 88 was announced concurrently with the new cGMP, as a new standard for therapeutic goods. This order constitutes a minimum standard for human blood, tissues and cellular therapeutic goods aimed at minimising the risk of infectious disease transmission. The order sets out specific requirements relating to donor selection, donor testing and minimisation of infectious disease transmission from collection and manufacture of these products. The Therapeutic Goods Manufacturing Principles Determination No. 1 of 2013 references the human blood and blood components, human tissues and human cellular therapy products 2013 (2013 cGMP). The name change for the 2013 cGMP has allowed a broadening of the scope of products to include human cellular therapy products. It is difficult to directly compare versions of the code as deletion of some clauses has not changed the requirements to be met, as they are found elsewhere amongst the various guidelines provided. Many sections that were specific for blood and blood components are now less prescriptive and apply to a wider range of cellular therapies, but the general overall intent remains the same. Use of 'should' throughout the document instead of 'must' allows flexibility for alternative processes, but these systems will still require justification by relevant logical argument and validation data to be acceptable to TGA. The cGMP has seemingly evolved so that specific issues identified at audit over the last decade have now been formalised in the new version. There is a notable risk management approach applied to most areas that refer to process justification and decision making. These requirements commenced on 31 May 2013 and a 12 month

  8. Serial Low Doses of Sorafenib Enhance Therapeutic Efficacy of Adoptive T Cell Therapy in a Murine Model by Improving Tumor Microenvironment

    PubMed Central

    Liu, Ren-Shyan; Hwang, Jeng-Jong

    2014-01-01

    Requirements of large numbers of transferred T cells and various immunosuppressive factors and cells in the tumor microenvironment limit the applications of adoptive T cells therapy (ACT) in clinic. Accumulating evidences show that chemotherapeutic drugs could act as immune supportive instead of immunosuppressive agents when proper dosage is used, and combined with immunotherapy often results in better treatment outcomes than monotherapy. Controversial immunomodulation effects of sorafenib, a multi-kinases inhibitor, at high and low doses have been reported in several types of cancer. However, what is the range of the low-dose sorafenib will influence the host immunity and responses of ACT is still ambiguous. Here we used a well-established E.G7/OT-1 murine model to understand the effects of serial low doses of sorafenib on both tumor microenvironment and transferred CD8+ T cells and the underlying mechanisms. Sorafenib lowered the expressions of immunosuppressive factors, and enhanced functions and migrations of transferred CD8+ T cells through inhibition of STAT3 and other immunosuppressive factors. CD8+ T cells were transduced with granzyme B promoter for driving imaging reporters to visualize the activation and distribution of transferred CD8+ T cells prior to adoptive transfer. Better activations of CD8+ T cells and tumor inhibitions were found in the combinational group compared with CD8+ T cells or sorafenib alone groups. Not only immunosuppressive factors but myeloid derived suppressive cells (MDSCs) and regulatory T cells (Tregs) were decreased in sorafenib-treated group, indicating that augmentation of tumor inhibition and function of CD8+ T cells by serial low doses of sorafenib were via reversing the immunosuppressive microenvironment. These results revealed that the tumor inhibitions of sorafenib not only through eradicating tumor cells but modifying tumor microenvironment, which helps outcomes of ACT significantly. PMID:25333973

  9. Optimized human CYP4B1 in combination with the alkylator prodrug 4-ipomeanol serves as a novel suicide gene system for adoptive T-cell therapies.

    PubMed

    Roellecke, K; Virts, E L; Einholz, R; Edson, K Z; Altvater, B; Rossig, C; von Laer, D; Scheckenbach, K; Wagenmann, M; Reinhardt, D; Kramm, C M; Rettie, A E; Wiek, C; Hanenberg, H

    2016-07-01

    Engineering autologous or allogeneic T cells to express a suicide gene can control potential toxicity in adoptive T-cell therapies. We recently reported the development of a novel human suicide gene system that is based on an orphan human cytochrome P450 enzyme, CYP4B1, and the naturally occurring alkylator prodrug 4-ipomeanol. The goal of this study was to systematically develop a clinically applicable self-inactivating lentiviral vector for efficient co-expression of CYP4B1 as an ER-located protein with two distinct types of cell surface proteins, either MACS selection genes for donor lymphocyte infusions after allogeneic stem cell transplantation or chimeric antigen receptors for retargeting primary T cells. The U3 region of the myeloproliferative sarcoma virus in combination with the T2A site was found to drive high-level expression of our CYP4B1 mutant with truncated CD34 or CD271 as MACS suitable selection markers. This lentiviral vector backbone was also well suited for co-expression of CYP4B1 with a codon-optimized CD19 chimeric antigen receptor (CAR) construct. Finally, 4-ipomeanol efficiently induced apoptosis in primary T cells that co-express mutant CYP4B1 and the divergently located MACS selection and CAR genes. In conclusion, we here developed a clinically suited lentiviral vector that supports high-level co-expression of cell surface proteins with a potent novel human suicide gene. PMID:27092941

  10. CASMI TSCC Launch Event, Paris, France, July 2013: An Assessment of the Key Barriers to the Commercialization and Clinical Adoption of Pluripotent Stem Cell Therapies*

    PubMed Central

    Bure, Kim; Brindley, David A.

    2014-01-01

    Abstract The high incidence of unmet medical needs in combination with the rising burden of chronic diseases, linked to an increasingly aging population, necessitates new approaches to therapeutic intervention. One potential class of health care innovation that may offer an alternative approach to addressing current shortfalls is stem cell therapies. The CASMI Translational Stem Cell Consortium (CTSCC) was formed to elucidate the key hurdles to the commercialization and clinical adoption of stem cell technologies, with a particular focus on pluripotent stem cell (PSC) technologies. As a global pre-competitive academic–industry consortium, the CTSCC unites thought leaders from a range of sectors and technical specialties in defining and discovering solutions to roadblocks that will impede the field. Targeted toward stakeholder requirements at the delivery end of the translational spectrum, the CTSCC aims to provide mechanisms for multidirectional dialogue and to produce academically rigorous and commercially practicable research outputs to accelerate industry progress. On the 30th and 31st of July, 2013, the CASMI Translational Stem Cell Consortium (CTSCC) held a launch event at the Saint James Club, Paris, France. PMID:24392658

  11. The weal and woe of costimulation in the adoptive therapy of cancer with chimeric antigen receptor (CAR)-redirected T cells.

    PubMed

    Hombach, A A; Holzinger, A; Abken, H

    2013-08-01

    Adoptive cell therapy has shown impressive efficacy to combat cancer in early phase clinical trials, in particular when T cells engineered to specifically target tumor cells were applied. The patient's T cells are genetically equipped with a chimeric antigen receptor (CAR) which allows them to be redirected in a predefined manner towards virtually any target; by using an antibody-derived domain for binding, CAR T cells can be redirected in a major histocompatibility complex (MHC) dependent and independent fashion. The CAR also provides the stimuli required to induce and maintain T cell activation. Recent clinical data sustain the notion that strong costimulation in conjunction with the primary activation signal is crucial for lasting therapeutic efficacy of CAR T cells. However, costimulation is a double-edged sword and the impact of the individual costimuli to optimize T cell activation is still under debate; some general rules are emerging. The review summarizes how costimulation modulates, improves and prolongs the redirected anti-tumor T cell response and how the same costimulatory signals may contribute to unintended side effects including "cytokine storm" and T cell repression. Upcoming strategies to break the activation/repression circle by using CAR's with modified costimulatory signals are also discussed. PMID:23116267

  12. Medical Therapies with Adult Stem/Progenitor Cells (MSCs): A Backward Journey from Dramatic Results in Vivo to the Cellular and Molecular Explanations

    PubMed Central

    Prockop, Darwin J.; Oh, Joo Youn

    2012-01-01

    There is currently great interest in the use of mesenchymal stem/stromal cells (MSCs) for the therapy of many diseases of animals and humans. However, we are still left with the serious challenges in explaining the beneficial effects of the cells. Hence, it is essential to work backward from dramatic results obtained in vivo to the cellular and molecular explanations in order to discover the secrets of MSCs. This review will focus on recent data that have changed the paradigms for understanding the therapeutic potentials of MSCs. PMID:22213121

  13. State-of-the-art on basic and applied stem cell therapy; Stem Cell Research Italy-International Society for Cellular Therapy Europe, Joint Meeting, Montesilvano (PE)-Italy, June 10-12, 2011.

    PubMed

    Siniscalco, Dario; Pandolfi, Assunta; Galderisi, Umberto

    2012-03-20

    Over 160 stem cell-based therapeutic products are undergoing development for the treatment of several diseases, ranging from cardiac and artery diseases to immune and neurodegenerative pathologies, including diabetes, spinal cord injury. Therefore, stem cell therapy plays a key role for developing new cell-based drugs for the future molecular and regenerative medicine. The second meeting organized by Stem Cell Research Italy (SCR Italy) and by the International Society for Cellular Therapy-Europe (ISCT) in Montesilvano/Città S. Angelo (Pescara)-Italy, on June 10th-12th, 2011, focused on the state-of-the-art of stem cell therapy and associated novel findings on stem cell research ( www.stemcellitaly.org ). PMID:22035042

  14. Adoption of Preoperative Radiation Therapy for Rectal Cancer From 2000 to 2006: A Surveillance, Epidemiology, and End Results Patterns-of-Care Study

    SciTech Connect

    Mak, Raymond H.; McCarthy, Ellen P.; Das, Prajnan; Hong, Theodore S.; Mamon, Harvey J.

    2011-07-15

    Purpose: The German rectal study determined that preoperative radiation therapy (RT) as a component of combined-modality therapy decreased local tumor recurrence, increased sphincter preservation, and decreased treatment toxicity compared with postoperative RT for rectal cancer. We evaluated the use of preoperative RT after the presentation of the landmark German rectal study results and examined the impact of tumor and sociodemographic factors on receiving preoperative RT. Methods and Materials: In total, 20,982 patients who underwent surgical resection for T3-T4 and/or node-positive rectal adenocarcinoma diagnosed from 2000 through 2006 were identified from the Surveillance, Epidemiology, and End Results tumor registries. We analyzed trends in preoperative RT use before and after publication of the findings from the German rectal study. We also performed multivariate logistic regression to identify factors associated with receiving preoperative RT. Results: Among those treated with RT, the proportion of patients treated with preoperative RT increased from 33.3% in 2000 to 63.8% in 2006. After adjustment for age; gender; race/ethnicity; marital status; Surveillance, Epidemiology, and End Results registry; county-level education; T stage; N stage; tumor size; and tumor grade, there was a significant association between later year of diagnosis and an increase in preoperative RT use (adjusted odds ratio, 1.26/y increase; 95% confidence interval, 1.23-1.29). When we compared the years before and after publication of the German rectal study (2000-2003 vs. 2004-2006), patients were more likely to receive preoperative RT than postoperative RT in 2004-2006 (adjusted odds ratio, 2.35; 95% confidence interval, 2.13-2.59). On multivariate analysis, patients who were older, who were female, and who resided in counties with lower educational levels had significantly decreased odds of receiving preoperative RT. Conclusions: After the publication of the landmark German rectal

  15. Preliminary study on forming microbubble-surrounded cells as carriers for cellular therapy and evaluation of ultrasound controllability by fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Demachi, Fumi; Murayama, Yuta; Hosaka, Naoto; Mochizuki, Takashi; Masuda, Kohji; Enosawa, Shin; Chiba, Toshio; Oda, Yusuke; Suzuki, Ryo; Maruyama, Kazuo

    2015-07-01

    Although various cellular immune therapies have been proposed and developed, because the therapeutic cells disperse upon injection into blood flow, there is a limitation on the accumulation of the cells to the target area. We previously reported our attempts to actively control microbubbles in artificial blood vessels, and here we propose a new method of carrying therapeutic cells for cellular therapy using microbubbles and ultrasound. When microbubbles and their aggregations attach to the surface of therapeutic cells, the acoustic force needed to propel the cells is increased because of the size expansion and the boundary in acoustic impedance on the cell surface. We fabricated a cylindrical chamber including two ultrasound transducers to emit a suspension of microbubbles (TF-BLs, transferrin-bubble liposomes) on the cells (Colon-26) to enhance the adhesion of microbubbles on the cells. We found that the optimum conditions for producing BL-surrounded cells were a sound pressure of 100 kPa-pp, an exposure time of 30 s, and a TF-BL concentration of 0.33 mg lipid/mL, when the cell concentration was constant at 0.77 × 105/mL in phosphate-buffered saline. Using these BL-surrounded cells, we confirmed the controllability of the cells under ultrasound exposure, where the displacement increased in proportion to the sound pressure and was not confirmed with the original cells.

  16. ASGE Bariatric Endoscopy Task Force systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting endoscopic bariatric therapies.

    PubMed

    Abu Dayyeh, Barham K; Kumar, Nitin; Edmundowicz, Steven A; Jonnalagadda, Sreenivasa; Larsen, Michael; Sullivan, Shelby; Thompson, Christopher C; Banerjee, Subhas

    2015-09-01

    The increasing global burden of obesity and its associated comorbidities has created an urgent need for additional treatment options to fight this pandemic. Endoscopic bariatric therapies (EBTs) provide an effective and minimally invasive treatment approach to obesity that would increase treatment options beyond surgery, medications, and lifestyle measures. This systematic review and meta-analysis were performed by the American Society for Gastrointestinal Endoscopy (ASGE) Bariatric Endoscopy Task Force comprising experts in the subject area and the ASGE Technology Committee Chair to specifically assess whether acceptable performance thresholds outlined by an ASGE Preservation and Incorporation of Valuable endoscopic Innovations (PIVI) document for clinical adoption of available EBTs have been met. After conducting a comprehensive search of several English-language databases, we performed direct meta-analyses by using random-effects models to assess whether the Orbera intragastric balloon (IGB) (Apollo Endosurgery, Austin, Tex) and the EndoBarrier duodenal-jejunal bypass sleeve (DJBS) (GI Dynamics, Lexington, Mass) have met the PIVI thresholds. The meta-analyses results indicate that the Orbera IGB meets the PIVI thresholds for both primary and nonprimary bridge obesity therapy. Based on a meta-analysis of 17 studies including 1683 patients, the percentage of excess weight loss (%EWL) with the Orbera IGB at 12 months was 25.44% (95% confidence interval [CI], 21.47%-29.41%) (random model) with a mean difference in %EWL over controls of 26.9% (95% CI, 15.66%-38.24%; P ≤ .01) in 3 randomized, controlled trials. Furthermore, the pooled percentage of total body weight loss (% TBWL) after Orbera IGB implantation was 12.3% (95% CI, 7.9%–16.73%), 13.16% (95% CI, 12.37%–13.95%), and 11.27% (95% CI, 8.17%–14.36%) at 3, 6, and 12 months after implantation, respectively, thus exceeding the PIVI threshold of 5% TBWL for nonprimary (bridge) obesity therapy. With the data

  17. Pharmacological Screening Using an FXN-EGFP Cellular Genomic Reporter Assay for the Therapy of Friedreich Ataxia

    PubMed Central

    Li, Lingli; Voullaire, Lucille; Sandi, Chiranjeevi; Pook, Mark A.

    2013-01-01

    Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol. PMID:23418481

  18. The role of nutraceuticals in pancreatic cancer prevention and therapy: Targeting cellular signaling, miRNAs and epigenome

    PubMed Central

    Li, Yiwei; Go, Vay Liang W.; Sarkar, Fazlul H.

    2014-01-01

    Pancreatic cancer is one of the most aggressive malignancies in US adults. The experimental studies have found that antioxidant nutrients could reduce oxidative DNA damage, suggesting that these antioxidants may protect against pancreatic carcinogenesis. Several epidemiologic studies showed that dietary intake of antioxidants was inversely associated with the risk of pancreatic cancer, demonstrating the inhibitory effects of antioxidants on pancreatic carcinogenesis. Moreover, nutraceuticals, the anti-cancer agents from diet or natural plants, have been found to inhibit the development and progression of pancreatic cancer through the regulation of cellular signaling pathways. Importantly, nutraceuticals also up-regulate the expression of tumor suppressive miRNAs and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of pancreatic cancer cell growth and pancreatic Cancer Stem Cell (CSC) self-renewal through modulation of cellular signaling network. Furthermore, nutraceuticals also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in pancreatic cancer cells. Therefore, nutraceuticals could have much broader use in the prevention and/or treatment of pancreatic cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of nutraceuticals in the prevention and/or treatment of pancreatic cancer. PMID:25493373

  19. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia.

    PubMed

    Skavland, J; Jørgensen, K M; Hadziavdic, K; Hovland, R; Jonassen, I; Bruserud, O; Gjertsen, B T

    2011-02-01

    Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial. PMID:22829110

  20. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

    PubMed Central

    Skavland, J; Jørgensen, K M; Hadziavdic, K; Hovland, R; Jonassen, I; Bruserud, Ø; Gjertsen, B T

    2011-01-01

    Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial. PMID:22829110

  1. Integrative approach in prevention and therapy of basal cellular carcinoma by association of three actives loaded into lipid nanocarriers.

    PubMed

    Badea, Gabriela; Lacatusu, Ioana; Ott, Cristina; Badea, Nicoleta; Grafu, Iulia; Meghea, Aurelia

    2015-06-01

    Basal cell carcinoma (BCC) is one of the commonest malignancies occurred on sun-exposed skin, mainly by UV-B radiation, of lighter-skinned individuals. The aim of the present study was to develop advanced drug delivery formulations used in BCC therapy that overcomes chemotherapy-induced side-effects of skin photosensitivity by an integrative approach of nanoencapsulation in conjunction with combination therapy that uses chemotherapeutic, chemoprotective and sunscreen agents. The combination of anticancer drug together with sunscreen agent is very useful in therapy, especially for individuals who are more exposed to the sun without using a sunscreen. Nanostructured lipid carriers (NLCs) employed as drug delivery systems were co-loaded with 5-fluorouracil (5-FU), a hydrophilic chemotherapeutic drug, and ethylhexyl salicylate (EHS), a lipophilic UV-B sunscreen agent. The NLCs were developed using bioactive squalene (50.8% w/w) from amaranth seed oil as chemoprotective agent. By varying the concentrations of 5-FU and EHS, the co-loaded NLCs presented particle sizes of about 100nm, acceptable physical stability with values smaller than -25mV and appropriate entrapment efficiency that reaches values over 65% for both types of drugs. The UV-B blocking ability of EHS loaded into NLCs were influenced by the concentration of 5-FU. The amaranth oil offered a capacity of 70% in scavenging the free radicals. In vitro drug release showed that NLCs presented sustained release of 5-FU that followed the Fick's law of diffusion. PMID:25828466

  2. Scotblood 2015: Improving and delivering blood products, novel cellular therapies, and celebrating patients and donor engagement within transfusion services.

    PubMed

    Colligan, David; McGowan, Neil; Seghatchian, Jerard

    2016-08-01

    Blood Transfusion Services are striving to continually improve the efficacy and quality of their blood products whilst also simultaneously diversifying into novel cellular products. For this to be successful the relationships between the various arms of the organisation must be strong and interlinked. As new technologies impact on the products that blood transfusion services supply it should be noted that the interaction between the service and its donor base is also affected by advancing technologies. Social media has fundamentally altered the way in which the public can access information and news, as such blood services must engage and interact appropriately with these new forms of media. As a reflection of these challenges the Scotblood 2015 programme was focussed on service and product improvement, donor engagement and people centred transfusion. This commentary comprises summaries of the presentations, based in part on the abstracts provided by the speakers. PMID:27524267

  3. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure.

    PubMed

    Madonna, Rosalinda; Van Laake, Linda W; Davidson, Sean M; Engel, Felix B; Hausenloy, Derek J; Lecour, Sandrine; Leor, Jonathan; Perrino, Cinzia; Schulz, Rainer; Ytrehus, Kirsti; Landmesser, Ulf; Mummery, Christine L; Janssens, Stefan; Willerson, James; Eschenhagen, Thomas; Ferdinandy, Péter; Sluijter, Joost P G

    2016-06-14

    Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair. PMID:27055812

  4. Immunostimulatory properties and enhanced TNF- α mediated cellular immunity for tumor therapy by C60(OH)20 nanoparticles

    NASA Astrophysics Data System (ADS)

    Liu, Ying; Jiao, Fang; Qiu, Yang; Li, Wei; Qu, Ying; Tian, Chixia; Li, Yufeng; Bai, Ru; Lao, Fang; Zhao, Yuliang; Chai, Zhifang; Chen, Chunying

    2009-10-01

    Publications concerning the mechanism of biological activity, especially the immunological mechanism of C60(OH)20 nanoparticles, are relatively limited. However, the structure and characteristics of this carbon allotrope have been widely investigated. In this paper, we have demonstrated that water-soluble C60(OH)20 nanoparticles have an efficient anti-tumor activity in vivo, and show specific immunomodulatory effects to the immune cells, such as T cells and macrophages, both in vivo and in vitro. For example, C60(OH)20 nanoparticles can increase the production of T-helper cell type 1 (Th1) cytokines (IL-2, IFN- γ and TNF-α), and decrease the production of Th2 cytokines (IL-4, IL-5 and IL-6) in serum samples. On the other hand, C60(OH)20 nanoparticles show almost no adverse effect to the viability of immune cells in vitro but stimulate the immune cells to release more cytokines, in particular TNF- α, which plays a key role in the cellular immune process to help eliminate abnormal cells. TNF- α production increased almost three-fold in treated T lymphocytes and macrophages. Accordingly, we conclude that C60(OH)20 nanoparticles have an efficient anti-tumor activity and this effect is associated with an increased CD4+/CD8+ lymphocyte ratio and the enhancement of TNF- α production. The data suggest that C60(OH)20 nanoparticles can improve the immune response to help to scavenge and kill tumor cells.

  5. Choline molecular imaging with small-animal PET for monitoring tumor cellular response to photodynamic therapy of cancer

    NASA Astrophysics Data System (ADS)

    Fei, Baowei; Wang, Hesheng; Wu, Chunying; Meyers, Joseph; Xue, Liang-Yan; MacLennan, Gregory; Schluchter, Mark

    2009-02-01

    We are developing and evaluating choline molecular imaging with positron emission tomography (PET) for monitoring tumor response to photodynamic therapy (PDT) in animal models. Human prostate cancer (PC-3) was studied in athymic nude mice. A second-generation photosensitizer Pc 4 was used for PDT in tumor-bearing mice. MicroPET images with 11C-choline were acquired before PDT and 48 h after PDT. Time-activity curves of 11C-choline uptake were analyzed before and after PDT. For treated tumors, normalized choline uptake decreased significantly 48 h after PDT, compared to the same tumors pre-PDT (p <~ 0.001). However, for the control tumors, normalized choline uptake increased significantly (p <~ 0.001). PET imaging with 11C-choline is sensitive to detect early tumor response to PDT in the animal model of human prostate cancer.

