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Sample records for adoptive cellular therapy

  1. Mouse Models in Bone Marrow Transplantation and Adoptive Cellular Therapy

    PubMed Central

    Arber, Caroline; Brenner, Malcolm K.; Reddy, Pavan

    2014-01-01

    Mouse models of transplantation have been indispensable to the development of bone marrow transplantation (BMT). Their role in the generation of basic science knowledge is invaluable and is subject to discussion below. However, this article focuses on the direct role and relevance of mouse models towards the clinical development and advances in BMT and adoptive T-cell therapy for human diseases. The authors aim to present a thoughtful perspective on the pros and cons of mouse models while noting that despite imperfections these models are obligatory for the development of science-based medicine. PMID:24216170

  2. Adoptive cellular therapy for chronic lymphocytic leukemia and B cell malignancies. CARs and more.

    PubMed

    Castro, Januario E; Kipps, Thomas J

    2016-03-01

    Treatment of patients with chronic lymphocytic leukemia and other B cell malignancies is evolving very rapidly. We have observed the quick transition during the last couple of years, from chemo-immunotherapy based treatments to oral targeted therapies based on B cell receptor signaling and Bcl-2 inhibitors, as well as the increasing use of second generation glyco-engineered antibodies. The next wave of revolution in the treatment for this conditions is approaching and it will be based on strategies that harness the power of the immune system to fight cancer. In the center of this biotechnological revolution is cellular engineering, the field that had made possible to redirect the immune system effector cells to achieve a more effective and targeted adoptive cellular therapy. In this chapter, we will review the historical context of these scientific developments, the most recent basic and clinical research in the field and some opinions regarding the future of adoptive cellular therapy in CLL and other B cell malignancies.

  3. Adoptive Cellular Therapy Targeting Recurrent Pediatric Brain Cancers During Hematopoietic Recovery from High-Dose Chemotherapy

    DTIC Science & Technology

    2011-04-01

    medulloblastoma and primitive neuroectodermal tumors (MB/PNETs), will still die from recurrent disease. Furthermore, survivors are often left with...REMATCH: ”Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy during Recovery from Myeloablative Chemotherapy and...Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy during Recovery from Myeloablative Chemotherapy and Hematopoietic

  4. 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

  5. Cellular genetic therapy.

    PubMed

    Del Vecchio, F; Filareto, A; Spitalieri, P; Sangiuolo, F; Novelli, G

    2005-01-01

    Cellular genetic therapy is the ultimate frontier for those pathologies that are consequent to a specific nonfunctional cellular type. A viable cure for there kinds of diseases is the replacement of sick cells with healthy ones, which can be obtained from the same patient or a different donor. In fact, structures can be corrected and strengthened with the introduction of undifferentiated cells within specific target tissues, where they will specialize into the desired cellular types. Furthermore, consequent to the recent results obtained with the transdifferentiation experiments, a process that allows the in vitro differentiation of embryonic and adult stem cells, it has also became clear that many advantages may be obtained from the use of stem cells to produce drugs, vaccines, and therapeutic molecules. Since stem cells can sustain lineage potentials, the capacity for differentiation, and better tolerance for the introduction of exogenous genes, they are also considered as feasible therapeutic vehicles for gene therapy. In fact, it is strongly believed that the combination of cellular genetic and gene therapy approaches will definitely allow the development of new therapeutic strategies as well as the production of totipotent cell lines to be used as experimental models for the cure of genetic disorders.

  6. 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

  7. 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…

  8. [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.

  9. Adoptive cell transfer therapy for malignant gliomas.

    PubMed

    Ishikawa, Eiichi; Takano, Shingo; Ohno, Tadao; Tsuboi, Koji

    2012-01-01

    To date, various adoptive immunotherapies have been attempted for treatment of malignant gliomas using nonspecific and/or specific effector cells. Since the late 1980s, with the development of rIL-2, the efficacy of lymphokine-activated killer (LAK) cell therapy with or without rIL-2 for malignant gliomas had been tested with some modifications in therapeutic protocols. With advancements in technology, ex vivo expanded tumor specific cytotoxic T-lymphocytes (CTL) or those lineages were used in clinical trials with higher tumor response rates. In addition, combinations of those adoptive cell transfer using LAK cells, CTLs or natural killer (NK) cells with autologous tumor vaccine (ATV) therapy were attempted. Also, a strategy of high-dose (or lymphodepleting) chemotherapy followed by adoptive cell transfer has been drawing attentions recently. The most important role of these clinical studies using cell therapy was to prove that these ex vivo expanded effector cells could kill tumor cells in vivo. Although recent clinical results could demonstrate radiologic tumor shrinkage in a number of cases, cell transfer therapy alone has been utilized less frequently, because of the high cost of ex vivo cell expansion, the short duration of antitumor activity in vivo, and the recent shift of interest to vaccine immunotherapy. Nevertheless, NK cell therapy using specific feeder cells or allergenic NK cell lines have potentials to be a good choice of treatment because of easy ex vivo expansion and their efficacy especially when combined with vaccine therapy as they are complementary to each other. Also, further studies are expected to clarify the efficacy of the high-dose chemotherapy followed by a large scale cell transfer therapy as a new therapeutic strategy for malignant gliomas.

  10. 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

  11. Cellular therapies for type 1 diabetes.

    PubMed

    Lee, D D; Grossman, E; Chong, A S

    2008-02-01

    Type 1 diabetes mellitus (T1DM) is a disease that results from the selective autoimmune destruction of insulin-producing beta-cells. This disease process lends itself to cellular therapy because of the single cell nature of insulin production. Murine models have provided opportunities for the study of cellular therapies for the treatment of diabetes, including the investigation of islet transplantation, and also the possibility of stem cell therapies and islet regeneration. Studies in islet transplantation have included both allo- and xeno-transplantation and have allowed for the study of new approaches for the reversal of autoimmunity and achieving immune tolerance. Stem cells from hematopoietic sources such as bone marrow and fetal cord blood, as well as from the pancreas, intestine, liver, and spleen promise either new sources of islets or may function as stimulators of islet regeneration. This review will summarize the various cellular interventions investigated as potential treatments of T1DM.

  12. Cancer gene therapy targeting cellular apoptosis machinery.

    PubMed

    Jia, Lin-Tao; Chen, Si-Yi; Yang, An-Gang

    2012-11-01

    The unraveling of cellular apoptosis machinery provides novel targets for cancer treatment, and gene therapy targeting this suicidal system has been corroborated to cause inflammation-free autonomous elimination of neoplastic cells. The apoptotic machinery can be targeted by introduction of a gene encoding an inducer, mediator or executioner of apoptotic cell death or by inhibition of anti-apoptotic gene expression. Strategies targeting cancer cells, which are achieved by selective gene delivery, specific gene expression or secretion of target proteins via genetic modification of autologous cells, dictate the outcome of apoptosis-based cancer gene therapy. Despite so far limited clinical success, gene therapy targeting the apoptotic machinery has great potential to benefit patients with threatening malignancies provided the availability of efficient and specific gene delivery and administration systems.

  13. [Cellular therapy and leg ulcers: Future approaches].

    PubMed

    Senet, P

    2015-01-01

    The prevalence of leg ulcers, which are most commonly caused by venous insufficiency, is high in Europe. Current treatments are fairly unsatisfactory, with long healing times in many cases, as well as a high risk of relapse. Over the last 15 years, improved understanding of the cellular and molecular mechanisms at work in delayed wound healing has contributed to the development of cellular therapy in this field. The use of keratinocytes or cultured fibroblasts, whether autogenic or allogenic, has been of little value in terms of either healing times or rates of complete healing. For the moment, there are very few allogenic skin substitutes available; they are expensive and have been insufficiently studied in the indication of leg ulcers. Pluripotent mesenchymal adult stem cells have proved capable of accelerating wound healing in animal models and their study in chronic wounds in humans is currently awaited.

  14. 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…

  15. 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.

  16. 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.

  17. Exploiting cytokines in adoptive T-cell therapy of cancer.

    PubMed

    Petrozziello, Elisabetta; Sturmheit, Tabea; Mondino, Anna

    2015-01-01

    Adoptive immunotherapy with tumor-reactive autologous T cells, either expanded from tumor specimens or genetically engineered to express tumor-reactive T-cell receptors and chimeric antigen receptors, is holding promising results in clinical trials. Several critical issues have been identified and results underline the possibility to exploit cytokines to further ameliorate the efficacy of current treatment protocols, also encompassing adoptive T-cell therapy. Here we review latest developments on the use of cytokines to better direct the nature of the T-cell infusion product, T-cell function and persistence in vivo, as well as to modulate the tumor microenvironment.

  18. Adoption

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Adoption KidsHealth > For Teens > Adoption Print A A A ... of Adoption en español La adopción What Is Adoption? Caz knew she'd been adopted as a ...

  19. Clinical application of adoptive T cell therapy in solid tumors

    PubMed Central

    Zang, Yi-Wen; Gu, Xiao-Dong; Xiang, Jian-Bin; Chen, Zong-You

    2014-01-01

    As an emerging therapeutic approach, adoptive T cell therapy shown promise in advanced solid malignancies. The results obtained in patients with metastatic melanoma and kidney cancer are encouraging because of the visible clinical benefits and limited adverse effects. Recently, the genetically-modified T cells expressing specific T cell receptors or chimeric antigen receptors are just now entering the clinical arena and show great potential for high avidity to tumor-associated antigens and long-lasting anti-tumor responses. However, continued investigations are necessary to improve the cell product quality so as to decrease adverse effects and clinical costs, and make adoptive T cell therapy a tool of choice for solid malignancies. PMID:24912947

  20. Transient stimulation expands superior antitumor T cells for adoptive therapy

    PubMed Central

    Kagoya, Yuki; Nakatsugawa, Munehide; Ochi, Toshiki; Guo, Tingxi; Anczurowski, Mark; Saso, Kayoko; Butler, Marcus O.

    2017-01-01

    Adoptive cell therapy is a potentially curative therapeutic approach for patients with cancer. In this treatment modality, antitumor T cells are exponentially expanded in vitro prior to infusion. Importantly, the results of recent clinical trials suggest that the quality of expanded T cells critically affects their therapeutic efficacy. Although anti-CD3 mAb-based stimulation is widely used to expand T cells in vitro, a protocol to generate T cell grafts for optimal adoptive therapy has yet to be established. In this study, we investigated the differences between T cell stimulation mediated by anti–CD3/CD28 mAb–coated beads and cell-based artificial antigen-presenting cells (aAPCs) expressing CD3/CD28 counter-receptors. We found that transient stimulation with cell-based aAPCs, but not prolonged stimulation with beads, resulted in the superior expansion of CD8+ T cells. Transiently stimulated CD8+ T cells maintained a stem cell–like memory phenotype and were capable of secreting multiple cytokines significantly more efficiently than chronically stimulated T cells. Importantly, the chimeric antigen receptor–engineered antitumor CD8+ T cells expanded via transient stimulation demonstrated superior persistence and antitumor responses in adoptive immunotherapy mouse models. These results suggest that restrained stimulation is critical for generating T cell grafts for optimal adoptive immunotherapy for cancer. PMID:28138559

  1. 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

  2. [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…

  3. 78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-25

    ... 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 Therapy... and Gene Therapies (OCTGT). The product areas covered by this guidance are cellular therapy,...

  4. Mechanically enhanced microcapsules for cellular gene therapy.

    PubMed

    Shen, F; Mazumder, M A J; Burke, N A D; Stöver, H D H; Potter, M A

    2009-07-01

    Microcapsules bearing a covalently cross-linked coating have been developed for cellular gene therapy as an improvement on alginate-poly(L-lysine)-alginate (APA) microcapsules that only have ionic cross-linking. In this study, two mutually reactive polyelectrolytes, a polycation (designated C70), poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride-co-2-aminoethyl methacrylate hydrochloride) and a polyanion (designated A70), poly(sodium methacrylate-co-2-(methacryloyloxy)ethyl acetoacetate), were used during the microcapsule fabrication. Ca-alginate beads were sequentially laminated with C70, A70, poly(L-lysine) (PLL), and alginate. The A70 reacts with both C70 and PLL to form a approximately 30 microm thick covalently cross-linked interpenetrating polymer network on the surface of the capsules. Confocal images confirmed the location of the C70/A70/PLL network and the stability of the network after 4 weeks implantation in mice. The mechanical and chemical resistance of the capsules was tested with a "stress test" where microcapsules were gently shaken in 0.003% EDTA for 15 min. APA capsules disappeared during this treatment, whereas the modified capsules, even those that had been retrieved from mice after 4-weeks implantation, remained intact. Analysis of solutions passing through model flat membranes showed that the molecular weight cut-off of alginate-C70-A70-PLL-alginate is similar to that of alginate-PLL-alginate. Recombinant cells encapsulated in APA and modified capsules were able to secrete luciferase into culture media. The modified capsules were found to capture some components of regular culture media used during preparation, causing an immune reaction in implanted mice, but use of UltraCulture serum-free medium was found to prevent this immune reaction. In vivo biocompatibility of the new capsules was similar to the APA capsules, with no sign of clinical toxicity on complete blood counts and liver function tests. The increased stability of the

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

    PubMed

    Chen, Yamei; Liu, Delong

    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.

  6. Adoption

    MedlinePlus

    ... biological families) and where they came from. This curiosity often becomes more intense as part of the ... adoptive family or feel close to them. This curiosity, which can feel quite intense, is a normal ...

  7. 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

  8. Biopolymer implants enhance the efficacy of adoptive T cell therapy

    PubMed Central

    Stephan, Sirkka B.; Taber, Alexandria M.; Jileaeva, Ilona; Pegues, Ericka P.; Sentman, Charles L.; Stephan, Matthias T.

    2014-01-01

    Although adoptive T cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and their inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely-removed tumors by situating implants near them, or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold-based T cell delivery may provide a viable treatment option for inoperable tumors, and reduce the rate of metastatic relapse after surgery. PMID:25503382

  9. Cellular therapy for sickle cell disease.

    PubMed

    Abraham, Allistair; Jacobsohn, David A; Bollard, Catherine M

    2016-11-01

    Sickle cell disease (SCD) is a monogenic red cell disorder affecting more than 300 000 annual births worldwide and leading to significant organ toxicity and premature mortality. Although chronic therapies such as hydroxyurea have improved outcomes, more durable therapeutic and curative options are still being investigated. Newer understanding of the disease has implicated invariant natural killer T cells as a critical immune profile that potentiates SCD. Hence, targeting this cell population may offer a new approach to disease management. Hematopoietic stem cell transplant is a curative option for patients with SCD, but the under-representation of minorities on the unrelated donor registry means that this is not a feasible option for more than 75% of patients. Work in this area has therefore focused on increasing the donor pool and decreasing transplant-related toxicities to make this a treatment option for the majority of patients with SCD. This review focuses on the currently available cell and gene therapies for patients with SCD and acknowledges that newer gene-editing approaches to improve gene therapy efficiency and safety are the next wave of potentially curative approaches.

  10. Opportunities and limitations of natural killer cells as adoptive therapy for malignant disease.

    PubMed

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

    2014-11-01

    Although natural killer (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 synergize with or antagonize each other. Individuals display wide differences in NK function that 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 anti-tumor activity. This can be achieved through selection of killer immunoglobulin-like receptor-mismatched NK donors and by use of 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 maximize the cytotoxic potential of NK cells for adoptive transfer to treat human malignancies.

  11. 78 FR 43889 - Synergizing Efforts in Standards Development for Cellular Therapies and Regenerative Medicine...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-22

    ... 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 is... activities involving cellular therapies and regenerative medicine products. Date and Time: The...

  12. Determinants of clinician adoption of regenerative therapies in the UK and Canada: an ophthalmology perspective.

    PubMed

    Rose, James B; May, Michael; Williams, David J

    2015-05-01

    The determinants of adoption of regenerative medicine therapies are currently poorly understood. This study aims to draw comparison between the UK and Canada in terms of factors likely to affect healthcare adoption of future regenerative therapies in ophthalmology. Conducting semi-structured interviews with senior ophthalmologists in the UK and Canada, their perceptions of factors either enabling or limiting adoption were recorded and analyzed. A number of key concepts were extracted from the interview data, perceived by stakeholders to contribute to adoption. The core factors developed in this work will be of use to those looking to understand the opportunities and risks involved in securing clinician adoption in both the UK and Canada.

  13. 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

  14. 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…

  15. 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... for Biologics Research and Evaluation (CBER), Office of Cellular, Tissue, and Gene Therapies (OCTGT). The product areas covered by this guidance are cellular therapy, gene therapy, therapeutic...

  16. 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.

  17. 77 FR 65693 - Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ... HUMAN SERVICES Food and Drug Administration Cellular, Tissue and Gene Therapies Advisory Committee... Register of October 17, 2012, FDA announced that a meeting of the Cellular, Tissue and Gene Therapies..., Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, FDA. On...

  18. 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...

  19. 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

    ... Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011. The guidance document provides manufacturers of cellular and gene therapy (CGT) products with recommendations for developing... document entitled ``Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products''...

  20. 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

  1. Advancing the cellular and molecular therapy for intervertebral disc disease.

    PubMed

    Sakai, Daisuke; Grad, Sibylle

    2015-04-01

    The healthy intervertebral disc (IVD) fulfils the essential function of load absorption, while maintaining multi-axial flexibility of the spine. The interrelated tissues of the IVD, the annulus fibrosus, the nucleus pulposus, and the cartilaginous endplate, are characterised by their specific niche, implying avascularity, hypoxia, acidic environment, low nutrition, and low cellularity. Anabolic and catabolic factors balance a slow physiological turnover of extracellular matrix synthesis and breakdown. Deviations in mechanical load, nutrient supply, cellular activity, matrix composition and metabolism may initiate a cascade ultimately leading to tissue dehydration, fibrosis, nerve and vessel ingrowth, disc height loss and disc herniation. Spinal instability, inflammation and neural sensitisation are sources of back pain, a worldwide leading burden that is challenging to cure. In this review, advances in cell and molecular therapy, including mobilisation and activation of endogenous progenitor cells, progenitor cell homing, and targeted delivery of cells, genes, or bioactive factors are discussed.

  2. Emerging cellular and gene therapies for congenital anemias.

    PubMed

    Ludwig, Leif S; Khajuria, Rajiv K; Sankaran, Vijay G

    2016-12-01

    Congenital anemias comprise a group of blood disorders characterized by a reduction in the number of peripherally circulating erythrocytes. Various genetic etiologies have been identified that affect diverse aspects of erythroid physiology and broadly fall into two main categories: impaired production or increased destruction of mature erythrocytes. Current therapies are largely focused on symptomatic treatment and are often based on transfusion of donor-derived erythrocytes and management of complications. Hematopoietic stem cell transplantation represents the only curative option currently available for the majority of congenital anemias. Recent advances in gene therapy and genome editing hold promise for the development of additional curative strategies for these blood disorders. The relative ease of access to the hematopoietic stem cell compartment, as well as the possibility of genetic manipulation ex vivo and subsequent transplantation in an autologous manner, make blood disorders among the most amenable to cellular therapies. Here we review cell-based and gene therapy approaches, and discuss the limitations and prospects of emerging avenues, including genome editing tools and the use of pluripotent stem cells, for the treatment of congenital forms of anemia. © 2016 Wiley Periodicals, Inc.

  3. Three-dimensional culture and bioreactors for cellular therapies.

    PubMed

    Naing, M W; Williams, D J

    2011-04-01

    A bioreactor is defined as a specifically designed vessel to facilitate the growth of organisms and cells through application of physical and/or electrical stimulus. When cells with therapeutic potential were first discovered, they were initially cultured and expanded in two-dimensional (2-D) culture vessels such as plates or T-flasks. However, it was soon discovered that bioreactors could be used to expand and maintain cultures more easily and efficiently. Since then, bioreactors have come to be accepted as an indispensable tool to advance cell and tissue culture further. A wide array of bioreactors has been developed to date, and in recent years businesses have started supplying bioreactors commercially. Bioreactors in the research arena range from stirred tank bioreactors for suspension culture to those with various mechanical actuators that can apply different fluidic and mechanical stresses to tissues and three-dimensional (3-D) scaffolds. As regenerative medicine gains more traction in the clinic, bioreactors for use with cellular therapies are being developed and marketed. While many of the simpler bioreactors are fit for purpose, others fail to satisfy the complex requirements of tissues in culture. We have examined the use of different types of bioreactors in regenerative medicine and evaluated the application of bioreactors in the realization of emerging cellular therapies.

  4. Coupled cellular therapy and magnetic targeting for airway regeneration.

    PubMed

    Ordidge, Katherine L; Gregori, Maria; Kalber, Tammy L; Lythgoe, Mark F; Janes, Sam M; Giangreco, Adam

    2014-06-01

    Airway diseases including COPD (chronic obstructive pulmonary disease), cystic fibrosis and lung cancer are leading causes of worldwide morbidity and mortality, with annual healthcare costs of billions of pounds. True regeneration of damaged airways offers the possibility of restoring lung function and protecting against airway transformation. Recently, advances in tissue engineering have allowed the development of cadaveric and biosynthetic airway grafts. Although these have produced encouraging results, the ability to achieve long-term functional airway regeneration remains a major challenge. To promote regeneration, exogenously delivered stem and progenitor cells are being trialled as cellular therapies. Unfortunately, current evidence suggests that only small numbers of exogenously delivered stem cells engraft within lungs, thereby limiting their utility for airway repair. In other organ systems, magnetic targeting has shown promise for improving long-term robust cell engraftment. This technique involves in vitro cell expansion, magnetic actuation and magnetically guided cell engraftment to sites of tissue damage. In the present paper, we discuss the utility of coupling stem cell-mediated cellular therapy with magnetic targeting for improving airway regeneration.

  5. Small Multifunctional Nanoclusters (Nanoroses) for Targeted Cellular Imaging and Therapy

    PubMed Central

    Ma, Li Leo; Feldman, Marc D.; Tam, Jasmine M.; Paranjape, Amit S.; Cheruku, Kiran K.; Larson, Timothy A.; Tam, Justina O.; Ingram, Davis R.; Paramita, Vidia; Villard, Joseph W.; Jenkins, James T.; Wang, Tianyi; Clarke, Geoffrey D.; Asmis, Reto; Sokolov, Konstantin; Chandrasekar, Bysani; Milner, Thomas E.; Johnston, Keith P.

    2010-01-01

    The ability of 20–50 nm nanoparticles to target and modulate the biology of specific types of cells will enable major advancements in cellular imaging and therapy in cancer and atherosclerosis. A key challenge is to load an extremely high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. Herein we report ~30 nm stable uniformly sized near-infrared (NIR) active, superparamagnetic nanoclusters formed by kinetically controlled self-assembly of gold-coated iron oxide nanoparticles. The controlled assembly of nanocomposite particles into clusters with small primary particle spacings produces collective responses of the electrons that shift the absorbance into the NIR region. The nanoclusters of ~70 iron oxide primary particles with thin gold coatings display intense NIR (700–850 nm) absorbance with a cross section of ~10−14 m2. Because of the thin gold shells with an average thickness of only 2 nm, the r2 spin–spin magnetic relaxivity is 219 mM−1 s−1, an order of magnitude larger than observed for typical iron oxide particles with thicker gold shells. Despite only 12% by weight polymeric stabilizer, the particle size and NIR absorbance change very little in deionized water over 8 months. High uptake of the nanoclusters by macrophages is facilitated by the dextran coating, producing intense NIR contrast in dark field and hyperspectral microscopy, both in cell culture and an in vivo rabbit model of atherosclerosis. Small nanoclusters with optical, magnetic, and therapeutic functionality, designed by assembly of nanoparticle building blocks, offer broad opportunities for targeted cellular imaging, therapy, and combined imaging and therapy. PMID:19711944

  6. [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.

  7. 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.

  8. 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...

  9. 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..., Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, and...

  10. 78 FR 79699 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-31

    ... No. FDA-2013-N-0001] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting... the public. Name of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General..., Tissue, and Gene Therapies, Center for Biologics Evaluation and Research (CBER), FDA. On February...

  11. 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...

  12. Cellular Immunotherapy for Neuroblastoma: A Review of Current Vaccine and Adoptive T Cell Therapeutics

    PubMed Central

    Louis, C.U.; Brenner, M.K.

    2014-01-01

    Immunotherapy is an attractive option for patients with high risk neuroblastoma due to their poor long-term survival rates after conventional treatment. Neuroblastoma cells are derived from the embryonic neural crest and therefore express tumor antigens not widely seen in normal cells, making them potential targets for immunologic attack. There is already considerable experience with monoclonal antibodies that target these tumor associated antigens, and in this review we focus on more exploratory approaches, using tumor vaccines and adoptive transfer of tumor-directed T cells. PMID:19199969

  13. 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

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

    PubMed

    Adhvaryu, Achyuta

    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.

  15. 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

  16. 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

  17. 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

  18. 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...

  19. Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants

    PubMed Central

    Kaluza, Karen M.; Thompson, Jill M.; Kottke, Timothy J.; Flynn Gilmer, Heather C.; Knutson, Darlene L.; Vile, Richard G.

    2014-01-01

    Adoptive T cell therapy has proven effective against melanoma in mice and humans. However, because most responses are incomplete or transient, cures remain rare. To maximize the efficacy of this therapy, it will be essential to gain a better understanding of the processes which result in tumor relapse. We studied these processes using B16ova murine melanoma and adoptive transfer of OT-I T cells. Transfer of T cells as a single therapy provided a significant survival benefit for mice with established subcutaneous tumors. However, tumors which initially regressed often recurred. By analyzing tumors which emerged in the presence of a potent OT-I response, we identified a novel tumor escape mechanism in which tumor cells evaded T cell pressure by undergoing major genomic changes involving loss of the gene encoding the target tumor antigen. Furthermore, we show that these in vivo processes can be recapitulated in vitro using T cell/tumor cell co-cultures. A single round of in vitro co-culture led to significant loss of the ova gene and a tumor cell population with rapidly induced and diverse karyotypic changes. Although these current studies focus on the model OVA antigen, the finding that T cells can directly promote genomic instability has important implications for the development of adoptive T cell therapies. PMID:21935923

  20. Adoptive transfer of experimental autoimmune hepatitis in mice: cellular interaction between donor and recipient mice

    PubMed Central

    Ogawa, M.; Mori, Y.; Mori, T.; Ueda, S.; Yoshida, H.; Kato, I.; Iesato, K.; Wakashin, Y.; Azemoto, R.; Wakashin, M.; Okuda, K.; Ohto, M.

    1988-01-01

    This report extends our previous study on experimental autoimmune hepatitis in C57BL/6 (B6) mice. Cellular immunity involved in the induction of liver injury in this model was studied by transfer of primed spleen cells from hepatitis donor mice to syngeneic normal recipient mice. The most prominent liver damage in recipient B6 mice was induced by transfer of nylon wool adherent spleen cells from hepatitis donor mice, and T cells in this fraction were the essential requirement for the liver damage in the recipient mice. Nylon wool adherent spleen cells from hepatitis donor mice after depletion of the suppressor T-cell function by low-dose (300 rad) irradiation induced more severe liver injury compared to the same cells without irradiation. When the recipient mice were depleted of lymphocytes by low or high dose (700 rad) whole body irradiation, transfer of primed spleen cells from hepatitis donor mice did not induce liver lesion in the lymphocyte-depleted mice. This low susceptibility of lymphocyte-depleted recipient mice to primed spleen cells of hepatitis mice was no longer demonstrated after reconstitution with normal spleen cells. In a cell-migration study using 51Cr-labelled spleen cells, it was shown that a considerable number of infiltrating cells in the liver of recipient mice were derived from recipient mice themselves. These results seem to indicate that cell-to-cell interaction between radiosensitive precursor cells of recipient mice and liver-antigen-primed T cells from hepatitis donor mice play an essential role in the induction of liver injury in the recipient mice. ImagesFig. 1 PMID:3052945

  1. 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

  2. 75 FR 67987 - Guidance for Industry: Cellular Therapy for Cardiac Disease; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-04

    ... No. FDA-2009-D-0132] Guidance for Industry: Cellular Therapy for Cardiac Disease; Availability AGENCY... Disease'' dated October 2010. The guidance document provides sponsors who are developing cellular therapies for the treatment of cardiac disease with recommendations on the design of preclinical...

  3. 78 FR 15726 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-12

    ... 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 Gene Therapies Advisory Committee. General Function of the Committee: To provide advice and recommendations...

  4. 76 FR 18768 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-05

    ... 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 Gene Therapies Advisory Committee. General Function of the Committee: To provide advice and recommendations...

  5. 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...

  6. Use and Adoption of an Assisted Cognition System to Support Therapies for People with Dementia

    PubMed Central

    Favela, Jesús

    2016-01-01

    The cognitive deficits in persons with dementia (PwD) can produce significant functional impairment from early stages. Although memory decline is most prominent, impairments in attention, orientation, language, reasoning, and executive functioning are also common. Dementia is also characterized by changes in personality and behavioral functioning that can be very challenging for caregivers and patients. This paper presents results on the use and adoption of an assisted cognition system to support occupational therapy to address psychological and behavioral symptoms of dementia. During 16 weeks, we conducted an in situ evaluation with two caregiver-PwD dyads to assess the adoption and effectiveness of the system to ameliorate challenging behaviors and reducing caregiver burden. Evaluation results indicate that intervention personalization and a touch-based interface encouraged the adoption of the system, helping reduce challenging behaviors in PwD and caregiver burden. PMID:27648106

  7. Use and Adoption of an Assisted Cognition System to Support Therapies for People with Dementia.

    PubMed

    Navarro, René F; Rodríguez, Marcela D; Favela, Jesús

    2016-01-01

    The cognitive deficits in persons with dementia (PwD) can produce significant functional impairment from early stages. Although memory decline is most prominent, impairments in attention, orientation, language, reasoning, and executive functioning are also common. Dementia is also characterized by changes in personality and behavioral functioning that can be very challenging for caregivers and patients. This paper presents results on the use and adoption of an assisted cognition system to support occupational therapy to address psychological and behavioral symptoms of dementia. During 16 weeks, we conducted an in situ evaluation with two caregiver-PwD dyads to assess the adoption and effectiveness of the system to ameliorate challenging behaviors and reducing caregiver burden. Evaluation results indicate that intervention personalization and a touch-based interface encouraged the adoption of the system, helping reduce challenging behaviors in PwD and caregiver burden.

  8. Cellular therapy for ovarian cancer: experimental and clinical perspectives.

    PubMed

    Ingersoll, Susan B; Ahmad, Sarfraz; Finkler, Neil J; Edwards, John R; Holloway, Robert W

    2012-01-01

    Ovarian cancer is the leading cause of death among gynecologic malignancies and the 5th leading cause of cancer deaths for women in the United States. Two-thirds of patients present with advanced-stage disease (Stage III and IV) and the majority will suffer recurrence of disease, require ongoing treatment, and eventually succumb to chemotherapy-resistant disease. To potentially circumvent chemo-resistance in recurrent ovarian cancer, immunotherapy is being explored as a novel treatment option. Our laboratory findings demonstrate that immune effector cells from healthy donors elicit a significant cytotoxic response in the presence of IL-2 and IFN alpha- 2b against ovarian cancer in vitro; however, peripheral blood mononuclear cells (PBMC) isolated from ovarian cancer patients fail to elicit a similar response. A major obstacle to immunotherapy is the immunosuppressive environment supported by tumors, which limits the immune system's ability to fight the tumor. Myeloid-derived suppressor cells are an immature population of myeloid cells, which have recently been implicated to play a major role in immunosuppression and tumor evasion. In addition to novel immunotherapies, new diagnostic and prognostic markers are being identified through applying molecular tools/approaches in clinical and pathological analyses of this malignancy, which will provide additional therapeutic targets. To test these experimental therapeutic options, pre-clinical murine models of ovarian cancer are being developed. Ultimately, treatment of ovarian cancer will benefit from the careful alignment of appropriate target, drug, patient, and trial design. This article provides an objective overview of cellular therapy (the use of immune cells to elicit an anti-tumor response) for ovarian cancer highlighting both experimental and clinical perspectives.

  9. 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...

  10. Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes.

    PubMed

    Ugel, Stefano; Scarselli, Elisa; Iezzi, Manuela; Mennuni, Carmela; Pannellini, Tania; Calvaruso, Francesco; Cipriani, Barbara; De Palma, Raffaele; Ricci-Vitiani, Lucia; Peranzoni, Elisa; Musiani, Piero; Zanovello, Paola; Bronte, Vincenzo

    2010-02-18

    Telomerase reverse transcriptase (TERT) is a good candidate for cancer immunotherapy because it is overexpressed in 85% of all human tumors and implicated in maintenance of the transformed phenotype. TERT-based cancer vaccines have been shown to be safe, not inducing any immune-related pathology, but their impact on tumor progression is modest. Here we show that adoptive cell therapy with the use of high-avidity T lymphocytes reactive against telomerase can control the growth of different established tumors. Moreover, in transgenic adenocarcinoma mouse prostate mice, which develop prostate cancer, TERT-based adoptive cell therapy halted the progression to more aggressive and poorly differentiated tumors, significantly prolonging mouse survival. We also demonstrated that human tumors, including Burkitt lymphoma, and human cancer stem cells, are targeted in vivo by TERT-specific cytotoxic T lymphocytes. Effective therapy with T cells against telomerase, different from active vaccination, however, led to autoimmunity marked by a consistent, although transient, B-cell depletion in primary and secondary lymphoid organs, associated with alteration of the spleen cytoarchitecture. These results indicate B cells as an in vivo target of TERT-specific cytotoxic T lymphocytes during successful immunotherapy.

  11. Natural Killer Cell Adoptive Transfer Therapy: Exploiting the First Line of Defense Against Cancer.

    PubMed

    Davis, Zachary B; Felices, Martin; Verneris, Michael R; Miller, Jeffrey S

    2015-01-01

    Natural killer (NK) cells constitute an important component of the initial immunological response against transformed cells. However, chronic exposure to the tumor microenvironment can fundamentally alter the ability of NK cells to sufficiently control tumor progression. Thus, the adoptive transfer of healthy, functional NK cells as an interventional therapy has been an area of great interest for improving patient outcomes. Recent developments in the field have provided a better understanding of what makes the NK compartment effective against malignant cells. Moreover, there are now multiple potential sources of NK cell products for infusion as well as techniques to manipulate these cells to enhance their antitumor functions. This review explores the advantages and disadvantages of various sources of NK cells as well as prospective therapeutic enhancements to adoptively transferred NK cells.

  12. Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors.

    PubMed

    Abken, Hinrich

    2015-01-01

    Recent spectacular success in the adoptive cell therapy of leukemia and lymphoma with chimeric antigen receptor (CAR)-modified T cells raised the expectations that this therapy may be efficacious in a wide range of cancer entities. The expectations are based on the predefined specificity of CAR T cells by an antibody-derived binding domain that acts independently of the natural T-cell receptor, recognizes targets independently of presentation by the major histocompatibility complex and allows targeting toward virtually any cell surface antigen. We here discuss that targeting CAR T cells toward solid tumors faces certain circumstances critical for the therapeutic success. Targeting tumor stroma and taking advantage of TRUCK cells, in other words, CAR T cells with inducible release of a transgenic payload, are some strategies envisaged to overcome current limitations in the near future.

  13. Adoptive T-cell therapy for cancer: The era of engineered T cells.

    PubMed

    Bonini, Chiara; Mondino, Anna

    2015-09-01

    Tumors originate from a number of genetic events that deregulate homeostatic mechanisms controlling normal cell behavior. The immune system, devoted to patrol the organism against pathogenic events, can identify transformed cells, and in several cases cause their elimination. It is however clear that several mechanisms encompassing both central and peripheral tolerance limit antitumor immunity, often resulting into progressive diseases. Adoptive T-cell therapy with either allogeneic or autologous T cells can transfer therapeutic immunity. To date, genetic engineering of T cells appears to be a powerful tool for shaping tumor immunity. In this review, we discuss the most recent achievements in the areas of suicide gene therapy, and TCR-modified T cells and chimeric antigen receptor gene-modified T cells. We provide an overview of current strategies aimed at improving the safety and efficacy of these approaches, with an outlook on prospective developments.

  14. Antibodies: Immunoconjugates and autologous cellular therapy in acute lymphoblastic leukemia.

    PubMed

    Advani, Anjali

    2015-01-01

    Using a case study of a 57-year-old man with relapsed/refractory precursor-B (pre-B) acute lymphoblastic leukemia (ALL), this review discusses treatment with immunoconjugates and autologous therapy in acute ALL. Three therapies--blinatumomab, inotuzumab, and CAR T cells--are considered here, each with advantages in specific clinical situations. These therapies represent some of the exciting advances that have been made in the treatment of ALL over the last several years.

  15. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

    PubMed Central

    Koehler, Philipp; Schmidt, Patrick; Hombach, Andreas A.; Hallek, Michael; Abken, Hinrich

    2012-01-01

    B-cell chronic lymphocytic leukaemia (B-CLL) remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR) which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells. PMID:21837241

  16. Peers, Regulators, and Professions: The Influence of Organizations in Intensive Insulin Therapy Adoption

    PubMed Central

    Campion, Thomas R.; Gadd, Cynthia S.

    2011-01-01

    Following the landmark Leuven study in 2001, health care organizations implemented intensive insulin therapy (IIT) as the standard of care for critically ill patients. However, a recent meta-analysis showed no mortality benefit and an increased safety risk for patients treated with IIT. IIT affects labor and capital decisions related to nurses, physicians, pharmacists, managers, laboratory personnel, and informatics staff. The expenditure of labor and capital to provide IIT without corresponding outcome improvements suggests the adoption of IIT produces inefficiency in hospitals. In sociology and organizational studies, the tendency for organizations to become more similar without necessarily becoming more efficient is called institutional isomorphism. Institutional isomorphism examines the pressure organizations encounter from peers, regulators, and professions through mimetic, coercive, and normative mechanisms, respectively. To enhance their prospects of survival, organizations establish and maintain legitimacy by adopting socially acceptable approaches to work endorsed by successful peer organizations, regulatory agencies, and professional societies. In this paper, the authors describe how organizational influence—through the Leuven study, the Joint Commission, and professional organizations—played a role in the widespread adoption of IIT. Divergence from institutionalized forms may explain variation in IIT studies following Leuven. Healthcare researchers, practitioners, and managers should consider organizational influence when implementing large scale clinical activities. PMID:19369854

  17. Cellular Therapies for Muscular Dystrophies: Frustrations and Clinical Successes.

    PubMed

    Negroni, Elisa; Bigot, Anne; Butler-Browne, Gillian S; Trollet, Capucine; Mouly, Vincent

    2016-02-01

    Cell-based therapy for muscular dystrophies was initiated in humans after promising results obtained in murine models. Early trials failed to show substantial clinical benefit, sending researchers back to the bench, which led to the discovery of many hurdles as well as many new venues to optimize this therapeutic strategy. In this review we summarize progress in preclinical cell therapy approaches, with a special emphasis on human cells potentially attractive for human clinical trials. Future perspectives for cell therapy in skeletal muscle are discussed, including the perspective of combined therapeutic approaches.

  18. Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice.

    PubMed

    Lu, Yuanqing; Tang, Mei; Wasserfall, Clive; Kou, Zhongchen; Campbell-Thompson, Martha; Gardemann, Thomas; Crawford, James; Atkinson, Mark; Song, Sihong

    2006-06-01

    An imbalance of the immune-regulatory pathways plays an important role in the development of type 1 diabetes. Therefore, immunoregulatory and antiinflammatory strategies hold great potential for the prevention of this autoimmune disease. Studies have demonstrated that two serine proteinase inhibitors, alpha1-antitrypsin (AAT) and elafin, act as potent antiinflammatory agents. In the present study, we sought to develop an efficient gene therapy approach to prevent type 1 diabetes. Cohorts of 4-week-old female nonobese diabetic (NOD) mice were injected intramuscularly with rAAV1-CB-hAAT, rAAV1-CB-hElafin, or saline. AAV1 vector mediated sustained high levels of transgene expression, sufficient to overcome a humoral immune response against hAAT. AAT gene therapy, contrary to elafin and saline, was remarkably effective in preventing type 1 diabetes. T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice. Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction. This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model. These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes.

  19. Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

    PubMed Central

    Redeker, Anke; Arens, Ramon

    2016-01-01

    Adoptive cellular therapy (ACT) is a form of immunotherapy whereby antigen-specific T cells are isolated or engineered, expanded ex vivo, and transferred back to patients. Clinical benefit after ACT has been obtained in treatment of infection, various hematological malignancies, and some solid tumors; however, due to poor functionality and persistence of the transferred T cells, the efficacy of ACT in the treatment of most solid tumors is often marginal. Hence, much effort is undertaken to improve T cell function and persistence in ACT and significant progress is being made. Herein, we will review strategies to improve ACT success rates in the treatment of cancer and infection. We will deliberate on the most favorable phenotype for the tumor-specific T cells that are infused into patients and on how to obtain T cells bearing this phenotype by applying novel ex vivo culture methods. Moreover, we will discuss T cell function and persistence after transfer into patients and how these factors can be manipulated by means of providing costimulatory signals, cytokines, blocking antibodies to inhibitory molecules, and vaccination. Incorporation of these T cell stimulation strategies and combinations of the different treatment modalities are likely to improve clinical response rates further. PMID:27656185

  20. Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination.

    PubMed

    Redeker, Anke; Arens, Ramon

    2016-01-01

    Adoptive cellular therapy (ACT) is a form of immunotherapy whereby antigen-specific T cells are isolated or engineered, expanded ex vivo, and transferred back to patients. Clinical benefit after ACT has been obtained in treatment of infection, various hematological malignancies, and some solid tumors; however, due to poor functionality and persistence of the transferred T cells, the efficacy of ACT in the treatment of most solid tumors is often marginal. Hence, much effort is undertaken to improve T cell function and persistence in ACT and significant progress is being made. Herein, we will review strategies to improve ACT success rates in the treatment of cancer and infection. We will deliberate on the most favorable phenotype for the tumor-specific T cells that are infused into patients and on how to obtain T cells bearing this phenotype by applying novel ex vivo culture methods. Moreover, we will discuss T cell function and persistence after transfer into patients and how these factors can be manipulated by means of providing costimulatory signals, cytokines, blocking antibodies to inhibitory molecules, and vaccination. Incorporation of these T cell stimulation strategies and combinations of the different treatment modalities are likely to improve clinical response rates further.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. Immunostimulatory Effects of Melphalan and Usefulness in Adoptive Cell Therapy with Antitumor CD4+ T Cells

    PubMed Central

    Kuczma, Michal; Ding, Zhi-Chun; Zhou, Gang

    2017-01-01

    The alkylating agent melphalan is used in the treatment of hematological malignancies, especially multiple myeloma. In the past, the usefulness of melphalan has been solely attributed to its cytotoxicity on fast-growing cancerous cells. Although the immunomodulatory effects of melphalan were suggested many years ago, only recently has this aspect of melphalan’s activity begun to be elucidated at the molecular level. Emerging evidence indicates that melphalan can foster an immunogenic microenvironment by inducing immunogenic cell death (ICD) as characterized by membrane translocation of endoplasmic reticulum protein calreticulin (CRT) and by release of chromatin-binding protein high-mobility group box 1 (HMGB1). In addition, the lympho-depletive effect of melphalan can induce the release of pro-inflammatory cytokines and growth factors, deplete regulatory T cells, and create space to facilitate the expansion of infused tumor-reactive T cells. These features suggest that melphalan can be used as a preparative chemotherapy for adoptive T-cell therapy. This notion is supported by our recent work demonstrating that the combination of melphalan and adoptive transfer of tumor-reactive CD4+ T cells can mediate potent antitumor effects in animal models. This review summarizes the recent advances in understanding and utilizing the immunomodulatory effects of melphalan. PMID:27910767

  7. Elimination of metastatic melanoma using gold nanoshell-enabled photothermal therapy and adoptive T cell transfer.

    PubMed

    Bear, Adham S; Kennedy, Laura C; Young, Joseph K; 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.

  8. Tumor exosomes: cellular postmen of cancer diagnosis and personalized therapy.

    PubMed

    Sharma, Aman; Khatun, Zamila; Shiras, Anjali

    2016-02-01

    Nanosized (30-150 nm) extracellular vesicles 'exosomes' are secreted by cells for intercellular communication during normal and pathological conditions. Exosomes carry biomacromolecules from cell-of-origin and, therefore, represent molecular bioprint of the cell. Tumor-derived exosomes or TDEx modulate tumor microenvironment by transfer of macromolecules locally as well as at distant metastatic sites. Due to their biological stability, TDEx are rich source of biomarkers in cancer patients. TDEx focused cancer diagnosis allows liquid biopsy-based tumor typing and may facilitate therapy response monitoring by developing novel exosomes diagnostics. Therefore, efficient and specific capturing of exosomes for subsequent amplification of the biomessages; for example, DNA, RNA, miRNA can reinvent cancer diagnosis. Here, in this review, we discuss advancements in exosomes isolation strategies, presence of exosomes biomarkers and importance of TDEx in gauging tumor heterogeneity for their potential use in cancer diagnosis, therapy.

  9. Equine cellular therapy--from stall to bench to bedside?

    PubMed

    Burk, Janina; Badylak, Stephen F; Kelly, Jeremy; Brehm, Walter

    2013-01-01

    Pioneering clinical stem cell research is being performed in the horse, a recipient of cutting edge veterinary medicine as well as a unique animal model, paving the way for human medical applications. Although demonstrable progress has been made on the clinical front, in vitro characterization of equine stem cells is still in comparatively early stages. To translate the promising results of clinical stem cell therapy in the horse, advances must be made in the characterization of equine stem cells. Aiming to improve communication between veterinarians and other natural scientists, this review gives an overview of veterinary "bedside" achievements, focusing on stem cell therapies in equine orthopedics as well as the current state of in vitro characterization of equine multipotent mesenchymal stromal cells (MSCs) and equine embryonic stem cells (ESCs).

  10. 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

  11. Neonatal cellular and gene therapies for mucopolysaccharidoses: the earlier the better?

    PubMed

    Tomatsu, Shunji; Azario, Isabella; Sawamoto, Kazuki; Pievani, Alice Silvia; Biondi, Andrea; Serafini, Marta

    2016-03-01

    Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs). The increasing interest in newborn screening procedures for LSDs underlines the need for alternative cellular and gene therapy approaches to be developed during the perinatal period, supporting the treatment of MPS patients before the onset of clinical signs and symptoms. The rationale for considering these early therapies results from the clinical experience in the treatment of MPSs and other genetic disorders. The normal or gene-corrected hematopoiesis transplanted in patients can produce the missing protein at levels sufficient to improve and/or halt the disease-related abnormalities. However, these current therapies are only partially successful, probably due to the limited efficacy of the protein provided through the hematopoiesis. An alternative explanation is that the time at which the cellular or gene therapy procedures are performed could be too late to prevent pre-existing or progressive organ damage. Considering these aspects, in the last several years, novel cellular and gene therapy approaches have been tested in different animal models at birth, a highly early stage, showing that precocious treatment is critical to prevent long-term pathological consequences. This review provides insights into the state-of-art accomplishments made with neonatal cellular and gene-based therapies and the major barriers that need to be overcome before they can be implemented in the medical community.

  12. Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough?

    PubMed

    Kwon, Brian K; Soril, Lesley J J; Bacon, Mark; Beattie, Michael S; Blesch, Armin; Bresnahan, Jacqueline C; Bunge, Mary Bartlett; Dunlop, Sarah A; Fehlings, Michael G; Ferguson, Adam R; Hill, Caitlin E; Karimi-Abdolrezaee, Soheila; Lu, Paul; McDonald, John W; Müller, Hans W; Oudega, Martin; Rosenzweig, Ephron S; Reier, Paul J; Silver, Jerry; Sykova, Eva; Xu, Xiao-Ming; Guest, James D; Tetzlaff, Wolfram

    2013-10-01

    Cellular therapies represent a novel treatment approach for spinal cord injury (SCI), with many different cellular substrates showing promise in preclinical animal models of SCI. Considerable interest therefore exists to translate such cellular interventions into human clinical trials. Balanced against the urgency for clinical translation is the desire to establish the robustness of a cellular therapy's efficacy in preclinical studies, thereby optimizing its chances of succeeding in human trials. Uncertainty exists, however, on the extent to which a therapy needs to demonstrate efficacy in the preclinical setting in order to justify the initiation of a lengthy, expensive, and potentially risky clinical trial. The purpose of this initiative was to seek perspectives on the level of evidence required in experimental studies of cellular therapies before proceeding with clinical trials of SCI. We conducted a survey of 27 SCI researchers actively involved in either preclinical and/or clinical research of cellular interventions for SCI, and then held a focus group meeting to facilitate more in-depth discussion around a number of translational issues. These included: the use of animal models, the use of injury models and mechanisms, the window for demonstrating efficacy, independent replication, defining "relevant, meaningful efficacy" in preclinical studies, and the expectation of therapeutic benefits for cellular interventions. Here we present the key findings from both the survey and focus group meeting in order to summarize and underscore the areas of consensus and disagreement amongst the sampled researchers. It is anticipated that the knowledge generated from this initiative will help to incite future scientific discussions and expert guidelines towards translation of a cell therapy for persons with SCI.

  13. 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

  14. Cellular therapy and bioartificial approaches to liver replacement

    PubMed Central

    Wertheim, Jason A.; Baptista, Pedro M.; Soto-Gutierrez, Alejandro

    2013-01-01

    Purpose of review The success of liver transplantation has increased over the past 20 years due to improved immunosuppressive medications, surgical technique and donor-recipient selection. To date, the number of patients waiting for a liver transplant exceeds the number of transplants performed yearly by over a 2: 1 ratio. Despite efforts to expand the donor pool, mortality of patients waiting for a liver remains high due to the shortage of donor organs. Herein, we discuss options for liver replacement that are currently under development. Recent findings Extracorporeal bioactive liver perfusion devices were investigated in the late 1990s and preliminarily demonstrated safety but failed to show clinical efficacy. Current research is ongoing, but the focus has shifted to xenotransplantation of whole organs, organ engineering and cell transplantation. These new modalities are limited to small and large animal studies and each present unique advantages and limitations. Summary Discovery of new sources of organs or cells to replace a damaged liver may be the only long-term solution to provide definitive therapy to all patients who require transplantation. The past 2 years have seen notable achievements in xenotransplantation, tissue engineering and cell transplantation. Though challenges remain, now identified, they may be readily solved. PMID:22476224

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. The survey on cellular and engineered tissue therapies in Europe in 2011.

    PubMed

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

    2014-02-01

    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.

  2. GMP-compliant human adipose tissue-derived mesenchymal stem cells for cellular therapy.

    PubMed

    Aghayan, Hamid-Reza; Goodarzi, Parisa; Arjmand, Babak

    2015-01-01

    Stem cells, which can be derived from different sources, demonstrate promising therapeutic evidences for cellular therapies. Among various types of stem cell, mesenchymal stem cells are one of the most common stem cells that are used in cellular therapy. Human subcutaneous adipose tissue provides an easy accessible source of mesenchymal stem cells with some considerable advantages. Accordingly, various preclinical and clinical investigations have shown enormous potential of adipose-derived stromal cells in regenerative medicine. Consequently, increasing clinical applications of these cells has elucidated the importance of safety concerns regarding clinical transplantation. Therefore, clinical-grade preparation of adipose-derived stromal cells in accordance with current good manufacturing practice guidelines is an essential part of their clinical applications to ensure the safety, quality, characteristics, and identity of cell products. Additionally, GMP-compliant cell manufacturing involves several issues to provide a quality assurance system during translation from the basic stem cell sciences into clinical investigations and applications. On the other hand, advanced cellular therapy requires extensive validation, process control, and documentation. It also evidently elucidates the critical importance of production methods and probable risks. Therefore, implementation of a quality management and assurance system in accordance with GMP guidelines can greatly reduce these risks particularly in the higher-risk category or "more than minimally manipulated" products.

  3. Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases

    PubMed Central

    Yarygin, Konstantin N.

    2017-01-01

    The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable. PMID:28210629

  4. Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases.

    PubMed

    Kholodenko, Irina V; Yarygin, Konstantin N

    2017-01-01

    The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.

  5. 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

  6. 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

  7. Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies.

    PubMed

    Besser, Michal J; Shoham, Tsipi; Harari-Steinberg, Orit; Zabari, Naama; Ortenberg, Rona; Yakirevitch, Arkadi; Nagler, Arnon; Loewenthal, Ron; Schachter, Jacob; Markel, Gal

    2013-01-01

    Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.

  8. 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.

  9. Cellular Therapies for Heart Disease: Unveiling the Ethical and Public Policy Challenges

    PubMed Central

    Raval, Amish N.; Kamp, Timothy J.; Hogle, Linda F.

    2008-01-01

    Cellular therapies have emerged as a potential revolutionary treatment for cardiovascular disease. Promising pre-clinical results have resulted in a flurry of basic research activity and spawned multiple clinical trials world-wide. However, the optimal cell type and delivery mode have not been determined for target patient populations. Nor has the mechanisms of benefit for the range of cellular interventions been clearly defined. Experiences to date have unveiled a myriad of ethical and public policy challenges which will affect the way researchers and clinicians make decisions for both basic and clinical research. Stem cells derived from embryos are at the forefront of the ethical and political debate, raising issues of which derivation methods are morally and socially permissible to pursue, as much as which are technically feasible. Adult stem cells are less controversial; however, important challenges exist in determining study design, cell processing, delivery mode, and target patient population. Pathways to successful commercialization and hence broad accessibility of cellular therapies for heart disease are only beginning to be explored. Comprehensive, multi-disciplinary and collaborative networks involving basic researchers, clinicians, regulatory officials and policymakers are required to share information, develop research, regulatory and policy standards and enable rational and ethical cell-based treatment approaches. PMID:18155721

  10. 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

  11. 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.

  12. CMV-Specific CD8 T Cell Differentiation and Localization: Implications for Adoptive Therapies.

    PubMed

    Smith, Corinne J; Quinn, Michael; Snyder, Christopher M

    2016-01-01

    Human cytomegalovirus (HCMV) is a ubiquitous virus that causes chronic infection and, thus, is one of the most common infectious complications of immune suppression. Adoptive transfer of HCMV-specific T cells has emerged as an effective method to reduce the risk for HCMV infection and/or reactivation by restoring immunity in transplant recipients. However, the CMV-specific CD8(+) T cell response is comprised of a heterogenous mixture of subsets with distinct functions and localization, and it is not clear if current adoptive immunotherapy protocols can reconstitute the full spectrum of CD8(+) T cell immunity. The aim of this review is to briefly summarize the role of these T cell subsets in CMV immunity and to describe how current adoptive immunotherapy practices might affect their reconstitution in patients. The bulk of the CMV-specific CD8(+) T cell population is made up of terminally differentiated effector T cells with immediate effector function and a short life span. Self-renewing memory T cells within the CMV-specific population retain the capacity to expand and differentiate upon challenge and are important for the long-term persistence of the CD8(+) T cell response. Finally, mucosal organs, which are frequent sites of CMV reactivation, are primarily inhabited by tissue-resident memory T cells, which do not recirculate. Future work on adoptive transfer strategies may need to focus on striking a balance between the formation of these subsets to ensure the development of long lasting and protective immune responses that can access the organs affected by CMV disease.

  13. CMV-Specific CD8 T Cell Differentiation and Localization: Implications for Adoptive Therapies

    PubMed Central

    Smith, Corinne J.; Quinn, Michael; Snyder, Christopher M.

    2016-01-01

    Human cytomegalovirus (HCMV) is a ubiquitous virus that causes chronic infection and, thus, is one of the most common infectious complications of immune suppression. Adoptive transfer of HCMV-specific T cells has emerged as an effective method to reduce the risk for HCMV infection and/or reactivation by restoring immunity in transplant recipients. However, the CMV-specific CD8+ T cell response is comprised of a heterogenous mixture of subsets with distinct functions and localization, and it is not clear if current adoptive immunotherapy protocols can reconstitute the full spectrum of CD8+ T cell immunity. The aim of this review is to briefly summarize the role of these T cell subsets in CMV immunity and to describe how current adoptive immunotherapy practices might affect their reconstitution in patients. The bulk of the CMV-specific CD8+ T cell population is made up of terminally differentiated effector T cells with immediate effector function and a short life span. Self-renewing memory T cells within the CMV-specific population retain the capacity to expand and differentiate upon challenge and are important for the long-term persistence of the CD8+ T cell response. Finally, mucosal organs, which are frequent sites of CMV reactivation, are primarily inhabited by tissue-resident memory T cells, which do not recirculate. Future work on adoptive transfer strategies may need to focus on striking a balance between the formation of these subsets to ensure the development of long lasting and protective immune responses that can access the organs affected by CMV disease. PMID:27695453

  14. 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.

  15. Sustained adoption of an evidence-based treatment: a survey of clinicians certified in problem-solving therapy.

    PubMed

    Crabb, Rebecca M; Areán, Patricia A; Hegel, Mark T

    2012-01-01

    Training models that incorporate case supervision in addition to didactic instruction appear to be effective in maximizing clinicians' proficiency in evidence-based treatments (EBTs). However, it is unknown the extent to which these models promote sustained adoption of EBTs. We describe the results of an online survey on post-training utilization of an EBT, problem-solving therapy (PST), among 40 clinicians highly trained in PST. Seventy-five percent of the survey's 40 respondents reported that they continued to use PST in their clinical practices. Many PST-trained clinicians reported that they had modified the PST protocol in their clinical practices according to patient characteristics or preferences. Considering these results, we recommend emphasizing patient variability and treatment tailoring throughout the training process as a means for promoting clinicians' sustained adoption of EBTs.

  16. 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…

  17. Low-dose ionizing radiation induces direct activation of natural killer cells and provides a novel approach for adoptive cellular immunotherapy.

    PubMed

    Yang, Guozi; Kong, Qingyu; Wang, Guanjun; Jin, Haofan; Zhou, Lei; Yu, Dehai; Niu, Chao; Han, Wei; Li, Wei; Cui, Jiuwei

    2014-12-01

    Recent evidence indicates that limited availability and cytotoxicity have restricted the development of natural killer (NK) cells in adoptive cellular immunotherapy (ACI). While it has been reported that low-dose ionizing radiation (LDIR) could enhance the immune response in animal studies, the influence of LDIR at the cellular level has been less well defined. In this study, the authors aim to investigate the direct effects of LDIR on NK cells and the potential mechanism, and explore the application of activation and expansion of NK cells by LDIR in ACI. The authors found that expansion and cytotoxicity of NK cells were markedly augmented by LDIR. The levels of IFN-γ and TNF-α in the supernatants of cultured NK cells were significantly increased after LDIR. Additionally, the effect of the P38 inhibitor (SB203580) significantly decreased the expanded NK cell cytotoxicity, cytokine levels, and expression levels of FasL and perforin. These findings indicate that LDIR induces a direct expansion and activation of NK cells through possibly the P38-MAPK pathway, which provides a potential mechanism for stimulation of NK cells by LDIR and a novel but simplified approach for ACI.

  18. Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors.

    PubMed

    Amara, Ikrame; Touati, Walid; Beaune, Philippe; de Waziers, Isabelle

    2014-10-01

    Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells of a suicide gene responsible for the in situ conversion of a prodrug into cytotoxic metabolites. One of the major impediments of GDEPT is to target specifically the tumor cells with the suicide gene. Among gene delivery methods, mesenchymal stem cells (MSCs) have emerged recently as potential cellular vehicles for gene delivery. MSCs are particularly suited for gene transduction. They exhibit remarkable migratory property towards tumors and their metastases and they are weakly immunogenic. This review will summarize the current knowledge about MSCs engineered to express different suicide genes (cytosine deaminase, thymidine kinase, carboxylesterase, cytochrome P450) to elicit a significant antitumor response against brain tumors, ovarian, hepatocellular, pancreatic, renal or medullary thyroid carcinomas, breast or prostate cancer and pulmonary metastases. The potential side effects of these MSC-based tumor therapies will also be considered to highlight certain aspects that need to be improved prior to clinical use.