  6. Modular adeno-associated virus (rAAV) vectors used for cellular virus-directed enzyme prodrug therapy.

    PubMed

    Hagen, Sven; Baumann, Tobias; Wagner, Hanna J; Morath, Volker; Kaufmann, Beate; Fischer, Adrian; Bergmann, Stefan; Schindler, Patrick; Arndt, Katja M; Müller, Kristian M

    2014-01-01

    The pre-clinical and clinical development of viral vehicles for gene transfer increased in recent years, and a recombinant adeno-associated virus (rAAV) drug took center stage upon approval in the European Union. However, lack of standardization, inefficient purification methods and complicated retargeting limit general usability. We address these obstacles by fusing rAAV-2 capsids with two modular targeting molecules (DARPin or Affibody) specific for a cancer cell-surface marker (EGFR) while simultaneously including an affinity tag (His-tag) in a surface-exposed loop. Equipping these particles with genes coding for prodrug converting enzymes (thymidine kinase or cytosine deaminase) we demonstrate tumor marker specific transduction and prodrug-dependent apoptosis of cancer cells. Coding terminal and loop modifications in one gene enabled specific and scalable purification. Our genetic parts for viral production adhere to a standardized cloning strategy facilitating rapid prototyping of virus directed enzyme prodrug therapy (VDEPT). PMID:24457557

  7. Strengthening Adoption Practice, Listening to Adoptive Families

    ERIC Educational Resources Information Center

    Atkinson, Anne; Gonet, Patricia

    2007-01-01

    In-depth interviews with 500 adoptive families who received postadoption services through Virginia's Adoptive Family Preservation (AFP) program paint a richly detailed picture of the challenges adoptive families face and what they need to sustain adoption for many years after finalization. Findings document the need for support in a variety of…

  8. Redefining Strategies to Introduce Tolerance-Inducing Cellular Therapy in Human beings to Combat Autoimmunity and Transplantation Reactions

    PubMed Central

    ten Brinke, Anja; Joosten, Irma; van Ham, S. Marieke; van Kooten, Cees; Prakken, Berent Jan

    2014-01-01

    Clinical translation of tolerance-inducing cell therapies requires a novel approach focused on innovative networks, patient involvement, and, foremost, a fundamental paradigm shift in thinking from both Academia, and Industry and Regulatory Agencies. Tolerance-inducing cell products differ essentially from conventional drugs. They are personalized and target interactive immunological networks to shift the balance toward tolerance. The human cell products are often absent or fundamentally different in animals. This creates important limitations of pre-clinical animal testing for safety and efficacy of these products and calls for novel translational approaches, which require the combined efforts of the different parties involved. Dedicated international and multidisciplinary consortia that focus on clinical translation are of utmost importance. They can help in informing and educating regulatory policy makers on the unique requirements for these cell products, ranging from pre-clinical studies in animals to in vitro human studies. In addition, they can promote reliable immunomonitoring tools. The development of tolerance-inducing cell products requires not only bench-to-bedside but also reverse translation, from bedside back to the bench. PMID:25177323

  9. Redefining Strategies to Introduce Tolerance-Inducing Cellular Therapy in Human beings to Combat Autoimmunity and Transplantation Reactions.

    PubMed

    Ten Brinke, Anja; Joosten, Irma; van Ham, S Marieke; van Kooten, Cees; Prakken, Berent Jan

    2014-01-01

    Clinical translation of tolerance-inducing cell therapies requires a novel approach focused on innovative networks, patient involvement, and, foremost, a fundamental paradigm shift in thinking from both Academia, and Industry and Regulatory Agencies. Tolerance-inducing cell products differ essentially from conventional drugs. They are personalized and target interactive immunological networks to shift the balance toward tolerance. The human cell products are often absent or fundamentally different in animals. This creates important limitations of pre-clinical animal testing for safety and efficacy of these products and calls for novel translational approaches, which require the combined efforts of the different parties involved. Dedicated international and multidisciplinary consortia that focus on clinical translation are of utmost importance. They can help in informing and educating regulatory policy makers on the unique requirements for these cell products, ranging from pre-clinical studies in animals to in vitro human studies. In addition, they can promote reliable immunomonitoring tools. The development of tolerance-inducing cell products requires not only bench-to-bedside but also reverse translation, from bedside back to the bench. PMID:25177323

  10. Application of human mesenchymal and pluripotent stem cell microcarrier cultures in cellular therapy: achievements and future direction.

    PubMed

    Chen, Allen Kuan-Liang; Reuveny, Shaul; Oh, Steve Kah Weng

    2013-11-15

    Mesenchymal stem cells (MSCs) have recently made significant progress with multiple clinical trials targeting modulation of immune responses, regeneration of bone, cartilage, myocardia, and diseases like Metachromatic leukodystrophy and Hurler syndrome. On the other hand, the use of human embryonic and induced pluripotent stem cells (hPSCs) in clinical trials is rather limited mainly due to safety issues. Only two clinical trials, retinal pigment epithelial transplantation and treatment of spinal cord injury were reported. Cell doses per treatment can range between 50,000 and 6 billion cells. The current 2-dimensional tissue culture platform can be used when low cell doses are needed and it becomes impractical when doses above 50 million are needed. This demand for future cell therapy has reinvigorated interests in the use of the microcarrier platform for generating stem cells in a scalable 3-dimensional manner. Microcarriers developed for culturing adherent cell lines in suspension have been used mainly in vaccine production and research purposes. Since MSCs grow as monolayers similar to conventional adherent cell lines, adapting MSCs to a microcarrier based expansion platform has been progressing rapidly. On the other hand, establishing a robust microcarrier platform for hPSCs is more challenging as these cells grow in multilayer colonies on extracellular matrices and are more susceptible to shear stress. This review describes properties of commercially available microcarriers developed for cultivation of anchorage dependent cells and present current achievements for expansion and differentiation of stem cells. Key issues such as microcarrier properties and coatings, cell seeding conditions, medium development and improved bioprocess parameters needed for optimal stem cell systems are discussed. PMID:23531528

  11. Immunomodulatory gene therapy in lysosomal storage disorders

    PubMed Central

    Koeberl, D.D.; Kishnani, P.S.

    2010-01-01

    Significant advances in therapy for lysosomal storage disorders have occurred with an accelerating pace over the past decade. Although enzyme replacement therapy has improved the outcome of lysosomal storage disorders, antibody responses have occurred and sometimes prevented efficacy, especially in cross-reacting immune material negative patients with Pompe disease. Preclinical gene therapy experiments have revealed the relevance of immune responses to long-term efficacy. The choice of regulatory cassette played a critical role in evading humoral and cellular immune responses to gene therapy in knockout mouse models, at least in adult animals. Liver-specific regulatory cassettes prevented antibody formation and enhanced the efficacy of gene therapy. Regulatory T cells prevented transgene directed immune responses, as shown by adoptive transfer of antigen-specific immune tolerance to enzyme therapy. Immunomodulatory gene therapy with a very low vector dose could enhance the efficacy of enzyme therapy in Pompe disease and other lysosomal storage disorders. PMID:19807648

  12. Immunomodulatory gene therapy in lysosomal storage disorders.

    PubMed

    Koeberl, Dwight D; Kishnani, Priya S

    2009-12-01

    Significant advances in therapy for lysosomal storage disorders have occurred with an accelerating pace over the past decade. Although enzyme replacement therapy has improved the outcome of lysosomal storage disorders, antibody responses have occurred and sometimes prevented efficacy, especially in cross-reacting immune material negative patients with Pompe disease. Preclinical gene therapy experiments have revealed the relevance of immune responses to long-term efficacy. The choice of regulatory cassette played a critical role in evading humoral and cellular immune responses to gene therapy in knockout mouse models, at least in adult animals. Liver-specific regulatory cassettes prevented antibody formation and enhanced the efficacy of gene therapy. Regulatory T cells prevented transgene directed immune responses, as shown by adoptive transfer of antigen-specific immune tolerance to enzyme therapy. Immunomodulatory gene therapy with a very low vector dose could enhance the efficacy of enzyme therapy in Pompe disease and other lysosomal storage disorders. PMID:19807648

  13. Medical Issues in Adoption

    MedlinePlus

    ... to Know About Zika & Pregnancy Medical Issues in Adoption KidsHealth > For Parents > Medical Issues in Adoption Print ... or emotional abuse of the child continue Agency Adoptions If you adopt through an agency, you might ...

  14. Adoptive immunotherapy against ovarian cancer.

    PubMed

    Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

    2016-01-01

    The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting. PMID:27188274

  15. HIV-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) -Mediating Antibodies Decline while NK Cell Function Increases during Antiretroviral Therapy (ART)

    PubMed Central

    Jensen, Sanne Skov; Fomsgaard, Anders; Borggren, Marie; Tingstedt, Jeanette Linnea; Gerstoft, Jan; Kronborg, Gitte; Rasmussen, Line Dahlerup; Pedersen, Court; Karlsson, Ingrid

    2015-01-01

    Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (<350 cells/μl blood) and the ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART. PMID:26696395

  16. The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders

    PubMed Central

    Merlo, Anna; Turrini, Riccardo; Dolcetti, Riccardo; Martorelli, Debora; Muraro, Elena; Comoli, Patrizia; Rosato, Antonio

    2010-01-01

    The Epstein-Barr virus has evolved a plethora of strategies to evade immune system recognition and to establish latent infection in memory B cells, where the virus resides lifelong without any consequence in the majority of individuals. However, some imbalances in the equilibrium between the inherent virus transforming properties and the host immune system can lead to the development of different tumors, such as lymphoproliferative disorders, Hodgkin’s lymphoma, Burkitt’s lymphoma, and nasopharyngeal carcinoma. The expression of viral antigens in malignant cells makes them suitable targets for immunotherapeutic approaches, which are mainly based on the ex vivo expansion of EBV-specific T cells. Indeed, the infusion of virus-specific cytotoxic T lymphocytes has proved not only to be safe and effective, but also capable of restoring or inducing a protective anti-virus immunity, which is lacking, albeit to a different extent, in every EBV-driven malignancy. The purpose of this review is to summarize the results of adoptive immunotherapy approaches for EBV-related malignancies, with particular emphasis on the immunological and virological aspects linked to the clinical responses obtained. Data collected confirm the clinical relevance of the use of EBV-specific cytotoxic T lymphocytes in the field of adoptive immunotherapy and suggest the increasing importance of this approach also against other tumors, concurrent with the increasing knowledge of the intimate and continuous interplay between the virus and the host immune system. PMID:20421267

  17. Adoption and Korea.

    ERIC Educational Resources Information Center

    Chun, Byung Hoon

    1989-01-01

    Because of Korean attitudes towards adoption and other reasons, attempts to promote intracountry adoption have met with limited success, and intercountry adoption is used as an alternative way of meeting children's needs. (RJC)

  18. Adopted Children and Discipline

    MedlinePlus

    ... a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families Media ... Your Community Healthy Children > Family Life > Family Dynamics > Adoption & Foster Care > Adopted Children & Discipline Family Life Listen ...

  19. Adoption & Foster Care

    MedlinePlus

    ... Children > Family Life > Family Dynamics > Adoption & Foster Care Adoption & Foster Care Article Body ​Each year, many children join families through adoption and foster care. These families may face unique ...

  20. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials.

    PubMed

    Galipeau, Jacques; Krampera, Mauro; Barrett, John; Dazzi, Francesco; Deans, Robert J; DeBruijn, Joost; Dominici, Massimo; Fibbe, Willem E; Gee, Adrian P; Gimble, Jeffery M; Hematti, Peiman; Koh, Mickey B C; LeBlanc, Katarina; Martin, Ivan; McNiece, Ian K; Mendicino, Michael; Oh, Steve; Ortiz, Luis; Phinney, Donald G; Planat, Valerie; Shi, Yufang; Stroncek, David F; Viswanathan, Sowmya; Weiss, Daniel J; Sensebe, Luc

    2016-02-01

    Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an "open-access" manner, such as through publication or database collection. PMID:26724220

  1. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials

    PubMed Central

    Galipeau, Jacques; Krampera, Mauro; Barrett, John; Dazzi, Francesco; Deans, Robert J.; Debruijn, Joost; Dominici, Massimo; Fibbe, Willem E.; Gee, Adrian P.; Gimble, Jeffery M.; Hematti, Peiman; Koh, Mickey B.C.; Leblanc, Katarina; Martin, Ivan; Mcniece, Ian K.; Mendicino, Michael; Oh, Steve; Ortiz, Luis; Phinney, Donald G.; Planat, Valerie; Shi, Yufang; Stroncek, David F.; Viswanathan, Sowmya; Weiss, Daniel J.; Sensebe, Luc

    2016-01-01

    Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an “open-access” manner, such as through publication or database collection. PMID:26724220

  2. Direct Toll-Like Receptor 8 signaling increases the functional avidity of human CD8+ T lymphocytes generated for adoptive T cell therapy strategies

    PubMed Central

    Chatillon, Jean-François; Hamieh, Mohamad; Bayeux, Florence; Abasq, Claire; Fauquembergue, Emilie; Drouet, Aurélie; Guisier, Florian; Latouche, Jean-Baptiste; Musette, Philippe

    2015-01-01

    Adoptive transfer of in vitro activated and expanded antigen-specific cytotoxic T lymphocytes (CTLs) is a promising therapeutic strategy for infectious diseases and cancers. Obtaining in vitro a sufficient amount of highly specific cytotoxic cells and capable of retaining cytotoxic activity in vivo remains problematic. We studied the role of Toll-Like Receptor-8 (TLR8) engagement on peripheral CTLs activated with melanoma antigen MART-1-expressing artificial antigen-presenting cells (AAPCs). After a 3-week co-culture, 3–27% of specific CTLs were consistently obtained. CTLs expressed TLR8 in the intracellular compartment and at the cell surface. Specific CTLs activated with a TLR8 agonist (CL075) 24 h before the end of the culture displayed neither any change in their production levels of molecules involved in cytotoxicity (IFN-γ, Granzyme B, and TNF-α) nor major significant change in their cell surface phenotype. However, these TLR8-stimulated lymphocytes displayed increased cytotoxic activity against specific peptide-pulsed target cells related to an increase in specific anti-melanoma CTL functional avidity. TLR8 engagement on CTLs could, therefore, be useful in different immunotherapy strategies. PMID:25866635

  3. The Family of Adoption.

    ERIC Educational Resources Information Center

    Pavao, Joyce Maguire

    This book aims to provide a broad framework within which to think about adoption as a whole system, so that everyone involved will learn to feel some empathy for the other members of the adoption process. The book, written by a family and adoption therapist who was adopted as an infant, describes predictable developmental stages and challenges for…

  4. Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer.

    PubMed

    Jin, Chuan; Fotaki, Grammatiki; Ramachandran, Mohanraj; Nilsson, Berith; Essand, Magnus; Yu, Di

    2016-01-01

    Chimeric antigen receptor (CAR) T-cell therapy is a new successful treatment for refractory B-cell leukemia. Successful therapeutic outcome depends on long-term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element, for either expression of transgenes or silencing of target genes. The insertional events of this vector into the genome of host cells are below detection level. CD19 CAR T cells engineered with a NILV-S/MAR vector have similar levels of CAR expression as T cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV-S/MAR-engineered CD19 CAR T cells exhibited similar cytotoxic capacity upon CD19(+) target cell recognition as LV-engineered T cells and are as effective in controlling tumor growth in vivo We propose that NILV-S/MAR vectors are superior to current options as they enable long-term transgene expression without the risk of insertional mutagenesis and genotoxicity. PMID:27189167

  5. Competitive potential of cellular mobile telecommunications

    SciTech Connect

    Ware, H.

    1983-02-03

    The Federal Communications Commission (FCC) has recently issued rules for the commercial operation of a telecommunications technology not previously in commercial use: the cellular mobile radio. The author has carefully considered the potential for competition between cellular systems and for competition between cellular radio and alternative communications technologies under the regulatory scheme which has been adopted by the FCC. He finds that competition between cellular and wire-line services can be viable if cellular cost and demand data are carefully tracked to avoid market congestion and if cellular or other techniques are not allowed to undercut selected local exchange rates.

  6. Questions about Adoption

    MedlinePlus

    ... Español Text Size Email Print Share Questions About Adoption Page Content Article Body What's the best way to handle my child's questions about her adoption? Many parents want to know when is the ...

  7. What's Happening in Adoption?

    ERIC Educational Resources Information Center

    Gallagher, Ursula M.

    1975-01-01

    Reviews current issues in adoption: termination of parental rights, rights of unwed fathers, subsidized adoption, the recent influx of Vietnamese children, black market babies, agency accountability in placing children, the right of the adoptee to know his biological parents. (ED)

  8. Artificial antigen presenting cells for use in adoptive immunotherapy

    PubMed Central

    Turtle, Cameron J.; Riddell, Stanley R.

    2010-01-01

    The observation that T cells can recognize and specifically eliminate cancer cells has spurred interest in the development of efficient methods to generate large numbers of T cells with specificity for tumor antigens that can be harnessed for use in cancer therapy. Recent studies have demonstrated that during encounter with tumor antigen, the signals delivered to T cells by professional antigen presenting cells can affect T cell programming and their subsequent therapeutic efficacy. This has stimulated efforts to develop artificial antigen presenting cells that allow optimal control over the signals provided to T cells. In this review, we will discuss the advantages and disadvantages of cellular and acellular artificial antigen presenting cell systems and their use in T cell adoptive immunotherapy for cancer. PMID:20693850

  9. Single Parent Adoptive Homes.

    ERIC Educational Resources Information Center

    Shireman, Joan F.

    1996-01-01

    Reviews research and reports on a longitudinal study of 15 single-parent adoptive homes over a 14-year period that demonstrated that these homes have the capacity to be successful adoptive placements. Identifies unique characteristics of single-parent adoptive homes, and notes the need for additional research to identify children for whom these…

  10. Adoption and Identity.

    ERIC Educational Resources Information Center

    Lieberman, E. James

    1998-01-01

    Discusses how adoption responds to ancient questions about origins. Maintains that one's identity hinges on actual relationships more than on pedigree and genes. Discusses reasons for informing a child about his or her adoption. Suggests that adoption is a constructive process involving too many worrisome warnings and anxiety-raising advice by the…

  11. The Transracial Adoption Paradox

    PubMed Central

    Lee, Richard M.

    2008-01-01

    The number of transracial adoptions in the United States, particularly international adoptions, is increasing annually. Counseling psychology as a profession, however, is a relatively silent voice in the research on and practice of transracial adoption. This article presents an overview of the history and research on transracial adoption to inform counseling psychologists of the set of racial and ethnic challenges and opportunities that transracial adoptive families face in everyday living. Particular attention is given to emergent theory and research on the cultural socialization process within these families. PMID:18458794

  12. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy.

    PubMed

    Duncan, Brynn B; Highfill, Steven L; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H; Jones, Barry; Mackall, Crystal L; Bachovchin, William W; Fry, Terry J

    2013-10-01

    Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT. PMID:23994886

  13. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy

    PubMed Central

    Duncan, Brynn B.; Highfill, Steven L.; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H.; Jones, Barry; Mackall, Crystal L.; Bachovchin, William W.; Fry, Terry J.

    2013-01-01

    Current multimodality therapy consisting of surgery, chemotherapy and radiation will fail in approximately 40% of patients with pediatric sarcomas and results in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (Dipeptidyl peptidase IV activity and/or structural homologues) enzymes can mediate tumor regression via immune-mediated mechanisms. Here we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma (RMS) cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b+) cells, particularly myeloid dendritic cells (DCs), to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11b+Ly6-ChiLy6-Glo) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1-/-) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared to either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies particularly as an adjuvant to tumor vaccines and ACT. PMID:23994886

  14. Companion animal adoption study.

    PubMed

    Neidhart, Laura; Boyd, Renee

    2002-01-01

    To better understand the outcomes of companion animal adoptions, Bardsley & Neidhart Inc. conducted a series of 3 surveys over a 1-year period with dog and cat owners who had adopted their pet through either a (a) Luv-A-Pet location, (b) Adopt-a-thon, or (c) traditional shelter. This article suggests opportunities to improve owners' perceptions of their pets and the adoption process through (a) providing more information before adoption about pet health and behaviors, (b) providing counseling to potential adopters to place pets appropriately, and (c) educating adopters to promote companion animal health and retention. Results demonstrate that the pet's relationship to the family unit, such as where the pet sleeps and how much time is spent with the pet, is related to the amount of veterinary care the companion animal receives, and to long-term retention. Satisfaction and retention are attributed to the pet's personality, compatibility, and behavior, rather than demographic differences among adopters or between adoption settings. The age of the companion animal at adoption, the intended recipient, and presence of children in the home also play a role. Health problems were an issue initially for half of all adopted pets, but most were resolved within 12 months. Roughly one fourth of adopters who no longer have their companion animal said their pet died. Characteristics of pets that died support the contention that spaying and neutering profoundly affects a companion animal's life span. Although retention is similar for dogs and cats, mortality is higher among cats in the first year after adoption. PMID:12578739

  15. Chimeric Antigen Receptor T Cell Therapy in Hematology.

    PubMed

    Ataca, Pınar; Arslan, Önder

    2015-12-01

    It is well demonstrated that the immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation. Adoptive T cell transfer has been improved to be more specific and potent and to cause less off-target toxicity. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells. On 1 July 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the benefits of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical and clinical studies, and the effectiveness and drawbacks of this strategy. PMID:26377367

  16. Single Parent Adoption.

    ERIC Educational Resources Information Center

    Administration for Children, Youth, and Families (DHHS), Washington, DC.

    Presenting two views of the single-parent family, this pamphlet includes an article by two researchers (William Feigelman and Arnold R. Silverman) and a short statement by a single adoptive parent (Amanda Richards). The first paper summarizes earlier research on single-parent adoptions and discusses the results of a nationwide survey of 713…

  17. A beacon of hope in stroke therapy-Blockade of pathologically activated cellular events in excitotoxic neuronal death as potential neuroprotective strategies.

    PubMed

    Hoque, Ashfaqul; Hossain, M Iqbal; Ameen, S Sadia; Ang, Ching-Seng; Williamson, Nicholas; Ng, Dominic C H; Chueh, Anderly C; Roulston, Carli; Cheng, Heung-Chin

    2016-04-01

    Excitotoxicity, a pathological process caused by over-stimulation of ionotropic glutamate receptors, is a major cause of neuronal loss in acute and chronic neurological conditions such as ischaemic stroke, Alzheimer's and Huntington's diseases. Effective neuroprotective drugs to reduce excitotoxic neuronal loss in patients suffering from these neurological conditions are urgently needed. One avenue to achieve this goal is to clearly define the intracellular events mediating the neurotoxic signals originating from the over-stimulated glutamate receptors in neurons. In this review, we first focus on the key cellular events directing neuronal death but not involved in normal physiological processes in the neurotoxic signalling pathways. These events, referred to as pathologically activated events, are potential targets for the development of neuroprotectant therapeutics. Inhibitors blocking some of the known pathologically activated cellular events have been proven to be effective in reducing stroke-induced brain damage in animal models. Notable examples are inhibitors suppressing the ion channel activity of neurotoxic glutamate receptors and those disrupting interactions of specific cellular proteins occurring only in neurons undergoing excitotoxic cell death. Among them, Tat-NR2B9c and memantine are clinically effective in reducing brain damage caused by some acute and chronic neurological conditions. Our second focus is evaluation of the suitability of the other inhibitors for use as neuroprotective therapeutics. We also discuss the experimental approaches suitable for bridging our knowledge gap in our current understanding of the excitotoxic signalling mechanism in neurons and discovery of new pathologically activated cellular events as potential targets for neuroprotection. PMID:26899498

  18. No evident dose-response relationship between cellular ROS level and its cytotoxicity--a paradoxical issue in ROS-based cancer therapy.

    PubMed

    Zhu, Chunpeng; Hu, Wei; Wu, Hao; Hu, Xun

    2014-01-01

    Targeting cancer via ROS-based mechanism has been proposed as a radical therapeutic approach. Cancer cells exhibit higher endogenous oxidative stress than normal cells and pharmacological ROS insults via either enhancing ROS production or inhibiting ROS-scavenging activity can selectively kill cancer cells. In this study, we randomly chose 4 cancer cell lines and primary colon or rectal cancer cells from 4 patients to test the hypothesis and obtained following paradoxical results: while piperlongumin (PL) and β-phenylethyl isothiocyanate (PEITC), 2 well-defined ROS-based anticancer agents, induced an increase of cellular ROS and killed effectively the tested cells, lactic acidosis (LA), a common tumor environmental factor that plays multifaceted roles in promoting cancer progression, induced a much higher ROS level in the tested cancer cells than PL and PEITC, but spared them; L-buthionine sulfoximine (L-BSO, 20 μM) depleted cellular GSH more effectively and increased higher ROS level than PL or PEITC but permitted progressive growth of the tested cancer cells. No evident dose-response relationship between cellular ROS level and cytotoxicity was observed. If ROS is the effecter, it should obey the fundamental therapeutic principle - the dose-response relationship. This is a major concern. PMID:24848642

  19. Induction of Specific Cellular and Humoral Responses against Renal Cell Carcinoma after Combination Therapy with Cryoablation and Granulocyte-Macrophage Colony Stimulating Factor: A Pilot Study

    PubMed Central

    Thakur, Archana; Littrup, Peter; Paul, Elyse N.; Adam, Barbara; Heilbrun, Lance K.; Lum, Lawrence G.

    2013-01-01

    Cryotherapy offers a minimally invasive treatment option for the management of both irresectable and localized prostate, liver, pulmonary and renal tumors. The anti-neoplastic effects of cryotherapy are mediated by direct tumor lysis and by indirect effects such as intracellular dehydration, pH changes, and microvascular damage resulting in ischemic necrosis. In this study, we investigated whether percutaneous cryoablation of lung metastasis from renal cell carcinoma (RCC) in combination with aerosolized granulocyte-macrophage colony stimulating factor (GM-CSF) can induce systemic cellular and humoral immune responses in 6 RCC patients. Peripheral blood mononuclear cells (PBMC) were sequentially studied up to 63 days post cryoimmunotherapy (CI). PBMC from pre and post CI were phenotyped for lymphocyte subsets and tested for cytotoxicity and IFNγ Elispots directed at RCC cells. Humoral responses were measured by in vitro antibody synthesis assay directed at RCC cells. The immune monitoring data showed that CI induced tumor specific CTL, specific in vitro anti-tumor antibody responses, and enhanced Th1 cytokine production in 4 out of 6 patients. More importantly, the magnitude of cellular and humoral anti-tumor response appears to be associated with clinical responses. These pilot data show that CI can induce robust and brisk cellular and humoral immune responses in metastatic RCC patients, but requires further evaluation in optimized protocols. PMID:21577139

  20. Cellular resilience.

    PubMed

    Smirnova, Lena; Harris, Georgina; Leist, Marcel; Hartung, Thomas

    2015-01-01

    Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after the hit or end in programmed cell death, the ensuing stress responses promote a new homeostasis under stress. The processes of reverting "back to normal" and reversal of apoptosis ("anastasis") have been studied little at the cellular level. Cell types show astonishingly similar vulnerability to most toxicants, except for those that require a very specific target, metabolism or mechanism present only in specific cell types. The majority of chemicals triggers "general cytotoxicity" in any cell at similar concentrations. We hypothesize that cells differ less in their vulnerability to a given toxicant than in their resilience (coping with the "hit"). In many cases, cells do not return to the naive state after a toxic insult. The phenomena of "pre-conditioning", "tolerance" and "hormesis" describe this for low-dose exposures to toxicants that render the cell more resistant to subsequent hits. The defense and resilience programs include epigenetic changes that leave a "memory/scar" - an alteration as a consequence of the stress the cell has experienced. These memories might have long-term consequences, both positive (resistance) and negative, that contribute to chronic and delayed manifestations of hazard and, ultimately, disease. This article calls for more systematic analyses of how cells cope with toxic perturbations in the long-term after stressor withdrawal. A technical prerequisite for these are stable (organotypic) cultures and a characterization of stress response molecular networks. PMID:26536287

  1. Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma12

    PubMed Central

    Han, Kyung Seok; Raven, Peter A.; Frees, Sebastian; Gust, Kilian; Fazli, Ladan; Ettinger, Susan; Hong, Sung Joon; Kollmannsberger, Cristian; Gleave, Martin E.; So, Alan I.

    2015-01-01

    Vascular endothelial growth factor (VEGF)–targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC. PMID:26678908

  2. Pre-Transplant Donor-Specific T-Cell Alloreactivity Is Strongly Associated with Early Acute Cellular Rejection in Kidney Transplant Recipients Not Receiving T-Cell Depleting Induction Therapy

    PubMed Central

    Crespo, Elena; Lucia, Marc; Cruzado, Josep M.; Luque, Sergio; Melilli, Edoardo; Manonelles, Anna; Lloberas, Nuria; Torras, Joan; Grinyó, Josep M.; Bestard, Oriol

    2015-01-01

    Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy. PMID:25689405

  3. Parenting Your Adopted Teenager

    MedlinePlus

    ... https: / / www. childwelfare. gov/ pubs/ f- openadopt/ .) The Internet and the explosion of social media sites (e. ... 4 Howard, J. (2012). Untangling the web: The Internet’s transformative impact on adoption . New York, NY: Evan ...

  4. Adoption and Sibling Rivalry

    MedlinePlus

    ... child in your family should understand her own origins, and those of her brothers and sisters. But ... children can seem exaggerated because of their different origins. For instance, i f your adoptive child does ...

  5. Travelers' Health: International Adoption

    MedlinePlus

    ... preadoption living standards, varying disease epidemiology in the countries of origin, the presence of previously unidentified medical problems, and ... know the disease risks in the adopted child’s country of origin and the medical and social histories of the ...

  6. Synthetic biology in cellular immunotherapy

    PubMed Central

    Chakravarti, Deboki; Wong, Wilson W.

    2015-01-01

    The adoptive transfer of genetically engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. This form of cellular immunotherapy presents a unique opportunity to incorporate advanced systems and synthetic biology approaches to create cancer therapeutics with novel functions. Here, we first review the development of synthetic receptors, switches, and circuits to control the location, duration, and strength of T cell activity against tumors. In addition, we discuss the cellular engineering and genome editing of host cells (or the chassis) to improve the efficacy of cell-based cancer therapeutics, and to reduce the time and cost of manufacturing. PMID:26088008

  7. Cellular Reprogramming

    PubMed Central

    Takahashi, Kazutoshi

    2014-01-01

    Nuclear reprogramming technology was first established more than 50 years ago. It can rejuvenate somatic cells by erasing the epigenetic memories and reconstructing a new pluripotent order. The recent discovery reviewed here that induced pluripotency can be achieved by a small set of transcription factors has opened up unprecedented opportunities in the pharmaceutical industry, the clinic, and laboratories. This technology allows us to access pathological studies by using patient-specific induced pluripotent stem (iPS) cells. In addition, iPS cells are also expected to be a rising star for regenerative medicine, as sources of transplantation therapy. PMID:24492711

  8. Bone Marrow–Derived Stromal Cell Therapy in Cirrhosis: Clinical Evidence, Cellular Mechanisms, and Implications for the Treatment of Hepatocellular Carcinoma

    SciTech Connect

    Vainshtein, Jeffrey M.; Kabarriti, Rafi; Mehta, Keyur J.; Roy-Chowdhury, Jayanta; Guha, Chandan

    2014-07-15

    Current treatment options for hepatocellular carcinoma (HCC) are often limited by the presence of underlying liver disease. In patients with liver cirrhosis, surgery, chemotherapy, and radiation therapy all carry a high risk of hepatic complications, ranging from ascites to fulminant liver failure. For patients receiving radiation therapy, cirrhosis dramatically reduces the already limited radiation tolerance of the liver and represents the most important clinical risk factor for the development of radiation-induced liver disease. Although improvements in conformal radiation delivery techniques have improved our ability to safely irradiate confined areas of the liver to increasingly higher doses with excellent local disease control, patients with moderate-to-severe liver cirrhosis continue to face a shortage of treatment options for HCC. In recent years, evidence has emerged supporting the use of bone marrow–derived stromal cells (BMSCs) as a promising treatment for liver cirrhosis, with several clinical studies demonstrating sustained improvement in clinical parameters of liver function after autologous BMSC infusion. Three predominant populations of BMSCs, namely hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, seem to have therapeutic potential in liver injury and cirrhosis. Preclinical studies of BMSC transplantation have identified a range of mechanisms through which these cells mediate their therapeutic effects, including hepatocyte transdifferentiation and fusion, paracrine stimulation of hepatocyte proliferation, inhibition of activated hepatic stellate cells, enhancement of fibrolytic matrix metalloproteinase activity, and neovascularization of regenerating liver. By bolstering liver function in patients with underlying Child's B or C cirrhosis, autologous BMSC infusion holds great promise as a therapy to improve the safety, efficacy, and utility of surgery, chemotherapy, and hepatic radiation therapy in the treatment

  9. Bioengineered fibrin-based niche to direct outgrowth of circulating progenitors into neuron-like cells for potential use in cellular therapy

    NASA Astrophysics Data System (ADS)

    Tara, S.; Krishnan, Lissy K.

    2015-06-01

    Objective. Autologous cells are considered to be the best choice for use in transplantation therapy. However, the challenges and risks associated with the harvest of transplantable autologous cells limit their successful therapeutic application. The current study explores the possibility of isolating neural progenitor cells from circulating multipotent adult progenitor cells for potential use in cell-based and patient-specific therapy for neurological diseases. Approach. To enable the selection of neural progenitor cells from human peripheral blood mononuclear cells, and to support their lineage maintenance, the composition of a fibrin-based niche was optimized. Morphological examination and specific marker analysis were carried out, employing a qualitative/quantitative polymerase chain reaction followed by immunocytochemistry to: (i) characterize neural progenitor cells in culture; (ii) monitor proliferation/survival; and (iii) track their differentiation status. Main results. The presence of neural progenitors in circulation was confirmed by the presence of nestin+ cells at the commencement of the culture. The isolation, proliferation and differentiation of circulating neural progenitors to neuron-like cells were directed by the engineered niche. Neural cell isolation to near homogeneity was confirmed by the expression of β-III tubulin in ∼95% of cells, whereas microtubule associated protein-2 expression confirmed their ability to differentiate. The concentration of potassium chloride in the niche was found to favour neuron-like cell lengthening, cell-cell contact, and expressions of synaptophysin and tyrosine hydroxylase. Significance. The purpose of this research was to find out if peripheral blood could serve as a potential source of neural progenitors for cell based therapy. The study established that neural progenitors could be selectively isolated from peripheral blood mononuclear cells using a biomimetic niche. The selected cells could multiply and

  10. Role of calcium channels in cellular antituberculosis effects: Potential of voltage-gated calcium-channel blockers in tuberculosis therapy.

    PubMed

    Song, Lele; Cui, Ruina; Yang, Yourong; Wu, Xueqiong

    2015-10-01

    The immunity of human immune cells and their ability to inhibit Mycobacterium tuberculosis (MTB) are key factors in the anti-MTB effect. However, MTB modulates the levels and activity of key intracellular second messengers, such as calcium, to evade protective immune responses. Recent studies suggest that inhibiting L-type calcium channel in immune cells using either antibodies or small interfering RNA increases calcium influx, upregulates the expression of proinflammation genes, and reduces MTB burden. First, we will review the key factors in calcium-signaling pathway that may affect the immunity of immune cells to MTB infection. Second, we will focus on the role of calcium channels in regulating cellular immunity to MTB. Finally, we will discuss the possibility of using calcium-channel blockers as anti-MTB chemotherapy drugs to enhance chemotherapy effects, shorten treatment period, and overcome drug resistance. PMID:25442874

  11. Extracellular vesicles in the biology of brain tumour stem cells--Implications for inter-cellular communication, therapy and biomarker development.

    PubMed

    Nakano, Ichiro; Garnier, Delphine; Minata, Mutsuko; Rak, Janusz

    2015-04-01

    Extracellular vesicles (EVs) act as carriers of molecular and oncogenic signatures present in subsets of tumour cells and tumour-associated stroma, and as mediators of intercellular communication. These processes likely involve cancer stem cells (CSCs). EVs represent a unique pathway of cellular export and cell-to-cell transfer of insoluble molecular regulators such as membrane receptors, signalling proteins and metabolites, thereby influencing the functional integration of cancer cell populations. While mechanisms that control biogenesis, cargo and uptake of different classes of EVs (exosomes, microvesicles, ectosomes, large oncosomes) are poorly understood, they likely remain under the influence of stress-responses, microenvironment and oncogenic processes that define the biology and heterogeneity of human cancers. In glioblastoma (GBM), recent molecular profiling approaches distinguished several disease subtypes driven by distinct molecular, epigenetic and mutational mechanisms, leading to formation of proneural, neural, classical and mesenchymal tumours. Moreover, molecularly distinct clonal cellular lineages co-exist within individual GBM lesions, where they differentiate according to distinct stem cell hierarchies resulting in several facets of tumour heterogeneity and the related potential for intercellular interactions. Glioma stem cells (GSCs) may carry signatures of either proneural or mesenchymal GBM subtypes and differ in several biological characteristics that are, at least in part, represented by the output and repertoire of EV production (vesiculome). We report that vesiculomes differ between known GBM subtypes. EVs may also reflect and influence the equilibrium of the stem cell hierarchy, contain oncogenic drivers and modulate the microenvironment (vascular niche). The GBM/GSC subtype-specific differentials in EV cargo of proteins, transcripts, microRNA and DNA may enable detection of the dynamics of the stem cell compartment and result in

  12. Adolescents' Feelings about Openness in Adoption: Implications for Adoption Agencies

    ERIC Educational Resources Information Center

    Berge, Jerica M.; Mendenhall, Tai J.; Wrobel, Gretchen M.; Grotevant, Harold D.; McRoy, Ruth G.

    2006-01-01

    Adoption research commonly uses parents' reports of satisfaction when examining openness in adoption arrangements. This qualitative study aimed to fill a gap in the adoption research by using adolescents' voices to gain a better understanding of their adoption experiences. Adopted adolescents (n = 152) were interviewed concerning their…

  13. Enhanced cellular uptake and phototoxicity of Verteporfin-conjugated gold nanoparticles as theranostic nanocarriers for targeted photodynamic therapy and imaging of cancers.

    PubMed

    Zhao, Linlin; Kim, Tae-Hyun; Kim, Hae-Won; Ahn, Jin-Chul; Kim, So Yeon

    2016-10-01

    Activatable theranostics with the capacity to respond to a given stimulus have recently been intensively explored to develop more specific, individualized therapies for various diseases, and to combine diagnostic and therapeutic capabilities into a single agent. In this work, we designed tumor-targeting ligand-conjugated block copolymer-gold nanoparticle (AuNP) conjugates as multifunctional nanocarriers of the hydrophobic photosensitizer (PS), verteporfin (Verte), for simultaneous photodynamic therapy and imaging of cancers. Folic acid (FA)-conjugated block copolymers composed of polyethylene glycol (PEG) and poly-β-benzyl-l-aspartate (PBLA) were attached to citrate-stabilized AuNPs through a bidentate dihydrolipoic acid (DHLA) linker. The resulting AuNP conjugates (FA-PEG-P(Asp-Hyd)-DHLA-AuNPs) were significantly more stable than unmodified AuNPs, and their optical properties were not affected by pH. The hydrophobic PS, Verte, was covalently incorporated onto the surfaces of the AuNP conjugates through a pH-sensitive linkage, which increased the water solubility of Verte from <1μg/ml to >2000μg/ml. The size of FA-PEG-P(Asp-Hyd)-DHLA-AuNPs-Verte as determined by light-scattering measurements was about 110.3nm, and FE-SEM and FE-TEM images showed that these nanoparticles were spherical and showed adequate dispersivity after modification. In particular, an in vitro cell study revealed high intracellular uptake of FA-PEG-P(Asp-Hyd)-DHLA-AuNPs-Verte (about 98.62%) and marked phototoxicity after laser irradiation compared with free Verte. These results suggest that FA-PEG-P(Asp-Hyd)-DHLA-AuNPs-Verte has great potential as an effective nanocarrier for dual imaging and photodynamic therapy. PMID:27287160

  14. Chimeric Antigen Receptor T Cell Therapy in Hematology

    PubMed Central

    Ataca, Pınar; Arslan, Önder

    2015-01-01

    It is well demonstrated that the immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation. Adoptive T cell transfer has been improved to be more specific and potent and to cause less off-target toxicity. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells. On 1 July 2014, the United States Food and Drug Administration granted ‘breakthrough therapy’ designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the benefits of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical and clinical studies, and the effectiveness and drawbacks of this strategy. PMID:26377367

  15. Toddler Adoption: The Weaver's Craft.

    ERIC Educational Resources Information Center

    Hopkins-Best, Mary

    Based on concern about the lack of information on adopting toddlers, this book examines the special needs of adopted toddlers and their adoptive parents. Chapter 1, "Why Write a Book on Toddler Adoption?" details the lack of information on the difficulties of adopted toddlers in forming attachments and parents' child rearing difficulties. Chapter…

  16. CERTS customer adoption model

    SciTech Connect

    Rubio, F. Javier; Siddiqui, Afzal S.; Marnay, Chris; Hamachi,Kristina S.

    2000-03-01

    This effort represents a contribution to the wider distributed energy resources (DER) research of the Consortium for Electric Reliability Technology Solutions (CERTS, http://certs.lbl.gov) that is intended to attack and, hopefully, resolve the technical barriers to DER adoption, particularly those that are unlikely to be of high priority to individual equipment vendors. The longer term goal of the Berkeley Lab effort is to guide the wider technical research towards the key technical problems by forecasting some likely patterns of DER adoption. In sharp contrast to traditional electricity utility planning, this work takes a customer-centric approach and focuses on DER adoption decision making at, what we currently think of as, the customer level. This study reports on Berkeley Lab's second year effort (completed in Federal fiscal year 2000, FY00) of a project aimed to anticipate patterns of customer adoption of distributed energy resources (DER). Marnay, et al., 2000 describes the earlier FY99 Berkeley Lab work. The results presented herein are not intended to represent definitive economic analyses of possible DER projects by any means. The paucity of data available and the importance of excluded factors, such as environmental implications, are simply too important to make such an analysis possible at this time. Rather, the work presented represents a demonstration of the current model and an indicator of the potential to conduct more relevant studies in the future.

  17. Obstacles to Interstate Adoption.

    ERIC Educational Resources Information Center

    Hunt, Roberta

    A documentation of the obstacles in law, policy and administrative procedure that interfere with effecting adoptions across State lines is presented. Major problems include: (1) Nonjudicial termination or relinquishment proceedings, although legal in many States, do not satisfy the courts in other states on the issue of the child's freedom for…

  18. The precaution adoption process.

    PubMed

    Weinstein, N D

    1988-01-01

    This article presents a critique of current models of preventive behavior. It discusses a variety of factors that are usually overlooked-including the appearance of costs and benefits over time, the role of cues to action, the problem of competing life demands, and the ways that actual decision behavior differs from the rational ideal implicit in expectancy-value and utility theories. Such considerations suggest that the adoption of new precautions should be viewed as a dynamic process with many determinants. The framework of a model that is able to accommodate these additional factors is described. This alternative model portrays the precaution adoption process as an orderly sequence of qualitatively different cognitive stages. Data illustrating a few of the suggestions made in the article are presented, and implications for prevention programs are discussed. PMID:3049068

  19. Cellular Therapy With Ixmyelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-blind, Placebo-controlled RESTORE-CLI Trial

    PubMed Central

    Powell, Richard J; Marston, William A; Berceli, Scott A; Guzman, Raul; Henry, Timothy D; Longcore, Amy T; Stern, Theresa P; Watling, Sharon; Bartel, Ronnda L

    2012-01-01

    Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option. PMID:22453769

  20. Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction

    PubMed Central

    Davy, Philip MC; Lye, Kevin D; Mathews, Juanita; Owens, Jesse B; Chow, Alice Y; Wong, Livingston; Moisyadi, Stefan; Allsopp, Richard C

    2015-01-01

    Background Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs) as well as induced cardiac-like progenitors (iCPs) derived from ASCs for the treatment of myocardial infarction. Methods and results Human bone marrow (BM)-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. PMID:26604802

  1. Open Adoption: Adoptive Parents' Reactions Two Decades Later

    ERIC Educational Resources Information Center

    Siegel, Deborah H.

    2013-01-01

    Unlike in the past, most adoption agencies today offer birth parents and adoptive parents the opportunity to share identifying information and have contact with each other. To understand the impacts of different open adoption arrangements, a qualitative descriptive study using a snowball sample of 44 adoptive parents throughout New England began…

  2. Hospitious Adoption: How Hospitality Empowers Children and Transforms Adoption

    ERIC Educational Resources Information Center

    Gritter, James L.

    2009-01-01

    Building on previous books by the author, "Hospitious Adoption: How Hospitality Empowers Children and Transforms Adoption" examines the next step after open adoption. Gritter takes the approach that practicing goodwill, respect, and courage within the realm of adoption makes the process move smoother and enriches children's lives. Following a…

  3. γδ T Cell and Other Immune Cells Crosstalk in Cellular Immunity

    PubMed Central

    He, Ying; Wu, Kangni; Hu, Yongxian; Sheng, Lixia; Tie, Ruxiu; Wang, Binsheng; Huang, He

    2014-01-01

    γδ T cells have been recognized as effectors with immunomodulatory functions in cellular immunity. These abilities enable them to interact with other immune cells, thus having the potential for treatment of various immune-mediated diseases with adoptive cell therapy. So far, the interactions between γδ T cell and other immune cells have not been well defined. Here we will discuss the interactivities among them and the perspective on γδ T cells for their use in immunotherapy could be imagined. The understanding of the crosstalk among the immune cells in immunopathology might be beneficial for the clinical application of γδ T cell. PMID:24741636

  4. Obstacles and future of gene therapy for hemophilia

    PubMed Central

    Arruda, Valder R; Samelson-Jones, Ben J

    2015-01-01

    Introduction The recent success of early-phase clinical trials for adeno-associated viral (AAV) liver-directed gene therapy for hemophilia B (HB) demonstrates the potential for gene therapy, in the future, to succeed protein-based prophylaxis therapy for HB. Significant obstacles, however, need to be overcome prior to widespread adoption. The largest obstacles include immune responses to the AAV capsid including preexisting neutralizing antibodies (NAbs) and a delayed cellular immune response. Emerging evidence suggests that the latter is vector-dose dependent. Furthermore, the development and eradication of inhibitors remains a significant safety concern. Similarly, biological differences between Factor VIII and Factor IX (FIX) impose challenges to direct adoption of the successes for HB to hemophilia A (HA). Areas covered The advantages and limitations of the current strategies addressing these obstacles for gene therapy for HB and HA are discussed, as well as vector manufacturing issues relevant to widespread adoption. Alternative strategies including both ex-vivo and in-vivo lentiviral-based methods are discussed, though we focus on AAV-based approaches because of their recent clinical success and potential. Expert opinion Our opinion is that these obstacles can be overcome with current approaches, and AAV-based gene therapy for HB will likely translate into future clinical care. Innovative approaches are, however, likely needed to solve the current problems obstructing HA gene therapy. PMID:26900534

  5. The Differences in the Cellular and Plasma Antioxidative Capacity Between Transient and Defined Focal Brain Ischemia: Does it Suggest Supporting Time-Dependent Neuroprotection Therapy?