  19. 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

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

    PubMed

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

    2015-12-01

    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.

  1. Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care.

    PubMed

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

    2015-02-16

    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.

  2. 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.

  3. 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.

  4. Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice.

    PubMed

    Stromnes, Ingunn M; Blattman, Joseph N; Tan, Xiaoxia; Jeevanjee, Sara; Gu, Hua; Greenberg, Philip D

    2010-10-01

    The clinical use of adoptive immunotherapy with tumor-reactive T cells to treat established cancers is limited in part by the poor in vivo survival and function of the transferred T cells. Although administration of exogenous cytokines such as IL-2 can promote T cell survival, such strategies have many nonspecific activities and are often associated with toxicity. We show here that abrogating expression of Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of lymphocyte activation, in tumor-reactive CD8(+) T cells expanded ex vivo increased the efficacy of adoptive immunotherapy of disseminated leukemia in mice. Mechanistically, Cbl-b abrogation bypassed the requirement for exogenous IL-2 administration for tumor eradication in vivo. In addition, CD8(+) T cells lacking Cbl-b demonstrated a lower threshold for activation, better survival following target recognition and stimulation, and enhanced proliferative responses as a result of both IL-2-dependent and -independent pathways. Importantly, siRNA knockdown of Cbl-b in human CD8(+)CD28- effector T cell clones similarly restored IL-2 production and proliferation following target recognition independent of exogenous IL-2, enhanced IFN-γ production, and increased target avidity. Thus, abrogating Cbl-b expression in effector T cells may improve the efficacy of adoptive therapy of some human malignancies.

  5. Allogeneic cellular and autologous stem cell therapy for sickle cell disease: 'whom, when and how'.

    PubMed

    Freed, J; Talano, J; Small, T; Ricci, A; Cairo, M S

    2012-12-01

    Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.

  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. 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

  8. The survey on cellular and engineered tissue therapies in Europe in 2012.

    PubMed

    Martin, Ivan; 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.

  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. Large-scale Isolation of Highly Pure "Untouched" Regulatory T Cells in a GMP Environment for Adoptive Cell Therapy.

    PubMed

    Haase, Doreen; Puan, Kia Joo; Starke, Mireille; Lai, Tuck Siong; Soh, Melissa Yan Ling; Karunanithi, Iyswariya; San Luis, Boris; Poh, Tuang Yeow; Yusof, Nurhashikin; Yeap, Chun Hsien; Phang, Chew Yen; Chye, Willis Soon Yuan; Chan, Marieta; Koh, Mickey Boon Chai; Goh, Yeow Tee; Bertin-Maghit, Sebastien; Nardin, Alessandra; Ho, Liam Pock; Rotzschke, Olaf

    2015-01-01

    Adoptive cell therapy is an emerging treatment strategy for a number of serious diseases. Regulatory T (Treg) cells represent 1 cell type of particular interest for therapy of inflammatory conditions, as they are responsible for controlling unwanted immune responses. Initial clinical trials of adoptive transfer of Treg cells in patients with graft-versus-host disease were shown to be safe. However, obtaining sufficient numbers of highly pure and functional Treg cells with minimal contamination remains a challenge. We developed a novel approach to isolate "untouched" human Treg cells from healthy donors on the basis of negative selection using the surface markers CD49d and CD127. This procedure, which uses an antibody cocktail and magnetic beads for separation in an automated system (RoboSep), was scaled up and adapted to be compatible with good manufacturing practice conditions. With this setup we performed 9 Treg isolations from large-scale leukapheresis samples in a good manufacturing practice facility. These runs yielded sufficient numbers of "untouched" Treg cells for immediate use in clinical applications. The cell preparations consisted of viable highly pure FoxP3-positive Treg cells that were functional in suppressing the proliferation of effector T cells. Contamination with CD4 effector T cells was <10%. All other cell types did not exceed 2% in the final product. Remaining isolation reagents were reduced to levels that are considered safe. Treg cells isolated with this procedure will be used in a phase I clinical trial of adoptive transfer into leukemia patients developing graft-versus-host disease after stem cell transplantation.

  11. Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies.

    PubMed

    Davila, Marco L; Bouhassira, Diana C G; Park, Jae H; Curran, Kevin J; Smith, Eric L; Pegram, Hollie J; Brentjens, Renier

    2014-04-01

    The genetic modification of autologous T cells with chimeric antigen receptors (CARs) represents a breakthrough for gene engineering as a cancer therapy for hematologic malignancies. By targeting the CD19 antigen, we have demonstrated robust and rapid anti-leukemia activity in patients with heavily pre-treated and chemotherapy-refractory B cell acute lymphoblastic leukemia (B-ALL). We demonstrated rapid induction of deep molecular remissions in adults, which has been recently confirmed in a case report involving a child with B-ALL. In contrast to the results when treating B-ALL, outcomes have been more modest in patients with chronic lymphocytic leukemia (CLL) or other non-hodgkin's lymphoma (NHL). We review the clinical trial experience targeting B-ALL and CLL and speculate on the possible reasons for the different outcomes and propose potential optimization to CAR T cell therapy when targeting CLL or other indolent NHL. Lastly, we discuss the pre-clinical development and potential for clinical translation for using CAR T cells against multiple myeloma and acute myeloid leukemia. We highlight the potential risks and benefits by targeting these poor outcome hematologic malignancies.

  12. Colon Cancer Patient Information Seeking and the Adoption of Targeted Therapy for On-Label and Off-Label Indications

    PubMed Central

    Gray, Stacy W.; Armstrong, Katrina; DeMichele, Angela; Schwartz, J. Sanford; Hornik, Robert C.

    2009-01-01

    Background Despite the rise in publicly available cancer information little is known about the association between patient information seeking and the adoption of cancer technologies. We investigated the relationship between patient information seeking and awareness about and receipt of novel targeted therapy (TT) for colon cancer among patients for whom therapy is FDA approved and for whom therapy is not FDA approved. Methods A retrospective population-based survey of 633 colon cancer patients identified through the Pennsylvania Cancer Registry. Outcome measures were self-reported awareness about and receipt of TT (Avastintm and Erbituxtm). Results After adjusting for sociodemographic characteristics, high levels of treatment information seeking were strongly associated with hearing about TT (odds ratio [OR] 2.83; 95% confidence interval [CI] 1.49-5.38) and receiving TT (OR 3.22; 95% CI, 1.36-7.62). These associations were present for patients with metastatic disease where use of TT is FDA approved and for patients with localized disease where use of TT is not FDA approved (p-value for interactions 0.29). Internet and newspaper/magazine use was associated with hearing about TT (OR 2.88; 95% CI 1.40-5.94; OR 3.44; 95% CI 1.34-8.84). Seeking information from non-treating doctors was associated with hearing about and receiving TT (OR 1.95; 95% CI, 1.03-3.68; OR 2.64; 95% CI, 1.16-5.97). Conclusion Patient information seeking is related to the adoption of TT for colon cancer in both appropriate and inappropriate clinical settings. These findings emphasize the importance of exploring patient influence on physician prescribing patterns and understanding the impact of information seeking on cancer outcomes. PMID:19235785

  13. Adoptive T-cell therapy improves treatment of canine non–Hodgkin lymphoma post chemotherapy

    PubMed Central

    O'Connor, Colleen M.; Sheppard, Sabina; Hartline, Cassie A.; Huls, Helen; Johnson, Mark; Palla, Shana L.; Maiti, Sourindra; Ma, Wencai; Davis, R. Eric; Craig, Suzanne; Lee, Dean A.; Champlin, Richard; Wilson, Heather; Cooper, Laurence J. N.

    2012-01-01

    Clinical observations reveal that an augmented pace of T-cell recovery after chemotherapy correlates with improved tumor-free survival, suggesting the add-back of T cells after chemotherapy may improve outcomes. To evaluate adoptive immunotherapy treatment for B-lineage non-Hodgkin lymphoma (NHL), we expanded T cells from client-owned canines diagnosed with NHL on artificial antigen presenting cells (aAPC) in the presence of human interleukin (IL)-2 and IL-21. Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival. Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells. Therefore, chemotherapy can be used to modulate infused T-cell responses to enhance anti-tumor effects. The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches. PMID:22355761

  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. 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.

  16. 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

  17. Direct consumer access to physical therapy in Michigan: challenges to policy adoption.

    PubMed

    Shoemaker, Michael J

    2012-02-01

    Background. Michigan is 1 of only 4 states that require a physician referral or prescription before a consumer can receive treatment from a physical therapist.Objective. The purpose of the present analysis was to examine why the most recent attempts to pass direct access legislation in Michigan failed.Methods. The Policy Analysis Triangle approach, which considers the relevant actors, processes, and context in which a policy must be considered, was used to analyze legislative efforts to attain direct access in Michigan during the 2001–2002, 2003–2004, and 2005–2006 legislative sessions. Data sources included Michigan House and Senate legislative analyses, literature review, stakeholder position statements, political action committee contributions, and expert opinion.Results. Three successive direct access legislative attempts failed despite an increasing body of evidence supporting direct access and an increasing number of states allowing direct access. Proponents represented a relatively small number of individuals with limited political influence. Opponents represented a larger number of individuals who were able to exert greater political influence through large political action committee contributions and through physician legislators in positions of power who had influence over the bills' dispositions.Conclusions. Several prominent contextual and process-related barriers to policy adoption must be overcome in future attempts at direct access based on the findings from this analysis: (1) a limited constituency supporting direct access with regard to number of individuals and their political influence, (2) a perception that only the physician can independently diagnose and treat patient problems, and (3) legislators in positions of power who oppose a bill [corrected].

  18. Institutional profile. The International Society for Cellular Therapy: evolving to meet the demands of the regenerative medicine industry.

    PubMed

    Maziarz, Richard T; Arthurs, Jane; Horwitz, Edwin

    2011-03-01

    The International Society for Cellular Therapy is a global association driving the translation of scientific research to deliver innovative cellular therapies to patients. Established in 1992, its membership and leadership comprises world-class scientists, clinicians, technologists, biotech/pharma and regulatory professionals from 40 countries focused on preclinical and translational aspects of developing cell therapy products. The International Society for Cellular Therapy has evolved in alignment with the maturation of the field of cell therapy and regenerative medicine to create forums for discussion of shared concerns for commercialization of cell therapies and of development of consensus standards, recognizing that true commercialization depends upon the translational scientific community, the regional regulatory and policy institutions, and the technology support and capital investment from industry. It exists to facilitate the international work of many, to spawn new initiatives, and to synergize with other stakeholders to create the best outcome for the many patients across the world depending on the answers and improved health that cellular therapeutics will provide them.

  19. Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy

    PubMed Central

    Hasumi, Kenichiro; Aoki, Yukimasa; Wantanabe, Ryuko; Mann, Dean L

    2013-01-01

    Patients afflicted with advanced cancers were treated with the intratumoral injection of autologous immature dendritic cells (iDCs) followed by activated T-cell infusion and intensity-modulated radiation therapy (IMRT). A second round of iDCs and activated T cells was then administered to patients after the last radiation cycle. This complete regimen was repeated for new and recurring lesions after 6 weeks of follow-up. One year post therapy, outcome analyses were performed to evaluate treatment efficacy. Patients were grouped according to both the number and size of tumors and clinical parameters at treatment initiation, including recurrent disease after standard cancer therapy, Stage IV disease, and no prior therapy. Irrespective of prior treatment status, 23/37 patients with ≤ 5 neoplastic lesions that were ≤ 3 cm in diameter achieved complete responses (CRs), and 5/37 exhibited partial responses (PRs). Among 130 individuals harboring larger and more numerous lesions, CRs were observed in 7/74 patients that had received prior SCT and in 2/56 previously untreated patients. Some patients manifested immune responses including an increase in CD8+CD56+ lymphocytes among circulating mononuclear cells in the course of treatment. To prospectively explore the therapeutic use of these cells, CD8+ cells were isolated from patients that had been treated with cellular immunotherapy and IMRT, expanded in vitro, and injected into recurrent metastatic sites in 13 individuals who underwent the same immunoradiotherapeutic regimens but failed to respond. CRs were achieved in 34 of 58 of such recurrent lesions while PRs in 17 of 58. These data support the expanded use of immunoradiotherapy in advanced cancer patients exhibiting progressive disease. PMID:24349874

  20. 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

  1. Haploidentical Hematopoietic Stem Cell Transplantation as Platform for Post-transplant Cellular Therapy

    PubMed Central

    Kongtim, Piyanuch; Lee, Dean A.; Cooper, Laurence J. N.; Kebriaei, Partow; Champlin, Richard E.; Ciurea, Stefan O.

    2016-01-01

    Haploidentical transplantation can extend the opportunity for transplantation to almost all patients who lack an HLA-matched donor. Advances in the field of haploidentical transplantation have led to a marked decrease in treatment-related mortality, allowing investigators to focus on developing rationale pre- and peri-remission therapies aimed at preventing disease relapse post-transplant. Due to widespread availability, low treatment-related mortality and cost, haploidentical donors may become the preferred “alternative” donors for allogeneic hematopoietic stem cell transplantation. One of the major advantages of using a related donor is the possibility to collect or generate additional cellular products from the same immediate available donor, which will not be rejected. Infusion of these cells in the peri-transplant period, derived from the same immune system, is opening the possibility to markedly enhance the anti-tumor effects of the graft and hasten immunologic reconstitution post-transplant. PMID:26172479

  2. Toxicity and Efficacy Probability Interval Design for Phase I Adoptive Cell Therapy Dose-Finding Clinical Trials.

    PubMed

    Li, Daniel H; Whitmore, James B; Guo, Wentian; Ji, Yuan

    2017-01-01

    Recent trials of adoptive cell therapy (ACT), such as the chimeric antigen receptor (CAR) T-cell therapy, have demonstrated promising therapeutic effects for cancer patients. A main issue in the product development is to determine the appropriate dose of ACT. Traditional phase I trial designs for cytotoxic agents explicitly assume that toxicity increases monotonically with dose levels and implicitly assume the same for efficacy to justify dose escalation. ACT usually induces rapid responses, and the monotonic dose-response assumption is unlikely to hold due to its immunobiologic activities. We propose a toxicity and efficacy probability interval (TEPI) design for dose finding in ACT trials. This approach incorporates efficacy outcomes to inform dosing decisions to optimize efficacy and safety simultaneously. Rather than finding the maximum tolerated dose (MTD), the TEPI design is aimed at finding the dose with the most desirable outcome for safety and efficacy. The key features of TEPI are its simplicity, flexibility, and transparency, because all decision rules can be prespecified prior to trial initiation. We conduct simulation studies to investigate the operating characteristics of the TEPI design and compare it to existing methods. In summary, the TEPI design is a novel method for ACT dose finding, which possesses superior performance and is easy to use, simple, and transparent. Clin Cancer Res; 23(1); 13-20. ©2016 AACR.

  3. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

    PubMed Central

    Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

    2012-01-01

    Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

  4. Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy

    PubMed Central

    You, Xue-Mei; Cucchetti, Alessandro; Yuan, Bao-Hong; Li, Ru-Hong; Li, Le-Qun

    2017-01-01

    Aims The role of adoptive immunotherapy (AIT) for patients with hepatocellular carcinoma (HCC) who have received curative therapy is still not well illustrated. This timely meta-analysis aims to update the current evidence on efficacy and safety of AIT for patients with HCC who have received curative therapy. Methods We searched PubMed, EMBASE, Scopus and the Cochrane Library Through January 2017 for relevant studies. Mortality and tumor recurrence were compared between patients with or without adjuvant AIT. The meta-analysis was performed using Review Manager 5.3. Results Eight studies involving 1861 patients met the eligibility criteria and were meta-analyzed. Adjuvant AIT was associated with significantly lower mortality at 1 year (RR 0.64, 95%CI 0.52–0.79), 3 years (RR 0.73, 95%CI 0.65–0.81) and 5 years (RR 0.86, 95%CI 0.79–0.94). Similarly, adjuvant AIT was associated with significantly lower recurrence rate than curative therapies alone at 1 year (RR 0.64, 95%CI 0.49–0.82), 3 years (RR 0.85, 95%CI 0.79–0.91) and 5 years (RR 0.90, 95%CI 0.85–0.95). Short-term outcomes were confirmed in sensitivity analyses based on randomized trials or choice of random- or fixed-effect meta-analysis model. None of the included patients experienced grade 4 adverse events. Conclusions This timely meta-analysis confirms the evidence that adjuvant AIT for patients with HCC after curative treatment lowers risk of mortality and tumor recurrence. PMID:28339493

  5. 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

  6. 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

  7. Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

    PubMed Central

    2013-01-01

    Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, “direct” action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus “indirect” action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits. PMID:24147833

  8. 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.

  9. Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer.

    PubMed

    Ingersoll, Susan B; Ahmad, Sarfraz; McGann, Hasina C; Banks, Robert K; Stavitzski, Nicole M; Srivastava, Milan; Ali, Ghazanfar; Finkler, Neil J; Edwards, John R; Holloway, Robert W

    2015-09-01

    Studies have shown enhanced survival of ovarian cancer patients in which the tumors are infiltrated with tumor infiltrating lymphocytes and natural killer cells showing the importance of immune surveillance and recognition in ovarian cancer. Therefore, in this study, we tested cellular immunotherapy and varying combinations of cytokines (IL-2 and/or pegylated-IFNα-2b) in a xenograft mouse model of ovarian cancer. SKOV3-AF2 ovarian cancer cells were injected intra-peritoneally (IP) into athymic nude mice. On day 7 post-tumor cell injection, mice were injected IP with peripheral blood mononuclear cells (PBMC; 5 × 10(6) PBMC) and cytokine combinations [IL-2 ± pegylated-IFNα-2b (IFN)]. Cytokine injections were continued weekly for IFN (12,000 U/injection) and thrice weekly for IL-2 (4000 U/injection). Mice were euthanized when they became moribund due to tumor burden at which time tumor and ascitic fluid were measured and collected. Treatment efficacy was measured by improved survival at 8 weeks and overall survival by Kaplan-Meier analysis. We observed that the mice tolerated all treatment combinations without significant weight loss or other apparent illness. Mice receiving PBMC plus IL-2 showed improved median survival (7.3 weeks) compared to mice with no treatment (4.2 weeks), IL-2 (3.5 weeks), PBMC (4.0 weeks), or PBMC plus IL-2 and IFN (4.3 weeks), although PBMC plus IL-2 was not statistically different than PBMC plus IFN (5.5 weeks, p > 0.05). We demonstrate that cytokine-stimulated cellular immune therapy with PBMC and IL-2 was well tolerated and resulted in survival advantage compared to untreated controls and other cytokine combinations in the nude-mouse model.

  10. Dynamic contrast enhanced MRI detects early response to adoptive NK cellular immunotherapy targeting the NG2 proteoglycan in a rat model of glioblastoma.

    PubMed

    Rygh, Cecilie Brekke; Wang, Jian; Thuen, Marte; Gras Navarro, Andrea; Huuse, Else Marie; Thorsen, Frits; Poli, Aurelie; Zimmer, Jacques; Haraldseth, Olav; Lie, Stein Atle; Enger, Per Øyvind; Chekenya, Martha

    2014-01-01

    conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy.

  11. Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma

    PubMed Central

    Thuen, Marte; Gras Navarro, Andrea; Huuse, Else Marie; Thorsen, Frits; Poli, Aurelie; Zimmer, Jacques; Haraldseth, Olav; Lie, Stein Atle; Enger, Per Øyvind; Chekenya, Martha

    2014-01-01

    conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy. PMID:25268630

  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. Severe Developmental B Lymphopoietic Defects in Foxp3-Deficient Mice are Refractory to Adoptive Regulatory T Cell Therapy.

    PubMed

    Riewaldt, Julia; Düber, Sandra; Boernert, Marie; Krey, Martina; Dembinski, Marcin; Weiss, Siegfried; Garbe, Annette I; Kretschmer, Karsten

    2012-01-01

    The role of Foxp3-expressing regulatory T (T(reg)) cells in tolerance and autoimmunity is well-established. However, although of considerable clinical interest, the role of T(reg) cells in the regulation of hematopoietic homeostasis remains poorly understood. Thus, we analysed B and T lymphopoiesis in the scurfy (Sf) mouse model of T(reg) cell deficiency. In these experiments, the near-complete block of B lymphopoiesis in the BM of adolescent Sf mice was attributed to autoimmune T cells. We could exclude a constitutive lympho-hematopoietic defect or a B cell-intrinsic function of Foxp3. Efficient B cell development in the BM early in ontogeny and pronounced extramedullary B lymphopoietic activity resulted in a peripheral pool of mature B cells in adolescent Sf mice. However, marginal zone B and B-1a cells were absent throughout ontogeny. Developmental B lymphopoietic defects largely correlated with defective thymopoiesis. Importantly, neonatal adoptive T(reg) cell therapy suppressed exacerbated production of inflammatory cytokines and restored thymopoiesis but was ineffective in recovering defective B lymphopoiesis, probably due to a failure to compensate production of stroma cell-derived IL-7 and CXCL12. Our observations on autoimmune-mediated incapacitation of the BM environment in Foxp3-deficient mice will have direct implications for the rational design of BM transplantation protocols for patients with severe genetic deficiencies in functional Foxp3(+) T(reg) cells.

  14. Severe Developmental B Lymphopoietic Defects in Foxp3-Deficient Mice are Refractory to Adoptive Regulatory T Cell Therapy

    PubMed Central

    Riewaldt, Julia; Düber, Sandra; Boernert, Marie; Krey, Martina; Dembinski, Marcin; Weiss, Siegfried; Garbe, Annette I.; Kretschmer, Karsten

    2012-01-01

    The role of Foxp3-expressing regulatory T (Treg) cells in tolerance and autoimmunity is well-established. However, although of considerable clinical interest, the role of Treg cells in the regulation of hematopoietic homeostasis remains poorly understood. Thus, we analysed B and T lymphopoiesis in the scurfy (Sf) mouse model of Treg cell deficiency. In these experiments, the near-complete block of B lymphopoiesis in the BM of adolescent Sf mice was attributed to autoimmune T cells. We could exclude a constitutive lympho-hematopoietic defect or a B cell-intrinsic function of Foxp3. Efficient B cell development in the BM early in ontogeny and pronounced extramedullary B lymphopoietic activity resulted in a peripheral pool of mature B cells in adolescent Sf mice. However, marginal zone B and B-1a cells were absent throughout ontogeny. Developmental B lymphopoietic defects largely correlated with defective thymopoiesis. Importantly, neonatal adoptive Treg cell therapy suppressed exacerbated production of inflammatory cytokines and restored thymopoiesis but was ineffective in recovering defective B lymphopoiesis, probably due to a failure to compensate production of stroma cell-derived IL-7 and CXCL12. Our observations on autoimmune-mediated incapacitation of the BM environment in Foxp3-deficient mice will have direct implications for the rational design of BM transplantation protocols for patients with severe genetic deficiencies in functional Foxp3+ Treg cells. PMID:22679447

  15. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

    PubMed Central

    Breart, Béatrice; Lemaître, Fabrice; Celli, Susanna; Bousso, Philippe

    2008-01-01

    CTLs have the potential to attack tumors, and adoptive transfer of CTLs can lead to tumor regression in mouse models and human clinical settings. However, the dynamics of tumor cell elimination during efficient T cell therapy is unknown, and it is unclear whether CTLs act directly by destroying tumor cells or indirectly by initiating the recruitment of innate immune cells that mediate tumor damage. To address these questions, we report real-time imaging of tumor cell apoptosis in vivo using intravital 2-photon microscopy and a Förster resonance energy transfer–based (FRET-based) reporter of caspase 3 activity. In a mouse model of solid tumor, we found that tumor regression after transfer of in vitro–activated CTLs occurred primarily through the direct action of CTLs on each individual tumor cell, with a minimal bystander effect. Surprisingly, the killing of 1 target cell by an individual CTL took an extended period of time, 6 hours on average, which suggested that the slow rate of killing intrinsically limits the efficiency of antitumor T cell responses. The ability to visualize when, where, and how tumor cells are killed in vivo offers new perspectives for understanding how immune effectors survey cancer cells and how local tumor microenvironments may subvert immune responses. PMID:18357341

  16. 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.

  17. Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy.

    PubMed

    Sukumar, Madhusudhanan; Liu, Jie; Mehta, Gautam U; Patel, Shashank J; Roychoudhuri, Rahul; Crompton, Joseph G; Klebanoff, Christopher A; Ji, Yun; Li, Peng; Yu, Zhiya; Whitehill, Greg D; Clever, David; Eil, Robert L; Palmer, Douglas C; Mitra, Suman; Rao, Mahadev; Keyvanfar, Keyvan; Schrump, David S; Wang, Ena; Marincola, Francesco M; Gattinoni, Luca; Leonard, Warren J; Muranski, Pawel; Finkel, Toren; Restifo, Nicholas P

    2016-01-12

    Long-term survival and antitumor immunity of adoptively transferred CD8(+) T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8(+) T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8(+), CD4(+) T cell subsets, and long-term hematopoietic stem cells. This metabolism-based approach to cell selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.

  18. Baseline Cellular HIV DNA Load Predicts HIV DNA Decline and Residual HIV Plasma Levels during Effective Antiretroviral Therapy

    PubMed Central

    Andreis, Samantha; Mengoli, Carlo; Scaggiante, Renzo; Ferretto, Roberto; Manfrin, Vinicio; Cruciani, Mario; Giobbia, Mario; Boldrin, Caterina; Basso, Monica; Andreoni, Massimo; Palù, Giorgio; Sarmati, Loredana

    2012-01-01

    Cellular human immunodeficiency virus type 1 (HIV-1) DNA may be considered a marker of disease progression with significant predictive power, but published data on its correlation with plasma HIV RNA levels and CD4 counts in acute and chronic patients are not conclusive. We evaluated a cohort of 180 patients naïve for antiretroviral therapy before the beginning of treatment and after a virological response in order to define the indicators correlated with HIV DNA load decrease until undetectability. The following variables were evaluated as continuous variables: age, CD4 cell count and log10 HIV DNA level at baseline and follow-up, and baseline log10 HIV RNA level. Primary HIV infection at the start of therapy, an HIV RNA level at follow-up of <2.5 copies/ml, origin, gender, and transmission risk were evaluated as binary variables. The decline of HIV DNA values during effective therapy was directly related to baseline HIV DNA and HIV RNA values, to an increase in the number of CD4 cells, and to the achievement of an HIV RNA load of <2.5 copies/ml. An undetectable cellular HIV DNA load was achieved by 21.6% of patients at the follow-up time point and correlated significantly with lower baseline cellular HIV DNA values and with being in the primary stage of infection when therapy started. In conclusion, early treatment facilitated the achievement of undetectable levels of plasma viremia and cellular HIV DNA and a better recovery of CD4 lymphocytes. HIV DNA levels before and during highly active antiretroviral therapy may be used as a new tool for monitoring treatment efficacy. PMID:22135262

  19. 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

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

    PubMed

    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

    2015-05-01

    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.

  1. Randomized Controlled Trial of a Personalized Cellular Phone Reminder System to Enhance Adherence to Antiretroviral Therapy

    PubMed Central

    Kumar, Vikram; Doros, Gheorghe; Farmer, Eric; Drainoni, Mari-Lynn; Rybin, Denis; Myung, Dan; Jackson, Jonathan; Backman, Elke; Stanic, Anela; Skolnik, Paul R.

    2011-01-01

    Abstract Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 ± 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue. PMID:21323532

  2. 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.

  3. Quantum dot tailored to single wall carbon nanotubes: a multifunctional hybrid nanoconstruct for cellular imaging and targeted photothermal therapy.

    PubMed

    Nair, Lakshmi V; Nagaoka, Yutaka; Maekawa, Toru; Sakthikumar, D; Jayasree, Ramapurath S

    2014-07-23

    Hybrid nanomaterial based on quantum dots and SWCNTs is used for cellular imaging and photothermal therapy. Furthermore, the ligand conjugated hybrid system (FaQd@CNT) enables selective targeting in cancer cells. The imaging capability of quantum dots and the therapeutic potential of SWCNT are available in a single system with cancer targeting property. Heat generated by the system is found to be high enough to destroy cancer cells.

  4. The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets

    PubMed Central

    Hartman, Tracy L.; Buckheit, Robert W.

    2012-01-01

    During the past three decades, over thirty-five anti-HIV-1 therapies have been developed for use in humans and the progression from monotherapeutic treatment regimens to today's highly active combination antiretroviral therapies has had a dramatic impact on disease progression in HIV-1-infected individuals. In spite of the success of AIDS therapies and the existence of inhibitors of HIV-1 reverse transcriptase, protease, entry and fusion, and integrase, HIV-1 therapies still have a variety of problems which require continued development efforts to improve efficacy and reduce toxicity, while making drugs that can be used throughout both the developed and developing world, in pediatric populations, and in pregnant women. Highly active antiretroviral therapies (HAARTs) have significantly delayed the progression to AIDS, and in the developed world HIV-1-infected individuals might be expected to live normal life spans while on lifelong therapies. However, the difficult treatment regimens, the presence of class-specific drug toxicities, and the emergence of drug-resistant virus isolates highlight the fact that improvements in our therapeutic regimens and the identification of new and novel viral and cellular targets for therapy are still necessary. Antiretroviral therapeutic strategies and targets continue to be explored, and the development of increasingly potent molecules within existing classes of drugs and the development of novel strategies are ongoing. PMID:22848825

  5. 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.

  6. 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

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

    PubMed

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

    2014-10-07

    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.

  8. Cellular and Mitochondrial Dual-Targeted Organic Dots with Aggregation-Induced Emission Characteristics for Image-Guided Photodynamic Therapy.