    PubMed

    Ljubisavljevic, Srdjan; Cvetkovic, Tatjana; Zvezdanovic, Lilika; Stojanovic, Svetlana; Stojanovic, Ivana; Kocic, Gordana; Zivkovic, Miroslava; Paunovic, Lidija; Milenkovic, Ljiljana; Lukic, Dragisa; Stamenovic, Jelena; Pavlovic, Dusica

    2016-07-01

    There are many opened questions about the precocious role of oxidative stress in the physiopathology of the early stage of transitory ischemic attack (TIA) and defined focal brain ischemia, as well as about its correlation with clinical severity, short-lasting and clinical outcome prediction in these conditions. The study evaluates the values of glutathione (GSH), glutathione peroxidase, and superoxide dismutase (SOD) in hemolysates and total thiol content (-SH), advanced oxidation protein products (AOPP), SOD, and malondialdehyde (MDA) in plasma, in TIA and stroke patients in the early stage of their neurological onset. The results are interpreted in view of the potential relationship between tested parameters and clinical severity and clinical outcome prediction. Better hemolysates' and total antioxidant profile with higher values of AOPP were observed in TIA compared to stroke patients (p < 0.05). The stroke patients with initially better clinical presentation showed better antioxidant profile with lower values of AOPP (p < 0.05). In TIA patients, this was observed for GSH, -SH content, and AOPP (p < 0.05), which correlated with a short risk for stroke occurrence in this group (p < 0.01). Beyond MDA values, all tested parameters showed correlation with clinical outcome in stroke patients (p < 0.05). The measurement of oxidative stress in TIA and stroke patients would be important for identifying patients' subgroups which might receive supporting therapy providing better neurological recovery and clinical outcome. That approach might give us an additional view of a short-lasting risk of stroke occurrence after TIA, and its clinical outcome and prognosis. PMID:26335597

  6. A novel platform for minimally invasive delivery of cellular therapy as a thin layer across the subretina for treatment of retinal degeneration

    NASA Astrophysics Data System (ADS)

    Rotenstreich, Ygal; Tzameret, Adi; Kalish, Sapir E.; Belkin, Michael; Meir, Amilia; Treves, Avraham J.; Nagler, Arnon; Sher, Ifat

    2015-03-01

    Incurable retinal degenerations affect millions worldwide. Stem cell transplantation rescued visual functions in animal models of retinal degeneration. In those studies cells were transplanted in subretinal "blebs", limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection sites. We developed a minimally-invasive surgical platform for drug and cell delivery in a thin layer across the subretina and extravascular spaces of the choroid. The novel system is comprised of a syringe with a blunt-tipped needle and an adjustable separator. Human bone marrow mesenchymal stem cells (hBM-MSCs) were transplanted in eyes of RCS rats and NZW rabbits through a longitudinal triangular scleral incision. No immunosuppressants were used. Retinal function was determined by electroretinogram analysis and retinal structure was determined by histological analysis and OCT. Transplanted cells were identified as a thin layer across the subretina and extravascular spaces of the choroid. In RCS rats, cell transplantation delayed photoreceptor degeneration across the entire retina and significantly enhanced retinal functions. No retinal detachment or choroidal hemorrhages were observed in rabbits following transplantation. This novel platform opens a new avenue for drug and cell delivery, placing the transplanted cells in close proximity to the damaged RPE and retina as a thin layer, across the subretina and thereby slowing down cell death and photoreceptor degeneration, without retinal detachment or choroidal hemorrhage. This new transplantation system may increase the therapeutic effect of other cell-based therapies and therapeutic agents. This study is expected to directly lead to phase I/II clinical trials for autologous hBM-MSCs transplantation in retinal degeneration patients.

  7. High-Efficiency Transduction of Fibroblasts and Mesenchymal Stem Cells by Tyrosine-Mutant AAV2 Vectors for Their Potential Use in Cellular Therapy

    PubMed Central

    Li, Mengxin; Jayandharan, Giridhara R.; Li, Baozheng; Ling, Chen; Ma, Wenqin; Srivastava, Arun

    2010-01-01

    Abstract Adeno-associated virus 2 (AAV2) vectors transduce fibroblasts and mesenchymal stem cells (MSCs) inefficiently, which limits their potential widespread applicability in combinatorial gene and cell therapy. We have reported that AAV2 vectors fail to traffic efficiently to the nucleus in murine fibroblasts. We have also reported that site-directed mutagenesis of surface-exposed tyrosine residues on viral capsids leads to improved intracellular trafficking of the mutant vectors, and the transduction efficiency of the single tyrosine-mutant vectors is ∼10-fold higher in human cells. In the current studies, we evaluated the transduction efficiency of single as well as multiple tyrosine-mutant AAV2 vectors in murine fibroblasts. Our results indicate that the Y444F mutant vectors transduce these cells most efficiently among the seven single-mutant vectors, with >30-fold increase in transgene expression compared with the wild-type vectors. When the Y444F mutation is combined with additional mutations (Y500F and Y730F), the transduction efficiency of the triple-mutant vectors is increased by ∼130-fold and the viral intracellular trafficking is also significant improved. Similarly, the triple-mutant vectors are capable of transducing up to 80–90% of bone marrow-derived primary murine as well as human MSCs. Thus, high-efficiency transduction of fibroblasts with reprogramming genes to generate induced pluripotent stem cells, and the MSCs for delivering therapeutic genes, should now be feasible with the tyrosine-mutant AAV vectors. PMID:20507237

  8. Quality cell therapy manufacturing by design.

    PubMed

    Lipsitz, Yonatan Y; Timmins, Nicholas E; Zandstra, Peter W

    2016-04-01

    Transplantation of live cells as therapeutic agents is poised to offer new treatment options for a wide range of acute and chronic diseases. However, the biological complexity of cells has hampered the translation of laboratory-scale experiments into industrial processes for reliable, cost-effective manufacturing of cell-based therapies. We argue here that a solution to this challenge is to design cell manufacturing processes according to quality-by-design (QbD) principles. QbD integrates scientific knowledge and risk analysis into manufacturing process development and is already being adopted by the biopharmaceutical industry. Many opportunities to incorporate QbD into cell therapy manufacturing exist, although further technology development is required for full implementation. Linking measurable molecular and cellular characteristics of a cell population to final product quality through QbD is a crucial step in realizing the potential for cell therapies to transform healthcare. PMID:27054995

  9. Therapeutic cloning and cellular reprogramming.

    PubMed

    Rodriguez, Ramon M; Ross, Pablo J; Cibelli, Jose B

    2012-01-01

    Embryonic stem cells are capable of differentiating into any cell-type present in an adult organism, and constitute a renewable source of tissue for regenerative therapies. The transplant of allogenic stem cells is challenging due to the risk of immune rejection. Nevertheless, somatic cell reprogramming techniques allow the generation of isogenic embryonic stem cells, genetically identical to the patient. In this chapter we will discuss the cellular reprogramming techniques in the context of regenerative therapy and the biological and technical barriers that they will need to overcome before clinical use. PMID:22457116

  10. Adoption Research: Trends, Topics, Outcomes

    ERIC Educational Resources Information Center

    Palacios, Jesus; Brodzinsky, David

    2010-01-01

    The current article provides a review of adoption research since its inception as a field of study. Three historical trends in adoption research are identified: the first focusing on risk in adoption and identifying adoptee-nonadoptee differences in adjustment; the second examining the capacity of adopted children to recover from early adversity;…

  11. The Development of Adoption Law.

    ERIC Educational Resources Information Center

    Bussiere, Alice

    1998-01-01

    Reviews the evolution of U.S. adoption law since 1851. Recounts changes in the perceived "best interests" of all members of the adoption triad over time, and growing recognition of links between adoption and child welfare policy. Discusses current controversies including open adoption, birth parents' rights, unmarried fathers, and the role of…

  12. Becoming Lesbian Adoptive Parents: An Exploratory Study of Lesbian Adoptive, Lesbian Birth, and Heterosexual Adoptive Parents.

    ERIC Educational Resources Information Center

    Shelley-Sireci, Lynn M.; Ciano-Boyce, Claudia

    2002-01-01

    Surveyed lesbian adoptive parents, heterosexual adoptive parents, and lesbian parents who had used assisted fertilization, regarding the adoption process. Found that the process was similar for both heterosexual and lesbian parents, but lesbian adoptive parents perceived more discrimination and were more inclined to omit information during the…

  13. EHR adopters vs. non-adopters: Impacts of, barriers to, and federal initiatives for EHR adoption

    PubMed Central

    Jamoom, Eric W.; Patel, Vaishali; Furukawa, Michael F.; King, Jennifer

    2016-01-01

    While adoption of electronic health record (EHR) systems has grown rapidly, little is known about physicians’ perspectives on its adoption and use. Nationally representative survey data from 2011 are used to compare the perspectives of physicians who have adopted EHRs with those that have yet to do so across three key areas: the impact of EHRs on clinical care, practice efficiency and operations; barriers to EHR adoption; and factors that influence physicians to adopt EHRs. Despite significant differences in perspectives between adopters and non-adopters, the majority of physicians perceive that EHR use yields overall clinical benefits, more efficient practices and financial benefits. Purchase cost and productivity loss are the greatest barriers to EHR adoption among both adopters and non-adopters; although non-adopters have significantly higher rates of reporting these as barriers. Financial incentives and penalties, technical assistance, and the capability for electronic health information exchange are factors with the greatest influence on EHR adoption among all physicians. However, a substantially higher proportion of non-adopters regard various national health IT policies, and in particular, financial incentives or penalties as a major influence in their decision to adopt an EHR system. Contrasting these perspectives provides a window into how national policies have shaped adoption thus far; and how these policies may shape adoption in the near future. PMID:26250087

  14. Special topics in international adoption.

    PubMed

    Jenista, Jerri Ann

    2005-10-01

    As international adoption has become more "mainstream," the issues recently addressed in domestic adoption have become more important in adoptions involving children originating in other countries. Certain groups of prospective adoptive parents, such as gay or lesbian couples, single parents, and parents with disabilities, have begun to apply to adopt in ever increasing numbers. Children who may have been considered unadoptable in the past are now routinely being offered to prospective adoptive parents. The numbers and ages of the children placed and the spacing between adoptions have come under scrutiny. The rates of adoption dissolutions and disruptions are being examined carefully by the receiving and sending countries. There is a pressing need for research into numerous social aspects of adoption. PMID:16154473

  15. The emotional aftermath of adoption.

    PubMed

    Nadelson, C C

    1976-09-01

    Adopted children are emotionally vulnerable. Adoptive parents must cope with more complex problems than biologic parents. The family physician can provide valuable counseling. Preadoption counseling focuses on motivation and ambivalence. After adoption, however, serious, sometimes predictable, issues arise, such as: how and when to tell the child he is adopted; the child's search for knowledge; the problem of subsequent divorce; the birth of a natural sibling, and the involvement of other family members. New concepts include "open adoption" and "single parent adoption." PMID:961560

  16. Adoptions Without Agencies: A Study of Independent Adoptions.

    ERIC Educational Resources Information Center

    Meezan, William; And Others

    The purposes of this national study of independent, nonagency adoptions were: (1) to determine the experience of the parties involved (biological parents, adoptive parents, agencies, intermediaries, and law enforcement agents); (2) to identify agency policies, procedures and resources that deter agency adoptions and thus encourage independent…

  17. Parents' Feelings towards Their Adoptive and Non-Adoptive Children

    ERIC Educational Resources Information Center

    Glover, Marshaun B.; Mullineaux, Paula Y.; Deater-Deckard, Kirby; Petrill, Stephen A.

    2010-01-01

    In the current study, we examined parent gender differences in feelings (negativity and positivity) and perceptions of child behavioural and emotional problems in adoptive and biological parent-child dyads. In a sample of 85 families, we used a novel within-family adoption design in which one child was adopted and one child was a biological child…

  18. A Phenomenological Exploration of Adoption

    ERIC Educational Resources Information Center

    Baltimore, Diana L.; Crase, Sedahlia Jasper

    2009-01-01

    This qualitative analysis explored children's and adults' experiences with adoption. We used phenomenological methodology and individually interviewed 25 participants and included adoptive mothers and fathers, and their children, each adopted before 18 months of age. Two research questions guided the data analysis: (a) What are children's and…

  19. Dogmatism and Attitudes Toward Adoption

    ERIC Educational Resources Information Center

    Dembroski, Betty G.; Johnson Dale L.

    1969-01-01

    Using Rokeach's Dogmatism Scale and an Adoption Attitude Scale administered to 113 college students study supports hypothesis that among males dogmatism and intolerance toward areas relating to adoption would be positively correlated. Negative correlation for females suggests that emphasis on maternal role makes adoption attitudes exception to…

  20. Adoption Resources for Black Children

    ERIC Educational Resources Information Center

    Gallagher, Ursula M.

    1971-01-01

    The growing number of adoptions in this country, including racially mixed adoptions, attest to the general acceptance of adoption as a way of bringing love to children in need of families of their own and the satisfactions of parenthood to childless couples, single men and women, and families who have room for one more. (Author/AJ)

  1. In vivo sensitized and in vitro activated B cells mediate tumor regression in cancer adoptive immunotherapy1

    PubMed Central

    Li, Qiao; Song, Hongbin; Teitz-Tennenbaum, Seagal; Donald, Elizabeth J.; Li, Mu; Chang, Alfred E.

    2011-01-01

    Adoptive cellular immunotherapy utilizing tumor-reactive T cells has proven to be a promising strategy for cancer treatment. However, we hypothesize that successful treatment strategies will have to appropriately stimulate not only cellular immunity, but also humoral immunity. We previously reported that B cells in tumor-draining lymph nodes (TDLN) may function as antigen-presenting cells. In this study, we identified TDLN B cells as effector cells in an adoptive immunotherapy model. In vivo primed and in vitro activated TDLN B cells alone mediated effective (p<0.05) tumor regression after adoptive transfer into two histologically distinct murine pulmonary metastatic tumor models. Prior lymphodepletion of the host with either chemotherapy or whole-body irradiation augmented the therapeutic efficacy of the adoptively transferred TDLN B cells in the treatment of subcutaneous tumors as well as metastatic pulmonary tumors. Furthermore, B cell plus T cell transfers resulted in substantially more efficient antitumor responses than B cells or T cells alone (p<0.05). Activated TDLN B cells conferred strong humoral responses to tumor. This was evident by the production of IgM, IgG and IgG2b, which bound specifically to tumor cells and led to specific tumor cell lysis in the presence of complement. Collectively, these data indicate that in vivo primed and in vitro activated B cells can be employed as effector cells for cancer therapy. The synergistic antitumor efficacy of co-transferred activated B effector cells and T effector cells represents a novel approach for cancer adoptive immunotherapy. PMID:19667089

  2. Nonengraftment Haploidentical Cellular Therapy for Hematologic Malignancies

    PubMed Central

    Reagan, John L.; Fast, Loren D.; Winer, Eric S.; Safran, Howard; Butera, James N.; Quesenberry, Peter J.

    2012-01-01

    Much of the therapeutic benefit of allogeneic transplant is by a graft versus tumor effect. Further data shows that transplant engraftment is not dependant on myeloablation, instead relying on quantitative competition between donor and host cells. In the clinical setting, engraftment by competition alone is not feasible due to the need for large numbers of infused cells. Instead, low-level host irradiation has proven to be an effective engraftment strategy that is stem cell toxic but not myeloablative. The above observations served as the foundation for clinical trials utilizing allogeneic matched and haploidentical peripheral blood stem cell infusions with minimal conditioning in patients with refractory malignancies. Although engraftment was transient or not apparent, there were compelling responses in a heavily pretreated patient population that appear to result from the breaking of tumor immune tolerance by the host through the actions of IFNγ, invariant NK T cells, CD8 T cells, NK cells, or antigen presenting cells. PMID:22312367

  3. Technology Adoption: an Interaction Perspective

    NASA Astrophysics Data System (ADS)

    Sitorus, Hotna M.; Govindaraju, Rajesri; Wiratmadja, I. I.; Sudirman, Iman

    2016-02-01

    The success of a new technology depends on how well it is accepted by its intended users. Many technologies face the problem of low adoption rate, despite the benefits. An understanding of what makes people accept or reject a new technology can help speed up the adoption rate. This paper presents a framework for technology adoption based on an interactive perspective, resulting from a literature study on technology adoption. In studying technology adoption, it is necessary to consider the interactions among elements involved in the system, for these interactions may generate new characteristics or new relationships. The interactions among elements in a system adoption have not received sufficient consideration in previous studies of technology adoption. Based on the proposed interaction perspective, technology adoption is elaborated by examining interactions among the individual (i.e. the user or prospective user), the technology, the task and the environment. The framework is formulated by adopting several theories, including Perceived Characteristics of Innovating, Diffusion of Innovation Theory, Technology Acceptance Model, Task-Technology Fit and usability theory. The proposed framework is illustrated in the context of mobile banking adoption. It is aimed to offer a better understanding of determinants of technology adoption in various contexts, including technology in manufacturing systems.

  4. Cellular reprogramming and hepatocellular carcinoma development.

    PubMed

    Zheng, Yun-Wen; Nie, Yun-Zhong; Taniguchi, Hideki

    2013-12-21

    Hepatocellular carcinoma (HCC) is one of the most common cancers, and is also the leading cause of death worldwide. Studies have shown that cellular reprogramming contributes to chemotherapy and/or radiotherapy resistance and the recurrence of cancers. In this article, we summarize and discuss the latest findings in the area of cellular reprogramming in HCC. The aberrant expression of transcription factors OCT4, KLF4, SOX2, c-MYC, NANOG, and LIN28 have been also observed, and the expression of these transcription factors is associated with unfavorable clinical outcomes in HCC. Studies indicate that cellular reprogramming may play a critical role in the occurrence and recurrence of HCC. Recent reports have shown that DNA methylation, miRNAs, tumor microenvironment, and signaling pathways can induce the expression of stemness transcription factors, which leads to cellular reprogramming in HCC. Furthermore, studies indicate that therapies based on cellular reprogramming could revolutionize HCC treatment. Finally, a novel therapeutic concept is discussed: reprogramming control therapy. A potential reprogramming control therapy method could be developed based on the reprogramming demonstrated in HCC studies and applied at two opposing levels: differentiation and reprogramming. Our increasing understanding and control of cellular programming should facilitate the exploitation of this novel therapeutic concept and its application in clinical HCC treatment, which may represent a promising strategy in the future that is not restricted to liver cancer. PMID:24379607

  5. Intercountry versus Transracial Adoption: Analysis of Adoptive Parents' Motivations and Preferences in Adoption

    ERIC Educational Resources Information Center

    Zhang, Yuanting; Lee, Gary R.

    2011-01-01

    The United States is one of the major baby-receiving countries in the world. Relatively little research has focused on why there is such a high demand for intercountry adoption. Using in-depth qualitative interviews with adoptive parents, the authors explored the reasons why Americans prefer to adopt foreign-born children instead of adopting…

  6. Cellular and molecular mechanisms in kidney fibrosis

    PubMed Central

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution. PMID:24892703

  7. Cellular Stress Responses and Monitored Cellular Activities.

    PubMed

    Sawa, Teiji; Naito, Yoshifumi; Kato, Hideya; Amaya, Fumimasa

    2016-08-01

    To survive, organisms require mechanisms that enable them to sense changes in the outside environment, introduce necessary responses, and resist unfavorable distortion. Consequently, through evolutionary adaptation, cells have become equipped with the apparatus required to monitor their fundamental intracellular processes and the mechanisms needed to try to offset malfunction without receiving any direct signals from the outside environment. It has been shown recently that eukaryotic cells are equipped with a special mechanism that monitors their fundamental cellular functions and that some pathogenic proteobacteria can override this monitoring mechanism to cause harm. The monitored cellular activities involved in the stressed intracellular response have been researched extensively in Caenorhabditis elegans, where discovery of an association between key mitochondrial activities and innate immune responses was named "cellular associated detoxification and defenses (cSADD)." This cellular surveillance pathway (cSADD) oversees core cellular activities such as mitochondrial respiration and protein transport into mitochondria, detects xenobiotics and invading pathogens, and activates the endocrine pathways controlling behavior, detoxification, and immunity. The cSADD pathway is probably associated with cellular responses to stress in human inflammatory diseases. In the critical care field, the pathogenesis of lethal inflammatory syndromes (e.g., respiratory distress syndromes and sepsis) involves the disturbance of mitochondrial respiration leading to cell death. Up-to-date knowledge about monitored cellular activities and cSADD, especially focusing on mitochondrial involvement, can probably help fill a knowledge gap regarding the pathogenesis of lethal inflammatory syndromes in the critical care field. PMID:26954943

  8. Cellular Phone Towers

    MedlinePlus

    ... the call. How are people exposed to the energy from cellular phone towers? As people use cell ... where people can be exposed to them. The energy from a cellular phone tower antenna, like that ...

  9. Hierarchical cellular materials

    SciTech Connect

    Gibson, L.J.

    1991-01-01

    In this paper a method for estimating the contributions of both the composite and the cellular microstructures to the overall material properties and the mechanical efficiency of natural cellular solids will be described. The method will be demonstrated by focusing on the Young's modulus; similar techniques can be used for other material properties. The results suggest efficient microstructures for engineered cellular materials.

  10. Hierarchical cellular materials

    SciTech Connect

    Gibson, L.J.

    1991-12-31

    In this paper a method for estimating the contributions of both the composite and the cellular microstructures to the overall material properties and the mechanical efficiency of natural cellular solids will be described. The method will be demonstrated by focusing on the Young`s modulus; similar techniques can be used for other material properties. The results suggest efficient microstructures for engineered cellular materials.

  11. Openness in Adoption: Research with the Adoption Kinship Network.

    ERIC Educational Resources Information Center

    Grotevant, Harold D.

    2000-01-01

    Summarizes current research on the outcomes of open adoption. Discusses issues involved in conducting research on openness and offers methodological recommendations. Provides examples from one research program with adoptive kinship networks. Concludes that psychological outcomes were less related to the level of openness than to the dynamics of…

  12. Adoption and Assisted Reproduction. Adoption and Ethics, Volume 4.

    ERIC Educational Resources Information Center

    Freundlich, Madelyn

    The controversies in adoption have extended across a spectrum of policy and practice issues, and although the issues have become clear, resolution has not been achieved nor has consensus developed regarding a framework on which to improve the quality of adoption policy and practice. This book is the fourth in a series to use an ethics-based…

  13. Homosexuality and adoption in Brazil.

    PubMed

    Uziel, A P

    2001-11-01

    Western societies are undergoing legal and policy changes in relation to laws governing the family, marital status, sexual orientation and the welfare of children, including in Brazil where, in the 1990s, the rights of homosexuals were incorporated into ongoing debates about what constitutes a family. This paper discusses the issue of adoption of children by homosexual men in Brazil, using information from court records from 1995-2000 in Rio de Janeiro, and from interviews with two judges, five psychologists and four social workers who evaluate those wishing to adopt. It uses the case records of one man's application to adopt, in which homosexuality became a central issue. Both the construction of masculinity in relation to parenting and concepts of the family were the parameters upon which the decision to allow him to adopt or not depended. Because the legislation does not specify what the sexual orientation of would-be adoptive parents should be, it is possible for single persons to adopt if they show they can be good parents. As more single people, alone or in couples, seek to adopt, it is important to clarify the criteria for judicial decisions on adoption applications. A dialogue is therefore needed on the meaning of family and whether and how it relates to sexual orientation. It is only on this basis that the courts can take a clear decision as to whether being homosexual is a relevant issue in regard to applications to adopt or not. PMID:11765396

  14. Stories of Aboriginal Transracial Adoption

    ERIC Educational Resources Information Center

    Nuttgens, Simon

    2013-01-01

    Despite the significant number of transracial Aboriginal adoptions that have taken place in Canada, little research is available that addresses the psychological and psychosocial ramifications for the children involved. The scant literature that does exist raises concerns about the psychological impact of this type of adoption. The present…

  15. Faculty Adoption of Educational Technology

    ERIC Educational Resources Information Center

    Moser, Franziska Zellweger

    2007-01-01

    Although faculty support has been identified as a critical factor in the success of educational-technology programs, many people involved in such efforts underestimate the complexities of integrating technology into teaching. In this article, the author proposes an adoption cycle to help tackle the complex issue of technology adoption for…

  16. The Temporal Context of Adoption.

    ERIC Educational Resources Information Center

    Pontius, Steven K.

    This paper analyzes the amount of time required by farmers in four villages on the western edge of the central plain of Thailand to adopt four agricultural innovations--fertilizer, herbicide, insecticide, and fungicide. The general objective is to help researchers interested in the relationship of the adoption of new ideas to economic development…

  17. Characteristics of adopted juvenile delinquents.

    PubMed

    Kim, W J; Zrull, J P; Davenport, C W; Weaver, M

    1992-05-01

    There have been many reports describing the uniqueness of adopted children and adolescents' delinquent behaviors in terms of both their delinquent characteristics and courts' treatment of them. A total of 43 adopted juveniles, 32 extrafamilial (1.0%) and 11 intrafamilial (0.3%) adoptions were initially identified out of 3,280 juvenile delinquents. The adopted subjects were then compared with the demographically matched and offense matched nonadopted subjects. The family variables, such as marital and employment status of parents, were significantly different. However, there were only a few discernible trends, and in general there were no significant differences between the adopted and nonadopted juveniles in terms of their offense characteristics and dispositions. PMID:1592787

  18. Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression.

    PubMed

    Sawitzki, Birgit; Brunstein, Claudio; Meisel, Christian; Schumann, Julia; Vogt, Katrin; Appelt, Christine; Curtsinger, Julie M; Verneris, Michael R; Miller, Jeffrey S; Wagner, John E; Blazar, Bruce R

    2014-02-01

    Acute graft-versus-host disease (GVHD) occurs in 40% to 60% of recipients of partially matched umbilical cord blood transplantation (UCBT). In a phase I study, adoptive transfer of expanded CD4(+)CD25(+)Foxp3(+) natural regulatory T cells (nTregs) resulted in a reduced incidence of grade II-IV acute GVHD. To investigate potential mechanisms responsible for the reduced GVHD risk, we analyzed peripheral blood mononuclear cell mRNA expression of a tolerance gene set previously identified in operation- tolerant kidney transplant recipients, comparing healthy controls and patients who received nTregs and those who did not receive nTregs with and without experiencing GVHD. Samples from patients receiving nTregs regardless of GVHD status showed increased expression of Foxp3 expression, as well as B cell-related tolerance marker. This was correlated with early B cell recovery, predominately of naïve B cells, and nearly normal T cell reconstitution. CD8(+) T cells showed reduced signs of activation (HLA-DR(+) expression) compared with conventionally treated patients developing GVHD. In contrast, patients with GVHD had significantly increased TLR5 mRNA expression, whereas nTreg-treated patients without GVHD had reduced TLR5 mRNA expression. We identified Lin(-)HLADR(-)CD33(+)CD16(+) cells and CD14(++)CD16(-) monocytes as the main TLR5 producers, especially in samples of conventionally treated patients developing GVHD. Taken together, these data reveal interesting similarities and differences between tolerant organ and nTreg-treated hematopoietic stem cell transplantation recipients. PMID:24184334

  19. The Roles of Cellular Nanomechanics in Cancer

    PubMed Central

    Yallapu, Murali M.; Katti, Kalpana S.; Katti, Dinesh R.; Mishra, Sanjay R.; Khan, Sheema; Jaggi, Meena; Chauhan, Subhash C.

    2014-01-01

    The biomechanical properties of cells and tissues may be instrumental in increasing our understanding of cellular behavior and cellular manifestations of diseases such as cancer. Nanomechanical properties can offer clinical translation of therapies beyond what are currently employed. Nanomechanical properties, often measured by nanoindentation methods using atomic force microscopy, may identify morphological variations, cellular binding forces, and surface adhesion behaviors that efficiently differentiate normal cells and cancer cells. The aim of this review is to examine current research involving the general use of atomic force microscopy/nanoindentation in measuring cellular nanomechanics; various factors and instrumental conditions that influence the nanomechanical properties of cells; and implementation of nanoindentation methods to distinguish cancer cells from normal cells or tissues. Applying these fundamental nanomechanical properties to current discoveries in clinical treatment may result in greater efficiency in diagnosis, treatment, and prevention of cancer, which ultimately can change the lives of patients. PMID:25137233

  20. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells

    PubMed Central

    Lu, Xiaoyun; Ding, Zhi-Chun; Cao, Yang; Liu, Chufeng; Habtetsion, Tsadik; Yu, Miao; Lemos, Henrique; Salman, Huda; Xu, Hongyan; Mellor, Andrew L.; Zhou, Gang

    2014-01-01

    In recent years the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the current study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4+ T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelo-leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum resident calreticulin (CRT), and extracellular release of high-mobility group box 1 (HMGB1). In addition, there was enhanced tumor antigen uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8+ T cells, and more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4+ T cells. Notably, the combination of melphalan and CD4+ T-cell adoptive cell therapy (ACT) was more efficacious than either treatment alone in prolonging the survival of mice with advanced B-cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan’s immunostimulatory effects, and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4+ T cells. PMID:25560408

  1. Modelling cellular behaviour

    NASA Astrophysics Data System (ADS)

    Endy, Drew; Brent, Roger

    2001-01-01

    Representations of cellular processes that can be used to compute their future behaviour would be of general scientific and practical value. But past attempts to construct such representations have been disappointing. This is now changing. Increases in biological understanding combined with advances in computational methods and in computer power make it possible to foresee construction of useful and predictive simulations of cellular processes.

  2. Possible alternatives to antimicrobial therapies.

    PubMed

    Zecca, Marco; Maccario, Rita; Basso, Sabrina; Comoli, Patrizia

    2014-03-01

    The care of immunosuppressed patients has constantly improved over the years, and pharmacologic developments contributed significantly to this success. However, despite these advances, current anti-infectious agents are limited in their efficacy by either weak specificity or side effects, including suppression of bone marrow function. Control of infection will ultimately depend on reconstitution of specific immunity. Thus, adoptive cellular immunotherapy represents an attractive, low-toxicity strategy to restore specific immune surveillance, and prevent/treat potentially life-threatening disease due to pathogens relevant to the immunosuppressed host. Evidence derived from trials conducted in recipients of hematopoietic stem cell transplantation indicate that adoptive transfer of antigen-specific T cells is a feasible and safe strategy to restore protective immunity and prevent or reverse virus-associated disease. Despite the great potential, immunotherapy for viral and fungal disease still has a marginal role in the management of immunosuppressed patients. This is due to limitations inherent to the technologies and products employed, and, more importantly, to the financial and structural requirements that are associated with GMP production. However, cell therapy offers a unique opportunity to restore antipathogen immune surveillance, and it is therefore conceivable that application of this strategy will increase in the next few years. PMID:24709448

  3. Cellular Reflectarray Antenna

    NASA Technical Reports Server (NTRS)

    Romanofsky, Robert R.

    2010-01-01

    The cellular reflectarray antenna is intended to replace conventional parabolic reflectors that must be physically aligned with a particular satellite in geostationary orbit. These arrays are designed for specified geographical locations, defined by latitude and longitude, each called a "cell." A particular cell occupies nominally 1,500 square miles (3,885 sq. km), but this varies according to latitude and longitude. The cellular reflectarray antenna designed for a particular cell is simply positioned to align with magnetic North, and the antenna surface is level (parallel to the ground). A given cellular reflectarray antenna will not operate in any other cell.

  4. Personality disorders in adopted versus non-adopted adults.

    PubMed

    Westermeyer, Joseph; Yoon, Gihyun; Amundson, Carla; Warwick, Marion; Kuskowski, Michael A

    2015-04-30

    The goal of this epidemiological study was to investigate lifetime history and odds ratios of personality disorders in adopted and non-adopted adults using a nationally representative sample. Data, drawn from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), were compared in adopted (n=378) versus non-adopted (n=42,503) adults to estimate the odds of seven personality disorders using logistic regression analyses. The seven personality disorders were histrionic, antisocial, avoidant, paranoid, schizoid, obsessive-compulsive, and dependent personality disorder. Adoptees had a 1.81-fold increase in the odds of any personality disorder compared with non-adoptees. Adoptees had increased odds of histrionic, antisocial, avoidant, paranoid, schizoid, and obsessive-compulsive personality disorder compared with non-adoptees. Two risk factors associated with lifetime history of a personality disorder in adoptees compared to non-adoptees were (1) being in the age cohort 18-29 years (but no difference in the age 30-44 cohort), using the age 45 or older cohort as the reference and (2) having 12 years of education (but no difference in higher education groups), using the 0-11 years of education as the reference. These findings support the higher rates of personality disorders among adoptees compared to non-adoptees. PMID:25752207

  5. Re an Adoption Application (Surrogacy)

    PubMed

    1987-03-01

    In England, it is illegal under the Adoption Act 1958 to pay or reward anyone in an effort to adopt a child. A family court was asked in this case whether a surrogacy arrangement involving the payment of 5,000 pounds violated the Act. The applicants, a husband and wife, were unable to have children and had entered into an informal arrangement with a woman who agreed to engage in sexual intercourse with the husband and bear a child for the couple in exchange for 10,000 pounds. Because the surrogate wrote a book about her experience from which she made money, and sincerely wanted to help out the childless couple, she accepted only half of her fee. Convinced that the surrogate arrangement was not commercial in nature, the court found no violation of English law, authorized the payment to the mother, and authorized adoption of the child by the father and his wife. PMID:11648176

  6. Photodynamic Therapy

    PubMed Central

    Dougherty, Thomas J.; Gomer, Charles J.; Henderson, Barbara W.; Jori, Giulio; Kessel, David; Korbelik, Mladen; Moan, Johan; Peng, Qian

    2015-01-01

    Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin®) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered. PMID:9637138

  7. Enhancing prescription drug innovation and adoption.

    PubMed

    Alexander, G Caleb; O'Connor, Alec B; Stafford, Randall S

    2011-06-21

    The adoption and use of a new drug would ideally be guided by its innovation and cost-effectiveness. However, information about the relative efficacy and safety of a drug is typically incomplete even well after market entry, and various other forces create a marketplace in which most new drugs are little better than their older counterparts. Five proposed mechanisms are considered for promoting innovation and reducing the use of therapies ultimately found to offer poor value or have unacceptable risks. These changes range from increasing the evidence required for U.S. Food and Drug Administration approval to modifying the structure of drug reimbursement. Despite the challenges of policy implementation, the United States has a long history of successfully improving the societal value and safe use of prescription medicines. PMID:21690598

  8. Adoptive T Cell Immunotherapy for Cancer

    PubMed Central

    Perica, Karlo; Varela, Juan Carlos; Oelke, Mathias; Schneck, Jonathan

    2015-01-01

    Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. In recent years, there has been an increased interest in optimizing this technology in order to make it a clinically feasible treatment. One of the main treatment modalities within cancer immunotherapy has been adoptive T cell therapy (ACT). Using this approach, tumor-specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. In the current review, we revisit some of the major successes of ACT, the major hurdles that have been overcome to optimize ACT, the remaining challenges, and future approaches to make ACT widely available. PMID:25717386

  9. Determinants of internet poker adoption.

    PubMed

    Philander, Kahlil S; Abarbanel, B Lillian

    2014-09-01

    In nearly all jurisdictions, adoption of a new form of gambling has been a controversial and contentious subject. Online gambling has been no different, though there are many aspects that affect online gambling that do not appear in the brick and mortar environment. This study seeks to identify whether demographic, economic, political, technological, and/or sociological determinants contribute to online poker gambling adoption. A theoretical discussion of these categories' importance to online poker is provided and exploratory empirical analysis is used to examine their potential validity. The analysis revealed support for all of the proposed categories of variables thought to be predictive of online gambling legality. PMID:23661279

  10. Cellular lifespan and senescence: a complex balance between multiple cellular pathways.

    PubMed

    Dolivo, David; Hernandez, Sarah; Dominko, Tanja

    2016-07-01

    The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD(+) and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age-related pathologies, which are caused by or exacerbated by senescent cells in vivo. PMID:27417120

  11. CELLULAR MAGNESIUM HOMEOSTASIS

    PubMed Central

    Romani, Andrea M.P.

    2011-01-01

    Magnesium, the second most abundant cellular cation after potassium, is essential to regulate numerous cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways, as attested by more than 1000 entries in the literature. Despite significant recent progress, however, our understanding of how cells regulate Mg2+ homeostasis and transport still remains incomplete. For example, the occurrence of major fluxes of Mg2+ in either direction across the plasma membrane of mammalian cells following metabolic or hormonal stimuli has been extensively documented. Yet, the mechanisms ultimately responsible for magnesium extrusion across the cell membrane have not been cloned. Even less is known about the regulation in cellular organelles. The present review is aimed at providing the reader with a comprehensive and up-to-date understanding of the mechanisms enacted by eukaryotic cells to regulate cellular Mg2+ homeostasis and how these mechanisms are altered under specific pathological conditions. PMID:21640700

  12. Adoption Failure: A Social Work Postmortem

    ERIC Educational Resources Information Center

    Kadushin, Alfred; Seidl, Frederick W.

    1971-01-01

    Failed adoption is defined as removal of the adoptive child at any time between placement and legal adoption. A study of failed adoptions in a statewide adoption agency found a failure rate of less than 3 percent. Reasons for failure are analyzed and implications for practice are suggested. (Author)

  13. Canadian Adoption Statistics: 1981-1990.

    ERIC Educational Resources Information Center

    Sobol, Michael P.; Daly, Kerry J.

    1994-01-01

    Obtained data on Canadian adoptions (1981-90) from adoption coordinators of all 10 provinces and 2 territories. Found downward trends in use of adoption as means of family formation across decade. By 1990, most infant adoptions were facilitated by private practitioners and agencies whereas older children were primarily adopted through public…

  14. CELLULAR PATHOGENESIS OF DIABETIC GASTROENTEROPATHY

    PubMed Central

    Ördög, Tamás; Hayashi, Yujiro; Gibbons, Simon J.

    2010-01-01

    SUMMARY Gastroenteropathy manifesting in upper gastrointestinal symptoms, delayed gastric emptying, constipation, diarrhea and fecal incontinence occurs frequently in patients with diabetes mellitus and represents a significant health care burden. Current treatments are largely symptomatic and ineffective. Better understanding of the cellular and molecular pathogenesis of these disorders is required for the development of more effective therapies. Recent advances in our understanding of the inherent, high-level complexities of the control systems that execute and regulate gastrointestinal motility, together with the utilization of new experimental models and sophisticated physiological, morphological and molecular techniques have lead to the realization that diabetic gastroenteropathies cannot be ascribed to any singular defect or dysfunction. In fact, these disorders are multifactorial and involve a spectrum of metabolic and dystrophic changes that can potentially affect all key components of motor control including the systemic autonomic and enteric nervous systems, interstitial cells of Cajal and smooth muscle cells. Candidate pathomechanisms are also varied and include imbalance between pro- and anti-oxidative factors, altered trophic stimuli to mature cells and their progenitors, and, possibly, autoimmune factors. The goal of this paper is to review the cellular changes underlying diabetic gastroenteropathies and their potential causes, with particular focus on functional interactions between various cell types. It is proposed that diabetic gastroenteropathies should be considered a form of gastrointestinal neuromuscular dystrophy rather than a “functional” disorder. Future research should identify ways to block cytotoxic factors, support the regeneration of damaged cells and translate the experimental findings into new treatment modalities. PMID:19829287

  15. Why Adoption of Standards Matters

    ERIC Educational Resources Information Center

    Journal of Staff Development, 2016

    2016-01-01

    A total of 39 states have adopted, adapted, or endorsed the Standards for Professional Learning, including the standards issued in 2011 (labeled in red) and those published earlier (labeled in blue). Making a commitment to the standards is a commitment to continuous learning for all educators in a school.

  16. Internet Adoption: An Empirical Investigation

    ERIC Educational Resources Information Center

    Ma, Junzhao

    2011-01-01

    The Internet has brought significant changes to the retail industry because it revolutionizes how information is transmitted and accessed. The main objective of this research is to enhance our understanding of people's adoption of the Internet and its implications for retail competition. This dissertation consists of two essays. The first essay…

  17. Has the Academy Adopted TQM?

    ERIC Educational Resources Information Center

    Birnbaum, Robert; Deshotels, Judy

    1999-01-01

    A survey of 469 colleges and universities assessed the degree to which colleges and universities have adopted total quality management (TQM) or continuous quality improvement (CQI) techniques. Results suggest use of TQM/CQI is lower than predicted, at about 13% of institutions. Variations in extent of use of the approach are discussed. (MSE)

  18. Adoption Issues, Trends and Networking.

    ERIC Educational Resources Information Center

    Pierce, William L.

    Teenage women with unplanned pregnancies constitute one of America's greatest challenges in terms of providing good services and sound counseling on options. Only about 7% of teenagers having babies make alternate childrearing plans either through formal adoption or informally with members of their families. The emphasis on making teenagers good…

  19. National Foster Care and Adoption Directory Search

    MedlinePlus

    ... Adoption Directory Search National Foster Care & Adoption Directory Search Many concerned individuals have expressed the desire to ... how to become a foster or adoptive parent. Search results for this category include contact information for: ...

  20. The Texas Adoption Project: Adopted Children and Their Intellectual Resemblance to Biological and Adoptive Parents.

    ERIC Educational Resources Information Center

    Horn, Joseph M.

    1983-01-01

    Intelligence test scores were obtained from parents and children in 300 adoptive families and compared with similar data available from the children's biological mothers. Results support the hypothesis that genetic variability is an important influence in the development of individual differences in intelligence. (Author/RH)

  1. How Chimeric Antigen Receptor Design Affects Adoptive T Cell Therapy.

    PubMed

    Gacerez, Albert T; Arellano, Benjamine; Sentman, Charles L

    2016-12-01

    Chimeric antigen receptor (CAR) T cells have been developed to treat tumors and have shown great success against B cell malignancies. Exploiting modular designs and swappable domains, CARs can target an array of cell surface antigens and, upon receptor-ligand interactions, direct signaling cascades, thereby driving T cell effector functions. CARs have been designed using receptors, ligands, or scFv binding domains. Different regions of a CAR have each been found to play a role in determining the overall efficacy of CAR T cells. Therefore, this review provides an overview of CAR construction and common designs. Each CAR region is discussed in the context of its importance to a CAR's function. Additionally, the review explores how various engineering strategies have been applied to CAR T cells in order to regulate CAR T cell function and activity. J. Cell. Physiol. 231: 2590-2598, 2016. © 2016 Wiley Periodicals, Inc. PMID:27163336

  2. Cellular membrane collapse by atmospheric-pressure plasma jet

    SciTech Connect

    Kim, Kangil; Sik Yang, Sang E-mail: ssyang@ajou.ac.kr; Jun Ahn, Hak; Lee, Jong-Soo E-mail: ssyang@ajou.ac.kr; Lee, Jae-Hyeok; Kim, Jae-Ho

    2014-01-06

    Cellular membrane dysfunction caused by air plasma in cancer cells has been studied to exploit atmospheric-pressure plasma jets for cancer therapy. Here, we report that plasma jet treatment of cervical cancer HeLa cells increased electrical conductivity across the cellular lipid membrane and caused simultaneous lipid oxidation and cellular membrane collapse. We made this finding by employing a self-manufactured microelectrode chip. Furthermore, increased roughness of the cellular lipid membrane and sequential collapse of the membrane were observed by atomic force microscopy following plasma jet treatment. These results suggest that the cellular membrane catastrophe occurs via coincident altered electrical conductivity, lipid oxidation, and membrane roughening caused by an atmospheric-pressure plasma jet, possibly resulting in cellular vulnerability to reactive species generated from the plasma as well as cytotoxicity to cancer cells.

  3. Embryo adoption: Some further considerations.

    PubMed

    Patterson, Colin

    2015-02-01

    Recent discussions of embryo adoption have sought to make sense of the teaching of the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae which appeared to provide a negative judgment on such a practice. This article aims to provide a personalist account of the process of fertilization and implantation that might serve as the basis for the negative judgment of the CDF document. In doing so, it relies upon the idea that a person, including an embryo, is not to be considered in isolation, but always in relation to God and to others. This approach extends the substantialist conceptualizations commonly employed in discussions of this issue. More generally, the article seeks to highlight the value of a personalist re-framing for an understanding of the moral questions surrounding the beginning of life. Lay summary: This article seeks to make sense of what appears to be a clear-cut rejection, set out in the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae, of the proposal for women to "adopt" surplus frozen embryos. It draws upon more recently developed modes of philosophical/theological reasoning to argue that, in human procreation, both fertilization and implantation represent constitutive dimensions of divine creative activity and so must be protected from manipulative technological intervention. Since embryo adoption requires this kind of technology, it makes sense for the Church document not to approve it. PMID:25698841

  4. Cellular senescence: when bad things happen to good cells.

    PubMed

    Campisi, Judith; d'Adda di Fagagna, Fabrizio

    2007-09-01

    Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing. PMID:17667954

  5. Cellular Homeostasis and Aging.

    PubMed

    Hartl, F Ulrich

    2016-06-01

    Aging and longevity are controlled by a multiplicity of molecular and cellular signaling events that interface with environmental factors to maintain cellular homeostasis. Modulation of these pathways to extend life span, including insulin-like signaling and the response to dietary restriction, identified the cellular machineries and networks of protein homeostasis (proteostasis) and stress resistance pathways as critical players in the aging process. A decline of proteostasis capacity during aging leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to a range of chronic diseases. This volume of the Annual Review of Biochemistry contains a set of two reviews addressing our current understanding of the molecular mechanisms underlying aging in model organisms and humans. PMID:27050288

  6. Architected Cellular Materials

    NASA Astrophysics Data System (ADS)

    Schaedler, Tobias A.; Carter, William B.

    2016-07-01

    Additive manufacturing enables fabrication of materials with intricate cellular architecture, whereby progress in 3D printing techniques is increasing the possible configurations of voids and solids ad infinitum. Examples are microlattices with graded porosity and truss structures optimized for specific loading conditions. The cellular architecture determines the mechanical properties and density of these materials and can influence a wide range of other properties, e.g., acoustic, thermal, and biological properties. By combining optimized cellular architectures with high-performance metals and ceramics, several lightweight materials that exhibit strength and stiffness previously unachievable at low densities were recently demonstrated. This review introduces the field of architected materials; summarizes the most common fabrication methods, with an emphasis on additive manufacturing; and discusses recent progress in the development of architected materials. The review also discusses important applications, including lightweight structures, energy absorption, metamaterials, thermal management, and bioscaffolds.

  7. Irregular Cellular Learning Automata.

    PubMed

    Esnaashari, Mehdi; Meybodi, Mohammad Reza

    2015-08-01

    Cellular learning automaton (CLA) is a recently introduced model that combines cellular automaton (CA) and learning automaton (LA). The basic idea of CLA is to use LA to adjust the state transition probability of stochastic CA. This model has been used to solve problems in areas such as channel assignment in cellular networks, call admission control, image processing, and very large scale integration placement. In this paper, an extension of CLA called irregular CLA (ICLA) is introduced. This extension is obtained by removing the structure regularity assumption in CLA. Irregularity in the structure of ICLA is needed in some applications, such as computer networks, web mining, and grid computing. The concept of expediency has been introduced for ICLA and then, conditions under which an ICLA becomes expedient are analytically found. PMID:25291810

  8. Aging cellular networks: chaperones as major participants.

    PubMed

    Soti, C; Csermely, P

    2007-01-01

    We increasingly rely on the network approach to understand the complexity of cellular functions. Chaperones (heat shock proteins) are key "networkers", which sequester and repair damaged proteins. In order to link the network approach and chaperones with the aging process, we first summarize the properties of aging networks suggesting a "weak link theory of aging". This theory suggests that age-related random damage primarily affects the overwhelming majority of the low affinity, transient interactions (weak links) in cellular networks leading to increased noise, destabilization and diversity. These processes may be further amplified by age-specific network remodelling and by the sequestration of weakly linked cellular proteins to protein aggregates of aging cells. Chaperones are weakly linked hubs (i.e., network elements with a large number of connections) and inter-modular bridge elements of protein-protein interaction, signalling and mitochondrial networks. As aging proceeds, the increased overload of damaged proteins is an especially important element contributing to cellular disintegration and destabilization. Additionally, chaperone overload may contribute to the increase of "noise" in aging cells, which leads to an increased stochastic resonance resulting in a deficient discrimination between signals and noise. Chaperone- and other multi-target therapies, which restore the missing weak links in aging cellular networks, may emerge as important anti-aging interventions. PMID:16814508

  9. EBV latency types adopt alternative chromatin conformations.

    PubMed

    Tempera, Italo; Klichinsky, Michael; Lieberman, Paul M

    2011-07-01

    Epstein-Barr Virus (EBV) can establish latent infections with distinct gene expression patterns referred to as latency types. These different latency types are epigenetically stable and correspond to different promoter utilization. Here we explore the three-dimensional conformations of the EBV genome in different latency types. We employed Chromosome Conformation Capture (3C) assay to investigate chromatin loop formation between the OriP enhancer and the promoters that determine type I (Qp) or type III (Cp) gene expression. We show that OriP is in close physical proximity to Qp in type I latency, and to Cp in type III latency. The cellular chromatin insulator and boundary factor CTCF was implicated in EBV chromatin loop formation. Combining 3C and ChIP assays we found that CTCF is physically associated with OriP-Qp loop formation in type I and OriP-Cp loop formation in type III latency. Mutations in the CTCF binding site located at Qp disrupt loop formation between Qp and OriP, and lead to the activation of Cp transcription. Mutation of the CTCF binding site at Cp, as well as siRNA depletion of CTCF eliminates both OriP-associated loops, indicating that CTCF plays an integral role in loop formation. These data indicate that epigenetically stable EBV latency types adopt distinct chromatin architectures that depend on CTCF and mediate alternative promoter targeting by the OriP enhancer. PMID:21829357

  10. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  11. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Adoption. 230.21 Section...