    PubMed

    Feng, Guangxue; Qin, Wei; Hu, Qinglian; Tang, Ben Zhong; Liu, Bin

    2015-12-09

    Targeted delivery of drugs toward mitochondria of specific cancer cells dramatically improves therapy efficiencies especially for photodynamic therapy (PDT), as reactive oxygen species (ROS) are short in lifetime and small in radius of action. Different from chemical modification, nanotechnology has been serving as a simple and nonchemical approach to deliver drugs to cells of interest or specific organelles, such as mitochondria, but there have been limited examples of dual-targeted delivery for both cells and mitochondria. Here, cellular and mitochondrial dual-targeted organic dots for image-guided PDT are reported based on a fluorogen with aggregation-induced emission (AIEgen) characteristics. The AIEgen possesses enhanced red fluorescence and efficient ROS production in aggregated states. The AIE dot surfaces are functionalized with folate and triphenylphosphine, which can selectively internalize into folate-receptor (FR) positive cancer cells, and subsequently accumulate at mitochondria. The direct ROS generation at mitochondria sites is found to depolarize mitochondrial membrane, affect cell migration, and lead to cell apoptosis and death with enhanced PDT effects as compared to ROS generated randomly in cytoplasm. This report demonstrates a simple and general nanocarrier approach for cellular and mitochondrial dual-targeted PDT, which opens new opportunities for dual-targeted delivery and therapy.

  9. The emergence and popularisation of autologous somatic cellular therapies in Australia: therapeutic innovation or regulatory failure?

    PubMed

    McLean, Alison K; Stewart, Cameron; Kerridge, Ian

    2014-09-01

    Private stem cell clinics throughout Australia are providing autologous stem cell therapies for a range of chronic and debilitating illnesses despite the lack of published literature to support the clinical application of these therapies. The Therapeutic Goods Administration has excluded autologous stem cell therapies from its regulatory domain leaving such therapies to be regulated by the same mechanisms that regulate research, such as the National Health and Medical Research Council Research Ethics Guidelines, and clinical practice, such as the Australian Health Practitioner Regulation Agency. However, the provision of these stem cell therapies does not follow the established pathways for legitimate medical advance--therapeutic innovation or research. The current regulatory framework is failing to achieve its aims of protecting vulnerable patients and ensuring the proper conduct of medical practitioners in the private stem cell industry.

  10. 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.

  11. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer

    PubMed Central

    1982-01-01

    Neonatal thymectomy during the critical period, 2-4 d after birth, can induce various organ-specific autoimmune diseases including oophoritis in A/J mice. The oophoritis thus induced was passively transferred into neonatal mice by injection of spleen cells obtained from syngeneic donors with the disease. Recipient ovaries were rapidly damaged with remarkable mononuclear cell infiltration and destruction of follicular structures. The phenotype of effector cells responsible for successful adoptive transfer was found to be Thy-1+, Lyt-1+,23-, Ia-, Qa-1-, and was sensitive to antithymocyte serum treatment but resistant to cyclophosphamide treatment or in vitro X-ray irradiation. The compatibility between donor and recipient at the major histocompatibility complex was not required for the effector phase of transfer. The oophoritis induced in BALB/c (nu/+ or +/+) was also shown to be transferred into athymic BALB/c nude mice with resulting ovarian lesion and circulating autoantibodies against oocytes. In this transfer system, the effector cells were also demonstrated to be T cells with the Lyt-1+,23- phenotype. Adoptive transfer experiments in both systems revealed that the destruction of ovaries in postthymectomy autoimmune oophoritis was mediated by Lyt-1 T cells. Whether these T cells can be distinguished from other Lyt-1 cells, such as T helper cells and effector T cells in delayed-type hypersensitivity (DTH), is not clear at present, but the results suggest that the effector mechanisms may be closely related to a DTH reaction. PMID:6983557

  12. 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

  13. The Molecular, Cellular and Clinical Consequences of Targeting the Estrogen Receptor Following Estrogen Deprivation Therapy

    PubMed Central

    Fan, Ping; Maximov, Philipp Y.; Curpan, Ramona F.; Abderrahman, Balkees; Jordan, V. Craig

    2015-01-01

    During the past twenty years our understanding of the control of breast tumor development, growth and survival has changed dramatically. The once long forgotten application of high dose synthetic estrogen therapy as the first chemical therapy to treat any cancer has been resurrected, refined and reinvented as the new biology of estrogen-induced apoptosis. High dose estrogen therapy was cast aside once tamoxifen, from its origins as a failed “morning after pill”, was reinvented as the first targeted therapy to treat any cancer. The current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long term antihormone therapy in estrogen receptor (ER) positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite “antiestrogen” resistance, but becomes a regulator of resistance. Multiple mechanisms of resistance come into play: Selective ER Modulator (SERM) stimulated growth, growth factor/ER crosstalk, estrogen-induced apoptosis and mutations of ER. But it is with the science of estrogen-induced apoptosis that the next innovation in women’s health will be developed. Recent evidence suggests that the glucocorticoid properties of medroxyprogesterone acetate blunt estrogen-induced apoptosis in estrogen deprived breast cancer cell populations. As a result breast cancer develops during long-term Hormone Replacement Therapy (HRT). A new synthetic progestin with estrogen-like properties, such as the 19 nortestosterone derivatives used in oral contraceptives, will continue to protect the uterus from unopposed estrogen stimulation but at the same time, reinforce apoptosis in vulnerable populations of nascent breast cancer cells. PMID:26052034

  14. Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice.

    PubMed

    Zhang, Yufei; Luo, Feifei; Li, Anning; Qian, Jiawen; Yao, Zhenwei; Feng, Xiaoyuan; Chu, Yiwei

    2014-09-01

    Adoptive immunotherapy is an attractive strategy for glioma treatment. However, some obstacles still need be overcome. In this study, GL261-bearing mice treated with adoptively transferred antigen-specific T cells and systemic injection of bacterial lipoprotein (BLP), a TLR1/2 agonist, got a long-term survival and even immune protection. By analyzing adoptive T cells, it was found that BLP maintained T cell survival, proliferation and anti-tumor efficacy in the brains of tumor-bearing hosts. Moreover, tumor microenvironment was modified by up-regulating IFN-γ-secreting CD8+ T cells and down-regulating MDSC, which might be related with high CXCL10 and low CCL2 expression. In addition, TLR2 deficiency abrogated therapeutic effect with increased MDSC accumulation and decreased IFN-γ-secreting CD8+ T cells in the brains. Thus, the systemic injection of BLP could improve the adoptive T cell therapy by maintaining T cell persistence, modifying the tumor microenvironment and even inducing systemic anti-tumor immunity, which might offer a clinically promising immunotherapeutic strategy for glioma.

  15. 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

  16. 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.

  17. Therapy in prion diseases: from molecular and cellular biology to therapeutic targets.

    PubMed

    Krammer, Carmen; Vorberg, Ina; Schätzl, Hermann M; Gilch, Sabine

    2009-02-01

    Prion diseases are infectious and fatal neurodegenerative disorders of man and animals which are characterized by spongiform degeneration in the central nervous system. In human diseases, the manifestation can be sporadic, familial or acquired by infection. Prion disorders are caused by the accumulation of an aberrantly folded isoform of the cellular prion protein (PrP(c)), commonly named PrP(Sc). Although prion diseases are usually rare, they have the potential to be transferred within and also between species by infection processes, giving then raise even to epidemic scenarios. As pathology is obviously restricted to the central nervous system pre-mortem diagnosis is usually hard to achieve. Promising approaches towards the development of therapeutic and even prophylactic anti-prion regimens were recently made. However, only a profound knowledge of the infectious agent and its replication strategy enables the design of effective anti-prion strategies. Cell culture models were highly instrumental in uncovering fundamental aspects of prion propagation. In this chapter, the cellular and molecular biology of prion proteins in general is discussed and prophylactic and therapeutic concepts derived thereof are introduced. In particular, emphasis is put on strategies targeting PrP(c) which is absolutely needed as substrate for prion conversion, and on intrinsic cellular clearance mechanisms for prions.

  18. Adoptive T-cell therapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors.

    PubMed

    Fujiwara, Hiroshi

    2014-02-01

    The functional properties of the adoptive immune response mediated by effector T lymphocytes are decisively regulated by their T-cell receptors (TCRs). Transfer of genes encoding target antigen-specific receptors enables polyclonal T cells to redirect toward cancer cells and virally infected cells expressing those defined antigens. Using this technology, a large population of redirected T cells displaying uniform therapeutic properties has been produced, powerfully advancing their clinical application as "cellular drugs" for adoptive immunotherapy against cancer. Clinically, anticancer adoptive immunotherapy using these genetically engineered T cells has an impressive and proven track record. Notable examples include the dramatic benefit of chimeric antigen receptor gene-modified T cells redirected towards B-cell lineage antigen CD19 in patients with chronic lymphocytic leukemia, and the impressive outcomes in the use of TCR gene-modified T cells redirected towards NY-ESO-1, a representative cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. In this review, we briefly overview the current status of this treatment option in the context of hematological malignancy, and discuss a number of challenges that still pose an obstacle to the full effectiveness of this strategy.

  19. Lipid Replacement Therapy: a natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function.

    PubMed

    Nicolson, Garth L; Ash, Michael E

    2014-06-01

    Lipid Replacement Therapy, the use of functional oral supplements containing cell membrane phospholipids and antioxidants, has been used to replace damaged, usually oxidized, membrane glycerophospholipids that accumulate during aging and in various clinical conditions in order to restore cellular function. This approach differs from other dietary and intravenous phospholipid interventions in the composition of phospholipids and their defense against oxidation during storage, ingestion, digestion and uptake as well as the use of protective molecules that noncovalently complex with phospholipid micelles and prevent their enzymatic and bile disruption. Once the phospholipids have been taken in by transport processes, they are protected by several natural mechanisms involving lipid receptors, transport and carrier molecules and circulating cells and lipoproteins until their delivery to tissues and cells where they can again be transferred to intracellular membranes by specific and nonspecific transport systems. Once delivered to membrane sites, they naturally replace and stimulate removal of damaged membrane lipids. Various chronic clinical conditions are characterized by membrane damage, mainly oxidative but also enzymatic, resulting in loss of cellular function. This is readily apparent in mitochondrial inner membranes where oxidative damage to phospholipids like cardiolipin and other molecules results in loss of trans-membrane potential, electron transport function and generation of high-energy molecules. Recent clinical trials have shown the benefits of Lipid Replacement Therapy in restoring mitochondrial function and reducing fatigue in aged subjects and patients with a variety of clinical diagnoses that are characterized by loss of mitochondrial function and include fatigue as a major symptom. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

  20. Enhancement of cancer stem cell susceptibility to conventional treatments through complementary yoga therapy: possible cellular and molecular mechanisms.

    PubMed

    Bhargav, Hemant; Metri, Kashinath; Raghuram, Nagarathna; Ramarao, Nagendra Hongasandra; Koka, Prasad S

    2012-01-01

    Cancer stem cells (CSCs) are stem-like tumor populations that are reported to contribute towards tumor growth, maintenance and recurrence after therapy. Hypoxia increases CSC fraction and promotes acquisition of a stem-cell-like state. Cancer stem cells are critically dependant on the hypoxia-inducible factor-1 (HIF-1) for survival, self-renewal, tumor growth and maintenance of their undifferentiated phenotype. Recent researches show that stage of differentiation of the tumor cells is predictive of their susceptibility to natural killer cell (NK) cell mediated cytotoxicity and cancer stem cells are significant targets of NK cell cytotoxicity. Studies also show that reversion of tumor cells to a less-differentiated phenotype can be achieved by blocking NFκB. Yoga therapy (yogic lifestyle modifications encompassing physical postures, breathing practices, relaxation techniques and meditations) is known to modulate neural, endocrine and immune functions at the cellular level through influencing cell cycle control, aging, oxidative stress, apoptosis and several pathways of stress signaling molecules. Yoga therapy has also been shown to enhance natural killer cell activity and modulate stress and DNA damage in breast cancer patients receiving radiotherapy. Recent study found that brief daily yogic meditation may reverse the pattern of increased NFκB-related transcription of pro-inflammatory cytokines in leukocytes. Thus, yoga therapy has the potential to reduce cancer stem cell survival, self -renewal and tumor growth by modifying the tumor micro-environment through various mechanisms such as; 1) reducing HIF-1 activity by enhanced oxygenation, 2) promoting NK cell activity directly (or indirectly through down regulating NFκB expression), thereby enhancing NK cell mediated CSC lysis, and 3) by minimizing the aberrant expressions or activities of various hormones, cytokines, chemokines and tumor signaling pathways. Yoga therapy may have a synergistic effect with

  1. Impaired and imbalanced cellular immunological status assessed in advanced cancer patients and restoration of the T cell immune status by adoptive T-cell immunotherapy.

    PubMed

    Noguchi, Atsutaka; Kaneko, Toru; Naitoh, Keiko; Saito, Masashi; Iwai, Kazuro; Maekawa, Ryuji; Kamigaki, Takashi; Goto, Shigenori

    2014-01-01

    Recent progress has been made in understanding the mechanisms of antitumor immune responses, which may further clarify the immune status of cancer patients. In this study, we performed a detailed evaluation of the immunological status of 47 patients with advanced solid cancer, who had received no immunosuppressive treatment, and compared the results with 32 healthy subjects. Flow-cytometry data for peripheral blood were obtained using 19 monoclonal antibodies against various cell surface and intracellular molecules. Absolute numbers of T cells, several T cell subsets, B cells, and NK cells were significantly decreased in patients compared with healthy subjects. The percentage of CD27(+)CD45RA(+) T cells was lower and that of CD27(-)CD45RA(-) T cells was higher in patients compared with controls. Regulatory and type 2 helper T cells were elevated in patients relative to healthy subjects. The percentage of perforin(+) NK cells was significantly lower in patients than in controls. These results suggest a dysfunctional anti-tumor immune response in cancer patients. Furthermore, peripheral blood from 26 of 47 cancer patients was analyzed after adoptive T cell immunotherapy (ATI). ATI increased the number of T cell subsets, but not B and NK cells. The number and percentage of regulatory T cells decreased significantly. These results suggest that ATI can restore impaired and imbalanced T cell immune status.

  2. 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.

  3. The use of endogenous T cells for adoptive transfer.

    PubMed

    Yee, Cassian

    2014-01-01

    Adoptive T-cell therapy involves the ex vivo enrichment and expansion of tumor-reactive T cells for infusion. As an immune-based approach, adoptive therapy has become an increasingly attractive modality for the treatment of patients with cancer due to its potential for high specificity, non-cross resistance with conventional therapies, and promise of long-term immunoprotection. In recent years, a resurgence in discoveries underlying T-cell recognition, tumor immune evasion, and T-cell memory and differentiation coupled with the development of several enabling technologies have facilitated a renewed focus in the field of adoptive therapy and its transition to the clinical arena as a treatment modality for patients with cancer. In this review, endogenous T cells derived from peripheral blood or tumor sites will be presented as a source of effector cells for adoptive therapy and strategies to isolate, manipulate, and enhance the function of antigen-specific T cells in vitro and to augment their in vivo efficacy and persistence by host immunomodulation are presented in the context of an ever-increasing inventory of preclinical and clinically available reagents. Optimizing the combination of adoptive cellular therapy and other immune-based and conventional approaches will herald a new generation of research and clinical opportunities for cancer immunotherapy.

  4. 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).

  5. Cellular and Animal Studies: Insights into Pathophysiology and Therapy of PCOS.

    PubMed

    Indran, Inthrani Raja; Lee, Bao Hui; Yong, Eu-Leong

    2016-11-01

    Basic science studies have advanced our understanding of the role of key enzymes in the steroidogenesis pathway and those that affect the pathophysiology of PCOS. Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities. Furthermore, overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS phenotype with increased androgen production. Notably, cellular steroidogenesis models have facilitated the understanding of the mechanistic effects of pharmacotherapies, including insulin sensitizers (e.g., pioglitazone and metformin) used for the treatment of insulin resistance in PCOS, on androgen production. In addition, animal models of PCOS have provided a critical platform to study the effects of therapeutic agents in a manner closer to the physiological state. Indeed, recent breakthroughs have demonstrated that natural derivatives such as the dietary medium-chain fatty acid decanoic acid (DA) can restore estrous cyclicity and lower androgen levels in an animal model of PCOS, thus laying the platform for novel therapeutic developments in PCOS. This chapter reviews the current understanding on the pathways modulating androgen biosynthesis, and the cellular and animal models that form the basis for preclinical research in PCOS, and sets the stage for clinical research.

  6. 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.

  7. T-cell depleted allogeneic hematopoietic cell transplants as a platform for adoptive therapy with leukemia selective or virus-specific T-cells.

    PubMed

    O'Reilly, R J; Koehne, G; Hasan, A N; Doubrovina, E; Prockop, S

    2015-06-01

    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.

  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. Phenotype and function of T cells infiltrating visceral metastases from gastrointestinal cancers and melanoma: implications for adoptive cell transfer therapy.

    PubMed

    Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S; Wunderlich, John R; Dudley, Mark E; Rosenberg, Steven A

    2013-09-01

    Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ~50 × 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3(+)CD8(+) cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.

  10. Open Adoption

    ERIC Educational Resources Information Center

    Baran, Annette; And Others

    1976-01-01

    Adult adoptees are increasingly challenging the practice of sealing their birth records. The authors examine the historical roots of adoptive practices in this country and suggest that the time has come for open adoption to gain acceptance as an alternative. (Author)

  11. Microfabricated Particles for Engineered Drug Therapies: Elucidation into the Mechanisms of Cellular Internalization of PRINT Particles

    PubMed Central

    Gratton, Stephanie E. A.; Napier, Mary E.; Ropp, Patricia A.; Tian, Shaomin; DeSimone, Joseph M.

    2008-01-01

    Purpose To investigate the cellular internalization pathways of shape- and size-specific particles as a function of zeta potential in different cell types. Methods A top-down particle fabrication technique called PRINT was utilized to fabricate monodisperse 1 μm cylindrical particles. Cellular internalization of these PRINT particles was monitored using confocal microscopy, flow cytometry, and transmission electron microscopy. The endocytic pathway used by 1 μm cationic PRINT particles was evaluated using different inhibitory strategies. Cytotoxicity assays were used to determine the toxicity of both cationic and anionic PRINT particles in multiple cell types. Results Particle internalization was confirmed using confocal microscopy, flow cytometry and transmission electron microscopy. The mechanism of internalization of positively charged PRINT particles was found to be predominantly clathrin-mediated endocytosis and macropinocytosis with very few particles utilizing a caveolae-mediated endocytic pathway. The exposed charge on the surface of the particles had a significant effect on the rate of endocytosis in all cell types tested, except for the macrophage cells. No significant cytotoxicity was observed for all PRINT particles used in the present study. Conclusions Cylindrical 1 μm PRINT particles were readily internalized into HeLa, NIH 3T3, OVCAR-3, MCF-7, and RAW 264.7 cells. Particles with a positive zeta potential exhibited an enhanced rate of endocytosis compared to negatively charged particles with identical sizes and shapes. It was found that PRINT particles with a positive zeta potential were endocytosed into HeLa cells using predominantely clathrin-mediated and macropinocytotic pathways. PMID:18592353

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

    PubMed

    Lord, Phillip; 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; Hilkens, Catharien M U

    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.

  13. One-pot synthesis of FePt/CNTs nanocomposites for efficient cellular imaging and cancer therapy

    NASA Astrophysics Data System (ADS)

    Chen, Weihong; Zheng, Xiuwen; Li, Shulian; Zhang, Wei; Wen, Xin; Yue, Ludan; Wang, Jinlong

    2015-11-01

    Here, we developed a facile route to synthesize carbon nanotube-based FePt nanocomposites (FePt/CNTs) as a potential theranostic platform in the cancer treatment. FePt/CNTs were firstly synthesized via one-pot polyol route, and then functionalized with 6-arm-polyethylene glycol-amine polymer. The average size of FePt nanoparticles (NPs) is 3-4 nm, which is dispersed on the CNT surface (ca.50-150 nm). The as-prepared FePt NPs display high cytotoxicity by highly reactive oxygen species in cancer cells. Folic acid and fluorescein isothiocyanate are assembled onto the surface of FePt/CNTs for effective targeting of folate receptor-positive cancer cells and simultaneously for the visualization of cellular uptake. Therefore, the FePt/CNTs NPs capability of simultaneously performing diagnosis, therapy, and targeting is, therefore, promising for future potential widespread application in biomedicine.

  14. 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. PMID:27635311

  15. Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory potential for cellular therapy in autoimmune arthritis

    PubMed Central

    Park, Min-Jung; Lee, Seung Hoon; Moon, Su-Jin; Lee, Jung-Ah; Lee, Eun-Jung; Kim, Eun-Kyung; Park, Jin-Sil; Lee, Jennifer; Min, Jun-Ki; Kim, Seok Jung; Park, Sung-Hwan; Cho, Mi-La

    2016-01-01

    Mesenchymal stem cells (MSCs) are attractive agents for cellular therapy in rheumatoid arthritis (RA). The receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for endogenous inflammatory ligands. Soluble RAGE (sRAGE) is a truncated form of RAGE that functions as a decoy and acts as an anti-inflammatory molecule. The aim of this study was to determine whether sRAGE has therapeutic effects and the mechanisms active in sRAGE-overexpressing MSCs (sRAGE-MSCs) in an experimental model of RA. sRAGE-MSCs were generated by DNA transfection of human adipose tissue-derived MSCs (Ad-hMSCs). MSCs showed increased expression of VEGF, IL-1β, IL-6, and HMGB-1 under inflammatory conditions. However, sRAGE-MSCs showed significantly lower production of these proinflammatory molecules. Expression of immunomodulatory molecules such as IL-10, TGF-β, and indoleamine 2, 3-dioxygenase was higher in sRAGE-MSCs than in mock-MSCs. sRAGE-MSCs showed enhanced migration potential. Transplantation of sRAGE-MSCs into arthritic IL-1Ra-knockout mice markedly suppressed inflammatory arthritis, decreased Th17 cells, and reciprocally increased regulatory T cells. The differentiation of IFN-γ+CD4+ and IL-17+CD4+ cells was inhibited by incubation with sRAGE-MSCs compared with mock-MSCs. These findings suggest that sRAGE overexpression in Ad-hMSCs optimizes their immunoregulatory properties, which may be useful as a novel cellular therapy for RA. PMID:27804999

  16. Stem cell therapy and cellular engineering for treatment of neuronal dysfunction in Huntington's disease.

    PubMed

    Choi, Kyung-Ah; Hwang, Insik; Park, Hang-soo; Oh, Seung-Ick; Kang, Seongman; Hong, Sunghoi

    2014-07-01

    Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by progressive loss of neurons in the striatum, a sub-cortical region of the forebrain. The sub-cortical region of the forebrain is associated with the control of movement and behavior, thus HD initially presents with coordination difficulty and cognitive decline. Recent reprogramming technologies, including induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs), have created opportunities to understand the pathological cascades that underlie HD and to develop new treatments for this currently incurable neurological disease. The ultimate objectives of stem cell-based therapies for HD are to replace lost neurons and to prevent neuronal dysfunction and death. In this review, we examine the current understanding of the molecular and pathological mechanisms involved in HD. We discuss disease modeling with HD-iPSCs derived from the somatic cells of patients, which could provide an invaluable platform for understanding HD pathogenesis. We speculate about the benefits and drawbacks of using iNSCs as an alternative stem cell source for HD treatment. Finally, we discuss cell culture and engineering systems that promote the directed differentiation of pluripotent stem cell-derived NSCs into a striatal DARPP32(+) GABAergic MSN phenotype for HD. In conclusion, this review summarizes the potentials of cell reprogramming and engineering technologies relevant to the development of cell-based therapies for HD.

  17. Efficiency of Human Epiphyseal Chondrocytes with Differential Replication Numbers for Cellular Therapy Products

    PubMed Central

    Nasu, Michiyo; Takayama, Shinichiro

    2016-01-01

    The cell-based therapy for cartilage or bone requires a large number of cells; serial passages of chondrocytes are, therefore, needed. However, fates of expanded chondrocytes from extra fingers remain unclarified. The chondrocytes from human epiphyses morphologically changed from small polygonal cells to bipolar elongated spindle cells and to large polygonal cells with degeneration at early passages. Gene of type II collagen was expressed in the cells only at a primary culture (Passage 0) and Passage 1 (P1) cells. The nodules by implantation of P0 to P8 cells were composed of cartilage and perichondrium. The cartilage consisted of chondrocytes with round nuclei and type II collagen-positive matrix, and the perichondrium consisted of spindle cells with type I collage-positive matrix. The cartilage and perichondrium developed to bone with marrow cavity through enchondral ossification. Chondrogenesis and osteogenesis by epiphyseal chondrocytes depended on replication number in culture. It is noteworthy to take population doubling level in correlation with pharmaceutical efficacy into consideration when we use chondrocytes for cell-based therapies. PMID:27999805

  18. Photodynamic therapy with photoactivated aluminum disulfonated phthalocyanine and cellular immune response

    NASA Astrophysics Data System (ADS)

    Canti, Gianfranco L.; Cubeddu, Rinaldo; Taroni, Paola; Valentini, Gianluca

    1998-05-01

    Photodynamic therapy (PDT) of cancer is based on the systemic administration of photosensitive drugs followed by exposure of the tumor mass to light of particular wavelength. The combination of drug uptake in malignant tissues and selective delivery of laser-generated light provides for an effective therapy with efficient tumor cytotoxicity and minimal normal tissue damage. There are various studies on the effect of photoactivated photosensitizers on host immune response in tumor bearing mice. Since immunity is important in the control of tumor growth and spreading in our laboratory we examine the effect of PDT on immune compartment. Spleen hyperplasia as well as spleen and marrow hypercellularities were observed in tumor bearing mice treated with Aluminum Disulfonated Phthalocyanine (AlS2Pc) and laser light. Phytohaemagglutinin (T lymphocytes mitogen) and Lypolisaccaride (B lymphocytes mitogen), stimulation of spleen lymphocytes caused an increase in blast transformation in tumor bearing mice. Furthermore splenocytes and macrophages collected from mice treated with PDT were cytotoxic in vivo (Winn Assay) parental against tumor cells. The results observed suggest that PDT is able to modulate the immune response and oncological patients treated with PDT could become immune versus a relapse or versus the minimal residual disease.

  19. 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.

  20. Effect of chirality on cellular uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a.

    PubMed

    Srivatsan, Avinash; Pera, Paula; Joshi, Penny; Wang, Yanfang; Missert, Joseph R; Tracy, Erin C; Tabaczynski, Walter A; Yao, Rutao; Sajjad, Munawwar; Baumann, Heinz; Pandey, Ravindra K

    2015-07-01

    We have previously shown that the (124)I-analog of methyl 3-(1'-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive ((124)I-) and non-radioactive ((127)I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-3(1) in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-17(2) were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors.

  1. 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

  2. Tracheal bioengineering: the next steps. Proceeds of an International Society of Cell Therapy Pulmonary Cellular Therapy Signature Series Workshop, Paris, France, April 22, 2014.

    PubMed

    Weiss, Daniel J; Elliott, Martin; Jang, Queenie; Poole, Brian; Birchall, Martin

    2014-12-01

    There has been significant and exciting recent progress in the development of bioengineering approaches for generating tracheal tissue that can be used for congenital and acquired tracheal diseases. This includes a growing clinical experience in both pediatric and adult patients with life-threatening tracheal diseases. However, not all of these attempts have been successful, and there is ongoing discussion and debate about the optimal approaches to be used. These include considerations of optimal materials, particularly use of synthetic versus biologic scaffolds, appropriate cellularization of the scaffolds, optimal surgical approaches and optimal measure of both clinical and biologic outcomes. To address these issues, the International Society of Cell Therapy convened a first-ever meeting of the leading clinicians and tracheal biologists, along with experts in regulatory and ethical affairs, to discuss and debate the issues. A series of recommendations are presented for how to best move the field ahead.

  3. Generation of T cell effectors using tumor cell-loaded dendritic cells for adoptive T cell therapy.

    PubMed

    Vavrova, Katerina; Vrabcova, Petra; Filipp, Dominik; Bartunkova, Jirina; Horvath, Rudolf

    2016-12-01

    Adoptive T cell transfer has been shown to be an effective method used to boost tumor-specific immune responses in several types of malignancies. In this study, we set out to optimize the ACT protocol for the experimental treatment of prostate cancer. The protocol includes a pre-stimulation step whereby T cells were primed with autologous dendritic cells loaded with the high hydrostatic pressure-treated prostate cancer cell line, LNCaP. Primed T cells were further expanded in vitro with anti-CD3/CD28 Dynabeads in the WAVE bioreactor 2/10 system and tested for cytotoxicity. Our data indicates that the combination of pre-stimulation and expansion steps resulted in the induction and enrichment of tumor-responsive CD4(+) and CD8(+) T cells at clinically relevant numbers. The majority of both CD4(+) and CD8(+) IFN-γ producing cells were CD62L, CCR7 and CD57 negative but CD28 and CD27 positive, indicating an early antigen experienced phenotype in non-terminal differentiation phase. Expanded T cells showed significantly greater cytotoxicity against LNCaP cells compared to the control SKOV-3, an ovarian cancer line. In summary, our results suggest that the ACT approach together with LNCaP-loaded dendritic cells provides a viable way to generate prostate cancer reactive T cell effectors that are capable of mounting efficient and targeted antitumor responses and can be thus considered for further testing in a clinical setting.

  4. Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia.

    PubMed

    Isgrò, Antonella; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2010-08-01

    Allogeneic hemopoietic stem cell transplantation (HSCT) represents one of the best cures for thalassemia. Currently, HSCT for thalassemia consists of allogeneic stem cell gene therapy and still awaits autologous genetically modified stem cell transplantation. HSCT for thalassemia has substantially improved over the last two decades, due in large part to improvements in preventive strategies, the effective control of transplant-related complications, and the development of new preparative regimens. A risk classes-based approach to transplantation in thalassemia has led to disease-free survival probability of 87, 85, and 80% in classes 1, 2, and 3 patients, respectively. Adult thalassemia patients, who are higher risk patients for transplant-related toxicity due to an advanced phase of the disease, have a cure rate of 65% with current treatment protocol. Patients who do not have matched family or unrelated donors could benefit from haploidentical mother-to-child transplantation. Overall, the results of this type of transplantation appear encouraging.