  12. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Adoption. 230.21 Section...

  13. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  14. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Adoption. 230.21 Section...

  15. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  16. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Adoption. 230.21 Section...

  17. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Adoption rule. 341.6... SUBJECT TO SECTION 6 OF THE INTERSTATE COMMERCE ACT § 341.6 Adoption rule. (a) Change in name of carrier... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  18. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally adopt... recirculated as provided in 40 CFR 1506.3 (b) or (c), the adopted EIS with the supplement, if any, will be... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Adoption. 230.21 Section...

  19. Experiences of Black Families as Adoptive Parents.

    ERIC Educational Resources Information Center

    Prater, Gwendolyn S.; King, Lula T.

    1988-01-01

    Conducted descriptive study in which 12 Black families shared their ideas about adoptive parenthood. Found most common reason for adopting was inability to have children biologically. Found need for post-adoptive services for Black families on an as-needed basis. Recommends adoption agencies and communities build on positive experiences of Black…

  20. Policy Issues in Gay and Lesbian Adoption.

    ERIC Educational Resources Information Center

    Sullivan, Ann

    1995-01-01

    Notes that adoption agencies have developed few specific policies on the issue of lesbian and gay adoption. Provides an overview of key considerations about homosexual adopters, including beliefs and values of agency professionals, the legal and social ramifications of adoption into a relationship not based on marriage, and possible consequences…

  1. Adoption and Single Parents: A Review.

    ERIC Educational Resources Information Center

    Groze, Vic

    1991-01-01

    Examines the literature about people who choose to become single adoptive parents. Reviews the demographic and personal characteristics of single parents who adopt, and summarizes the experiences of single parents with the children they adopt. Calls for further research on single parents who adopt special needs children. (GH)

  2. Genetic Dominance & Cellular Processes

    ERIC Educational Resources Information Center

    Seager, Robert D.

    2014-01-01

    In learning genetics, many students misunderstand and misinterpret what "dominance" means. Understanding is easier if students realize that dominance is not a mechanism, but rather a consequence of underlying cellular processes. For example, metabolic pathways are often little affected by changes in enzyme concentration. This means that…

  3. Teaching cellular engineering.

    PubMed

    Hammer, Daniel A; Waugh, Richard E

    2006-02-01

    Cellular engineering is one of the fastest growing subdisciplines in the field of Biomedical Engineering. It involves the application of engineering analysis to understand and control cellular behavior, with the ultimate objective of developing novel therapeutic or diagnostic approaches for the clinic or harnessing cellular function for commercial applications. Well-educated students in this area need strong foundational knowledge in engineering science, chemistry, and cell and molecular biology. In undergraduate curricula, the challenge is to include essential engineering skills plus appropriate levels of training in chemistry and biology while satisfying accreditation-mandated breadth in engineering training. At the graduate level, educators must accommodate students with diverse backgrounds and provide them with both a state-of-the-art understanding of the life sciences and the most advanced engineering skills. Engineering curricular content should include mechanics and materials, physical chemistry, transport phenomena, and control theory. Training from faculty with appointments and research programs in the life sciences is generally recommended, and additional life science content should also be integrated within the engineering curriculum. A capstone course in cellular engineering that includes opportunities for students to have hands-on experiences with state-of-the-art laboratory techniques is highly recommended. PMID:16450196

  4. Auxin and Cellular Elongation.

    PubMed

    Velasquez, Silvia Melina; Barbez, Elke; Kleine-Vehn, Jürgen; Estevez, José M

    2016-03-01

    Auxin is a crucial growth regulator in plants. However, a comprehensive understanding of how auxin induces cell expansion is perplexing, because auxin acts in a concentration- and cell type-dependent manner. Consequently, it is desirable to focus on certain cell types to exemplify the underlying growth mechanisms. On the other hand, plant tissues display supracellular growth (beyond the level of single cells); hence, other cell types might compromise the growth of a certain tissue. Tip-growing cells do not display neighbor-induced growth constraints and, therefore, are a valuable source of information for growth-controlling mechanisms. Here, we focus on auxin-induced cellular elongation in root hairs, exposing a mechanistic view of plant growth regulation. We highlight a complex interplay between auxin metabolism and transport, steering root hair development in response to internal and external triggers. Auxin signaling modules and downstream cascades of transcription factors define a developmental program that appears rate limiting for cellular growth. With this knowledge in mind, the root hair cell is a very suitable model system in which to dissect cellular effectors required for cellular expansion. PMID:26787325

  5. The New Cellular Immunology

    ERIC Educational Resources Information Center

    Claman, Henry N.

    1973-01-01

    Discusses the nature of the immune response and traces many of the discoveries that have led to the present state of knowledge in immunology. The new cellular immunology is directing its efforts toward improving health by proper manipulation of the immune mechanisms of the body. (JR)

  6. Adoption: Pediatric, Legislative and Social Issues

    PubMed Central

    Davis, Joseph H.; Brown, Dirck W.

    1981-01-01

    Physicians may find themselves involved in many phases of the adoption process, ranging from advising infertile couples who wish to adopt a child to caring for adopted children, adolescents or adults. Recent legislation has been aimed at making it possible for children to be adopted who have been receiving foster care and at providing financial assistance to implement the adoption of children with handicaps and with medical problems. The adoption process is becoming more open. Adoptees are searching for and finding their biological parents and all parties in the “adoption triangle” are developing relationships with one another. PMID:7257384

  7. Commercialization of cellular immunotherapies for cancer.

    PubMed

    Walker, Anthony; Johnson, Robert

    2016-04-15

    Successful commercialization of a cell therapy requires more than proving safety and efficacy to the regulators. The inherent complexity of cellular products delivers particular manufacturing, logistical and reimbursement hurdles that threaten commercial viability for any therapy with a less than spectacular clinical profile that truly changes the standard of care. This is particularly acute for autologous cell therapies where patients receive bespoke treatments manufactured from a sample of their own cells and where economies of scale, which play an important role in containing the production costs for small molecule and antibody therapeutics, are highly limited. Nevertheless, the promise of 'game-changing' efficacy, as exemplified by very high levels of complete responses in refractory haematological malignancies, has attracted capital investments on a vast scale, and the attendant pace of technology development provides promising indicators for future clinical and commercial success. PMID:27068936

  8. Council Adopts Two Major Statements

    NASA Astrophysics Data System (ADS)

    2005-06-01

    On 27 May, the AGU Council approved an update to the Union's vision statement and adopted a position statement concerning the U.S. plans for a Moon-Mars initiative. The vision statement, which is reproduced in this section of Eos, describes what the AGU is expected to look like 10 years in the future. The Planning Committee, under the chairmanship of President-elect Tim Killeen, and with input from the policy committees, Sections, and Focus Groups, is updating AGU's strategic plan, which is intended to move measurably toward the vision.

  9. Immunometabolism: Cellular Metabolism Turns Immune Regulator.

    PubMed

    Loftus, Róisín M; Finlay, David K

    2016-01-01

    Immune cells are highly dynamic in terms of their growth, proliferation, and effector functions as they respond to immunological challenges. Different immune cells can adopt distinct metabolic configurations that allow the cell to balance its requirements for energy, molecular biosynthesis, and longevity. However, in addition to facilitating immune cell responses, it is now becoming clear that cellular metabolism has direct roles in regulating immune cell function. This review article describes the distinct metabolic signatures of key immune cells, explains how these metabolic setups facilitate immune function, and discusses the emerging evidence that intracellular metabolism has an integral role in controlling immune responses. PMID:26534957

  10. Bridging the Divide: Openness in Adoption and Post-adoption Psychosocial Adjustment among Birth and Adoptive Parents

    PubMed Central

    Ge, Xiaojia; Natsuaki, Misaki N.; Martin, David; Leve, Leslie; Neiderhiser, Jenae; Shaw, Daniel S.; Villareal, Georgette; Scaramella, Laura; Reid, John; Reiss, David

    2008-01-01

    Using 323 matched parties of birth mothers and adoptive parents, this study examined the association between the degree of adoption openness (e.g., contact and knowledge between parties) and birth and adoptive parents’ post-adoption adjustment shortly after the adoption placement (6 to 9 months). Data from birth fathers (N=112), an understudied sample, also were explored. Openness was assessed by multiple informants. Results indicated that openness was significantly related to satisfaction with adoption process among adoptive parents and birth mothers. Increased openness was positively associated with birth mothers’ post-placement adjustment as indexed by birth mothers’ self reports and the interviewers’ impression of birth mothers’ adjustment. Birth fathers’ report of openness was associated with their greater satisfaction with the adoption process and better post-adoption adjustment. PMID:18729667

  11. Cellular tolerance to pulsed heating

    NASA Astrophysics Data System (ADS)

    Simanovski, Dimitrii; Sarkar, M.; Irani, A.; O'Connell-Rodwell, C.; Contag, C.; Schwettman, H. Alan; Palanker, D.

    2005-04-01

    Many laser therapies involve significant heating of tissue with pulses varying from picoseconds to minutes in duration. In some of the applications heating is a primary goal, while in others it is an undesirable side effect. In both cases, if a hyperthermia is involved, the knowledge about the threshold temperature leading to irreversible cellular damage is critically important. We study the dependence of the threshold temperature on duration of the heat exposure in the range of 0.3 ms to 5 seconds. Thin layer of cells cultured in a Petri dish was exposed to a pulsed CO2 laser radiation. Laser beam was focused onto sample providing Gaussian intensity distribution in the focal plane with a beam diameter (2w) 2-10 mm. Surface temperature in the central part of the focal spot (1mm in diameter) was measured by thermal infrared (IR) emission from the sample, recorded with a fast IR detector. For pulses shorter than 1 s the temperature profile across the focal spot was found to closely correspond to the radial distribution of the laser beam intensity, thus allowing for accurate determination of temperature at any given distance from the center of the spot. Immediate cellular damage was assessed using vital staining with the live/dead fluorescent assay. Threshold temperatures were found to vary from 65 °C at 5 s of heating to 160 °C at pulses of 0.3 ms in duration. The shorter end of this range was limited by vaporization, which occurs during the laser pulse and results in mechanical damage to cells. Dependence of the maximal temperature on pulse duration could be approximated by Arrhenius law with activation energy being about 1 eV.

  12. Adoptive T-cell Immunotherapy

    PubMed Central

    Gottschalk, Stephen; Rooney, Cliona

    2015-01-01

    Epstein-Barr virus (EBV) is associated with a range of malignancies involving B-cells, T-cells, natural killer (NK)-cells, epithelial cells and smooth muscle. All of these are associated with the latent life cycles of EBV, but the pattern of latency-associated viral antigens expressed in tumor cells depends on the type of tumor. EBV-specific T cells (EBVSTs) have been explored as prophylaxis and therapy for EBV-associated malignancies for more than two decades. EBVSTs have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD), which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem cell transplant recipients. While less effective, clinical studies have also demonstrated their therapeutic potential for PTLD post solid organ transplant, and for EBV-associated malignancies such as Hodgkin’s Lymphoma, Non-Hodgkin’s Lymphoma, and nasopharyngeal carcinoma that express a limited array of latent EBV antigens (type 2 latency),. Several approaches are actively being pursued to improve the antitumor activity of EBVSTs including activation and expansion of T cells specific for the EBV antigens expressed in type 2 latency, genetic approaches to render EBVSTs resistant to the immunosuppressive tumor environment and combination approaches with other immune-modulating modalities. Given the recent advances and renewed interest in cell therapy, we hope that EBVSTs will become an integral part of our treatment armamentarium against EBV-positive malignancies in the near future. PMID:26428384

  13. Embryo adoption: Some further considerations

    PubMed Central

    Patterson, Colin

    2015-01-01

    Recent discussions of embryo adoption have sought to make sense of the teaching of the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae which appeared to provide a negative judgment on such a practice. This article aims to provide a personalist account of the process of fertilization and implantation that might serve as the basis for the negative judgment of the CDF document. In doing so, it relies upon the idea that a person, including an embryo, is not to be considered in isolation, but always in relation to God and to others. This approach extends the substantialist conceptualizations commonly employed in discussions of this issue. More generally, the article seeks to highlight the value of a personalist re-framing for an understanding of the moral questions surrounding the beginning of life. Lay summary: This article seeks to make sense of what appears to be a clear-cut rejection, set out in the Congregation for the Doctrine of the Faith (CDF) document Dignitas personae, of the proposal for women to “adopt” surplus frozen embryos. It draws upon more recently developed modes of philosophical/theological reasoning to argue that, in human procreation, both fertilization and implantation represent constitutive dimensions of divine creative activity and so must be protected from manipulative technological intervention. Since embryo adoption requires this kind of technology, it makes sense for the Church document not to approve it. PMID:25698841

  14. Fabrication of cellular materials

    NASA Astrophysics Data System (ADS)

    Prud'homme, Robert K.; Aksay, Ilhan A.; Garg, Rajeev

    1996-02-01

    Nature uses cellular materials in applications requiring strength while, simultaneously, minimizing raw materials requirements. Minimizing raw materials is efficient both in terms of the energy expended by the organism to synthesize the structure and in terms of the strength- to-weight ratio of the structure. Wood is the most obvious example of cellular bio-materials, and it is the focus of other presentations in this symposium. The lightweight bone structure of birds is another excellent example where weight is a key criterion. The anchoring foot of the common muscle [Mytilus edulis] whereby it attaches itself to objects is a further example of a biological system that uses a foam to fill space and yet conserve on raw materials. In the case of the muscle the foam is water filled and the foot structure distributes stress over a larger area so that the strength of the byssal thread from which it is suspended is matched to the strength of interfacial attachment of the foot to a substrate. In these examples the synthesis and fabrication of the cellular material is directed by intercellular, genetically coded, biochemical reactions. The resulting cell sizes are microns in scale. Cellular materials at the next larger scale are created by organisms at the next higher level of integration. For example an African tree frog lays her eggs in a gas/fluid foam sack she builds on a branch overhanging a pond. The outside of the foam sack hardens in the sun and prevents water evaporation. The foam structure minimizes the amount of fluid that needs to be incorporated into the sack and minimizes its weight. However, as far as the developing eggs are concerned, they are in an aqueous medium, i.e. the continuous fluid phase of the foam. After precisely six days the eggs hatch, and the solidified outer wall re-liquefies and dumps the emerging tadpoles into the pond below. The bee honeycomb is an example of a cellular material with exquisite periodicity at millimeter length scales. The

  15. Cellular Host Responses to Gliomas

    PubMed Central

    Barish, Michael E.; Garcia, Elizabeth; Metz, Marianne Z.; Myers, Sarah M.; Gutova, Margarita; Frank, Richard T.; Miletic, Hrvoje; Kendall, Stephen E.; Glackin, Carlotta A.; Bjerkvig, Rolf; Aboody, Karen S.

    2012-01-01

    together with pericytes give rise to tumor vasculature. Mapping the cellular composition of glioma microenvironment and deciphering the complex ‘crosstalk’ between tumor and host may ultimately aid the development of novel anti-glioma therapies. PMID:22539956

  16. Cellular growth in biofilms

    SciTech Connect

    Wood, B.D.; Whitaker, S.

    1999-09-20

    In this paper the authors develop a macroscopic evolutionary equation for the growth of the cellular phase starting from a microscopic description of mass transport and a simple structured model for product formation. The methods of continuum mechanics and volume averaging are used to develop the macroscopic representation by carefully considering the fluxes of chemical species that pertain to cell growth. The concept of structured models is extended to include the transport of reacting chemical species at the microscopic scale. The resulting macroscopic growth model is similar in form to previously published models for the transport of a single substrate and electron donor and for the production of cellular mass and exopolymer. The method of volume averaging indicated under what conditions the developed growth model is valid and provides an explicit connection between the relevant microscopic model parameters and their corresponding macroscopic counterparts.

  17. Cellular dysfunction in sepsis.

    PubMed

    Singer, Mervyn

    2008-12-01

    Cellular dysfunction is a commonplace sequelum of sepsis and other systemic inflammatory conditions. Impaired energy production (related to mitochondrial inhibition, damage, and reduced protein turnover) appears to be a core mechanism underlying the development of organ dysfunction. The reduction in energy availability appears to trigger a metabolic shutdown that impairs normal functioning of the cell. This may well represent an adaptive mechanism analogous to hibernation that prevents a massive degree of cell death and thus enables eventual recovery in survivors. PMID:18954700

  18. Radiolabeled cellular blood elements

    SciTech Connect

    Thakur, M.L.; Ezikowitz, M.D.; Hardeman, M.R.

    1985-01-01

    This book contains papers delivered by guest lectures and participants at the Advanced Study Institute's colloquium on Radiolabeled Cellular Blood Elements at Maratea, Italy on August 29, to September 9, 1982. The book includes chapters on basic cell physiology and critical reviews of data and experience in the preparation and use of radiolabeled cells, as well as reports on very recent developments, from a faculty that included experts on cell physiology in health and disease and on the technology of in vivo labeling.

  19. Presenilin adopts the ClC channel fold.

    PubMed

    Theobald, Douglas L

    2016-07-01

    Presenilin is an integral membrane aspartate protease that regulates cellular processes by cleaving proteins within the cell membrane. The recent crystal structure of presenilin reveals a conspicuous pore in a bundle of nine α-helices, which was originally thought to adopt a novel protein fold. However, here I show that the presenilin fold is a variant of the ClC chloride channel/transporter fold. This observation may have important implications for presenilin's postulated biological role as a calcium leak channel. PMID:26971579

  20. Predictability in cellular automata.

    PubMed

    Agapie, Alexandru; Andreica, Anca; Chira, Camelia; Giuclea, Marius

    2014-01-01

    Modelled as finite homogeneous Markov chains, probabilistic cellular automata with local transition probabilities in (0, 1) always posses a stationary distribution. This result alone is not very helpful when it comes to predicting the final configuration; one needs also a formula connecting the probabilities in the stationary distribution to some intrinsic feature of the lattice configuration. Previous results on the asynchronous cellular automata have showed that such feature really exists. It is the number of zero-one borders within the automaton's binary configuration. An exponential formula in the number of zero-one borders has been proved for the 1-D, 2-D and 3-D asynchronous automata with neighborhood three, five and seven, respectively. We perform computer experiments on a synchronous cellular automaton to check whether the empirical distribution obeys also that theoretical formula. The numerical results indicate a perfect fit for neighbourhood three and five, which opens the way for a rigorous proof of the formula in this new, synchronous case. PMID:25271778

  1. Probabilistic cellular automata.

    PubMed

    Agapie, Alexandru; Andreica, Anca; Giuclea, Marius

    2014-09-01

    Cellular automata are binary lattices used for modeling complex dynamical systems. The automaton evolves iteratively from one configuration to another, using some local transition rule based on the number of ones in the neighborhood of each cell. With respect to the number of cells allowed to change per iteration, we speak of either synchronous or asynchronous automata. If randomness is involved to some degree in the transition rule, we speak of probabilistic automata, otherwise they are called deterministic. With either type of cellular automaton we are dealing with, the main theoretical challenge stays the same: starting from an arbitrary initial configuration, predict (with highest accuracy) the end configuration. If the automaton is deterministic, the outcome simplifies to one of two configurations, all zeros or all ones. If the automaton is probabilistic, the whole process is modeled by a finite homogeneous Markov chain, and the outcome is the corresponding stationary distribution. Based on our previous results for the asynchronous case-connecting the probability of a configuration in the stationary distribution to its number of zero-one borders-the article offers both numerical and theoretical insight into the long-term behavior of synchronous cellular automata. PMID:24999557

  2. Quantum cellular automata

    NASA Astrophysics Data System (ADS)

    Porod, Wolfgang; Lent, Craig S.; Bernstein, Gary H.

    1994-06-01

    The Notre Dame group has developed a new paradigm for ultra-dense and ultra-fast information processing in nanoelectronic systems. These Quantum Cellular Automata (QCA's) are the first concrete proposal for a technology based on arrays of coupled quantum dots. The basic building block of these cellular arrays is the Notre Dame Logic Cell, as it has been called in the literature. The phenomenon of Coulomb exclusion, which is a synergistic interplay of quantum confinement and Coulomb interaction, leads to a bistable behavior of each cell which makes possible their use in large-scale cellular arrays. The physical interaction between neighboring cells has been exploited to implement logic functions. New functionality may be achieved in this fashion, and the Notre Dame group invented a versatile majority logic gate. In a series of papers, the feasibility of QCA wires, wire crossing, inverters, and Boolean logic gates was demonstrated. A major finding is that all logic functions may be integrated in a hierarchial fashion which allows the design of complicated QCA structures. The most complicated system which was simulated to date is a one-bit full adder consisting of some 200 cells. In addition to exploring these new concepts, efforts are under way to physically realize such structures both in semiconductor and metal systems. Extensive modeling work of semiconductor quantum dot structures has helped identify optimum design parameters for QCA experimental implementations.

  3. Electronic Dental Records System Adoption.

    PubMed

    Abramovicz-Finkelsztain, Renata; Barsottini, Claudia G N; Marin, Heimar Fatima

    2015-01-01

    The use of Electronic Dental Records (EDRs) and management software has become more frequent, following the increase in prevelance of new technologies and computers in dental offices. The purpose of this study is to identify and evaluate the use of EDRs by the dental community in the São Paulo city area. A quantitative case study was performed using a survey on the phone. A total of 54 offices were contacted and only one declinedparticipation in this study. Only one office did not have a computer. EDRs were used in 28 offices and only four were paperless. The lack of studies in this area suggests the need for more usability and implementation studies on EDRs so that we can improve EDR adoption by the dental community. PMID:26262001

  4. Effects of dabigatran on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. Results from a prospective, randomised, double-blind, placebo-controlled study.

    PubMed

    Franchi, Francesco; Rollini, Fabiana; Cho, Jung Rae; King, Rhodri; Phoenix, Fladia; Bhatti, Mona; DeGroat, Christopher; Tello-Montoliu, Antonio; Zenni, Martin M; Guzman, Luis A; Bass, Theodore A; Ajjan, Ramzi A; Angiolillo, Dominick J

    2016-03-01

    There is growing interest in understanding the effects of adding an oral anticoagulant in patients on dual antiplatelet therapy (DAPT). Vitamin K antagonists (VKAs) and clopidogrel represent the most broadly utilised oral anticoagulant and P2Y12 receptor inhibitor, respectively. However, VKAs can interfere with clopidogrel metabolism via the cytochrome P450 (CYP) system which in turn may result in an increase in platelet reactivity. Dabigatran is a direct acting (anti-II) oral anticoagulant which does not interfere with CYP and has favourable safety and efficacy profiles compared with VKAs. The pharmacodynamic (PD) effects on platelet reactivity and clot kinetic of adjunctive dabigatran therapy in patients on DAPT are poorly explored. In this prospective, randomised, double-blind, placebo-controlled PD study, patients (n=30) on maintenance DAPT with aspirin and clopidogrel were randomised to either dabigatran 150 mg bid or placebo for seven days. PD testing was performed before and after treatment using four different assays exploring multiple pathways of platelet aggregation and fibrin clot kinetics: light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA), kaolin-activated thromboelastography (TEG) and turbidimetric assays. There were no differences in multiple measures of platelet reactivity investigating purinergic and non-purinergic signaling pathways assessed by LTA, MEA and TEG platelet mapping. Dabigatran significantly increased parameters related to thrombin activity and thrombus generation, and delayed fibrin clot formation, without affecting clot structure or fibrinolysis. In conclusion, in patients on DAPT with aspirin and clopidogrel, adjunctive dabigatran therapy is not associated with modulation of profiles of platelet reactivity as determined by several assays assessing multiple platelet signalling pathways. However, dabigatran significantly interferes with parameters related to thrombin activity and delays fibrin clot formation

  5. In Their Own Words: Adopted Persons' Experiences of Adoption Disclosure and Discussion in Their Families

    ERIC Educational Resources Information Center

    Wydra, Maria; O'Brien, Karen M.; Merson, Erica S.