  5. A consensus introduction to serum replacements and serum-free media for cellular therapies.

    PubMed

    Karnieli, Ohad; Friedner, Oryan Makler; Allickson, Julie G; Zhang, Nan; Jung, Sunghoon; Fiorentini, David; Abraham, Eytan; Eaker, Shannon S; Yong, Tan Kah; Chan, Allan; Griffiths, Sarah; When, Amy K; Oh, Steve; Karnieli, Ohad

    2017-02-01

    The cell therapy industry is a fast-growing industry targeted toward a myriad of clinical indications. As the cell therapy industry matures and clinical trials hit their pivotal Phase 3 studies, there will be a significant need for scale-up, process validation, and critical raw material quality assurance. Part of the well discussed challenges of upscaling manufacturing processes there is a less discussed issue relating to the availability of raw materials in the needed quality and quantities. The FDA recently noted that over 80% of the 66 investigational new drug (IND) applications for mesenchymal stem cell (MSC) products analyzed described the use of FBS during manufacturing. Accumulated data from the past years show an acceleration in serum consumption by at least 10%-15% annually, which suggests that the global demand for serum may soon exceed the supply. Ongoing concerns of safety issues due to risks of various pathogen contaminations, as well as issues related to the aforementioned serum variability that can affect final product reproducibility, are strong motivators to search for serum substitutes or serum-free media. it is important to note that there are no accepted definitions for most of these terms which leads to misleading's and misunderstandings, where the same term might be defined differently by different vendors, manufacturer, and users. It is the drug developer's responsibility to clarify what the supplied labels mean and to identify the correct questions and audits to ensure quality. The paper reviews the available serum replacements, main components, basic strategies for replacement of serum and suggests definitions.

  6. 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

  7. 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

  8. [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

  9. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets.

    PubMed

    Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

    2014-01-01

    Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

  10. 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

  11. Allogeneic cellular gene therapy in hemoglobinopathies--evaluation of hematopoietic SCT in sickle cell anemia.

    PubMed

    Lucarelli, G; Gaziev, J; Isgrò, A; Sodani, P; Paciaroni, K; Alfieri, C; De Angelis, G; Marziali, M; Simone, M D; Gallucci, C; Roveda, A; Saltarelli, F; Torelli, F; Andreani, M

    2012-02-01

    Many patients with thalassemia have been cured with BMT since the first successful transplant in 1981. Allogeneic stem cell gene therapy is the only treatment option for patients with sickle cell anemia (SCA). A total of 11 patients with a median age of 12 years (range, 2-16), affected by SCA, received hematopoietic SCT from HLA-identical, related donors following a myeloablative-conditioning regimen. Indications for transplantation were vaso-occlusive crisis, acute chest syndrome, avascular bone necrosis, chronic RBC transfusions, or hemorrhagic stroke. All patients had sustained engraftment. One patient became a stable mixed chimera with 25% of donor cells at 4 years after transplantation. One patient died at 1 year after transplantation. The probability of survival, SCA-free survival and TRM at 5 years after transplant were 90, 90 and 10%, respectively. All 10 surviving patients remained free of any SCA-related events after transplantation. In conclusion, these data confirm SCT from a suitable HLA-matched, related donor should become the primary option for curing children with SCA. There is an excellent survival rate and a return to normal life, free of SCA-related events.

  12. 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

    2015-08-07

    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.

  13. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy.

    PubMed Central

    Sher, E R; Leung, D Y; Surs, W; Kam, J C; Zieg, G; Kamada, A K; Szefler, S J

    1994-01-01

    The current study examined whether alterations in glucocorticoid receptor (GR) binding contribute to poor response to glucocorticoid therapy in asthma. 29 asthma patients with forced expiratory volume in 1 s (FEV1) < 70% predicted were studied. Patients were classified as steroid sensitive (SS) if their morning FEV1 increased > 30% after a 1-wk course of oral prednisone 20 mg twice daily and steroid resistant (SR) if they failed to increase > 15%. PBMC obtained from these two groups, 17 SR and 12 SS, as well as 12 normal controls were analyzed. SR patients had two distinguishable GR binding abnormalities: 15 of the 17 SR patients demonstrated a significantly reduced GR binding affinity, as compared with SS patients (P = 0.0001) and normal controls (P = 0.0001). This defect was localized to T cells and reverted to normal after 48 h in culture media. However, incubation with a combination of IL-2 and IL-4 sustained this abnormality. The other two SR patients had an abnormally low GR number with normal binding affinity that was not limited to T cells. Furthermore, GR number failed to normalize after incubation in media alone or IL-2 and IL-4. Therefore, SR asthma may be due to more than one abnormality, the majority related to a reversible cytokine-induced reduction in GR binding affinity and the second related to an irreversible reduction in GR number. These findings may have important implications for the design of alternative treatment approaches for recalcitrant asthma. Images PMID:8282803

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Functional DNA-containing nanomaterials: cellular applications in biosensing, imaging, and targeted therapy.

    PubMed

    Liang, Hao; Zhang, Xiao-Bing; Lv, Yifan; Gong, Liang; Wang, Ruowen; Zhu, Xiaoyan; Yang, Ronghua; Tan, Weihong

    2014-06-17

    CONSPECTUS: DNA performs a vital function as a carrier of genetic code, but in the field of nanotechnology, DNA molecules can catalyze chemical reactions in the cell, that is, DNAzymes, or bind with target-specific ligands, that is, aptamers. These functional DNAs with different modifications have been developed for sensing, imaging, and therapeutic systems. Thus, functional DNAs hold great promise for future applications in nanotechnology and bioanalysis. However, these functional DNAs face challenges, especially in the field of biomedicine. For example, functional DNAs typically require the use of cationic transfection reagents to realize cellular uptake. Such reagents enter the cells, increasing the difficulty of performing bioassays in vivo and potentially damaging the cell's nucleus. To address this obstacle, nanomaterials, such as metallic, carbon, silica, or magnetic materials, have been utilized as DNA carriers or assistants. In this Account, we describe selected examples of functional DNA-containing nanomaterials and their applications from our recent research and those of others. As models, we have chosen to highlight DNA/nanomaterial complexes consisting of gold nanoparticles, graphene oxides, and aptamer-micelles, and we illustrate the potential of such complexes in biosensing, imaging, and medical diagnostics. Under proper conditions, multiple ligand-receptor interactions, decreased steric hindrance, and increased surface roughness can be achieved from a high density of DNA that is bound to the surface of nanomaterials, resulting in a higher affinity for complementary DNA and other targets. In addition, this high density of DNA causes a high local salt concentration and negative charge density, which can prevent DNA degradation. For example, DNAzymes assembled on gold nanoparticles can effectively catalyze chemical reactions even in living cells. And it has been confirmed that DNA-nanomaterial complexes can enter cells more easily than free single

  2. Virus-Surface-Mimicking Surface Clustering of AuNPs onto DNA-Entrapped Polymeric Nanoparticle for Enhanced Cellular Internalization and Nanocluster-Induced NIR Photothermal Therapy.

    PubMed

    Jia, Hui-Zhen; Chen, Wei-Hai; Wang, Xuli; Lei, Qi; Yin, Wei-Na; Wang, Yan; Zhuo, Ren-Xi; Feng, Jun; Zhang, Xian-Zheng

    2015-12-01

    Virus-surface-mimicking decoration of deoxyribonucleic acid (DNA)-entrapped polymeric nanoparticle with AuNPs is demonstrated to lead to enhanced cellular uptake, improved gene transfection, and particularly efficient near-infrared photothermal therapy that cannot be achieved by both of them separately. This hybrid nanosystem represents a novel paradigm of multipurpose organic-inorganic nanoplatform, especially for cancer treatments.

  3. Post-transplant adoptive T-cell immunotherapy

    PubMed Central

    Aqui, Nicole A.; June, Carl H.

    2008-01-01

    Immune reconstitution following haematopoietic stem cell transplantation (SCT) is an often slow and incomplete process that leads to increased risk of infection and malignant disease. Immunization in SCT is frequently unsuccessful due to the prolonged lymphopenia, especially of CD4 T cells, seen following transplant. The transfusion of T cells, also called ‘adoptive T-cell therapy’, has the potential to enhance anti-tumour and overall immunity, and augment vaccine efficacy in the post-transplant setting. Recent advances in tissue culture, cellular immunology and tumour biology are guiding new approaches to adoptive T-cell therapy. This chapter will discuss the challenges that face the field before adoptive T-cell therapy can be translated into routine clinical practice. PMID:18790452

  4. Versatile Polymer Nanoparticles as Two-Photon-Triggered Photosensitizers for Simultaneous Cellular, Deep-Tissue Imaging, and Photodynamic Therapy.

    PubMed

    Guo, Liang; Ge, Jiechao; Liu, Qian; Jia, Qingyan; Zhang, Hongyan; Liu, Weimin; Niu, Guangle; Liu, Sha; Gong, Jianru; Hackbarth, Steffen; Wang, Pengfei

    2017-03-24

    Clinical applications of current photodynamic therapy (PDT) photosensitizers (PSs) are often limited by their absorption in the UV-vis range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep-seated tumors. Alternatively, two-photon excited PS (TPE-PS) using NIR light triggered is one the most promising candidates for PDT improvement. Herein, multimodal polymer nanoparticles (PNPs) from polythiophene derivative as two-photon fluorescence imaging as well as two-photon-excited PDT agent are developed. The prepared PNPs exhibit excellent water dispersibility, high photostability and pH stability, strong fluorescence brightness, and low dark toxicity. More importantly, the PNPs also possess other outstanding features including: (1) the high (1) O2 quantum yield; (2) the strong two-photon-induced fluorescence and efficient (1) O2 generation; (3) the specific accumulation in lysosomes of HeLa cells; and (4) the imaging detection depth up to 2100 µm in the mock tissue under two-photon. The multifunctional PNPs are promising candidates as TPE-PDT agent for simultaneous cellular, deep-tissue imaging, and highly efficient in vivo PDT of cancer.

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

    PubMed

    Ma, Yunzhi; Geng, JinPeng; Gao, Song; Bao, Shanglian

    2006-12-01

    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 10B(n,alpha)7Li, 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 11B-DPK, was calculated by GEANT4 Monte Carlo simulation code. The DPK curve drops suddenly at the radius of 4.26 microm, 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 microm, 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 microm and a nucleus radius of 5 microm 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.

  6. 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.

  7. 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…

  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. MHC class II/ESO tetramer-based generation of in vitro primed anti-tumor T-helper lines for adoptive cell therapy of cancer.

    PubMed

    Poli, Caroline; Raffin, Caroline; Dojcinovic, Danijel; Luescher, Immanuel; Ayyoub, Maha; Valmori, Danila

    2013-02-01

    Generation of tumor-antigen specific CD4(+) T-helper (T(H)) lines through in vitro priming is of interest for adoptive cell therapy of cancer, but the development of this approach has been limited by the lack of appropriate tools to identify and isolate low frequency tumor antigen-specific CD4(+) T cells. Here, we have used recently developed MHC class II/peptide tetramers incorporating an immunodominant peptide from NY-ESO-1 (ESO), a tumor antigen frequently expressed in different human solid and hematologic cancers, to implement an in vitro priming platform allowing the generation of ESO-specific T(H) lines. We isolated phenotypically defined CD4(+) T-cell subpopulations from circulating lymphocytes of DR52b(+) healthy donors by flow cytometry cell sorting and stimulated them in vitro with peptide ESO(119-143), autologous APC and IL-2. We assessed the frequency of ESO-specific cells in the cultures by staining with DR52b/ESO(119-143) tetramers (ESO-tetramers) and TCR repertoire of ESO-tetramer(+) cells by co-staining with TCR variable β chain (BV) specific antibodies. We isolated ESO-tetramer(+) cells by flow cytometry cell sorting and expanded them with PHA, APC and IL-2 to generate ESO-specific T(H) lines. We characterized the lines for antigen recognition, by stimulation with ESO peptide or recombinant protein, cytokine production, by intracellular staining using specific antibodies, and alloreactivity, by stimulation with allo-APC. Using this approach, we could consistently generate ESO-tetramer(+) T(H) lines from conventional CD4(+)CD25(-) naïve and central memory populations, but not from effector memory populations or CD4(+)CD25(+) Treg. In vitro primed T(H) lines recognized ESO with affinities comparable to ESO-tetramer(+) cells from patients immunized with an ESO vaccine and used a similar TCR repertoire. In this study, using MHC class II/ESO tetramers, we have implemented an in vitro priming platform allowing the generation of ESO

  10. Adoptive immunotherapy for cancer.

    PubMed

    Ruella, Marco; Kalos, Michael

    2014-01-01

    Recent clinical success has underscored the potential for immunotherapy based on the adoptive cell transfer (ACT) of engineered T lymphocytes to mediate dramatic, potent, and durable clinical responses. This success has led to the broader evaluation of engineered T-lymphocyte-based adoptive cell therapy to treat a broad range of malignancies. In this review, we summarize concepts, successes, and challenges for the broader development of this promising field, focusing principally on lessons gleaned from immunological principles and clinical thought. We present ACT in the context of integrating T-cell and tumor biology and the broader systemic immune response.

  11. 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

  12. Glyceryl Tribenzoate: A Flavoring Ingredient, Inhibits the Adoptive Transfer of Experimental Allergic Encephalomyelitis via TGF-β: Implications for Multiple Sclerosis Therapy

    PubMed Central

    Mondal, Susanta; Dasarathi, Sridevi; Pahan, Kalipada

    2017-01-01

    Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS). Here, we have explored a novel use of glyceryl tribenzoate (GTB), a flavoring ingredient, in ameliorating the disease process of experimental allergic encephalomyelitis (EAE), an animal model of MS, via TGF-β. Oral feeding of GTB suppressed clinical symptoms of adoptively-transferred relapsing-remitting (RR) EAE in recipient mice and suppressed the generation of encephalitogenic T cells in donor mice. GTB also attenuated clinical symptoms of RR-EAE in PLP-TCR transgenic mice and chronic EAE in male C57/BL6 mice. Accordingly, GTB also suppressed perivascular cuffing, preserved the integrity of blood-brain barrier and blood-spinal cord barrier, inhibited inflammation, and stopped demyelination in the CNS of EAE mice. Interestingly, GTB treatment upregulated TGF-β and enriched regulatory T cells (Tregs) in splenocytes as well as in vivo in EAE mice. Blocking TGF-β by neutralizing antibodies abrogated GTB-mediated enrichment of Tregs and protection of EAE. These results suggest that oral GTB may be considered as a possible therapy for MS patients. PMID:28367355

  13. The immunosuppressive effects of phthalocyanine photodynamic therapy in mice are mediated by CD4+ and CD8+ T cells and can be adoptively transferred to naive recipients.

    PubMed

    Yusuf, Nabiha; Katiyar, Santosh K; Elmets, Craig A

    2008-01-01

    Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors but it is also immunosuppressive which may reduce its therapeutic efficacy. The purpose of our study was to elucidate the role of CD4+ and CD8+ T cells in PDT immunosuppression. Using silicon phthalocyanine 4 (Pc4) as photosensitizer, nontumor-bearing CD4 knockout (CD4-/-) mice and their wild type (WT) counterparts were subjected to Pc4-PDT in a manner identical to that used for tumor regression (1 cm spot size, 0.5 mg kg(-1) Pc4, 110 J cm(-2) light) to assess the effect of Pc4-PDT on cell-mediated immunity. There was a decrease in immunosuppression in CD4-/- mice compared with WT mice. We next examined the role of CD8+ T cells in Pc4-PDT-induced immunosuppression using CD8-/- mice following the same treatment regimen used for CD4-/- mice. Similar to CD4-/- mice, CD8-/- mice exhibited less immunosuppression than WT mice. Pc4-PDT-induced immunosuppression could be adoptively transferred with spleen cells from Pc4-PDT treated donor mice to syngenic naive recipients (P < 0.05) and was mediated primarily by T cells, although macrophages were also found to play a role. Procedures that limit PDT-induced immunosuppression but do not affect PDT-induced regression of tumors may prove superior to PDT alone in promoting long-term antitumor responses.

  14. 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

  15. 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

  16. Delivery of Nano-Tethered Therapies to Brain Metastases of Primary Breast Cancer Using a Cellular Trojan Horse

    DTIC Science & Technology

    2014-10-01

    REFERENCES: 1. M.-R. Choi et al., Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol. 3...subtype”, Ann Oncol, 2010, 21: 942– 948. [2] Mi-Ran Choi, et al., “Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan...horse”, Cancer Nano, 2012; 3: 47- 54. [3] Mi-Ran Choi, et al., “A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors

  17. [Improving diagnosis coding in the ProMise database: Guidelines of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC)].

    PubMed

    Polge, Emmanuelle; Bourgue, Françoise; Cuvelier, Mathilde; Pires, Berta; Hugon, Nathalie; Laurent, Nathalie; Leclerc, Nathalie; Leroux, Séverine; Le Bars, Laëtitia; Marion, Stéphanie; Meziane, Youcef; Moukhtari, Leila; Renault, Myriam; Peffault de Latour, Régis; Yakoub-Agha, Ibrahim; Raus, Nicole

    2016-11-01

    In the attempt to harmonize clinical practices between different centers belonging to the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), our society set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. Here, we report our recommendations regarding diagnosis and disease status coding in the ProMISe database used by the SFGM-TC.

  18. 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

  19. Delivery of Nano-Tethered Therapies to Brain Metastases of Primary Breast Cancer Using a Cellular Trojan Horse

    DTIC Science & Technology

    2014-10-01

    Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse. Cancer Nanotechnol. 3, 47–54 (2012). 2. C. Qiao et...nn5002886. 8. H. Gao et al., Behavior and anti-glioma effect of lapatinib-incorporated lipoprotein-like nanoparticles . Nanotechnology . 23, 435101 (2012...948. [2] Mi-Ran Choi, et al., “Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse”, Cancer Nano, 2012; 3

  20. Cytotoxic T lymphocyte-associated antigen 4 inhibition increases the antitumor activity of adoptive T-cell therapy when carried out with naïve rather than differentiated T cells.

    PubMed

    Ishikawa, Takeshi; Adachi, Satoko; Okayama, Tetsuya; Kokura, Satoshi; Mizushima, Katsura; Doi, Toshifumi; Matsuyama, Tatsuzo; Sakamoto, Naoyuki; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Naito, Yuji; Itoh, Yoshito; Yoshikawa, Toshikazu

    2015-05-01

    Although treatment with an antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) combined with multiple therapeutic interventions has been explored, the effect of combination therapy with CTLA-4 inhibition and adoptive T-cell therapy has not been determined. In the present study, our aim was to determine whether CTLA-4 inhibition, combined with adoptive transfer of T cells at different stages of differentiation, exhibits synergistic antitumor effects in a murine colon cancer model. Mice bearing subcutaneous tumors were administered adoptive T-cell transfer of CD62Lhigh or CD62Llow cells combined with an anti-CTLA-4 antibody (α-CTLA-4) or control immunoglobulin G. Subcutaneous tumors were harvested, and the antitumor effects and helper T-cell polarization were analyzed. CTLA-4 inhibition combined with CD62Lhigh cell administration showed the strongest antitumor effect. Combination therapy increased the number of CD3+ cells within the tumor. Moreover, CTLA-4 inhibition induced polarization of T cells infiltrating the tumor toward the T helper 1 lineage, and suppressed the frequency of regulatory T cells within the tumor, particularly in combination with CD62Lhigh T-cell transfer. This is the first report demonstrating that the efficacy of α-CTLA-4 and adoptive T-cell transfer combination therapy depends on the state of differentiation of the transferred T cells. Our data support the notion that a combination of α-CTLA-4 and adoptive T-cell transfer containing an abundance of naïve phenotype cells could potentially exert antitumor effects in a clinical setting.

  1. T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ) signaling mediate superior tumor regression in an animal model of adoptive cell therapy

    PubMed Central

    2012-01-01

    Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFβ), which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFβ by transduction with a TGFβ dominant negative receptor II (DN), were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-γ in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer. PMID:22713761

  2. 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…

  3. 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.

  4. 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

  5. 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.

  6. Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals.

    PubMed

    Arruda, Mônica Barcellos; Campagnari, Francine; de Almeida, Tailah Bernardo; Couto-Fernandez, José Carlos; Tanuri, Amilcar; Cardoso, Cynthia Chester

    2016-01-01

    Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.

  7. Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals

    PubMed Central

    Arruda, Mônica Barcellos; Campagnari, Francine; de Almeida, Tailah Bernardo; Couto-Fernandez, José Carlos; Tanuri, Amilcar; Cardoso, Cynthia Chester

    2016-01-01

    Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies. PMID:27648838

  8. Pathological proof of cellular death in radiofrequency ablation therapy and correlation with flash echo imaging--an experiment study.

    PubMed

    Fujiki, Kei

    2004-01-01

    The aims of this study were to clarify the geographic distribution of complete cell death in the radiofrequency ablated area in a porcine liver experiment, and to evaluate the efficacy of ultrasonography using contrast media in detecting the area of Radiofrequency-induced cell death. Radiofrequency ablation was performed at 3 sites in each liver in seven swine with a RF2000TM radiofrequency generator using an expandable type needle electrode. The ablation area was investigated histologically by Hematoxylin-Eosin staining and NADH staining. The area of radiofrequency-induced cell death was correlated to the ultrasonographic findings using contrast media, by means of contrast harmonic imaging, flash echo imaging-subtraction and flash echo imaging-power Doppler. The ablation area showed three distinct regions. Although the HE staining did not indicate necrosis, the NADH staining showed a complete loss of cellular activity in the inner and middle layers of the ablation area. However, in the outer layer cells displaying cellular integrity were intermingled with the necrotic cells, indicating that some of the cells in this layer had a chance to survive. Further, in some cases the outer layer of the ablated area had irregular margins. The flash-echo power-doppler images were accurately correlated in size and shape to the pathologically proved region of complete cell death in the radiofrequency-induced lesions. In the marginal part of the radiofrequency ablation area, cell death was incomplete. Flash echo imaging-power doppler was a useful and sensitive real time imaging technique for accurate evaluation of the region of complete cell death.

  9. [General and ethical considerations for the informed consent process: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    PubMed

    Thibert, Jean-Baptiste; Polomeni, Alice; Yakoub-Agha, Ibrahim; Bordessoule, Dominique

    2016-11-01

    Informed consent is not restricted to clinical research and must be applied to high-risk care such as hematopoietic stem cell transplantation. If standardized informed consent might improve inequalities in medical practices between different transplantation centers, it is strongly recommended that it be adapted with an honest dialogue between physicians and patients and physicians and donors. In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country. The purpose of this paper is to highlight the French law concerning patients' rights and ethical practices for an informed consent process to be applied to care or research.

  10. Imaging of Caenorhabditis elegans samples and sub-cellular localization of new generation photosensitizers for photodynamic therapy, using non-linear microscopy

    NASA Astrophysics Data System (ADS)

    Filippidis, G.; Kouloumentas, C.; Kapsokalyvas, D.; Voglis, G.; Tavernarakis, N.; Papazoglou, T. G.

    2005-08-01

    Two-photon excitation fluorescence (TPEF) and second-harmonic generation (SHG) are relatively new promising tools for the imaging and mapping of biological structures and processes at the microscopic level. The combination of the two image-contrast modes in a single instrument can provide unique and complementary information concerning the structure and the function of tissues and individual cells. The extended application of this novel, innovative technique by the biological community is limited due to the high price of commercial multiphoton microscopes. In this study, a compact, inexpensive and reliable setup utilizing femtosecond pulses for excitation was developed for the TPEF and SHG imaging of biological samples. Specific cell types of the nematode Caenorhabditis elegans were imaged. Detection of the endogenous structural proteins of the worm, which are responsible for observation of SHG signals, was achieved. Additionally, the binding of different photosensitizers in the HL-60 cell line was investigated, using non-linear microscopy. The sub-cellular localization of photosensitizers of a new generation, very promising for photodynamic therapy (PDT), (Hypericum perforatum L. extracts) was achieved. The sub-cellular localization of these novel photosensitizers was linked with their photodynamic action during PDT, and the possible mechanisms for cell killing have been elucidated.

  11. Adopted Children and Discipline

    MedlinePlus

    ... Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families Media Work & Play ... Community Healthy Children > Family Life > Family Dynamics > Adoption & Foster Care > Adopted Children & Discipline Family Life Listen Español Text ...

  12. 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.

  13. 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.

  14. Adoptive transfer of Aspergillus-specific T cells as a novel anti-fungal therapy for hematopoietic stem cell transplant recipients: Progress and challenges.

    PubMed

    Papadopoulou, Anastasia; Kaloyannidis, Panayotis; Yannaki, Evangelia; Cruz, Conrad Russell

    2016-02-01

    Although newer antifungal drugs have substantially altered the natural history of invasive aspergillosis, the disease still accounts for significant morbidity and mortality in hematopoietic stem cell transplant recipients. Both the evidence supporting a protective role of T cells against this fungal pathogen and the documented efficacy of adoptive transfer of antigen-specific T cells for prophylaxis and treatment of viral infections post-transplant have stimulated much interest towards development of Aspergillus-specific T cells (Asp-STs) for adoptive immunotherapy in the allogeneic transplant setting. In contrast to the remarkable progress with virus-specific T cells, clinical development of fungus-specific T cells is still in its infancy. Several groups have characterized Asp-STs in healthy individuals and patients with malignant hematological diseases, while others sought to develop GMP-compliant methods of expanding or bioengineering Asp-STs ex vivo as immunotherapy. This review highlights the recent advances in this field, and discusses critical issues involved in development and protocol design of Asp-ST immunotherapy.

  15. 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.

  16. 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…

  17. Adoptive immunotherapy with donor lymphocyte infusions and interleukin-2 after high-dose therapy and autologous stem cell rescue for multiple myeloma.

    PubMed

    Ballester, O F; Fang, T; Raptis, A; Ballester, G; Wilcox, P; Hiemenz, J; Tan, B

    2004-09-01

    In an attempt to induce a graft-versus-myeloma effect, we administered donor lymphocyte infusions (DLI) after high-dose therapy with autologous stem cell transplant rescue to seven patients with refractory or relapsed multiple myeloma. High-dose therapy consisted of melphalan, idarubicin and etoposide (days -9 to -6) followed by autologous stem cell infusion on day 0. DLI (five of seven donors with two or three HLA antigens mismatched) were administered on days +1, +5 and +10 along with IL-2 (from day +1 through +12). Six of the seven patients developed acute graft-versus-host disease (GVHD), which resolved spontaneously, coincidentally with autologous hematopoietic reconstitution. One patient failed to engraft and received a second autologous graft. One patient died from complications of a pulmonary hemorrhage after experiencing GVHD. With a minimum follow-up of 38 months, five patients remain without disease progression in complete remission or with minimal residual disease. In this setting, DLI/IL-2 is biologically active resulting in GVHD. A graft-versus-myeloma effect is suggested by the improved outcome of our small cohort of high-risk patients. The use of partially mismatched related donors makes this approach potentially available to nearly all patients.

  18. Cognitive Behavioral Therapy and Tai Chi Reverse Cellular and Genomic Markers of Inflammation in Late Life Insomnia: A Randomized Controlled Trial

    PubMed Central

    Irwin, Michael R.; Olmstead, Richard; Breen, Elizabeth C.; Witarama, Tuff; Carrillo, Carmen; Sadeghi, Nina; Arevalo, Jesusa M. G.; Ma, Jeffrey; Nicassio, Perry; Bootzin, Richard; Cole, Steve

    2015-01-01

    Background Sleep disturbance is associated with activation of systemic and cellular inflammation, as well as pro-inflammatory transcriptional profiles in circulating leukocytes. Whether treatments that target insomnia-related complaints might reverse these markers of inflammation in older adults with insomnia is not known. Methods In this randomized trial, 123 older adults with insomnia were randomly assigned to cognitive behavioral therapy for insomnia (CBT-I), tai chi chih (TCC), or sleep seminar education active control condition (SS) for two hour sessions weekly over 4 months with follow-up at 7- and 16-months. We measured C-reactive protein (CRP) at baseline, month 4 and 16, Toll-like receptor-4 (TLR-4)-activated monocyte production of proinflammatory cytokines at baseline, month 2, 4, 7, and 16, and genome-wide transcriptional profiling at baseline and month 4. Results As compared to SS active control, CBT-I reduced levels of CRP (month 4, 16, P’s<0.05), monocyte production of proinflammatory cytokines (month 2 only, P<0.05), and pro-inflammatory gene expression (month 4, P<0.01). TCC marginally reduced CRP (month 4, P=0.06), and significantly reduced monocyte production of proinflammatory cytokines (month 2, 4, 7, 16, all P’s<0.05) and proinflammatory gene expression (month 4, P<0.001). In CBT and TCC, TELIS promoter-based bioinformatics analyses indicated reduced activity of nuclear factor (NF)-κB and AP1. Conclusions Among older adults with insomnia, CBT-I reduced systemic inflammation, TCC reduced cellular inflammatory responses, and both treatments reduced expression of genes encoding proinflammatory mediators. The findings provide an evidence-based molecular framework to understand the potential salutary effects of insomnia treatment on inflammation, with implications for inflammatory disease risk. PMID:25748580

  19. 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

  20. 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.

  1. 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

    2016-07-01

    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.

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

    PubMed

    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.

  3. CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy.

    PubMed

    Bridgeman, J S; Ladell, K; Sheard, V E; Miners, K; Hawkins, R E; Price, D A; Gilham, D E

    2014-02-01

    Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions.

  4. Plasmonic Nanostructured Cellular Automata

    NASA Astrophysics Data System (ADS)

    Alkhazraji, Emad; Ghalib, A.; Manzoor, K.; Alsunaidi, M. A.

    2017-03-01

    In this work, we have investigated the scattering plasmonic resonance characteristics of silver nanospheres with a geometrical distribution that is modelled by Cellular Automata using time-domain numerical analysis. Cellular Automata are discrete mathematical structures that model different natural phenomena. Two binary one-dimensional Cellular Automata rules are considered to model the nanostructure, namely rule 30 and rule 33. The analysis produces three-dimensional scattering profiles of the entire plasmonic nanostructure. For the Cellular Automaton rule 33, the introduction of more Cellular Automata generations resulted only in slight red and blue shifts in the plasmonic modes with respect to the first generation. On the other hand, while rule 30 introduced significant red shifts in the resonance peaks at early generations, at later generations however, a peculiar effect is witnessed in the scattering profile as new peaks emerge as a feature of the overall Cellular Automata structure rather than the sum of the smaller parts that compose it. We strongly believe that these features that emerge as a result adopting the different 256 Cellular Automata rules as configuration models of nanostructures in different applications and systems might possess a great potential in enhancing their capability, sensitivity, efficiency, and power utilization.

  5. Textbook Evaluation and Adoption.

    ERIC Educational Resources Information Center

    Stein, Marcy; Stuen, Carol; Carnine, Douglas; Long, Roger M.

    2001-01-01

    Encourages educators to carefully examine the textbook adoption process, especially the way in which adoption committees evaluate and select instructional materials. Reviews the available research literature on the textbook adoption process and includes recommendations for improving the process. Discusses guidelines for designing evaluation…

  6. 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…

  7. 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

  8. 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

  9. Achieving timely adoption.

    PubMed

    Carnochan, Sarah; Moore, Megan; Austin, Michael J

    2013-01-01

    While family reunification is the primary permanency objective for children who must be placed temporarily outside of their homes, reunification is not possible for all children. For those children who do not return to their parents and cannot find permanent homes with other family members, adoption is the favored outcome. This review examines the composite measure in the federal Child and Family Services Review that measures agency performance related to the timeliness of adoptions of foster children. It summarizes the multiple factors that research has found to be associated with increased risk for adoption delay and disruption. These include child characteristics, family of origin and adoptive family characteristics, and features of child welfare services and systems. Practices that have been broadly linked to adoption timeliness or address risk factors associated with delays in adoption are described, including social worker activities and agency or system-wide practice.

  10. Post adoption depression.

    PubMed

    Fields, Eve S; Meuchel, Jennifer M; Jaffe, Chiara J; Jha, Manish; Payne, Jennifer L

    2010-04-01

    We sought to evaluate the prevalence rate and factors associated with post adoption depression. One hundred and twelve adoptive mothers of infants under 12 months of age were recruited from local and national adoption organizations. A modified Edinburgh Postnatal Depression Scale (EPDS) and a questionnaire collecting medical and psychiatric history, perceived stress, and demographics were administered retrospectively. The rates of significant depressive symptoms (defined as EPDS >or=12) were calculated at three time points post adoption, and associations with specific clinical variables (personal or family psychiatric history, stress, and adjustment difficulty) were assessed. Eighty-six mothers were included. Rates of significant depressive symptoms (EPDS >or=12) were found in 27.9% of subjects at 0-4 weeks, 25.6% at 5-12 weeks, and 12.8% at 13-52 weeks post adoption. Significant depressive symptoms were not associated with personal or family psychiatric history but were associated with stress (p = 0.0011) and adjustment difficulties (p = 0.042) post adoption. Significant depressive symptoms were relatively common in adoptive mothers within the first year after adoption and were associated with environmental stress. Prospective studies are needed to confirm the existence of post adoption depression and the factors associated with it.

  11. Travelers' Health: International Adoption

    MedlinePlus

    ... a malaria-endemic area (See Chapter 3, Malaria ). Tuberculosis All internationally adopted children should be screened for tuberculosis (TB) after arriving in the United States. Internationally ...

  12. Adoption: Misunderstood, Mythologized, Marginalized

    ERIC Educational Resources Information Center

    Friedlander, Myrna L.

    2003-01-01

    Implications are discussed in response to the Major Contribution in this issue reviewing the history, controversies, and theoretical and research literature related to adoption. Practice recommendations for therapists working with adopted children and their families are clustered around three prominent themes in the reviews by Lee, O'Brien and…

  13. Subsidized Adoption in America.

    ERIC Educational Resources Information Center

    Gallagher, Ursula; Katz, Sanford N.

    The Model State Subsidized Adoption Act, developed to supplement existing state statutes, is presented in full, with accompanying Model Regulations. The act is designed to help provide a child in special circumstances with a permanent adoptive home. When efforts to achieve placement without subsidy have failed, the Act would provide that the child…

  14. Adoption & Foster Care

    MedlinePlus

    ... Family Life Family Life Family Life Medical Home Family Dynamics Media Work & Play Getting Involved in Your Community ... AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families ...

  15. Questions about Adoption

    MedlinePlus

    ... Family Life Family Life Family Life Medical Home Family Dynamics Media Work & Play Getting Involved in Your Community ... AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families ...

  16. Adoption and Sibling Rivalry

    MedlinePlus

    ... Family Life Family Life Family Life Medical Home Family Dynamics Media Work & Play Getting Involved in Your Community ... AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families ...

  17. The immunosuppressive effects of phthalocyanine photodynamic therapy in mice are mediated by CD4+ and CD8+ T cells and can be adoptively transferred to naïve recipients

    PubMed Central

    Yusuf, Nabiha; Katiyar, Santosh K; Elmets, Craig A

    2013-01-01

    Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors but it is also immunosuppressive which may reduce its therapeutic efficacy. The purpose of our study was to elucidate the role of CD4+ and CD8+ T-cells in PDT immunosuppression. Using silicon phthalocyanine 4 (Pc4) as photosensitizer, non-tumor bearing CD4 knockout (CD4−/−) mice and their wild type (WT) counterparts were subjected to Pc4-PDT in a manner identical to that used for tumor regression (1 cm spot size, 0.5 mg/kg Pc4, 110 J/cm2 light) to assess the effect of Pc4-PDT on cell-mediated immunity. There was a decrease in immunosuppression in CD4−/− mice as compared to WT mice. We next examined the role of CD8+ T-cells in Pc4-PDT induced immunosuppression using CD8−/− mice following the same treatment regimen used for CD4−/− mice. Similar to CD4−/− mice, CD8−/− mice exhibited less immunosuppression than WT mice. Pc4-PDT induced immunosuppression could be adoptively transferred with spleen cells from Pc4-PDT treated donor mice to syngenic naive recipients (p<0.05) and was mediated primarily by T cells, although macrophages were also found to play a role. Procedures that limit PDT induced immunosuppression but do not affect PDT induced regression of tumors may prove superior to PDT alone in promoting long term anti-tumor responses. PMID:18208456

  18. 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…

  19. The Colorado Adoption Project.

    PubMed

    Rhea, Sally-Ann; Bricker, Josh B; Wadsworth, Sally J; Corley, Robin P

    2013-02-01

    This paper describes the Colorado Adoption Project (CAP), an ongoing genetically informative longitudinal study of behavioral development. We describe the features of the adoption design used in CAP, and discuss how this type of design uses data from both parent-offspring and related- versus unrelated-sibling comparisons to estimate the importance of genetic and shared environmental influences for resemblance among family members. The paper provides an overview of CAP's history, how subjects were ascertained, recruited, and retained, and the domains of assessment that have been explored since the CAP's initiation in 1975. Findings from some representative papers that make use of data from CAP participants illustrate the study's multifaceted nature as a parent-offspring and sibling behavioral genetic study, a study that parallels a complimentary twin study, a longitudinal study of development, a source of subjects for molecular genetic investigation, and a study of the outcomes of the adoption process itself. As subjects assessed first at age 1 approach age 40, we hope the CAP will establish itself as the first prospective adoption study of lifespan development.

  20. School Adoption Program.

    ERIC Educational Resources Information Center

    Taggart, Doris

    Zions First National Bank in Utah adopted a local school in Garrison with a student body of 11, and invited them to participate in their Christmas tree program and a field trip to Salt Lake City. The venture proved so popular and rewarding for the children and bank staff that more field trips were funded and later, when the school burned down, the…

  1. 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.

  2. Assisting adoptive families: children adopted at older ages.

    PubMed

    Singer, Ellen; Krebs, Madeleine

    2008-01-01

    Understanding the adoption experience can help health care providers develop sensitivity to the special tasks of adopted children and their families. Children who are adopted at older ages may face particular challenges. Age at adoptive placement, the burden of loss, pre-adoptive experiences, and the challenge of attachment are all significant issues in older-child adoption. Pediatric nurses demonstrate sensitivity and support to adopted children and their families by using appropriate language about adoption; understanding the significance of missing health information; providing appropriate referrals as needed; and displaying an open, caring attitude.

  3. Guide to CASE Adoption

    DTIC Science & Technology

    1992-11-01

    from Ovum Ltd. and the Software Technology Support Center at Hill Air Force Base (UT 84056). Overviews of relevant issues, including CASE adoption, can...Integration Battle." Ovum , 1989. Feuche, M. "How to Use CASE Technology." MIS Week, 10, 37 (Sep 1989), 29. Firth, R., Mosley, V., Pethia, R., Roberts, L...Computer Science Berkeey CA 94704 symllable on Internet. anonomcus FTP laGpll ubicatkin sue-isnodeunomc~Icasa-nniduct-11 hax OVUM Ltd 7 Rathbon Street A

  4. 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…

  5. 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…

  6. 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

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

    PubMed

    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

    2015-11-01

    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.

  8. 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

  9. After adoption: dissolution or permanence?

    PubMed

    Festinger, Trudy

    2002-01-01

    Results are presented on the whereabouts of 516 adopted children, based on a random sample of children adopted from placement in New York City in 1996. Data from interviews with adoptive parents were augmented by information from adoption subsidy records and state child tracking files, as well as interviews with caregivers of children whose adoptive parents were deceased. There were few dissolutions, but postadoption service needs were many.

  10. 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

  11. 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

  12. [Assessment and management of post-transplant iron overload: Guidelines of the Francophone Society of Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    PubMed

    Jaspers, Aurélie; Bouhya, Salaheddine; Belaiche, Stéphanie; Chevallier, Patrice; Hermet, Eric; Hospital-Gustems, Carole; Michallet, Mauricette; Rialland, Fanny; Samsonova, Olga; Sirvent, Anne; Yakoub-Agha, Ibrahim; Rohrlich, Pierre-Simon; Beguin, Yves

    2016-11-01

    To harmonize clinical practice in hematopoietic stem cell transplantation, the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. The main aim of this session was to describe the impact, evaluation and treatment of post-transplant iron overload.

  13. 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

  14. 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…

  15. Prospects and limitations of T cell receptor gene therapy.

    PubMed

    Jorritsma, Annelies; Schotte, Remko; Coccoris, Miriam; de Witte, Moniek A; Schumacher, Ton N M

    2011-08-01

    Adoptive transfer of antigen-specific T cells is an attractive means to provide cancer patients with immune cells of a desired specificity and the efficacy of such adoptive transfers has been demonstrated in several clinical trials. Because the T cell receptor is the single specificity-determining molecule in T cell function, adoptive transfer of TCR genes into patient T cells may be used as an alternative approach for the transfer of tumor-specific T cell immunity. On theoretical grounds, TCR gene therapy has two substantial advantages over conventional cellular transfer. First, it circumvents the demanding process of in vitro generation of large numbers of specific immune cells. Second, it allows the use of a set of particularly effective TCR genes in large patient groups. Conversely, TCR gene therapy may be associated with a number of specific problems that are not confronted during classical cellular therapy. Here we review our current understanding of the potential and possible problems of TCR gene therapy, as based on in vitro experiments, mouse model systems and phase I clinical trials. Furthermore, we discuss the prospects of widespread clinical application of this gene therapy approach for the treatment of human cancer.

  16. 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

  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. Open adoption: adoptive parents' reactions two decades later.

    PubMed

    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 in 1988. Every seven years these parents who adopted infants in open adoptions have participated in tape-recorded interviews to explore their evolving reactions to their open adoption experiences. This article reports the results of in-depth interviews with these parents now that their children have reached young adulthood. This longitudinal research illuminates how open adoptions change over the course of childhood and adolescence, parents' feelings about open adoption, challenges that emerge in their relationships with their children's birth families, how those challenges are managed and viewed, and parents' advice for others living with open adoption and for clinical social work practice and policy. Findings reveal that regardless of the type of openness, these adoptive parents generally feel positive about knowing the birth parents and having contact with them, are comfortable with open adoption, and see it serving the child's best interests.

  19. Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy.

    PubMed

    Cillo, Anthony R; Krishnan, Supriya; McMahon, Deborah K; Mitsuyasu, Ronald T; Para, Michael F; Mellors, John W

    2014-01-01

    The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical trials registration unique identifier: NCT00001137.

  20. Impact of Chemotherapy for HIV-1 Related Lymphoma on Residual Viremia and Cellular HIV-1 DNA in Patients on Suppressive Antiretroviral Therapy

    PubMed Central

    Cillo, Anthony R.; Krishnan, Supriya; McMahon, Deborah K.; Mitsuyasu, Ronald T.; Para, Michael F.; Mellors, John W.

    2014-01-01

    The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. Clinical Trials Registration Unique Identifier: NCT00001137 PMID:24638072

  1. Cellular glutathione as a determinant of the sensitivity of colorectal tumour cell-lines to ZD2767 antibody-directed enzyme prodrug therapy (ADEPT)

    PubMed Central

    Monks, N R; Calvete, J A; Curtin, N J; Blakey, D C; East, S J; Newell, D R

    2000-01-01

    ZD2767P, a nitrogen mustard glutamate prodrug, is currently being evaluated in Phase 1 clinical trials of antibody directed enzyme prodrug therapy (ADEPT). There was no significant relationship between basal glutathione (GSH) concentration and sensitivity to ZD2767P + carboxpeptidase G2 (CPG2) in colorectal tumour cell-lines. Depletion of intracellular GSH using buthionine sulfoximine (BSO) resulted in only a modest potentiation of ZD2767P + CPG2 activity and hence BSO is unlikely to markedly enhance the activity of this ADEPT treatment. © 2000 Cancer Research Campaign PMID:10901381

  2. Subsidized Adoption across the Atlantic.

    ERIC Educational Resources Information Center

    Hill, Malcolm; Triseliotis, John

    1991-01-01

    Notes differences between American and British contexts and formulations of adoption payments. Highlights key findings from a research project that evaluated the impact of adoption allowances in Scotland. Gives particular attention to children's views about being adopted with financial help. (GH)

  3. Adoption: medical and legal aspects.

    PubMed

    Bhalla, C K

    1978-06-01

    The problem of abandoned children is of great magnitude in India. Placement of these children in a family environment is essential for their physical, mental, and emotional development. Adoption must be approached from the child welfare perspective. The pediatrician can play an important role in the adoption process. The pediatrician should perform a thorough medical examination of infants to be adopted, both to ensure the child's welfare and to give adoptive parents an assessment of the child's health. Information should be collected on the medical history of the child's biologic parents to aid in the evaluation process. Adoptive parents should also undergo medical and pyschological examinations. Pediatricians can additionally work with social welfare departments in establishing criteria for matching children with adoptive parents. Adoptions in India are currently governed by provisions or the 1956 Hindu Adoptions and Maintenance Act. Since this legislation excludes groups such as Muslims, Christians, and Parsis from its purview, there has been a demand for national legislation providing a uniform adoption law for all the communities in India. The Union Government introduced such a comprehensive bill in 1972, the Adoption of Children Bill; however, no action was ever taken. It is urged that this legislation be reactivated, and that the restriction on the removal of children for adoption outside India be lifted.

  4. 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.

  5. Strong and sustained effector function of memory- versus naïve-derived T cells upon T-cell receptor RNA transfer: implications for cellular therapy.

    PubMed

    Thomas, Simone; Klobuch, Sebastian; Besold, Katrin; Plachter, Bodo; Dörrie, Jan; Schaft, Niels; Theobald, Matthias; Herr, Wolfgang

    2012-12-01

    Current protocols used to select CMV-specific T cells for adoptive immunotherapy focus on virus-specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem-cell transplantation (HSCT) from CMV-seronegative donors. Here, we redirected T cells of CMV-seronegative donors with a human genetically engineered TCR recognizing an HLA-A*0201-binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non-viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve-derived T-cell subsets were both efficiently transfected by TCR-RNA, memory-derived T cells showed much stronger levels of HLA-A*0201-restricted cytolytic activity to CMV-infected fibroblasts and maintained acquired function for 5-10 days. In addition to redirection of CD8(+) cytotoxic T cells, TCR-RNA transfection was capable of redirecting CD4(+) T cells into potent Ag-specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve-derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus-specific CD4(+) and CD8(+) T-cell function. CMV TCR-RNA may represent a suitable therapeutic 'off-the-shelf' reagent to be used in severe CMV infections of HSCT patients when endogenous CMV-specific T-cell immunity is insufficient.

  6. 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…

  7. Long term effects on the immune system following local radiation therapy for breast cancer. I. Cellular composition of the peripheral blood lymphocyte population

    SciTech Connect

    Rotstein, S.; Blomgren, H.; Petrini, B.; Wasserman, J.; Baral, E.

    1985-05-01

    Local radiation therapy for breast cancer depletes the blood of various subsets of lymphocytes. Previous studies showed that the recovery is still incomplete at 30 months. To further elucidate the recovery the authors examined blood lymphocyte counts of 138 disease-free women and various lymphocyte subsets in 102 of these patients. Total lymphocyte counts of the irradiated patients were still significantly reduced 10-11 years after treatment. This reduction was mainly attributable to a subnormal level of T-cells as determined by the monoclonal antibody Leu-1 and the ability to form rosettes with sheep erythrocytes, whereas the number of non-T cells, expressing C'3 receptors, did not differ significantly from the controls. Within the T-cell population a subset with helper/inducer phenotypes, detected by Leu-3a antibodies, was significantly reduced even 10-11 years after irradiation. The duration of the radiation induced reductions of different lymphocyte subsets may be related to the physiological turn-over of the cells or a changed distribution of cells in the body.

  8. Inhibitory effects of merocyanine 540-mediated photodynamic therapy on cellular immune functions: A role in the prophylaxis of graft-versus-host disease?

    PubMed

    Traul, Donald L; Sieber, Fritz

    2015-12-01

    Merocyanine 540-mediated photodynamic therapy (MC540-PDT) has been used in clinical trials for the purging of autologous hematopoietic stem cell grafts. When the same combinations of dye and light were applied to human peripheral blood lymphocytes, a broad range of T- and B-cell functions were impaired, prompting speculations about a potential role of MC540-PDT in the prophylaxis of graft-versus-host disease (GVHD). We here report on the effects of MC540-PDT on in vitro functions of murine lymphocytes as well as a preliminary evaluation of MC540-PDT for the prevention of GVHD in murine models of allogeneic bone marrow transplantation. Mixed lymphocyte reactions, proliferative responses to lectins, interleukin-2 and lipopolysaccharide, T-cell-mediated lysis, and NK activity were all inhibited by moderate doses of MC540-PDT. Whether MC540-PDT reduced the incidence and/or the severity of GVHD in murine models of allogeneic hematopoietic stem cell transplantation depended on the composition of the mismatched grafts and the intensity of the preparative regimen. MC540-PDT was only beneficial (i.e. reduced the incidence and/or severity of GVHD) when the spleen cell content of grafts was low and/or the radiation dose of the preparative regimen was not myeloablative, and, therefore, may have encouraged mixed chimerism.

  9. [Senescence and cellular immortality].

    PubMed

    Trentesaux, C; Riou, J-F

    2010-11-01

    Senescence was originally described from the observation of the limited ability of normal cells to grow in culture, and may be generated by telomere erosion, accumulation of DNA damages, oxidative stress and modulation of oncogenes or tumor suppressor genes. Senescence corresponds to a cellular response aiming to control tumor progression by limiting cell proliferation and thus constitutes an anticancer barrier. Senescence is observed in pre-malignant tumor stages and disappears from malignant tumors. Agents used in standard chemotherapy also have the potential to induce senescence, which may partly explain their therapeutic activities. It is possible to restore senescence in tumors using targeted therapies that triggers telomere dysfunction or reactivates suppressor genes functions, which are essential for the onset of senescence.

  10. Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity

    PubMed Central

    Ghosh, Arnab; Dogan, Yildirim; Moroz, Maxim; Holland, Amanda M.; Yim, Nury L.; Rao, Uttam K.; Young, Lauren F.; Tannenbaum, Daniel; Masih, Durva; Velardi, Enrico; Tsai, Jennifer J.; Jenq, Robert R.; Penack, Olaf; Hanash, Alan M.; Smith, Odette M.; Piersanti, Kelly; Lezcano, Cecilia; Murphy, George F.; Liu, Chen; Palomba, M. Lia; Sauer, Martin G.; Sadelain, Michel; Ponomarev, Vladimir; van den Brink, Marcel R.M.

    2013-01-01

    Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro–generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. PMID:23676461

  11. 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.

  12. Recent Developments in Cellular Immunotherapy for HSCT-Associated Complications

    PubMed Central

    Reis, Monica; Ogonek, Justyna; Qesari, Marsela; Borges, Nuno M.; Nicholson, Lindsay; Preußner, Liane; Dickinson, Anne Mary; Wang, Xiao-nong; Weissinger, Eva M.; Richter, Anne

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation is associated with serious complications, and improvement of the overall clinical outcome of patients with hematological malignancies is necessary. During the last decades, posttransplant donor-derived adoptive cellular immunotherapeutic strategies have been progressively developed for the treatment of graft-versus-host disease (GvHD), infectious complications, and tumor relapses. To date, the common challenge of all these cell-based approaches is their implementation for clinical application. Establishing an appropriate manufacturing process, to guarantee safe and effective therapeutics with simultaneous consideration of economic requirements is one of the most critical hurdles. In this review, we will discuss the recent scientific findings, clinical experiences, and technological advances for cell processing toward the application of mesenchymal stromal cells as a therapy for treatment of severe GvHD, virus-specific T cells for targeting life-threating infections, and of chimeric antigen receptors-engineered T cells to treat relapsed leukemia. PMID:27895644

  13. ENHANCING PRESCRIPTION DRUG INNOVATION AND ADOPTION

    PubMed Central

    Alexander, G. Caleb; O’Connor, Alec B.; Stafford, Randall S.

    2014-01-01

    The adoption and use of a new drug would ideally be guided by its Innovation and cost-effectiveness. 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 market place 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

  14. 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…

  15. The Market Forces in Adoption. Adoption and Ethics, Volume 2.

    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 second in a series to use an ethics-based…

  16. 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.

  17. 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…

  18. Adopting Children with Attachment Problems.

    ERIC Educational Resources Information Center

    Hughes, Daniel A.

    1999-01-01

    Notes that attachment behavior in infants is a facet of normal child development, and that children with attachment problems require special attention during and after the adoption process. Presents actions needed to increase the probability that such children can be successfully adopted, detailed attachment patterns, and parenting strategies and…

  19. Parents’ Feelings Towards Their Adoptive and Non-Adoptive Children

    PubMed Central

    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 of the couple, and tested whether the links between parent feelings and child maladjustment included effects of passive gene–environment correlation. Parents reported more negativity and less positivity as well as higher levels of externalizing behaviour for the adopted child compared to the non-adopted child, although effect sizes were small and no longer statistically significant after correcting for multiple comparisons. Fathers and mothers did not differ significantly in their reports of positive and negative feelings towards their children or in regard to child externalizing and internalizing behaviours. The correlations between parental negativity and positivity and child externalizing and internalizing were similar for fathers and mothers, and for adopted and non-adopted children. The findings suggest similar parent–child relationship processes for fathers and mothers, and that genetic transmission of behaviour from parent to child does not account for the association between parental warmth and hostility and child-adjustment problems. PMID:21088705

  20. Ex vivo expansion of CD3(depleted) cord blood-MNCs in the presence of bone marrow stromal cells; an appropriate strategy to provide functional NK cells applicable for cellular therapy.

    PubMed

    Hosseini, Ehteramolsadat; Ghasemzadeh, Mehran; Kamalizad, Maedeh; Schwarer, Anthony P

    2017-03-01

    Considering umbilical cord blood (UCB) as a rich source of hematopoietic stem cells, we introduced a cost-effective approach to expand CD3(depleted) UCB-MNCs into functional NK cells. CD3(depleted) UCB-MNCs were expanded in the presence or absence of a feeder [bone marrow stem cells (BMSCs) or osteoblasts], with or without cytokines and their differentiation into NK cells was determined by flow cytometry. NK cell function was quantified by LAMP-1/CD107a expression, TNF-α/IFN-γ release, and LDH release/PI staining in targets. Higher expansion of NK cells was observed after two weeks in the presence of BMSCs and cytokines (104±15) compared to osteoblasts and cytokines (84±29, p<0.05). On day 14, CD3(depleted) UCB-MNCs in the presence of BMSCs and cytokines showed lower expression of CD3, CD19, CD14, CD15 and CD69 as well as higher expression of CD2 and CD7, which were suggestive of cell differentiation into mature NK cell lineage. Strong cytotoxicity of expanded cells was also identified with higher LDH release and PI% in targets. Significant upregulation of LAMP-1 with decreased release of IFN-γ and TNF-α from effectors were observed. We demonstrate an effective expansion of UCB-NK cells that maintained their functional capabilities applicable for cellular therapies.

  1. Adopting a Districtwide Reading Program.

    ERIC Educational Resources Information Center

    Miller, Jerry

    2002-01-01

    Describes a Washington school district's eight-step process leading to the adoption of a districtwide reading program. Includes data collection, research analysis, skill tracing, and field-testing. (PKP)

  2. Cellular Therapy to Obtain Spine Fusion

    DTIC Science & Technology

    2012-07-01

    paraspinous musculature. To prolong cell survival and insure cells are maintained at the target site, we have encapsulated them in a nondegradable...through encapsulation . Here we provide preliminary data; demonstrating spine fusion using this system at 6 weeks after induction. This is the first step

  3. Novel Immune-Modulating Cellular Vaccine for Prostate Cancer Immunotherapy

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0423 TITLE: Novel Immune-Modulating Cellular Vaccine for Prostate Cancer Immunotherapy PRINCIPAL INVESTIGATOR: Smita...SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0423 Novel Immune-Modulating Cellular Vaccine for Prostate Cancer Immunotherapy 5b. GRANT NUMBER 5c...immune modulation of CTLA4 and have generated a lead cellular therapy that will safely enhance vaccine -mediated immunity. This lead cellular

  4. Open adoption and adoptive mothers: attitudes toward birthmothers, adopted children, and parenting.

    PubMed

    Lee, J S; Twaite, J A

    1997-10-01

    The nature and extent of contact between 238 adoptive mothers and their child's biological mother was assessed for the period prior to the birth of the child and during the first two years of the child's life. Adoptive mothers who reported such contact prior to the child's birth had significantly more favorable attitudes toward both the biological mother and the adopted child. Those with contact either before or after the birth also demonstrated significantly more favorable parenting attitudes. Policy implications and the need for further research are noted.

  5. The cellular memory disc of reprogrammed cells.

    PubMed

    Anjamrooz, Seyed Hadi

    2013-04-01

    The crucial facts underlying the low efficiency of cellular reprogramming are poorly understood. Cellular reprogramming occurs in nuclear transfer, induced pluripotent stem cell (iPSC) formation, cell fusion, and lineage-switching experiments. Despite these advances, there are three fundamental problems to be addressed: (1) the majority of cells cannot be reprogrammed, (2) the efficiency of reprogramming cells is usually low, and (3) the reprogrammed cells developed from a patient's own cells activate immune responses. These shortcomings present major obstacles for using reprogramming approaches in customised cell therapy. In this Perspective, the author synthesises past and present observations in the field of cellular reprogramming to propose a theoretical picture of the cellular memory disc. The current hypothesis is that all cells undergo an endogenous and exogenous holographic memorisation such that parts of the cellular memory dramatically decrease the efficiency of reprogramming cells, act like a barrier against reprogramming in the majority of cells, and activate immune responses. Accordingly, the focus of this review is mainly to describe the cellular memory disc (CMD). Based on the present theory, cellular memory includes three parts: a reprogramming-resistance memory (RRM), a switch-promoting memory (SPM) and a culture-induced memory (CIM). The cellular memory arises genetically, epigenetically and non-genetically and affects cellular behaviours. [corrected].

  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 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Adopt-A-School Program.

    ERIC Educational Resources Information Center

    Los Angeles Unified School District, CA.

    The Los Angeles Unified School District's Adopt-A-School Program is described as a program where a business or an industry sponsors a school. Some of the ways business and industry can help students are to provide role models, tutor students, give mini-course lectures, share hobbies, offer counseling, give club sponsorship, provide summer…

  14. 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…

  15. International Adoptions: The Quiet Migration.

    ERIC Educational Resources Information Center

    Weil, Richard H.

    1984-01-01

    Examines patterns in the international migration of children for adoption since World War II, with emphasis on those going to Sweden, the United Kingdom, and the United States. Relates findings to political and cultural factors. Observes that Latin America became a major source area for the United States in the 1970s, but that Asia remained…

  16. 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.

  17. 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…

  18. Adoptive T cell immunotherapy for cancer.

    PubMed

    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.

  19. Adoptive cell transfer in autoimmune hepatitis.

    PubMed

    Czaja, Albert J

    2015-06-01

    Adoptive cell transfer is an intervention in which autologous immune cells that have been expanded ex vivo are re-introduced to mitigate a pathological process. Tregs, mesenchymal stromal cells, dendritic cells, macrophages and myeloid-derived suppressor cells have been transferred in diverse immune-mediated diseases, and Tregs have been the focus of investigations in autoimmune hepatitis. Transferred Tregs have improved histological findings in animal models of autoimmune hepatitis and autoimmune cholangitis. Key challenges relate to discrepant findings among studies, phenotypic instability of the transferred population, uncertain side effects and possible need for staged therapy involving anti-inflammatory drugs. Future investigations must resolve issues about the purification, durability and safety of these cells and consider alternative populations if necessary.

  20. Adoption: A Lifelong Journey for Children & Families.

    ERIC Educational Resources Information Center

    McManus, Marilyn, C., Ed.

    1996-01-01

    Several issues surrounding adoption are addressed in this journal. "Openness in Adoption," by Ruth G. McRoy and others, explores the movement away from confidentiality in adoption. "Mid-Life Reflections on Adoption" by Carol Yttri and "An Adoption Journey" by Shannon Latimer detail the experiences of adults who were…

  1. National Foster Care and Adoption Directory Search

    MedlinePlus

    ... in foster care, adoption, residential treatment, or juvenile justice programs. This person should be contacted by adoption ... in foster care, adoption, residential treatment, or juvenile justice programs in each State or territory. State Postadoption ...