    2012-01-01

    This study explored adoption disclosure in a sample of 18 adult adoptees who were adopted as infants. A qualitative analysis of semistructured interviews with adoptees was used to learn about participants' experiences of adoption disclosure. The majority always knew they were adopted, were able to talk openly with parents about adoption, and had…

  6. Adoption of Children with Disabilities: An Exploration of the Issues for Adoptive Families

    ERIC Educational Resources Information Center

    Good, Gretchen A.

    2016-01-01

    This systematic literature review is an exploration of issues for adoptive families throughout the adoption process and into the various phases of the life of the adoptive family. Although there has been much recent research related to adoption, in general, very little adoption literature addresses the often unspoken needs of families who want to…

  7. Lysosomal storage disorders: The cellular impact of lysosomal dysfunction

    PubMed Central

    2012-01-01

    Lysosomal storage diseases (LSDs) are a family of disorders that result from inherited gene mutations that perturb lysosomal homeostasis. LSDs mainly stem from deficiencies in lysosomal enzymes, but also in some non-enzymatic lysosomal proteins, which lead to abnormal storage of macromolecular substrates. Valuable insights into lysosome functions have emerged from research into these diseases. In addition to primary lysosomal dysfunction, cellular pathways associated with other membrane-bound organelles are perturbed in these disorders. Through selective examples, we illustrate why the term “cellular storage disorders” may be a more appropriate description of these diseases and discuss therapies that can alleviate storage and restore normal cellular function. PMID:23185029

  8. High-throughput screening for modulators of cellular contractile force†

    PubMed Central

    Park, Chan Young; Zhou, Enhua H.; Tambe, Dhananjay; Chen, Bohao; Lavoie, Tera; Dowell, Maria; Simeonov, Anton; Maloney, David J.; Marinkovic, Aleksandar; Tschumperlin, Daniel J.; Burger, Stephanie; Frykenberg, Matthew; Butler, James P.; Stamer, W. Daniel; Johnson, Mark; Solway, Julian; Fredberg, Jeffrey J.

    2015-01-01

    When cellular contractile forces are central to pathophysiology, these forces comprise a logical target of therapy. Nevertheless, existing high-throughput screens are limited to upstream signalling intermediates with poorly defined relationships to such a physiological endpoint. Using cellular force as the target, here we report a new screening technology and demonstrate its applications using human airway smooth muscle cells in the context of asthma and Schlemm's canal endothelial cells in the context of glaucoma. This approach identified several drug candidates for both asthma and glaucoma. We attained rates of 1000 compounds per screening day, thus establishing a force-based cellular platform for high-throughput drug discovery. PMID:25953078

  9. Impact of Adoption on Birth Parents

    MedlinePlus

    ... This relationship, as well as the birth parent’s perception of his or her identity, may change over ... McRoy, R. G., & Grotevant, H. D. (2000). Birthmother perceptions of the psychologically present adopted child: Adoption openness ...

  10. Macro influencers of electronic health records adoption.

    PubMed

    Raghavan, Vijay V; Chinta, Ravi; Zhirkin, Nikita

    2015-01-01

    While adoption rates for electronic health records (EHRs) have improved, the reasons for significant geographical differences in EHR adoption within the USA have remained unclear. To understand the reasons for these variations across states, we have compiled from secondary sources a profile of different states within the USA, based on macroeconomic and macro health-environment factors. Regression analyses were performed using these indicator factors on EHR adoption. The results showed that internet usage and literacy are significantly associated with certain measures of EHR adoption. Income level was not significantly associated with EHR adoption. Per capita patient days (a proxy for healthcare need intensity within a state) is negatively correlated with EHR adoption rate. Health insurance coverage is positively correlated with EHR adoption rate. Older physicians (>60 years) tend to adopt EHR systems less than their younger counterparts. These findings have policy implications on formulating regionally focused incentive programs. PMID:26559074

  11. The Place of Genetic Counselling in Adoption.

    ERIC Educational Resources Information Center

    Hockey, Athel; Bain, Jill

    1982-01-01

    An approach combining social worker and geneticist expertise in adoption is outlined in the study involving 180 families. Genetic counseling has shown to be an essential safeguard to the preservation of the adoptive family unit. (Author/SW)

  12. When to Tell Your Child About Adoption

    MedlinePlus

    ... adopted youngsters need to be told about their origins, ideally even before middle childhood. Introducing the Information ... needs to have an honest understanding of his origin. Adopted children who have not been told seem ...

  13. Innovation Type, Radicalness, and the Adoption Process.

    ERIC Educational Resources Information Center

    Damanpour, Fariborz

    1988-01-01

    Reviews studies on the impact of organizational factors on the adoption of innovations along three dimensions (innovation type, innovation radicalness, and stages of adoption), finding considerable agreement. Proposes a research agenda for future studies. (SR)

  14. Animal and cellular models of Friedreich ataxia.

    PubMed

    Perdomini, Morgane; Hick, Aurore; Puccio, Hélène; Pook, Mark A

    2013-08-01

    The development and use of animal and cellular models of Friedreich ataxia (FRDA) are essential requirements for the understanding of FRDA disease mechanisms and the investigation of potential FRDA therapeutic strategies. Although animal and cellular models of lower organisms have provided valuable information on certain aspects of FRDA disease and therapy, it is intuitive that the most useful models are those of mammals and mammalian cells, which are the closest in physiological terms to FRDA patients. To date, there have been considerable efforts put into the development of several different FRDA mouse models and relevant FRDA mouse and human cell line systems. We summarize the principal mammalian FRDA models, discuss the pros and cons of each system, and describe the ways in which such models have been used to address two of the fundamental, as yet unanswered, questions regarding FRDA. Namely, what is the exact pathophysiology of FRDA and what is the detailed genetic and epigenetic basis of FRDA? PMID:23859342

  15. The Adopted Adolescent. Selected Papers Number 55.

    ERIC Educational Resources Information Center

    Banning, Anne

    This review of studies on clinical and nonclinical populations explores outcomes of adoption and developmental issues for adolescents, and in particular, developmental problems for adopted adolescents. Studies on nonclinical populations demonstrate that adoption is a highly successful form of substitute care. Prospective longitudinal studies show…

  16. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 3 2013-10-01 2013-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  17. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 3 2014-10-01 2014-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  18. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  19. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 3 2011-07-01 2009-07-01 true Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  20. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  1. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  2. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  3. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 3 2014-07-01 2014-07-01 false Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  4. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  5. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  6. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  7. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 3 2013-07-01 2013-07-01 false Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  8. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  9. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  10. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  11. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  12. A Narrative Inquiry of International Adoption Stories

    ERIC Educational Resources Information Center

    Pryor, Christin; Pettinelli, J. Douglas

    2011-01-01

    The international adoption entrance story is an unexplored topic in the adoption literature. The stories that families tell of beginning life with their new children has important implications for the development of an autobiographical narrative of an adopted child. A coherent autobiographical narrative is vital for healthy childhood development.…

  13. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  14. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  15. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  16. 47 CFR 61.171 - Adoption notice.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 3 2012-10-01 2012-10-01 false Adoption notice. 61.171 Section 61.171 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) TARIFFS Adoption of Tariffs and Other Documents of Predecessor Carriers § 61.171 Adoption notice. When a...

  17. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 3 2012-07-01 2009-07-01 true Adoption proceedings. 584.4 Section 584.4... CUSTODY, AND PATERNITY § 584.4 Adoption proceedings. (a) General. This chapter does not apply to those... normally may not be put up for adoption without the consent of the parents. Therefore, communications...

  18. 40 CFR 1506.3 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 33 2011-07-01 2011-07-01 false Adoption. 1506.3 Section 1506.3 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY OTHER REQUIREMENTS OF NEPA § 1506.3 Adoption. (a) An agency may adopt a Federal draft or final environmental impact statement or portion...

  19. 25 CFR 75.18 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Adoption. 75.18 Section 75.18 Indians BUREAU OF INDIAN... OF CHEROKEE INDIANS, NORTH CAROLINA § 75.18 Adoption. The Tribal Council of the Eastern Band of Cherokee Indians shall be empowered to enact ordinances governing the adoption of new members....

  20. 14 CFR 221.160 - Adoption notice.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Adoption notice. 221.160 Section 221.160... REGULATIONS TARIFFS Adoption Publications Required To Show Change in Carrier's Name or Transfer of Operating Control § 221.160 Adoption notice. (a) When the name of a carrier is changed or when its operating...

  1. Modeling technology adoption in developing countries

    SciTech Connect

    Besley, T.; Case, A. )

    1993-05-01

    An analysis of technology adoption decisions by poor farmers is provided. Some possible empirical models for studying technology adoption are reviewed. The issue of theoretical consistency is dealt with in terms of the costs of such consistency, measured in data needs and model complexity, and the benefits, measured in terms of understanding the micro-economic foundations of adoption.

  2. Adoption Bibliography and Multi-Ethnic Sourcebook.

    ERIC Educational Resources Information Center

    Van Why, Elizabeth Wharton, Comp.

    Designed for parents who have adopted or who contemplate adoption, and for educational, legal, medical, social, and theological professionals, this bibliography and source book contains over 1250 citations relating to adoption. The book is divided into two parts. The first section is a bibliography of articles, personal narratives, dissertations,…

  3. Child Adoption in Contemporary Rural China

    ERIC Educational Resources Information Center

    Zhang, Weiguo

    2006-01-01

    Based on qualitative information from in-depth interviews and quantitative data from a survey of 425 adoptive families conducted in summer 2001 in rural China, this study attempts to explain the social and demographic patterns of adoption and investigate the roles of the State and families in adoption processes in contemporary rural China. Within…

  4. International Adoption: Current Status and Future Prospects.

    ERIC Educational Resources Information Center

    Bartholet, Elizabeth

    1993-01-01

    Laws regulating adoption are varied and complex in countries that offer children for international adoption (IA), while United States Immigration laws pose additional obstacles to Americans wishing to adopt foreign-born children. Declarations by the United Nations and the development of a convention on IA by the Hague Conference offer some hope…

  5. Formin’ cellular structures

    PubMed Central

    Bogdan, Sven; Schultz, Jörg; Grosshans, Jörg

    2014-01-01

    Members of the Diaphanous (Dia) protein family are key regulators of fundamental actin driven cellular processes, which are conserved from yeast to humans. Researchers have uncovered diverse physiological roles in cell morphology, cell motility, cell polarity, and cell division, which are involved in shaping cells into tissues and organs. The identification of numerous binding partners led to substantial progress in our understanding of the differential functions of Dia proteins. Genetic approaches and new microscopy techniques allow important new insights into their localization, activity, and molecular principles of regulation. PMID:24719676

  6. Control of cellular automata

    NASA Astrophysics Data System (ADS)

    Bagnoli, Franco; Rechtman, Raúl; El Yacoubi, Samira

    2012-12-01

    We study the problem of master-slave synchronization and control of totalistic cellular automata. The synchronization mechanism is that of setting a fraction of sites of the slave system equal to those of the master one (pinching synchronization). The synchronization observable is the distance between the two configurations. We present three control strategies that exploit local information (the number of nonzero first-order Boolean derivatives) in order to choose the sites to be synchronized. When no local information is used, we speak of simple pinching synchronization. We find the critical properties of control and discuss the best control strategy compared with simple synchronization.

  7. Cellular mechanics and motility

    NASA Astrophysics Data System (ADS)

    Hénon, Sylvie; Sykes, Cécile

    2015-10-01

    The term motility defines the movement of a living organism. One widely known example is the motility of sperm cells, or the one of flagellar bacteria. The propulsive element of such organisms is a cilium(or flagellum) that beats. Although cells in our tissues do not have a flagellum in general, they are still able to move, as we will discover in this chapter. In fact, in both cases of movement, with or without a flagellum, cell motility is due to a dynamic re-arrangement of polymers inside the cell. Let us first have a closer look at the propulsion mechanism in the case of a flagellum or a cilium, which is the best known, but also the simplest, and which will help us to define the hydrodynamic general conditions of cell movement. A flagellum is sustained by cellular polymers arranged in semi-flexible bundles and flagellar beating generates cell displacement. These polymers or filaments are part of the cellular skeleton, or "cytoskeleton", which is, in this case, external to the cellular main body of the organism. In fact, bacteria move in a hydrodynamic regime in which viscosity dominates over inertia. The system is thus in a hydrodynamic regime of low Reynolds number (Box 5.1), which is nearly exclusively the case in all cell movements. Bacteria and their propulsion mode by flagella beating are our unicellular ancestors 3.5 billion years ago. Since then, we have evolved to form pluricellular organisms. However, to keep the ability of displacement, to heal our wounds for example, our cells lost their flagellum, since it was not optimal in a dense cell environment: cells are too close to each other to leave enough space for the flagella to accomplish propulsion. The cytoskeleton thus developed inside the cell body to ensure cell shape changes and movement, and also mechanical strength within a tissue. The cytoskeleton of our cells, like the polymers or filaments that sustain the flagellum, is also composed of semi-flexible filaments arranged in bundles, and also in

  8. Robotic Therapy

    PubMed Central

    Krebs, H. I.; Hogan, N.

    2012-01-01

    The last two decades have seen a remarkable shift in the neuro-rehabilitation paradigm. Neuroscientists and clinicians moved away from the perception that the brain is static and hardwired, to a new dynamic understanding that plasticity is a fundamental property of the adult human brain and might be harnessed to remap or create new neural pathways. Capitalizing on this innovative understanding, we introduced a paradigm shift in the clinical practice in 1989 when we initiated the development of the MIT-Manus robot for neuro-rehabilitation and deployed it in the clinic in 1994 10. Since then, we and others have developed and tested a multitude of robotic devices for stroke, spinal cord injury, cerebral palsy, multiple sclerosis, and Parkinson’s disease. Here we discuss whether robotic therapy has achieved a level of maturity to justify its broad adoption in the clinical realm as a tool for motor recovery. PMID:23080044

  9. Immune Therapies for Neuroblastoma

    PubMed Central

    Navid, Fariba; Armstrong, Michael; Barfield, Raymond C.

    2009-01-01

    Neuroblastoma, a solid tumor arising from developing cells of the sympathetic nervous system, is the most common extracranial tumor in children. The prognosis for high-risk neuroblastoma remains poor with conventional treatment, and new approaches are therefore being explored to treat this disease. One such alternative therapy that holds promise is immune therapy. We review here the recent advances in 4 types of immune therapy – cytokine, vaccine, antibody, and cellular therapy – to treat neuroblastoma. We present preclinical research and clinical trials on several promising candidates such as IL-12, dendritic cell vaccines, anti-GD2 antibodies, and allogeneic hematopoietic stem cell transplant. An optimal treatment plan for neuroblastoma will most likely involve multimodal approaches and combinations of immune therapies. PMID:19342881

  10. Shanghai adopts family planning regulations.

    PubMed

    1990-04-01

    These Regulations, adopted by the Municipal People's Congress of Shanghai on 14 March 1990, do the following: a) strictly prohibit any units and individuals from identifying the sex of a fetus without medical reasons; b) add 1 additional week to the marriage leave of couples who marry at the age set for late marriage (25 for males and 23 for females); c) add 15 days of maternity leave for women who give birth at the age set for late birth (24) and 3 days for their spouses; d) impose a fine equal to 3 to 6 times their average annual income if a couple have an unplanned birth (calculated on the basis of their income 2 years before the birth); and e) subject a couple who have an unplanned birth to disciplinary action by their working units if they work for others or by the administrative department of industry and commerce if they are self employed. Second births are allowed if a first child "can not become normal because of nonhereditary diseases," if both husband and wife are single children, or if a "remarried couple had only one child before their remarriage." The Regulations provide that "the improvement of birth quality and good upbringing of children should be promoted, advice on heredity should be provided, and premarital examinations [should] be conducted." They also stipulate that "A woman should terminate her pregnancy or undergo a sterilization operation if both husband and wife (or either of them) have [a] hereditary or other disease not medically suitable for birth." The provisions of these Regulations prohibiting prenatal sex selection were reported in Annual Review of Population Law, Vol. 17, 1990, Section 240. PMID:12348767

  11. Cellular Contraction and Polarization Drive Collective Cellular Motion.

    PubMed

    Notbohm, Jacob; Banerjee, Shiladitya; Utuje, Kazage J C; Gweon, Bomi; Jang, Hwanseok; Park, Yongdoo; Shin, Jennifer; Butler, James P; Fredberg, Jeffrey J; Marchetti, M Cristina

    2016-06-21

    Coordinated motions of close-packed multicellular systems typically generate cooperative packs, swirls, and clusters. These cooperative motions are driven by active cellular forces, but the physical nature of these forces and how they generate collective cellular motion remain poorly understood. Here, we study forces and motions in a confined epithelial monolayer and make two experimental observations: 1) the direction of local cellular motion deviates systematically from the direction of the local traction exerted by each cell upon its substrate; and 2) oscillating waves of cellular motion arise spontaneously. Based on these observations, we propose a theory that connects forces and motions using two internal state variables, one of which generates an effective cellular polarization, and the other, through contractile forces, an effective cellular inertia. In agreement with theoretical predictions, drugs that inhibit contractility reduce both the cellular effective elastic modulus and the frequency of oscillations. Together, theory and experiment provide evidence suggesting that collective cellular motion is driven by at least two internal variables that serve to sustain waves and to polarize local cellular traction in a direction that deviates systematically from local cellular velocity. PMID:27332131

  12. Integrated cellular systems

    NASA Astrophysics Data System (ADS)

    Harper, Jason C.

    The generation of new three-dimensional (3D) matrices that enable integration of biomolecular components and whole cells into device architectures, without adversely altering their morphology or activity, continues to be an expanding and challenging field of research. This research is driven by the promise that encapsulated biomolecules and cells can significantly impact areas as diverse as biocatalysis, controlled delivery of therapeutics, environmental and industrial process monitoring, early warning of warfare agents, bioelectronics, photonics, smart prosthetics, advanced physiological sensors, portable medical diagnostic devices, and tissue/organ replacement. This work focuses on the development of a fundamental understanding of the biochemical and nanomaterial mechanisms that govern the cell directed assembly and integration process. It was shown that this integration process relies on the ability of cells to actively develop a pH gradient in response to evaporation induced osmotic stress, which catalyzes silica condensation within a thin 3D volume surrounding the cells, creating a functional bio/nano interface. The mechanism responsible for introducing functional foreign membrane-bound proteins via proteoliposome addition to the silica-lipid-cell matrix was also determined. Utilizing this new understanding, 3D cellular immobilization capabilities were extended using sol-gel matrices endowed with glycerol, trehalose, and media components. The effects of these additives, and the metabolic phase of encapsulated S. cerivisiase cells, on long-term viability and the rate of inducible gene expression was studied. This enabled the entrapment of cells within a novel microfluidic platform capable of simultaneous colorimetric, fluorescent, and electrochemical detection of a single analyte, significantly improving confidence in the biosensor output. As a complementary approach, multiphoton protein lithography was utilized to engineer 3D protein matrices in which to

  13. Engineering Cellular Metabolism.

    PubMed

    Nielsen, Jens; Keasling, Jay D

    2016-03-10

    Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds, and pharmaceuticals. However, making cells into efficient factories is challenging because cells have evolved robust metabolic networks with hard-wired, tightly regulated lines of communication between molecular pathways that resist efforts to divert resources. Here, we will review the current status and challenges of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation. PMID:26967285

  14. Cellular Morphogenesis In Silico

    PubMed Central

    Shinbrot, Troy; Chun, Young; Caicedo-Carvajal, Carlos; Foty, Ramsey

    2009-01-01

    Abstract We describe a model that simulates spherical cells of different types that can migrate and interact either attractively or repulsively. We find that both expected morphologies and previously unreported patterns spontaneously self-assemble. Among the newly discovered patterns are a segmented state of alternating discs, and a “shish-kebab” state, in which one cell type forms a ring around a second type. We show that these unique states result from cellular attraction that increases with distance (e.g., as membranes stretch viscoelastically), and would not be seen in traditional, e.g., molecular, potentials that diminish with distance. Most of the states found computationally have been observed in vitro, and it remains to be established what role these self-assembled states may play in in vivo morphogenesis. PMID:19686642

  15. Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy.

    PubMed

    Mirzaei, Hamid Reza; Mirzaei, Hamed; Lee, Sang Yun; Hadjati, Jamshid; Till, Brian G

    2016-10-01

    Excitement is growing for therapies that harness the power of patients' immune systems to combat their diseases. One approach to immunotherapy involves engineering patients' own T cells to express a chimeric antigen receptor (CAR) to treat advanced cancers, particularly those refractory to conventional therapeutic agents. Although these engineered immune cells have made remarkable strides in the treatment of patients with certain hematologic malignancies, success with solid tumors has been limited, probably due to immunosuppressive mechanisms in the tumor niche. In nearly all studies to date, T cells bearing αβ receptors have been used to generate CAR T cells. In this review, we highlight biological characteristics of γδ T cells that are distinct from those of αβ T cells, including homing to epithelial and mucosal tissues and unique functions such as direct antigen recognition, lack of alloreactivity, and ability to present antigens. We offer our perspective that these features make γδ T cells promising for use in cellular therapy against several types of solid tumors, including melanoma and gastrointestinal cancers. Engineered γδ T cells should be considered as a new platform for adoptive T cell cancer therapy for mucosal tumors. PMID:27392648

  16. Cellular cardiomyoplasty: what have we learned?

    PubMed

    Kao, Race L; Browder, William; Li, Chuanfu

    2009-01-01

    Restoring blood flow, improving perfusion, reducing clinical symptoms, and augmenting ventricular function are the goals after acute myocardial infarction. Other than cardiac transplantation, no standard clinical procedure is available to restore damaged myocardium. Since we first reported cellular cardiomyoplasty in 1989, successful outcomes have been confirmed by experimental and clinical studies, but definitive long-term efficacy requires large-scale placebo-controlled double-blind randomized trials. On meta-analysis, stem cell-treated groups had significantly improved left ventricular ejection fraction, reduced infarct scar size, and decreased left ventricular end-systolic volume. Fewer myocardial infarctions, deaths, readmissions for heart failure, and repeat revascularizations were additional benefits. Encouraging clinical findings have been reported using satellite or bone marrow stem cells, but understanding of the benefit mechanisms demands additional studies. Adult mammalian ventricular myocardium lacks adequate regeneration capability, and cellular cardiomyoplasty offers a new way to overcome this; the poor retention and engraftment rate and high apoptotic rate of the implanted stem cells limit outcomes. The ideal type and number of cells, optimal timing of cell therapy, and ideal cell delivery method depend on determining the beneficial mechanisms. Cellular cardiomyoplasty has progressed rapidly in the last decade. A critical review may help us to better plan the future direction. PMID:19515892

  17. Reprogramming cellular identity for regenerative medicine

    PubMed Central

    Cherry, Anne B.C.; Daley, George Q.

    2012-01-01

    The choreographed development of over 200 distinct differentiated cell types from a single zygote is a complex and poorly understood process. Whereas development leads unidirectionally towards more restricted cell fates, recent work in cellular reprogramming has proven that striking conversions of one cellular identity into another can be engineered, promising countless applications in biomedical research and paving the way for modeling disease with patient-derived stem cells. To date, there has been little discussion of which disease models are likely to be most informative. We here review evidence demonstrating that because environmental influences and epigenetic signatures are largely erased during reprogramming, patient-specific models of diseases with strong genetic bases and high penetrance are likely to prove most informative in the near term. However, manipulating in vitro culture conditions may ultimately enable cell-based models to recapitulate gene-environment interactions. Here, we discuss the implications of the new reprogramming paradigm in biomedicine and outline how reprogramming of cell identities is enhancing our understanding of cell differentiation and prospects for cellular therapies and in vivo regeneration. PMID:22424223

  18. Building Adoption of Visual Analytics Software

    SciTech Connect

    Chinchor, Nancy; Cook, Kristin A.; Scholtz, Jean

    2012-01-05

    Adoption of technology is always difficult. Issues such as having the infrastructure necessary to support the technology, training for users, integrating the technology into current processes and tools, and having the time, managerial support, and necessary funds need to be addressed. In addition to these issues, the adoption of visual analytics tools presents specific challenges that need to be addressed. This paper discusses technology adoption challenges and approaches for visual analytics technologies.