  2. Human adoption in evolutionary perspective.

    PubMed

    Silk, J B

    1990-03-01

    Exploitation is a fundamental element of the parental strategies of many species of birds. Cuckoos, for example, lay their eggs in the nest of other birds, who often unwittingly rear the alien nestlings as their own. Nest parasitism is an efficient reproductive strategy for cuckoos, who do not have to worry about building a nest, incubating their eggs, or feeding their nestlings. But not all hosts respond passively to such intrusions. In response to parasitic cowbirds, for example, robins have evolved the ability to detect and selectively eject alien young from their nests. Human parenting strategies differ sharply from the strategies of cuckoos and robins. Unlike cuckoos, we are reluctant to allow our children to be raised by others. Unlike robins, we knowingly rear strange young. What makes human behavior toward children so different from that of cuckoos and robins? Humans seem to share a number of predispositions that facilitate successful adoptive relationships, and the desire to raise children seems to be pervasive among modern humans. Despite these commonalities, patterns of adoption transactions vary greatly among contemporary human societies. This paper considers the origins and causes of cross-cultural variation in human adoptive behavior from an evolutionary perspective.

  3. A Cellular Biophysics Textbook

    NASA Astrophysics Data System (ADS)

    Wilder, Alan Joseph

    2011-12-01

    In the past two decades, great advances have been made in understanding of the biophysical mechanisms of the protein machines that carry out the fundamental processes of the cell. It is now known that all major eukaryotic cellular processes require a complicated assemblage of proteins acting via a series of concerted motions. In order to grasp current understanding of cellular mechanisms, the new generation of cell biologists needs to be trained in the general characteristics of these cellular properties and the methods with which to study them. This cellular biophysics textbook, to be used in conjunction with the cellular biophysics course (MCB143) at UC-Davis, provides a great tool in the instruction of the new generation of cellular biologists. It provides a hierarchical view of the cell, from atoms to protein machines and explains in depth the mechanisms of cytoskeletal force generators as an example of these principles.

  4. 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

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

    MedlinePlus

    ... search for single letter changes to the DNA code on patients’ chromosomes, which may increase or decrease ... characterized by three letter repeats in the DNA code, called CAG-repeats. Disease-causing versions of the ...

  6. UN adopts Law of Sea

    NASA Astrophysics Data System (ADS)

    Richman, Barbara T.

    After more than 8 years of diplomatic wrangling, the United Nations Convention on the Law of the Sea was adopted on April 30 by a vote of 130 to 4. The United States, Israel, Turkey, and Venezuela voted against the treaty; 17 nations—including the Soviet Union, West Germany, and Britain—abstained.The treaty, which would give nations the exclusive rights to natural resources in the continental shelf up to approximately 650 km offshore, will be signed in December. The treaty becomes effective 1 year after at least 60 nations ratify it.

  7. 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....

  8. 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....

  9. 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....

  10. 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…

  11. 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)

  12. Novel Immune Modulating Cellular Vaccine for Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0423 TITLE: Novel immune modulating cellular vaccine for prostate cancer PRINCIPAL INVESTIGATOR: Smita Nair...2014 2. REPORT TYPE Annual 3. DATES COVERED 30 Sept 2013 to 29 Sept 2014 4. TITLE AND SUBTITLE Novel immune modulating cellular vaccine for...that will safely enhance vaccine -mediated immunity. This lead cellular therapy, called DC-PAPvac-C, consists of dendritic cells (DCs) co-transfected

  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. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer.

    PubMed

    Kandalaft, Lana E; Powell, Daniel J; Chiang, Cheryl L; Tanyi, Janos; Kim, Sarah; Bosch, Marnix; Montone, Kathy; Mick, Rosemarie; Levine, Bruce L; Torigian, Drew A; June, Carl H; Coukos, George

    2013-01-01

    Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 10(9) autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8(+) lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes.

  15. 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

  16. [Adoptive parents' satisfaction with the adoption experience and with its impact on family life].

    PubMed

    Sánchez-Sandoval, Yolanda

    2011-11-01

    In this study, we discuss the relevance of adoptive families' satisfaction in the assessment of adoption processes. The effects of adoption on a sample group of 272 adoptive families are analyzed. Most families show high levels of satisfaction as to: their decision to adopt, the features of their adopted children and how adoption has affected them as individuals and as a family. Statistical analyses show that these families can have different satisfaction levels depending on certain features of the adoptees, of the adoptive families or of their educational style. Life satisfaction of the adoptees is also related to how their adoptive parents evaluate the adoption.

  17. 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.

  18. [Adoption: an alternative to assisted reproductive techniques?].

    PubMed

    Blanchy, S

    2011-09-01

    Information on adoption must be given to couples who seek treatment for medically-assisted procreation. But is adoption a real alternative? What are the chances for a couple who consults to see its desire for adoption be achieved according to its own situation, the characteristics of the child he wants, and the general situation of adoption? Can adoption, just like assisted procreation, often described by the couples as a "obstacle course", go parallel? Or should one try adoption once assisted reproduction failed? Is the couple willing to suffer the social and legal control of adoption after having supported the medical control of the ART? In all cases, the reality is that two out of three couples engaged in assisted reproduction will have a child whereas scarcely more than one candidate to adoption will be offered to adopt a child after three or four-years procedure.

  19. Adoption law: a district nurse's guide.

    PubMed

    Griffith, Richard; Tengnah, Cassam

    2011-04-01

    The Government wants to see a large rise in the use of adoption as a means of giving children a secure, loving and permanent home. Guidance coming into effect from April calls for a more pragmatic approach to adoption placements, and calls for the active promotion of the adoption process by health and social care professionals. District nurses will encounter people interested in becoming prospective adopters, but who are unsure if their background or lifestyle makes them eligible. It is essential that district nurses have a working understanding of the guidance and provisions of the Adoption and Children Act 2002 to confidently advise others about adoption and clarify any issues raised.

  20. Cellular aging and cancer

    PubMed Central

    Hornsby, Peter J.

    2010-01-01

    Aging is manifest in a variety of changes over time, including changes at the cellular level. Cellular aging acts primarily as a tumor suppressor mechanism, but also may enhance cancer development under certain circumstances. One important process of cellular aging is oncogene-induced senescence, which acts as an important anti-cancer mechanism. Cellular senescence resulting from damage caused by activated oncogenes prevents the growth or potentially neoplastic cells. Moreover, cells that have entered senescence appear to be targets for elimination by the innnate immune system. In another aspect of cellular aging, the absence of telomerase activity in normal tissues results in such cells lacking a telomere maintenance mechanism. One consequence is that in aging there is an increase in cells with shortened telomeres. In the presence of active oncogenes that cause expansion of a neoplastic clone, shortening of telomeres leading to telomere dysfunction prevents the indefinite expansion of the clone because the cells enter crisis. Crisis results from fusions and other defects caused by dysfunctional telomeres and is a terminal state of the neoplastic clone. In this way the absence of telomerase in human cells, while one cause of cellular aging, also acts as an anti-cancer mechanism. PMID:20705476

  1. 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…

  2. 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…

  3. Gene therapy for blindness.

    PubMed

    Sahel, José-Alain; Roska, Botond

    2013-07-08

    Sight-restoring therapy for the visually impaired and blind is a major unmet medical need. Ocular gene therapy is a rational choice for restoring vision or preventing the loss of vision because most blinding diseases originate in cellular components of the eye, a compartment that is optimally suited for the delivery of genes, and many of these diseases have a genetic origin or genetic component. In recent years we have witnessed major advances in the field of ocular gene therapy, and proof-of-concept studies are under way to evaluate the safety and efficacy of human gene therapies. Here we discuss the concepts and recent advances in gene therapy in the retina. Our review discusses traditional approaches such as gene replacement and neuroprotection and also new avenues such as optogenetic therapies. We conjecture that advances in gene therapy in the retina will pave the way for gene therapies in other parts of the brain.

  4. Impact of Adoption on Birth Parents

    MedlinePlus

    ... disclosed and 40 percent being mediated (Siegel & Livingston Smith, 2012). Although the context around each adoption is ... Society, 78 , 522–529. Siegel, D. H., & Livingston Smith, S. (2012). Openness in adoption: From secrecy and stigma ...

  5. 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)

  6. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 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...

  7. 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.

  8. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction

    PubMed Central

    de Couto, Geoffrey; Liu, Weixin; Tseliou, Eleni; Sun, Baiming; Makkar, Nupur; Kanazawa, Hideaki; Arditi, Moshe; Marbán, Eduardo

    2015-01-01

    Ischemic injury in the heart induces an inflammatory cascade that both repairs damage and exacerbates scar tissue formation. Cardiosphere-derived cells (CDCs) are a stem-like population that is derived ex vivo from cardiac biopsies; they confer both cardioprotection and regeneration in acute myocardial infarction (MI). While the regenerative effects of CDCs in chronic settings have been studied extensively, little is known about how CDCs confer the cardioprotective process known as cellular postconditioning. Here, we used an in vivo rat model of ischemia/reperfusion (IR) injury–induced MI and in vitro coculture assays to investigate how CDCs protect stressed cardiomyocytes. Compared with control animals, animals that received CDCs 20 minutes after IR had reduced infarct size when measured at 48 hours. CDCs modified the myocardial leukocyte population after ischemic injury. Specifically, introduction of CDCs reduced the number of CD68+ macrophages, and these CDCs secreted factors that polarized macrophages toward a distinctive cardioprotective phenotype that was not M1 or M2. Systemic depletion of macrophages with clodronate abolished CDC-mediated cardioprotection. Using both in vitro coculture assays and a rat model of adoptive transfer after IR, we determined that CDC-conditioned macrophages attenuated cardiomyocyte apoptosis and reduced infarct size, thereby recapitulating the beneficial effects of CDC therapy. Together, our data indicate that CDCs limit acute injury by polarizing an effector macrophage population within the heart. PMID:26214527

  9. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction.

    PubMed

    de Couto, Geoffrey; Liu, Weixin; Tseliou, Eleni; Sun, Baiming; Makkar, Nupur; Kanazawa, Hideaki; Arditi, Moshe; Marbán, Eduardo

    2015-08-03

    Ischemic injury in the heart induces an inflammatory cascade that both repairs damage and exacerbates scar tissue formation. Cardiosphere-derived cells (CDCs) are a stem-like population that is derived ex vivo from cardiac biopsies; they confer both cardioprotection and regeneration in acute myocardial infarction (MI). While the regenerative effects of CDCs in chronic settings have been studied extensively, little is known about how CDCs confer the cardioprotective process known as cellular postconditioning. Here, we used an in vivo rat model of ischemia/reperfusion (IR) injury-induced MI and in vitro coculture assays to investigate how CDCs protect stressed cardiomyocytes. Compared with control animals, animals that received CDCs 20 minutes after IR had reduced infarct size when measured at 48 hours. CDCs modified the myocardial leukocyte population after ischemic injury. Specifically, introduction of CDCs reduced the number of CD68+ macrophages, and these CDCs secreted factors that polarized macrophages toward a distinctive cardioprotective phenotype that was not M1 or M2. Systemic depletion of macrophages with clodronate abolished CDC-mediated cardioprotection. Using both in vitro coculture assays and a rat model of adoptive transfer after IR, we determined that CDC-conditioned macrophages attenuated cardiomyocyte apoptosis and reduced infarct size, thereby recapitulating the beneficial effects of CDC therapy. Together, our data indicate that CDCs limit acute injury by polarizing an effector macrophage population within the heart.

  10. 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…

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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....

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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....

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. 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....

  8. 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....

  9. 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...

  10. 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...

  11. 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...

  12. 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....

  13. 32 CFR 584.4 - Adoption proceedings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 3 2010-07-01 2010-07-01 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...

  14. 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…

  15. 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…

  16. Talking with Young Children about Adoption.

    ERIC Educational Resources Information Center

    Watkins, Mary; Fisher, Susan

    Even though current wisdom holds that adoptive parents should talk with their child about adoption as early as possible, no guidelines exist to prepare parents for the various ways their children might respond when these conversations take place. This book discusses how young children make sense of the fact that they are adopted, how their…

  17. 78 FR 66609 - National Adoption Month, 2013

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-05

    ... 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 stand... parents and children. This month, we celebrate adopted children, teenagers, and their diverse families....

  18. [Modalities for preparation, cryopreservation, thawing of hematopoietic stem cells and precautions for infusion to patient: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    PubMed

    Boulanger, Florence; Decot, Véronique; Bulliard, Geneviève; Calmels, Boris; Giraud, Christine; Lacassagne, Marie-Noëlle; Magnani, Alessandra; Pouthier, Fabienne; Thibert, Jean-Baptiste; Tirefort, Yordanka; Yakoub-Agha, Ibrahim; Baudoux, Etienne

    2016-11-01

    To date, despite an existing regulatory framework and standards, there are no true technical recommendations. A survey of 23 cell processing facilities (France, Belgium and Switzerland) has allowed to overview current practices according to cellular products specifications upon arrival at the facility, with modalities for their preparation prior to cryopreservation, storage, thawing and finally for infusion to patient. Data analysis shows great variability of collected volumes and cell concentrations in cellular products. Despite homogeneous practices for handling cells at the facility, methods vary between centers, especially for the choice of cryoprotective solutions and thawing methods. During the workshop, practices have been discussed and summarized to write of recommendations about the following topics: processing and cryopreservation, thawing, bedside precautions (for infusion). This work identifies some improvements in terms of collection, choice of wash solution of thawed cells and validation of the conditions of carriage.

  19. Adoption of Electronic Health Records

    PubMed Central

    Grabenbauer, L; Fraser, R.; McClay, J.; Woelfl, N.; Thompson, C.B.; Cambell, J.; Windle, J.

    2011-01-01

    Objective Less than 20% of hospitals in the US have an electronic health record (EHR). In this qualitative study, we examine the perspectives of both academic and private physicians and administrators as stakeholders, and their alignment, to explore their perspectives on the use of technology in the clinical environment. Methods Focus groups were conducted with 74 participants who were asked a series of open-ended questions. Grounded theory was used to analyze the transcribed data and build convergent themes. The relevance and importance of themes was constructed by examining frequency, convergence, and intensity. A model was proposed that represents the interactions between themes. Results Six major themes emerged, which include the impact of EHR systems on workflow, patient care, communication, research/outcomes/billing, education/learning, and institutional culture. Academic and private physicians were confident of the future benefits of EHR systems, yet cautious about the current implementations of EHR, and its impact on interactions with other members of the healthcare team and with patients, and the amount of time necessary to use EHR’s. Private physicians differed on education and were uneasy about the steep learning curve necessary for use of new systems. In contrast to physicians, university and hospital administrators are optimistic, and value the availability of data for use in reporting. Conclusion The results of our study indicate that both private and academic physicians concur on the need for features that maintain and enhance the relationship with the patient and the healthcare team. Resistance to adoption is related to insufficient functionality and its potential negative impact on patient care. Integration of data collection into clinical workflows must consider the unexpected costs of data acquisition. PMID:23616868

  20. Fatigue of cellular materials

    SciTech Connect

    Huang, J.S.; Lin, J.Y.

    1996-01-01

    The fatigue of cellular materials is analyzed using dimensional arguments. When the first unbroken cell wall ahead of the macrocrack tip fails after some cycles of loading, the macrocrack advances one cell diameter, giving the macrocrack growth rate of cellular materials. Paris law for microcrack propagation, Basquin law for high cycle fatigue and Coffin-Manson law for low cycle fatigue are employed in calculating the number of cycles to failure of the first unbroken cell wall ahead of the macrocrack tip. It is found that fatigue of cellular materials depends on cyclic stress intensity range, cell size, relative density and the fatigue parameters of the solid from which they are made. Theoretical modelling of fatigue of foams is compared to data in polymer foams; agreement is good.

  1. 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.

  2. Epigenetics and Cellular Metabolism

    PubMed Central

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375

  3. Origins of cellular geometry

    PubMed Central

    2011-01-01

    Cells are highly complex and orderly machines, with defined shapes and a startling variety of internal organizations. Complex geometry is a feature of both free-living unicellular organisms and cells inside multicellular animals. Where does the geometry of a cell come from? Many of the same questions that arise in developmental biology can also be asked of cells, but in most cases we do not know the answers. How much of cellular organization is dictated by global cell polarity cues as opposed to local interactions between cellular components? Does cellular structure persist across cell generations? What is the relationship between cell geometry and tissue organization? What ensures that intracellular structures are scaled to the overall size of the cell? Cell biology is only now beginning to come to grips with these questions. PMID:21880160

  4. 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.

  5. Cellular membrane collapse by atmospheric-pressure plasma jet

    NASA Astrophysics Data System (ADS)

    Kim, Kangil; Jun Ahn, Hak; Lee, Jae-Hyeok; Kim, Jae-Ho; Sik Yang, Sang; Lee, Jong-Soo

    2014-01-01

    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.

  6. Cell and gene therapy.

    PubMed

    Rao, Rajesh C; Zacks, David N

    2014-01-01

    Replacement or repair of a dysfunctional gene combined with promoting cell survival is a two-pronged approach that addresses an unmet need in the therapy of retinal degenerative diseases. In this chapter, we discuss various strategies toward achieving both goals: transplantation of wild-type cells to replace degenerating cells and to rescue gene function, sequential gene and cell therapy, and in vivo reprogramming of rods to cones. These approaches highlight cutting-edge advances in cell and gene therapy, and cellular lineage conversion in order to devise new therapies for various retinal degenerative diseases.

  7. Economic incentives and foster child adoption.

    PubMed

    Argys, Laura; Duncan, Brian

    2013-06-01

    Every year, a large number of children in the United States enter the foster care system. Many of them are eventually reunited with their biological parents or quickly adopted. A significant number, however, face long-term foster care, and some of these children are eventually adopted by their foster parents. The decision by foster parents to adopt their foster child carries significant economic consequences, including for feiting foster care payments while also assuming responsibility for medical, legal, and educational expenses, to name a few. Since 1980, U.S. states have begun to offer adoption subsidies to offset some of these expenses, significantly lowering the cost of adopting a child who is in the foster care system. This article presents empirical evidence of the role that these economic incentives play in foster parents' decision of when, or if, to adopt their foster child. We find that adoption subsidies increase adoptions through two distinct price mechanisms: by lowering the absolute cost of adoption, and by lowering the relative cost of adoption versus long-term foster care.

  8. 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)

  9. 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…

  10. The Concerns-Based Adoption Model: A Developmental Conceptualization of the Adoption Process Within Educational Institutions.

    ERIC Educational Resources Information Center

    Hall, Gene E.

    The Concerns-Based Adoption Model (CBAM), a representation of the process by which an educational institution adopts an innovation, views adoption as a developmental process involving complex interaction between an adopting institution, a user system, and a resource system. The resource system is usually a formal organization whose expert…

  11. "Adoption Wisdom: A Guide to the Issues and Feelings of Adoption" by Marlou Russell. Book Review.

    ERIC Educational Resources Information Center

    Simonson, Tracy

    1998-01-01

    Reviews "Adoption Wisdom: A Guide to the Issues and Feelings of Adoption" by Marlou Russell. Maintains that its narrative/comment format and accounts of those involved in adoption validate the feelings of the adoption-triad members. Suggests that the book lacks information on individuals who contributed comments and contains few narratives from…

  12. Immunometabolism: Cellular Metabolism Turns Immune Regulator*

    PubMed Central

    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

  13. 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.

  14. Role of memory T cell subsets for adoptive immunotherapy.

    PubMed

    Busch, Dirk H; Fräßle, Simon P; Sommermeyer, Daniel; Buchholz, Veit R; Riddell, Stanley R

    2016-02-01

    Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e.g. central memory, effector memory, tissue-resident memory T cells). This diversification process is crucial for effective immune protection, with probably distinct dependencies on the presence of individual subsets dependent on the disease to which the immune response is directed as well as its organ location. Adoptive T cell therapy intends to therapeutically transfer defined T cell immunity into patients. Efficacy of this approach often requires long-term maintenance of transferred cells, which depends on the presence and persistence of memory T cells. However, engraftment and survival of highly differentiated memory T cell subsets upon adoptive transfer is still difficult to achieve. Therefore, the recent observation that a distinct subset of weakly differentiated memory T cells shows all characteristics of adult tissue stem cells and can reconstitute all types of effector and memory T cell subsets, became highly relevant. We here review our current understanding of memory subset formation and T cell subset purification, and its implications for adoptive immunotherapy.

  15. 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.

  16. Spatial effects on hybrid electric vehicle adoption

    DOE PAGES

    Liu, Xiaoli; Roberts, Matthew C.; Sioshansi, Ramteen

    2017-03-08

    This paper examines spatial effects on hybrid-electric vehicle (HEV) adoption. This is in contrast to most existing analyses, which concentrate on analyzing socioeconomic factors and demographics. This paper uses a general spatial model to estimate the strength of ‘neighbor effects’ on HEV adoption—namely that each consumer’s HEV-adoption decision can be influenced by the HEV-adoption decisions of geographic neighbors. We use detailed census tract-level demographic data from the 2010 United States Census and the 2012 American Community Survey and vehicle registration data collected by the Ohio Bureau of Motor Vehicles. We find that HEV adoption exhibits significant spatial effects. We furthermore » conduct a time-series analysis and show that historical HEV adoption has a spatial effect on future adoption. Lastly, these results suggest that HEVs may appear in more dense clusters than models that do not consider spatial effects predict.« less

  17. 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.

  18. Measures for Predictors of Innovation Adoption.

    PubMed

    Chor, Ka Ho Brian; Wisdom, Jennifer P; Olin, Su-Chin Serene; Hoagwood, Kimberly E; Horwitz, Sarah M

    2015-09-01

    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.

  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. 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.

  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.

  2. Healthy depictions? Depicting adoption and adoption news events on broadcast news.

    PubMed

    Kline, Susan L; Chatterjee, Karishma; Karel, Amanda I

    2009-01-01

    Given that the public uses the media to learn about adoption as a family form, this study analyzes U.S. television news coverage of adoption between 2001 and 2005 (N = 309 stories), to identify the types of news events covered about adoption. A majority of news stories covered fraud, crime, legal disputes, and negative international adoption cases. Adoptees as defective or unhealthy were depicted more in negative news event stories, birth parents appeared less overall, and adoptive parents were most likely to have healthy depictions in positively oriented adoption experience, big family, and reunion stories. Although three quarters of the stories used primary adoption participants as news sources, one-third of the negative event stories did not contain healthy depictions of adoption participants. The authors discuss ways journalists and researchers might improve adoption news coverage.

  3. Contact Between Adoptive and Birth Families: Perspectives from the Minnesota Texas Adoption Research Project

    PubMed Central

    Grotevant, Harold D.; McRoy, Ruth G.; Wrobel, Gretchen M.; Ayers-Lopez, Susan

    2013-01-01

    A growing number of adoptive families have contact with their children’s birth relatives. The Minnesota Texas Adoption Research Project is examining longitudinally the consequences of variations in contact arrangements for birth mothers, adoptive parents, and adopted children in domestic infant adoptions, and is studying the dynamics of relationships within these family systems. Individuals who had contact were more satisfied with their arrangements than those who did not have contact. Satisfaction with contact predicted more optimal adjustment among adopted adolescents and emerging adults. Adoption-related communication predicted identity development among adopted adolescents and emerging adults. Birth mothers who were more satisfied with their contact arrangements, regardless of level of contact, had less unresolved grief 12 to 20 years after placement. Adoptive and birth relatives who engage in contact need flexibility, strong interpersonal skills, and commitment to the relationship. These skills can be learned, and they can be supported by others, through informal, psychoeducational, and therapeutic means. PMID:23956791

  4. 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.

  5. 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.

  6. Chimeric antigen receptor engineered stem cells: a novel HIV therapy.

    PubMed

    Zhen, Anjie; Carrillo, Mayra A; Kitchen, Scott G

    2017-03-01

    Despite the success of combination antiretroviral therapy (cART) for suppressing HIV and improving patients' quality of life, HIV persists in cART-treated patients and remains an incurable disease. Financial burdens and health consequences of lifelong cART treatment call for novel HIV therapies that result in a permanent cure. Cellular immunity is central in controlling HIV replication. However, HIV adopts numerous strategies to evade immune surveillance. Engineered immunity via genetic manipulation could offer a functional cure by generating cells that have enhanced antiviral activity and are resistant to HIV infection. Recently, encouraging reports from several human clinical trials using an anti-CD19 chimeric antigen receptor (CAR) modified T-cell therapy for treating B-cell malignancies have provided valuable insights and generated remarkable enthusiasm in engineered T-cell therapy. In this review, we discuss the development of HIV-specific chimeric antigen receptors and the use of stem cell based therapies to generate lifelong anti-HIV immunity.

  7. 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%…

  8. 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…

  9. 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…

  10. 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 ...

  11. 75 FR 68166 - National Adoption Month, 2010

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-04

    ... countless American lives, and to encourage the adoption of children from foster care. Currently, thousands of children await adoption or are in foster care, looking forward to permanent homes. These children... children out of foster care. Last year, Health and Human Services Secretary Kathleen Sebelius was...

  12. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Adoption. 230.21 Section 230.21 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE PROCEDURES FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally...

  13. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Adoption. 230.21 Section 230.21 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE PROCEDURES FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally...

  14. MSW Students' Attitudes toward Transracial Adoption

    ERIC Educational Resources Information Center

    Lee, Jaegoo; Crolley-Simic, Josie; Vonk, M. Elizabeth

    2013-01-01

    This study explored the attitudes of MSW students ("N"?=?147) toward transracial adoption and included an investigation of the students' personal experiences that may affect their attitudes. Statistical analyses revealed that although the majority of students supported the practice of transracial adoption, a number of students gave…

  15. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Adoption. 230.21 Section 230.21 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE PROCEDURES FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally...

  16. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Adoption. 230.21 Section 230.21 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE PROCEDURES FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally...

  17. 33 CFR 230.21 - Adoption.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Adoption. 230.21 Section 230.21 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE PROCEDURES FOR IMPLEMENTING NEPA § 230.21 Adoption. See 40 CFR 1506.3. A district commander will normally...

  18. Mother-infant attachment in adoptive families.

    PubMed

    Singer, L M; Brodzinsky, D M; Ramsay, D; Steir, M; Waters, E

    1985-12-01

    Data from 2 separate samples using the Strange Situation paradigm were combined to assess the quality of attachment relationships in adoptive and nonadoptive mother-infant pairs. Infants were between 13 and 18 months at the time of observation. Results indicated no differences in mother-infant attachment between nonadopted and intraracial adopted subjects or between intraracial and interracial adopted subjects. Interracial adoptive mother-infant pairs did show a higher incidence of insecure attachment in comparison to nonadoptive pairs. Mothers of interracial adopted infants also were less comfortable having others care for their babies and perceived less emotional support from extended family and friends for their decision to adopt a child prior to the actual adoption than did other mothers. No relation was found, however, between quality of mother-infant attachment and either perceived social support, infant developmental quotient, infant temperament, number of foster homes experienced by the infant, or infant's age at the time of adoption placement. It was suggested that the higher incidence of psychological problems found among adoptees in middle childhood and adolescence cannot be explained in terms of insecure attachment relationships during the infancy years.

  19. 18 CFR 341.6 - Adoption rule.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Section 341.6 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE INTERSTATE COMMERCE ACT OIL PIPELINE TARIFFS: OIL PIPELINE COMPANIES... such occurrence. The filing of adoption notices and adoption supplements requires no notice period....

  20. 77 FR 66517 - National Adoption Month, 2012

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-06

    ... 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 to... nurture their development and well-being. Later this month, many Americans will also mark...

  1. Understanding Innovation Adoption in the Air Force

    DTIC Science & Technology

    2006-03-01

    Production Management, 22: 152-194 (Spring 2002). Frambach, Ruud T. “An Integrated Model of Organizational Adoption and Diffusion of Innovations...European Journal of Marketing, 27: 22-41 (May 1993). Frambach, Ruud T. and Niels Schillewaert. “Organizational Innovation Adoption. A Multi

  2. Wrongful Adoption: Law, Policy and Practice.

    ERIC Educational Resources Information Center

    Freundlich, Madelyn; Peterson, Lisa

    The past decade has seen an increase in cases where adoptive parents fail to receive accurate or complete information about a child's physical, emotional, or developmental problems or about the child's birth family and history. In these cases adoptive parents are confronted with extremely expensive medical care or mental health care. This…

  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. Adoptive Parents' Attitudes Toward Open Birth Records.

    ERIC Educational Resources Information Center

    Geissinger, Shirley

    1984-01-01

    Investigated adoptive parents' (N=42) attitudes toward the open birth record issues using a mail survey. Analysis indicated that parental fear was the most important variable. Most supported a measure allowing adult adoptees access to birth records, provided such access was agreeable to birth and adoptive parents. (JAC)

  5. 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)

  6. 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…

  7. Is managed care restraining the adoption of technology by hospitals?

    PubMed

    Mas, Núria; Seinfeld, Janice

    2008-07-01

    As health care costs increase, cost-control mechanisms become more widespread and it is crucial to understand their implications for the health care market. This paper examines the effect that managed care activity (based on the aim to control health care expenditure) has on the adoption of technologies by hospitals. We use a hazard rate model to investigate whether higher levels of managed care market share are associated with a decrease on medical technology adoption during the period 1982-1995. We analyze annual data on 5390 US hospitals regarding the adoption of 13 different technologies. Our results are threefold: first, we find that managed care has a negative effect on hospitals' technology acquisition for each of the 13 medical technologies in our study, and its effect is stronger for those technologies diffusing in the 1990s, when the managed care sector is at its largest. If managed care enrollment had remained at its 1984 level, there would be 5.3%, 7.3% and 4.1% more hospitals with diagnostic radiology, radiation therapy and cardiac technologies, respectively. Second, we find that the rise in managed care leads to long-term reductions in medical cost growth. Finally, we take into account that profitability analysis is one of the main dimensions considered by hospitals when deciding about the adoption of new technologies. In order to determine whether managed care affects technologies differently if they have a different cost-reimbursement ratio (CRR), we have created a unique data set with information on the cost-reimbursement for each of the 13 technologies and we find that managed care enrollment has a considerably larger negative effect on the adoption of less profitable technologies.

  8. Terminology and labeling of cellular products: 1. Standards.

    PubMed

    Ashford, P; Distler, P; Gee, A; Lankester, A; Larsson, S; Feller, I; Loper, K; Pamphilon, D; Poston, L; Rabe, F; Slaper-Cortenbach, I; Szczepiorkowski, Z; Warkentin, P

    2007-12-01

    The International Cellular Therapy Coding and Labeling Advisory Group was established to address the growing need for standardization of terminology and labeling for cellular therapy products as a result of increasing international transfer of these products. This paper presents new standards for terminology and labeling. These standards have been developed through a consultative process and are supported by key professional and accreditation bodies. By using these standards, together with the unique donation identification numbers and international product reference tables provided by the International Society of Blood Transfusion (ISBT) 128 Standard, consistency and traceability can be assured at the global level. A companion paper provides guidance on the implementation of the ISBT 128 system.

  9. Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT.

    PubMed

    Paviglianiti, Annalisa; Xavier, Erick; Ruggeri, Annalisa; Ceballos, Patrice; Deconinck, Eric; Cornelissen, Jan J; Nguyen-Quoc, Stephanie; Maillard, Natacha; Sanz, Guillermo; Rohrlich, Pierre-Simon; Garderet, Laurent; Volt, Fernanda; Rocha, Vanderson; Kroeger, Nicolaus; Gluckman, Eliane; Fegueux, Nathalie; Mohty, Mohamad

    2016-09-01

    Although allogeneic stem cell transplantation is not a standard therapy for multiple myeloma, some patients can benefit from this intense therapy. There are few reports on outcomes after umbilical cord blood transplantation in multiple myeloma, and investigation of this procedure is warranted. We retrospectively analyzed 95 patients, 85 with multiple myeloma and 10 with plasma cell leukemia, receiving single or double umbilical cord blood transplantation from 2001 to 2013. Median follow up was 41 months. The majority of patients received a reduced intensity conditioning. The cumulative incidence of neutrophil engraftment was 97%±3% at 60 days, and that of 100-day acute graft-versus-host disease grade II-IV was 41%±5%. Chronic graft-versus-host disease at two years was 22%±4%. Relapse and non-relapse mortality was 47%±5% and 29%±5% at three years, respectively. Three-year progression-free survival and overall survival were 24%±5% and 40%±5%, respectively. Anti-thymocyte globulin was associated with decreased incidence of acute graft-versus-host disease, higher non-relapse mortality, decreased overall and progression-free survival. Patients with high cytogenetic risk had higher relapse, and worse overall and progression-free survival. In conclusion, umbilical cord blood transplantation is feasible for multiple myeloma patients.

  10. Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT

    PubMed Central

    Paviglianiti, Annalisa; Xavier, Erick; Ruggeri, Annalisa; Ceballos, Patrice; Deconinck, Eric; Cornelissen, Jan J.; Nguyen-Quoc, Stephanie; Maillard, Natacha; Sanz, Guillermo; Rohrlich, Pierre-Simon; Garderet, Laurent; Volt, Fernanda; Rocha, Vanderson; Kroeger, Nicolaus; Gluckman, Eliane; Fegueux, Nathalie; Mohty, Mohamad

    2016-01-01

    Although allogeneic stem cell transplantation is not a standard therapy for multiple myeloma, some patients can benefit from this intense therapy. There are few reports on outcomes after umbilical cord blood transplantation in multiple myeloma, and investigation of this procedure is warranted. We retrospectively analyzed 95 patients, 85 with multiple myeloma and 10 with plasma cell leukemia, receiving single or double umbilical cord blood transplantation from 2001 to 2013. Median follow up was 41 months. The majority of patients received a reduced intensity conditioning. The cumulative incidence of neutrophil engraftment was 97%±3% at 60 days, and that of 100-day acute graft-versus-host disease grade II-IV was 41%±5%. Chronic graft-versus-host disease at two years was 22%±4%. Relapse and non-relapse mortality was 47%±5% and 29%±5% at three years, respectively. Three-year progression-free survival and overall survival were 24%±5% and 40%±5%, respectively. Anti-thymocyte globulin was associated with decreased incidence of acute graft-versus-host disease, higher non-relapse mortality, decreased overall and progression-free survival. Patients with high cytogenetic risk had higher relapse, and worse overall and progression-free survival. In conclusion, umbilical cord blood transplantation is feasible for multiple myeloma patients. PMID:27229716

  11. 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

  12. 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?

  13. 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

  14. 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

  15. Oral Cellular Neurothekeoma

    PubMed Central

    Emami, Nader; Zawawi, Faisal; Ywakim, Rania; Daniel, Sam J.

    2013-01-01

    Cellular neurothekeoma is known as a cutaneous tumor with uncertain histogenesis. Very little involvement of mucosal membrane has been reported in the literature so far. This is a case report of an intraoral lesion in a 15-years-old girl. Histopathologic evaluation showed a tumor-consists of spindle to epitheloid cells forming micronodules in a concentric whorled shape pattern. Tumor cells were positive for CD63, vimentin, and NKI-C3. Total excision was performed and no recurrence happened after 16-month followup. PMID:23691398

  16. 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.

  17. 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

  18. [International adoption: children's health risk evolution].

    PubMed

    Dartiguenave, C

    2012-05-01

    The socioeconomic and sanitary conditions in many countries make it necessary to weigh as precisely as possible the uncertainties which might affect the health of internationally adopted children, which is one of the key drivers to adoption decision. Indeed, health troubles are more and more frequent among children proposed by countries, at a time when there are fewer children to be adopted. Hence the institutions and the actors in the field of international adoption are compelled to frequently update their professional practices, so as to cope both with the declining offer for adoptable children and with the increasing pressure from the birth countries of children to make host countries adopt children with high age or with special needs. It also requires from the administrations the will to provide better initial information and to implement the demand for an agreement. Meanwhile, in spite of those growing constraints, adopting families have been more and more risk adverse during the latest decades, this being a common trend in our developed countries.

  19. Open Adoption of Infants: Adoptive Parents' Perceptions of Advantages and Disadvantages.

    ERIC Educational Resources Information Center

    Siegel, Deborah H.

    1993-01-01

    Conducted qualitative study of adoptive parents' (n=21 couples) reactions to recent open adoptions of their infants. Findings indicated overwhelmingly positive feelings about open adoption. Respondents often noted that issue of openness was eclipsed by other concerns: coping with infertility, finding a baby, dealing with personnel, and dealing…

  20. Cultural Tourism in Transnational Adoption: "Staged Authenticity" and Its Implications for Adopted Children

    ERIC Educational Resources Information Center

    Quiroz, Pamela Anne

    2012-01-01

    The discursive practices of adoptive parents in two online transnational adoption forums (2006-2008) and observations of five international adoption workshops suggest that what Heather Jacobson described as "culture keeping", the cultural socialization of children that retains a sense of native group identity, is more aptly characterized as…

  1. Factors Influencing the Adoption Decision: An Analysis of Adopters and Nonadopters.

    ERIC Educational Resources Information Center

    King, Robert N.; Rollins, Timothy

    1995-01-01

    An agricultural innovation (nitrogen testing) had been used by 127 of a sample of 220 farmers. Adoption of the technique was influenced by information and change agents' attitudes. Adopters were also motivated by cost savings. Both adopters and nonadopters either did not have or use soil sampling skills needed to perform the test correctly.…

  2. Characterisation of adopters and non-adopters of dairy technologies in Ethiopia and Kenya.

    PubMed

    Kebebe, E G; Oosting, S J; Baltenweck, I; Duncan, A J

    2017-04-01

    While there is a general consensus that using dairy technologies, such as improved breeds of dairy cows, can substantially increase farm productivity and income, adoption of such technologies has been generally low in developing countries. The underlying reasons for non-adoption of beneficial technologies in the dairy sector are not fully understood. In this study, we characterised adopters and non-adopters of dairy technologies in Ethiopia and Kenya based on farmers' resources ownership in order to identify why many farmers in Ethiopia and Kenya have not adopted improved dairy technologies. As compared to non-adopters, farmers who adopt dairy technology own relatively more farm resources. The result signals that differences in resource endowments could lead to divergent technology adoption scenarios. Results show that a higher proportion of sample smallholders in Kenya have adopted dairy technologies than those in Ethiopia. Except for the use of veterinary services, fewer than 10% of sample farmers in Ethiopia have adopted dairy technologies-less than half the number of adopters in Kenya. The higher level of dairy technology adoption in Kenya can be ascribed partly to the long history of dairy development, including improvements in the value chain for the delivery of inputs, services and fluid milk marketing. Interventions that deal with the constraints related to access to farm resources and input and output markets could facilitate uptake of dairy technology in developing countries.

  3. Korean Adoptee Identity: Adoptive and Ethnic Identity Profiles of Adopted Korean Americans

    ERIC Educational Resources Information Center

    Beaupre, Adam J.; Reichwald, Reed; Zhou, Xiang; Raleigh, Elizabeth; Lee, Richard M.

    2015-01-01

    Adopted Korean adolescents face the task of grappling with their identity as Koreans and coming to terms with their adoptive status. In order to explore these dual identities, the authors conducted a person-centered study of the identity profiles of 189 adopted Korean American adolescents. Using cluster analytic procedures, the study examined…

  4. Adoptive immunotherapy for cancer: building on success.

    PubMed

    Gattinoni, Luca; Powell, Daniel J; Rosenberg, Steven A; Restifo, Nicholas P

    2006-05-01

    Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new findings might further improve the efficacy of adoptive cell transfer through the use of vaccines, haematopoietic-stem-cell transplantation, modified preconditioning regimens, and alternative methods for the generation and selection of the T cells to be transferred.

  5. Pricing Health Behavior Interventions to Promote Adoption

    PubMed Central

    Ribisl, Kurt M.; Leeman, Jennifer; Glasser, Allison M.

    2015-01-01

    The relatively high cost of delivering many public health interventions limits their potential for broad public impact by reducing their likelihood of adoption and maintenance over time. Practitioners identify cost as the primary factor for which interventions they select to implement, but researchers rarely disseminate cost information or consider its importance when developing new interventions. A new approach is proposed, whereby intervention developers assess what individuals and agencies adopting their interventions are willing to pay and then design interventions that are responsive to this price range. The ultimate goal is to develop effective and affordable interventions, called lean interventions, which are widely adopted and have greater public health impact. PMID:24842743

  6. Revisiting Cardiac Cellular Composition

    PubMed Central

    Pinto, Alexander R.; Ilinykh, Alexei; Ivey, Malina J.; Kuwabara, Jill T.; D'Antoni, Michelle L.; Debuque, Ryan; Chandran, Anjana; Wang, Lina; Arora, Komal; Rosenthal, Nadia; Tallquist, Michelle D.

    2015-01-01

    Rationale Accurate knowledge of the cellular composition of the heart is essential to fully understand the changes that occur during pathogenesis and to devise strategies for tissue engineering and regeneration. Objective To examine the relative frequency of cardiac endothelial cells, hematopoietic-derived cells and fibroblasts in the mouse and human heart. Methods and Results Using a combination of genetic tools and cellular markers, we examined the occurrence of the most prominent cell types in the adult mouse heart. Immunohistochemistry revealed that endothelial cells constitute over 60%, hematopoietic-derived cells 5–10%, and fibroblasts under 20% of the non-myocytes in the heart. A refined cell isolation protocol and an improved flow cytometry approach provided an independent means of determining the relative abundance of non-myocytes. High dimensional analysis and unsupervised clustering of cell populations confirmed that endothelial cells are the most abundant cell population. Interestingly, fibroblast numbers are smaller than previously estimated, and two commonly assigned fibroblast markers, Sca-1 and CD90, underrepresent fibroblast numbers. We also describe an alternative fibroblast surface marker that more accurately identifies the resident cardiac fibroblast population. Conclusions This new perspective on the abundance of different cell types in the heart demonstrates that fibroblasts comprise a relatively minor population. By contrast, endothelial cells constitute the majority of non-cardiomyocytes and are likely to play a greater role in physiologic function and response to injury than previously appreciated. PMID:26635390

  7. Multifunctional periodic cellular metals.

    PubMed

    Wadley, Haydn N G

    2006-01-15

    Periodic cellular metals with honeycomb and corrugated topologies are widely used for the cores of light weight sandwich panel structures. Honeycombs have closed cell pores and are well suited for thermal protection while also providing efficient load support. Corrugated core structures provide less efficient and highly anisotropic load support, but enable cross flow heat exchange opportunities because their pores are continuous in one direction. Recent advances in topology design and fabrication have led to the emergence of lattice truss structures with open cell structures. These three classes of periodic cellular metals can now be fabricated from a wide variety of structural alloys. Many topologies are found to provide adequate stiffness and strength for structural load support when configured as the cores of sandwich panels. Sandwich panels with core relative densities of 2-10% and cell sizes in the millimetre range are being assessed for use as multifunctional structures. The open, three-dimensional interconnected pore networks of lattice truss topologies provide opportunities for simultaneously supporting high stresses while also enabling cross flow heat exchange. These highly compressible structures also provide opportunities for the mitigation of high intensity dynamic loads created by impacts and shock waves in air or water. By filling the voids with polymers and hard ceramics, these structures have also been found to offer significant resistance to penetration by projectiles.

  8. Cellular Array Processing Simulation

    NASA Astrophysics Data System (ADS)

    Lee, Harry C.; Preston, Earl W.

    1981-11-01

    The Cellular Array Processing Simulation (CAPS) system is a high-level image language that runs on a multiprocessor configuration. CAPS is interpretively decoded on a conventional minicomputer with all image operation instructions executed on an array processor. The synergistic environment that exists between the minicomputer and the array processor gives CAPS its high-speed throughput, while maintaining a convenient conversational user language. CAPS was designed to be both modular and table driven so that it can be easily maintained and modified. CAPS uses the image convolution operator as one of its primitives and performs this cellular operation by decomposing it into parallel image steps that are scheduled to be executed on the array processor. Among its features is the ability to observe the imagery in real time as a user's algorithm is executed. This feature reduces the need for image storage space, since it is feasible to retain only original images and produce resultant images when needed. CAPS also contains a language processor that permits users to develop re-entrant image processing subroutines or algorithms.

  9. Distributed PV Adoption in Maine Through 2021

    SciTech Connect

    Gagnon, Pieter; Sigrin, Ben

    2015-11-06

    NREL has used its dSolar (distributed solar) model to generate low-medium-high estimates of distributed PV adoption in Maine through 2021. This presentation gives a high-level overview of the model and modeling results.

  10. Drivers and Barriers in Health IT Adoption

    PubMed Central

    Avgar, A.C.; Litwin, A.S.; Pronovost, P.J.

    2012-01-01

    Despite near (and rare) consensus that the adoption and diffusion of health information technology (health IT) will bolster outcomes for organizations, individuals, and the healthcare system as a whole, there has been surprisingly little consideration of the structures and processes within organizations that might drive the adoption and effective use of the technology. Management research provides a useful lens through which to analyze both the determinants of investment and the benefits that can ultimately be derived from these investments. This paper provides a conceptual framework for understanding health IT adoption. In doing so, this paper highlights specific organizational barriers or enablers at different stages of the adoption process – investment, implementation, and use – and at different levels of organizational decision-making – strategic, operational, and frontline. This framework will aid both policymakers and organizational actors as they make sense of the transition from paper-based to electronic systems. PMID:23646093

  11. Parental Bonding in Older-Child Adoptions.

    ERIC Educational Resources Information Center

    Ward, Margaret

    1981-01-01

    Examines various factors (such as periods of high emotion, ritual and claiming behaviors and positive interaction) in the attachment process between adoptive parents and older children. Shows that most components parallel those of bonding in biological parents. (Author/RH)

  12. 76 FR 81 - Adoption of Recommendation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-03

    ...; ] ADMINISTRATIVE CONFERENCE OF THE UNITED STATES Adoption of Recommendation AGENCY: Administrative Conference of... the attached recommendation at its Fifty-third Plenary Session. The recommendation addresses issues... makes recommendations for improvements to the agencies, collectively or individually, and to...

  13. Disparities in Primary Care EHR Adoption Rates

    PubMed Central

    Mack, Dominic; Zhang, Shun; Douglas, Megan; Sow, Charles; Strothers, Harry; Rust, George

    2016-01-01

    This study evaluates electronic health record (EHR) adoption by primary care providers in Georgia to assess adoption disparities according to practice size and type, payer mix, and community characteristics. Frequency variances of EHR “Go Live” status were estimated. Odds ratios were calculated by univariate and multivariate logistic regression models. Large practices and community health centers (CHCs) were more likely to Go Live (>80% EHR adoption) than rural health clinics and other underserved settings (53%). A significantly lower proportion (68.9%) of Medicaid predominant providers had achieved Go Live status and had a 47% higher risk of not achieving Go Live status than private insurance predominant practices. Disparities in EHR adoption rates may exacerbate existing disparities in health outcomes of patients served by these practices. Targeted support such as that provided to CHCs would level the playing field for practices now at a disadvantage. PMID:27587942

  14. When to Tell Your Child About Adoption

    MedlinePlus

    ... Family Life Family Life Family Life Medical Home Family Dynamics Media Work & Play Getting Involved in Your Community ... AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families ...

  15. Internationally Adopted Children: Important Information for Parents

    MedlinePlus

    ... Family Life Family Life Family Life Medical Home Family Dynamics Media Work & Play Getting Involved in Your Community ... AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families ...

  16. Inducing Lactation: Breastfeeding for Adoptive Moms

    MedlinePlus

    ... Family Life Family Life Family Life Medical Home Family Dynamics Media Work & Play Getting Involved in Your Community ... AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care Communication & Discipline Types of Families ...

  17. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... augment such an EA when it is essentially, but not entirely, in compliance in order to make it so. (c) If an EA or augmented EA is adopted, the responsible Commission official must prepare his/her own NOI...

  18. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... augment such an EA when it is essentially, but not entirely, in compliance in order to make it so. (c) If an EA or augmented EA is adopted, the responsible Commission official must prepare his/her own NOI...

  19. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... augment such an EA when it is essentially, but not entirely, in compliance in order to make it so. (c) If an EA or augmented EA is adopted, the responsible Commission official must prepare his/her own NOI...

  20. 43 CFR 10010.20 - Adoption.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... augment such an EA when it is essentially, but not entirely, in compliance in order to make it so. (c) If an EA or augmented EA is adopted, the responsible Commission official must prepare his/her own NOI...

  1. Adopting Integrated Pest Management in Schools.

    ERIC Educational Resources Information Center

    Currie, William E.

    1991-01-01

    The development of an effective Integrated Pest Management program is discussed. Provided are the common goals and procedures involved in adopting an Integrated Pest Management program for schools. (CW)

  2. Are You Pregnant and Thinking about Adoption?

    MedlinePlus

    ... place their children for adoption include money problems, personal goals, and family attitudes. Why do some expectant ... your child learn more about his or her personal history, family background, medical information, and the reasons ...

  3. [The outcomes of Adoption in the Case of the "British Chinese Adoption Study"].

    PubMed

    Rushton, Alan

    2015-01-01

    Practitioners can over-estimate the incidence of problems in adopted children and adults because they do not see those who make good psychological and social adjustments. Research into adoption outcomes can be hard to interpret without information about differing pre-adoption histories. Examples are given of research into three types of adoption: domestic infant adoption, adoptions from public care of maltreated children and international adoption of ex-orphanage children. Although negative outcomes are indisputably evident for some, recovery from adversity is more common than many would predict. It is important to recognize that subsequent nurturing in consistent and stimulating environments can build a platform for effective adaptations to challenges in the future. However, a proper understanding of the consequences of adoption has been limited by the fact that follow-up studies have rarely extended beyond adolescence and early adulthood. The British Chinese Adoption Study is a 50 year follow-up of orphanage girls internationally adopted into the United Kingdom, and is given as an example of good outcomes despite early years of adversity. Scores on mental health assessments were equivalent to the non-adopted, age-matched comparison group of UK women. Most of the women were rated as "good functioning" and educational achievements were many times higher than the comparison women. Life-long adverse effects are not inevitable following early adversity. Improved circumstances can promote recovery and good adult adjustment. Practice and research implications are discussed.

  4. Adoption first? The disposition of human embryos.

    PubMed

    Murphy, Timothy F

    2014-06-01

    Anja Karnein has suggested that because of the importance of respect for persons, law and policy should require some human embryos created in vitro to be available for adoption for a period of time. If no one comes forward to adopt the embryos during that time, they may be destroyed (in the case of embryos left over from fertility medicine) or used in research (in the case of embryos created for that purpose or left over from fertility medicine). This adoption option would increase the number of embryos available for couples looking for help in having children, but that effect is less important--Karnein argues--than the observance of respect for human persons. As possible persons, she holds that embryos ought to be treated, as if they will become children, if only for a while. If enacted as a matter of law and policy, an 'adoption option' would wrongly interfere with the dispositional rights women and men ought to have over embryos they create in the course of trying to have children. Karnein's proposal would also deprive researchers of certainty that the embryos they create for research would actually be available that way, leading to increased burdens of time and money and maybe even to more embryos than would otherwise be produced. Karnein's analysis does not show, moreover, that any duty of rescue applies to embryos. No woman is required to adopt any embryo, which significantly undercuts the justification for an obligatory adoption period.

  5. Enhancing adoptive parenting: a randomized controlled trial.

    PubMed

    Rushton, Alan; Monck, Elizabeth; Leese, Morven; McCrone, Paul; Sharac, Jessica

    2010-10-01

    The aim was to conduct a pragmatic randomized controlled trial (RCT) to evaluate two parenting programmes designed for adopters of children late placed from care. Adoptive parents, with children between 3 and 8 years who were screened to have serious behavioural problems early in the placement, participated in home-based, manualized, parenting programmes delivered by trained and supervised family social workers. The adopters who agreed to join the study were randomly allocated to one of two parenting interventions or to a "services as usual" group. Baseline, immediate post-intervention and six-month follow-ups were assessed using questionnaires and adopter interviews. No cases were lost to follow-up at any point and satisfaction was high with both parenting interventions. At the six-month follow-up, a significant difference (p < 0.007) was found for "satisfaction with parenting" in favour of the intervention group (Effect Size d = 0.7). Negative parenting approaches were reduced in the intervention group. However, no significant differences in child problems were found between the intervention groups and control group, adjusting for baseline scores. Costs analysis showed that a relatively modest investment in post-adoption support would be well spent in improving adopters' satisfaction with parenting in the intervention group compared to the routine service group.

  6. Social Context and Hearing Aid Adoption

    PubMed Central

    Launer, Stefan

    2016-01-01

    Hearing rehabilitation tends to focus on the influence of intraindividual factors and concepts such as readiness for change and health beliefs. In contrast, less is known about the role of social context and the potential role of significant others on hearing aid adoption. This explorative retrospective study investigated whether hearing aid adoption is associated with significant other attendance at audiology appointments. The study sample consisted of 33,933 and 27,031 individuals who attended appointments either alone or with a significant other, respectively (n = 60,964). It was found that hearing aid adoption was significantly greater when patients attended audiology appointments with a significant other (63.8%) than when attending appointments alone (50.6%). The association between hearing aid adoption and attendance by a significant other was hearing dependent, with 96% higher hearing aid adoption for patients with mild hearing losses when patients attended appointments with a significant other than when attending appointments alone. Hearing aid return rates were comparable when patients attended appointments alone (27%) or with a significant other (24%). Several potential explanations for the observed association are discussed. The pattern of results is consistent with the view that greater adherence is observed when audiologic care is provided from a patient-centered care perspective. Future research should establish whether there is a causal relationship between attendance at appointments by significant others and hearing aid adoption and should attempt to better understand the mechanisms underpinning the relationship between these variables. PMID:27733672

  7. Bridging the divide: openness in adoption and postadoption psychosocial adjustment among birth and adoptive parents.

    PubMed

    Ge, Xiaojia; Natsuaki, Misaki N; Martin, David M; Leve, Leslie D; Neiderhiser, Jenae M; Shaw, Daniel S; Villareal, Georgette; Scaramella, Laura; Reid, John B; Reiss, David

    2008-08-01

    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' postadoption adjustment shortly after the adoption placement (6 to 9 months). Data from birth fathers (N = 112), an understudied sample, were also 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' postplacement 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 postadoption adjustment.

  8. 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

  9. Moses and Superman Come Home: Counseling Adoptees and Adoptive Families.

    ERIC Educational Resources Information Center

    Saiz, Stephen G.

    This paper looks at three parties impacted by adoption: the adoptive parents, the adopted child, and the adoptive family. When working with adoptive parents, counselors should respect the strength of the couple, their commitment to parenthood, and the closeness that may develop from weathering the issue of childlessness. Adoptive parents are…

  10. 5 CFR 843.404 - Proof of adoption.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Proof of adoption. 843.404 Section 843... Proof of adoption. (a) An adopted child is— (1) A child adopted by the employee or retiree before the... petition for adoption was filed by the employee or retiree and who is adopted by the current spouse of...

  11. 5 CFR 843.404 - Proof of adoption.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Proof of adoption. 843.404 Section 843... Proof of adoption. (a) An adopted child is— (1) A child adopted by the employee or retiree before the... petition for adoption was filed by the employee or retiree and who is adopted by the current spouse of...

  12. 5 CFR 843.404 - Proof of adoption.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Proof of adoption. 843.404 Section 843... Proof of adoption. (a) An adopted child is— (1) A child adopted by the employee or retiree before the... petition for adoption was filed by the employee or retiree and who is adopted by the current spouse of...

  13. Adoption Activities on the Internet: A Call for Regulation

    ERIC Educational Resources Information Center

    Roby, Jini L.; White, Holly

    2010-01-01

    There is a growing practice of adoption services on the Internet with varying degrees of regulation, depending on whether it is domestic infant adoption, public foster care adoption, or international adoption. Regulation is particularly lacking in domestic infant adoptions, with Web sites connecting prospective birth and adoptive parents,…

  14. 5 CFR 843.404 - Proof of adoption.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Proof of adoption. 843.404 Section 843... Proof of adoption. (a) An adopted child is— (1) A child adopted by the employee or retiree before the... petition for adoption was filed by the employee or retiree and who is adopted by the current spouse of...

  15. 5 CFR 843.404 - Proof of adoption.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Proof of adoption. 843.404 Section 843... Proof of adoption. (a) An adopted child is— (1) A child adopted by the employee or retiree before the... petition for adoption was filed by the employee or retiree and who is adopted by the current spouse of...

  16. Cellular phagocytic studies in rheumatoid arthritis patients treated with levamisole.

    PubMed Central

    Wynne, K M; Dieppe, P A; Scott, J; Huskisson, E C

    1981-01-01

    A simple method is described which allows sequential monitoring of the endocytic activity of blood and synovial fluid cells from rheumatoid arthritis patients undergoing therapy with levamisole. Evidence of immediate (24 hours) and long-term (5-7 weeks) cellular phagocytic enhancement is presented. Images PMID:7259330

  17. Who Adopts Queer and Pansexual Sexual Identities?

    PubMed

    Morandini, James S; Blaszczynski, Alexander; Dar-Nimrod, Ilan

    2016-12-02

    Some nonheterosexual individuals are eschewing lesbian/gay and bisexual identities for queer and pansexual identities. The present study aimed to examine the sexual and demographic characteristics of nonheterosexual individuals who adopt these labels. A convenience sample of 2,220 nonheterosexual (1,459 lesbian/gay, 413 bisexual, 168 queer, 146 pansexual, and 34 other "write-in") individuals were recruited for a cross-sectional online survey. In support of our hypotheses, those adopting pansexual identities were younger than those adopting lesbian, gay, and bisexual identities, and those adopting queer and pansexual identities were more likely to be noncisgender than cisgender, and more likely to be cisgender women than men. The majority of pansexual individuals demonstrated sexual orientation indices within the bisexual range, and showed equivalent patterns of sexual attraction, romantic attraction, sexual behavior, and partner gender as bisexual-identified men and women. In contrast, three-quarters of queer men, and more than half of queer women, reported sexual attraction in the homosexual range. This study found that rather than a general movement toward nontraditional sexual identities, queer and pansexual identities appear most appealing to nonheterosexual women and noncisgender individuals. These findings contribute important information regarding who adopts queer and pansexual identities in contemporary sexual minority populations.

  18. Targeting cellular metabolism to improve cancer therapeutics.

    PubMed

    Zhao, Y; Butler, E B; Tan, M

    2013-03-07

    The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.

  19. The Consumer Health Information System Adoption Model.

    PubMed

    Monkman, Helen; Kushniruk, Andre W

    2015-01-01

    Derived from overlapping concepts in consumer health, a consumer health information system refers to any of the broad range of applications, tools, and educational resources developed to empower consumers with knowledge, techniques, and strategies, to manage their own health. As consumer health information systems become increasingly popular, it is important to explore the factors that impact their adoption and success. Accumulating evidence indicates a relationship between usability and consumers' eHealth Literacy skills and the demands consumer HISs place on their skills. Here, we present a new model called the Consumer Health Information System Adoption Model, which depicts both consumer eHealth literacy skills and system demands on eHealth literacy as moderators with the potential to affect the strength of relationship between usefulness and usability (predictors of usage) and adoption, value, and successful use (actual usage outcomes). Strategies for aligning these two moderating factors are described.

  20. Disinhibited social behavior among internationally adopted children.

    PubMed

    Bruce, Jacqueline; Tarullo, Amanda R; Gunnar, Megan R

    2009-01-01

    Postinstitutionalized children frequently demonstrate persistent socioemotional difficulties. For example, some postinstitutionalized children display an unusual lack of social reserve with unfamiliar adults. This behavior, which has been referred to as indiscriminate friendliness, disinhibited attachment behavior, and disinhibited social behavior, was examined by comparing children internationally adopted from institutional care to children internationally adopted from foster care and children raised by their biological families. Etiological factors and behavioral correlates were also investigated. Both groups of adopted children displayed more disinhibited social behavior than the nonadopted children. Of the etiological factors examined, only the length of time in institutional care was related to disinhibited social behavior. Disinhibited social behavior was not significantly correlated with general cognitive ability, attachment-related behaviors, or basic emotion abilities. However, this behavior was negatively associated with inhibitory control abilities even after controlling for the length of time in institutional care. These results suggest that disinhibited social behavior might reflect underlying deficits in inhibitory control.