  19. Measures for Predictors of Innovation Adoption

    PubMed Central

    Chor, Ka Ho Brian; Wisdom, Jennifer P.; Olin, Su-Chin Serene; Hoagwood, Kimberly E.; Horwitz, Sarah M.

    2014-01-01

    Building on a narrative synthesis of adoption theories by Wisdom et al. (2013), this review identifies 118 measures associated with the 27 adoption predictors in the synthesis. The distribution of measures is uneven across the predictors and predictors vary in modifiability. Multiple dimensions and definitions of predictors further complicate measurement efforts. For state policymakers and researchers, more effective and integrated measurement can advance the adoption of complex innovations such as evidence-based practices. PMID:24740175

  20. [Health-related problems in adopted children].

    PubMed

    Laubjerg, Merete; Petersson, Birgit H

    2006-10-01

    International research shows that the standard of health among children adopted from abroad, especially those adopted by single parents, is not as good as that of other children. Danish studies indicate similar problems. The causes could be several, such as poor development in the embryonic and fetal stages, low birth weight, starvation, neglect, infections, and the lack of the natural bonds between mother and child. Surveys indicate that many adoptive parents, single parents in particular, receive children with health problems. There is no Danish research available, but it is important to be aware of these issues in order for both adoptees and adoptants to receive the most support. PMID:17059801

  1. Molecular and cellular mechanisms of anthracycline cardiotoxicity.

    PubMed

    Chen, Billy; Peng, Xuyang; Pentassuglia, Laura; Lim, Chee Chew; Sawyer, Douglas B

    2007-01-01

    The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \\'sarcopenia\\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to

  2. Cellular energy metabolism

    SciTech Connect

    Glaser, M.

    1991-06-01

    Studies have been carried out on adenylate kinase which is an important enzyme in determining the concentrations of the adenine nucleotides. An efficient method has been developed to clone mutant adenylate kinase genes in E. coli. Site-specific mutagenesis of the wild type gene also has been used to obtain forms of adenylate kinase with altered amino acids. The wild type and mutant forms of adenylate kinase have been overexpressed and large quantities were readily isolated. The kinetic and fluorescence properties of the different forms of adenylate kinase were characterized. This has led to a new model for the location of the AMP and ATP bindings sites on the enzyme and a proposal for the mechanism of substrate inhibition. Crystals of the wild type enzyme were obtained that diffract to at least 2.3 {angstrom} resolution. Experiments were also initiated to determine the function of adenylate kinase in vivo. In one set of experiments, E. coli strains with mutations in adenylate kinase showed large changes in cellular nucleotides after reaching the stationary phase in a low phosphate medium. This was caused by selective proteolytic degradation of the mutant adenylate kinase caused by phosphate starvation.

  3. Molecular and Cellular Biophysics

    NASA Astrophysics Data System (ADS)

    Jackson, Meyer B.

    2006-01-01

    Molecular and Cellular Biophysics provides advanced undergraduate and graduate students with a foundation in the basic concepts of biophysics. Students who have taken physical chemistry and calculus courses will find this book an accessible and valuable aid in learning how these concepts can be used in biological research. The text provides a rigorous treatment of the fundamental theories in biophysics and illustrates their application with examples. Conformational transitions of proteins are studied first using thermodynamics, and subsequently with kinetics. Allosteric theory is developed as the synthesis of conformational transitions and association reactions. Basic ideas of thermodynamics and kinetics are applied to topics such as protein folding, enzyme catalysis and ion channel permeation. These concepts are then used as the building blocks in a treatment of membrane excitability. Through these examples, students will gain an understanding of the general importance and broad applicability of biophysical principles to biological problems. Offers a unique synthesis of concepts across a wide range of biophysical topics Provides a rigorous theoretical treatment, alongside applications in biological systems Author has been teaching biophysics for nearly 25 years

  4. Electrosurgery with cellular precision.

    PubMed

    Palanker, Daniel V; Vankov, Alexander; Huie, Philip

    2008-02-01

    Electrosurgery, one of the most-often used surgical tools, is a robust but somewhat crude technology that has changed surprisingly little since its invention almost a century ago. Continuous radiofrequency is still used for tissue cutting, with thermal damage extending to hundreds of micrometers. In contrast, lasers developed 70 years later, have been constantly perfected, and the laser-tissue interactions explored in great detail, which has allowed tissue ablation with cellular precision in many laser applications. We discuss mechanisms of tissue damage by electric field, and demonstrate that electrosurgery with properly optimized waveforms and microelectrodes can rival many advanced lasers. Pulsed electric waveforms with burst durations ranging from 10 to 100 micros applied via insulated planar electrodes with 12 microm wide exposed edges produced plasma-mediated dissection of tissues with the collateral damage zone ranging from 2 to 10 microm. Length of the electrodes can vary from micrometers to centimeters and all types of soft tissues-from membranes to cartilage and skin could be dissected in liquid medium and in a dry field. This technology may allow for major improvements in outcomes of the current surgical procedures and development of much more refined surgical techniques. PMID:18270030

  5. Active Cellular Nematics

    NASA Astrophysics Data System (ADS)

    Duclos, Guillaume; Erlenkaemper, Christoph; Garcia, Simon; Yevick, Hannah; Joanny, Jean-François; Silberzan, Pascal; Biology inspired physics at mesoscales Team; Physical approach of biological problems Team

    We study the emergence of a nematic order in a two-dimensional tissue of apolar elongated fibroblast cells. Initially, these cells are very motile and the monolayer is characterized by giant density fluctuations, a signature of far-from-equilibrium systems. As the cell density increases because of proliferation, the cells align with each other forming large perfectly oriented domains while the cellular movements slow down and eventually freeze. Therefore topological defects characteristic of nematic phases remain trapped at long times, preventing the development of infinite domains. By analogy with classical non-active nematics, we have investigated the role of boundaries and we have shown that cells confined in stripes of width smaller than typically 500 µm are perfectly aligned in the stripe direction. Experiments performed in cross-shaped patterns show that both the number of cells and the degree of alignment impact the final orientation. Reference: Duclos G., Garcia S., Yevick H.G. and Silberzan P., ''Perfect nematic order in confined monolayers of spindle-shaped cells'', Soft Matter, 10, 14, 2014

  6. Predictors of race, adoption, and sexual orientation related socialization of adoptive parents of young children.

    PubMed

    Goldberg, Abbie E; Smith, JuliAnna Z

    2016-04-01

    Using a sample of 125 lesbian, gay, and heterosexual adoptive parent couples with young children (M = 6.32 years), this study examined predictors of direct socialization (preparation for adoptism, racism, and heterosexism) and indirect socialization (modeling interactions by responding to outsiders' inquiries about their child's adoptive status, racial background, or family structure). In terms of direct socialization, parents of older children tended to engage in more socialization around adoptism and heterosexism, and parents of daughters tended to engage in more socialization around racism and heterosexism. Greater perceived child interest in adoption was related to more direct socialization around adoptism. Parents of color reported more direct socialization around racism. Having a child of color was related to more direct socialization around heterosexism. Regarding indirect socialization, sexual minority parents reported more socialization around adoption and race. Greater perceived child interest in adoption was related to more indirect adoption socialization. Being more "out" was related to more indirect socialization around parent sexual orientation. PMID:26371450

  7. Envisaging the adoption process to strengthen gay- and lesbian-headed families: recommendations for adoption professionals.

    PubMed

    Matthews, John D; Cramer, Elizabeth P

    2006-01-01

    Although a growing number of child placement agencies are serving lesbians and gay men, a dearth of literature exists for adoption agency policies and practices related to working with this population. This article explores the unique characteristics and strengths of prospective gay and lesbian adoptive parents throughout each of the three phases of the adoption process-preplacement, placement, and postplacement-as well as provides suggestions for adoption professionals working with gays and lesbians. Data from a recent qualitative study of single, gay adoptive fathers are used to illustrate examples and expose areas of potential strengths of adoptive parents not generally explored in the preplacement or preparatory stage. Special attention also is given to the continuing needs of adoptive families headed by gays and lesbians after adoptive placement. Specifically explored are the needs for developing linkages with similar families, as well as providing resources designed to promote successful outcomes of adopted children raised by gays and lesbians. PMID:16846118

  8. Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell-based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies.

    PubMed

    Babizhayev, Mark A; Yegorov, Yegor E

    2015-12-01

    . Nuclear export is initiated by ROS-induced phosphorylation of tyrosine 707 within hTERT by the Src kinase family. It might be presumed that protection of mitochondria against oxidative stress is an important telomere length-independent function for telomerase in cell survival. Biotechnology companies are focused on development of therapeutic telomerase vaccines, telomerase inhibitors, and telomerase promoter-driven cell killing in oncology, have a telomerase antagonist in late preclinical studies. Anti-aging medicine-oriented groups have intervened on the market with products working on telomerase activation for a broad range of degenerative diseases in which replicative senescence or telomere dysfunction may play an important role. Since oxidative damage has been shown to shorten telomeres in tissue culture models, the adequate topical, transdermal, or systemic administration of antioxidants (such as, patented ocular administration of 1% N-acetylcarnosine lubricant eye drops in the treatment of cataracts) may be beneficial at preserving telomere lengths and delaying the onset or in treatment of disease in susceptible individuals. Therapeutic strategies toward controlled transient activation of telomerase are targeted to cells and replicative potential in cell-based therapies, tissue engineering and regenerative medicine. PMID:26034007

  9. Natural Products as Tools for Defining How Cellular Metabolism Influences Cellular Immune and Inflammatory Function during Chronic Infection

    PubMed Central

    Lovelace, Erica S.; Polyak, Stephen J.

    2015-01-01

    Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping HIV viral loads below detection with antiretroviral therapy (ART), there is still a need to control inflammation in these diseases. Recent studies indicate that many natural products like curcumin, resveratrol and silymarin alter cellular metabolism and signal transduction pathways via enzymes such as adenosine monophosphate kinase (AMPK) and mechanistic target of rapamycin (mTOR), and these pathways directly influence cellular inflammatory status (such as NF-κB) and immune function. Natural products represent a vast toolkit to dissect and define how cellular metabolism controls cellular immune and inflammatory function. PMID:26633463

  10. 47 CFR 22.909 - Cellular markets.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 2 2013-10-01 2013-10-01 false Cellular markets. 22.909 Section 22.909... Cellular Radiotelephone Service § 22.909 Cellular markets. Cellular markets are standard geographic areas used by the FCC for administrative convenience in the licensing of cellular systems. Cellular...

  11. 47 CFR 22.909 - Cellular markets.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 2 2014-10-01 2014-10-01 false Cellular markets. 22.909 Section 22.909... Cellular Radiotelephone Service § 22.909 Cellular markets. Cellular markets are standard geographic areas used by the FCC for administrative convenience in the licensing of cellular systems. Cellular...

  12. Adoption of Information Technology by Advertising Agencies.

    ERIC Educational Resources Information Center

    Herling, Thomas J.; Merskin, Debra

    Since little empirical research has been conducted on adoption of currently available information technology by the advertising industry, a study explored the extent of advertising agencies' adoption of selected information technologies such as online database services and electronic mail. The study discussed data from earlier studies and analyzed…

  13. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... situations were a soldier is trying to adopt a child. It applies to those situations where another person is trying to adopt a legitimate or illegitimate child of a soldier. A child born in or out of wedlock... has stated that he or she is not the natural parent of the child. (v) Since the soldier is not...

  14. Faculty Adoption of Active Learning Classrooms

    ERIC Educational Resources Information Center

    Van Horne, Sam; Murniati, Cecilia Titiek

    2016-01-01

    Although post-secondary educational institutions are incorporating more active learning classrooms (ALCs) that support collaborative learning, researchers have less often examined the cultural obstacles to adoption of those environments. In this qualitative research study, we adopted the conceptual framework of activity theory to examine the…

  15. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  16. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  17. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  18. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Adoption. 10010.20 Section 10010.20 Public Lands: Interior Regulations Relating to Public Lands (Continued) UTAH RECLAMATION MITIGATION AND... Environmental Assessments § 10010.20 Adoption. (a) An EA prepared for a proposal before the Commission...

  19. Single Adoptive Mothers and Their Children

    ERIC Educational Resources Information Center

    Dougherty, Sharon Ann

    1978-01-01

    In view of the increasing number of single women who adopt children, the social work profession has an obligation to learn more about this group of mothers. This article is based on a research study to identify characteristics of single adoptive mothers and their children and to learn what community supports the mothers believe would be helpful.…

  20. 76 FR 68613 - National Adoption Month, 2011

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-04

    ... Sig.) [FR Doc. 2011-28839 Filed 11-3-11; 11:15 am] Billing code 3295-F2-P ... Documents#0;#0; ] Proclamation 8744 of November 1, 2011 National Adoption Month, 2011 By the President of... basic support, and still more children abroad live without families. During National Adoption Month,...

  1. 78 FR 66609 - National Adoption Month, 2013

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-05

    .... (Presidential Sig.) [FR Doc. 2013-26669 Filed 11-4-13; 11:15 am] Billing code 3295-F4 ... Documents#0;#0; ] Proclamation 9049 of October 31, 2013 National Adoption Month, 2013 By the President of... million children and teenagers. During National Adoption Month, we celebrate these families and...

  2. 77 FR 66517 - National Adoption Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-06

    ... Sig.) [FR Doc. 2012-27190 Filed 11-5-12; 8:45 am] Billing code 3295-F3 ... Documents#0;#0; ] Proclamation 8896 of November 1, 2012 National Adoption Month, 2012 By the President of... knowing the love and protection of a permanent family. During National Adoption Month, we give voice...

  3. Covering Adoption: General Depictions in Broadcast News

    ERIC Educational Resources Information Center

    Kline, Susan L.; Karel, Amanda I.; Chatterjee, Karishma

    2006-01-01

    Using theories of stigma (Goffman, 1963) and media frames (Iyengar, 1991), 292 news stories pertaining to adoption that appeared on major broadcast networks between 2001 and 2004 were analyzed. Media coverage of adoptees contained more problematic than positive depictions. Although birth parents were not always depicted, adoptive parent and…

  4. Predicting Language Outcomes for Internationally Adopted Children

    ERIC Educational Resources Information Center

    Glennen, Sharon L.

    2007-01-01

    Purpose: Language and speech are difficult to assess in newly arrived internationally adopted children. The purpose of this study was to determine if assessments completed when toddlers were first adopted could predict language outcomes at age 2. Local norms were used to develop early intervention guidelines that were evaluated against age 2…

  5. States Adopt Standards at Fast Clip

    ERIC Educational Resources Information Center

    Gewertz, Catherine

    2010-01-01

    Nearly half the states have adopted a new set of common academic standards, barely a month after their final release and, in most cases, with little opposition. As of July 9, 23 states had decided to replace their mathematics and English/language arts standards with the common set. Another flurry of adoptions is expected by Aug. 2, since the $4…

  6. Adoption of Improved Agricultural Practices in Uruguay.

    ERIC Educational Resources Information Center

    Rucks, Carlos Alberto

    Conducted in Uruguay during 1965-68, this study compared adoption rates for selected agricultural practices between one area which received an extension program and one which did not; and sought relationships between selected characteristics of individual farmers and the adoption of new practices. Data came from interviews with 69 experimental and…

  7. Fuzzy Cognitive Map Modelling Educational Software Adoption

    ERIC Educational Resources Information Center

    Hossain, Sarmin; Brooks, Laurence

    2008-01-01

    Educational software adoption across UK secondary schools is seen as unsatisfactory. Based on stakeholders' perceptions, this paper uses fuzzy cognitive maps (FCMs) to model this adoption context. It discusses the development of the FCM model, using a mixed-methods approach and drawing on participants from three UK secondary schools. The study…

  8. Why Wasn't This Child Adopted?

    ERIC Educational Resources Information Center

    Raspberry, William

    1982-01-01

    Critizes the public child care policy with regard to adoption services through the story of "Joey", a black child in his teens. Shortly after his birth, Joey was sent by his teenage mother to a city agency for adoption and until now no real effort has been made to place him in a permanent home. (Author/MP)

  9. Nurturing Development of Foster and Adopted Children

    ERIC Educational Resources Information Center

    Nowak-Fabrykowski, Krystyna Teresa

    2015-01-01

    The goal of this study is to investigate early childhood teachers' perspective of teaching foster and adopted children. The main purpose is to seek suggestions how teachers can nurture the development of foster and adopted children. A 6 question survey was sent to 44 teachers pursuing graduate studies in early childhood education. Of this 50%…

  10. Issues in Adoption and Foster Care.

    ERIC Educational Resources Information Center

    Hepworth, H. Philip

    This speech presents an overview of issues and trends in the provision of foster care and adoption services in Canada. The number of children "in care" in Canada (in foster homes, institutions, or adoptive homes) appears to have peaked around 1969 and declined thereafter. Information on contraceptives and the availaibility of abortions are seen as…

  11. A Research and Development Adoption Model

    ERIC Educational Resources Information Center

    Hull, Ronald E.

    1974-01-01

    An elaboration of the adoption phase of the Clark and Guba R and D model. A brief discussion of the normative structures of the organizations and organizational boundary permeability provides the rationale for a set of suggested procedures for adoption of innovations at the school building level. (Author)

  12. Conservation Tillage: Monitoring Adoption with Satellite Imagery

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Conservation tillage is a commonly adopted best management practice for improving soil quality and reducing erosion. However, there are currently no methods in place to monitor conservation tillage adoption at the watershed scale. The primary objective of this study was to evaluate the utility of ...

  13. Clinical manufacturing of CAR T cells: foundation of a promising therapy.

    PubMed

    Wang, Xiuyan; Rivière, Isabelle

    2016-01-01

    The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available. CAR-T cell therapy may be on the verge of becoming standard of care for a few clinical indications. Yet, many challenges pertaining to manufacturing standardization and product characterization remain to be overcome in order to achieve broad usage and eventual commercialization of this therapeutic modality. PMID:27347557

  14. Clinical manufacturing of CAR T cells: foundation of a promising therapy

    PubMed Central

    Wang, Xiuyan; Rivière, Isabelle

    2016-01-01

    The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available. CAR-T cell therapy may be on the verge of becoming standard of care for a few clinical indications. Yet, many challenges pertaining to manufacturing standardization and product characterization remain to be overcome in order to achieve broad usage and eventual commercialization of this therapeutic modality. PMID:27347557

  15. MSAT and cellular hybrid networking

    NASA Technical Reports Server (NTRS)

    Baranowsky, Patrick W., II

    1993-01-01

    Westinghouse Electric Corporation is developing both the Communications Ground Segment and the Series 1000 Mobile Phone for American Mobile Satellite Corporation's (AMSC's) Mobile Satellite (MSAT) system. The success of the voice services portion of this system depends, to some extent, upon the interoperability of the cellular network and the satellite communication circuit switched communication channels. This paper will describe the set of user-selectable cellular interoperable modes (cellular first/satellite second, etc.) provided by the Mobile Phone and described how they are implemented with the ground segment. Topics including roaming registration and cellular-to-satellite 'seamless' call handoff will be discussed, along with the relevant Interim Standard IS-41 Revision B Cellular Radiotelecommunications Intersystem Operations and IOS-553 Mobile Station - Land Station Compatibility Specification.

  16. Cellular immunotherapy for pediatric solid tumors

    PubMed Central

    HEGDE, MEENAKSHI; MOLL, ALEXANDER; BYRD, TIARA T.; LOUIS, CHRYSTAL U.; AHMED, NABIL

    2015-01-01

    Substantial progress has been made in the treatment of pediatric solid tumors over the past 4 decades. However, children with metastatic and or recurrent disease continue to do poorly despite the aggressive multi-modality conventional therapies. The increasing understanding of the tumor biology and the interaction between the tumor and the immune system over the recent years have led to the development of novel immune-based therapies as alternative options for some of these high-risk malignancies. The safety and anti-tumor efficacy of various tumor vaccines and tumor-antigen specific immune cells are currently being investigated for various solid tumors. In early clinical trials, most of these cellular therapies have been well tolerated and have shown promising clinical responses. Although substantial work is being done in this field, the available knowledge for pediatric tumors remains limited. We review the contemporary early phase cell-based immunotherapy efforts for pediatric solid tumors and discuss the rationale and the challenges thereof. PMID:25082406

  17. Leucocyte cellular adhesion molecules.

    PubMed

    Yong, K; Khwaja, A

    1990-12-01

    Leucocytes express adhesion promoting receptors which mediate cell-cell and cell-matrix interactions. These adhesive interactions are crucial to the regulation of haemopoiesis and thymocyte maturation, the direction and control of leucocyte traffic and migration through tissues, and in the development of immune and non-immune inflammatory responses. Several families of adhesion receptors have been identified (Table). The leucocyte integrin family comprises 3 alpha beta heterodimeric membrane glycoproteins which share a common beta subunit, designated CD18. The alpha subunits of each of the 3 members, lymphocyte function associated antigen-1 (LFA-1), macrophage antigen-1 (Mac-1) and p150,95 are designated CD11a, b and c respectively. These adhesion molecules play a critical part in the immune and inflammatory responses of leucocytes. The leucocyte integrin family is, in turn, part of the integrin superfamily, members of which are evolutionally, structurally and functionally related. Another Integrin subfamily found on leucocytes is the VLA group, so-called because the 'very late activation antigens' VLA-1 and VLA-2 were originally found to appear late in T-cell activation. Members of this family function mainly as extracellular matrix adhesion receptors and are found both on haemopoietic and non-haemopoietic cells. They play a part in diverse cellular functions including tissue organisation, lymphocyte recirculation and T-cell immune responses. A third integrin subfamily, the cytoadhesins, are receptors on platelets and endothelial cells which bind extracellular matrix proteins. A second family of adhesion receptors is the immunoglobulin superfamily, members of which include CD2, LFA-3 and ICAM-1, which participate in T-cell adhesive interactions, and the antigen-specific receptors of T and B cells, CD4, CD8 and the MHC Class I and II molecules. A recently recognised family of adhesion receptors is the selectins, characterised by a common lectin domain. Leucocyte

  18. Developmental Outcomes of Internationally Adopted Children

    PubMed Central

    Welsh, Janet A.; Viana, Andres G.

    2013-01-01

    This study followed the development of a sample of 106 (67 girls) internationally adopted children over a period of 18 months. Children were adopted from five birth regions, including China, Korea, Latin America, Eastern Europe, and other Asian countries. Mean age at adoption was 11 months. Mothers completed the Ages and Stages Questionnaire (ASQ) at 6, 12, and 24 months post-adoption, assessing children's gross and fine motor, communicative, personal-social, and problem solving skills. Results revealed that the sample as a whole demonstrated linear improvement over time in most developmental domains, but children with initially low scores remained significantly lower than other children at the 18-month follow-up. At the first time point, communication was the domain where children most commonly experienced delays. Children with medical problems had significantly lower developmental scores than those without medical diagnoses. ASQ scores were unrelated to age at adoption, but significant differences by birth country region were found. Across most domains, children adopted from Eastern Europe showed generally lower scores than children adopted from other birth regions. PMID:23908583

  19. 20 CFR 404.733 - Evidence you are the legally adopting parent or legally adopted child.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... needed, evidence of the date of adoption; (b) If the widow or widower adopted the child after the insured... or legally adopted child. 404.733 Section 404.733 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Evidence Evidence for Child's and...

  20. Parallel Process Issues for Lesbian and Gay Adoptive Parents and Their Adopted Children

    ERIC Educational Resources Information Center

    Matthews, John D.; Cramer, Elizabeth P.

    2005-01-01

    Gays and lesbians, both single and coupled, are increasingly turning to adoption to create or expand their families. This manuscript specifically addresses the continuing needs of adoptees and adoptive parents by exploring key issues in the life course of gays and lesbians and their adopted children, and identifying potential parallel development…