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Sample records for primate xenograft transplantation

  1. [Heart Transplantation;Allograft and Xenograft].

    PubMed

    Fukushima, Norihide

    2017-01-01

    Prior to starting clinical cardiac allotransplantation, cardiac xenotransplantation was performed in human in 1960s. In 1964, Hardy performed cardiac transplantation using a chimpanzee heart and Bailey performed cardiac transplantation using a baboon heart to an infant with hypoplastic left heart. The use of cyclosporine has greatly improved the outcome of clinical cardiac transplantation and cardiac allotransplantation became an established treatment strategy for the patients with end-stage heart failure. Although concordant cardiac xenotransplantation from a primate to a human may be successfully performed using current immunosuppressive regimen, a primate heart is not a good candidate for cardiac xenograft due to animal light issues and its size. Therefore, many investigators have tried to extend the survival period in discordant xenograft from pig to primate, but no prolonged surviving orthotropic cardiac xenograft has been established yet. In this review, experiments of concordant and discordant cardiac xenografts which were performed by the authors were introduced.

  2. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model.

    PubMed

    Higginbotham, Laura; Mathews, Dave; Breeden, Cynthia A; Song, Mingqing; Farris, Alton Brad; Larsen, Christian P; Ford, Mandy L; Lutz, Andrew J; Tector, Matthew; Newell, Kenneth A; Tector, A Joseph; Adams, Andrew B

    2015-01-01

    Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Primate Models in Organ Transplantation

    PubMed Central

    Anderson, Douglas J.; Kirk, Allan D.

    2013-01-01

    Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic- and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed. PMID:24003248

  4. Monitoring pig-to-primate cardiac xenografts with live Internet images of recipients and xenograft telemetric signals: histologic and immunohistochemical correlations.

    PubMed

    Chen, R H; Kadner, A; Adams, D H

    2000-06-01

    Monitoring pig-to-primate cardiac xenografts is often difficult in awake and uncooperative primates. We investigated the possibility of monitoring xenotransplantation through Internet broadcasting of (1) continuous video images of transplant recipients and (2) xenograft telemetric signals detected by an implanted device. The telemetric readings were later compared with histology and immunohistochemistry for signs of rejection. Heterotopic baboon-to-baboon (n = 2) and transgenic pig (human complement regulatory proteins CD59/DAF, n = 3; MCP, n = 1)-to-baboon transplants were performed with serial biopsies for hematoxylin-and-eosin staining and immunohistochemical detection of immunoglobulin M (IgM) and complement membrane attack complex (MAC) deposition. Baboon recipients were continuously monitored with a QuickCamPro digital camera, whereas grafts were monitored with a Data Science International implantable telemetric system. Video images and telemetric signals were broadcast over the Internet through a laptop computer. Baboon allografts remained healthy until explant on Day 14, whereas pig xenografts were rejected on Day 5, 6, 7, and 11. Telemetry of allografts and xenografts documented regular rhythm with an average heart rate of 80 to 120, but xenografts developed bradycardia and widened/dampened QRS complexes 24 to 48 hours before graft loss. Continuous video monitoring of recipient activities was vital in differentiating between graft arrhythmias and telemetric artifacts. Allograft biopsies showed little cellular infiltrate, whereas xenograft biopsies showed increasing IgM and MAC deposition, with extensive thrombi and myocardial damage 24 hours before cessation of cardiac activities. Combined video surveillance of recipient activities and graft telemetric signals is a useful method to continuously monitor abdominal cardiac grafts in large, uncooperative, awake primates. QRS-complex widening associated with progressive bradycardia correlated with histologic

  5. SYSTEMIC INFLAMMATION IN XENOGRAFT RECIPIENTS (SIXR): A NEW PARADIGM IN PIG-TO-PRIMATE XENOTRANSPLANTATION?

    PubMed Central

    Ezzelarab, Mohamed B.; Cooper, David K C

    2015-01-01

    Inflammation is a complex response that involves interactions between multiple proteins in the human body. The interaction between inflammation and coagulation is well-recognized, but its role in the dysregulation of coagulation in xenograft recipients is not well-understood. Additionally, inflammation is known to prevent the development of T cell tolerance after transplantation. Recent evidence indicates that systemic inflammation precedes and may be promoting activation of coagulation after pig-to-primate xenotransplantation. Activated recipient innate immune cells expressing tissue factor are increased after xenotransplantation, irrespective of immunosuppressive therapy. With immunosuppression, C-reactive protein (C-RP), fibrinogen, and interleukin-6 levels are significantly increased in pig artery patch recipients. In pig organ recipients, increased C-RP levels are observed prior to the development of features of consumptive coagulopathy. Systemic inflammation in xenograft recipients (SIXR) may be a key factor in the development of dysregulation of coagulation, as well as in resistance to immunosuppressive therapy. While genetic modification of the donor pigs provides protection against humoral responses and the development of thrombotic microangiopathy, therapeutic prevention of SIXR may be essential in order to prevent systemic dysregulation of coagulation in xenograft recipients without the use of intensive immunosuppression. PMID:26209584

  6. Gallbladder small cell carcinoma Xenograft established by serial transplantation in nude mice.

    PubMed

    Nishime, Chiyoko; Ohnishi, Yasuyuki; Suemizu, Hiroshi; Tamaoki, Norikazu; Suematsu, Makoto; Oida, Yasuhisa; Yamazaki, Hitoshi; Nakamura, Masato; Ueyama, Yoshito; Kijima, Hiroshi

    2006-01-01

    The GB-04-JCK xenograft line of human gallbladder small cell carcinoma was established in nude mice by serial transplantation. The xenotransplantability has been maintained for more than 20 years. The carcinoma cells grew in a solid-sheet pattern and were found to have hyperchromatic nuclei, finely dispersed chromatin and inconspicuous nucleoli in the primary gallbladder tumor, as well as in the established xenograft GB-04-JCK The carcinoma cells also had Grimelius argyrophil granules, electron-dense neuroendocrine granules bounded by a single membrane. The xenograft line retained histological and immunohistochemical characteristics of the primary gallbladder tumor and is the first reported xenotransplantable tumor of human gallbladder small cell carcinoma.

  7. Using non-human primates to benefit humans: research and organ transplantation.

    PubMed

    Shaw, David; Dondorp, Wybo; de Wert, Guido

    2014-11-01

    Emerging biotechnology may soon allow the creation of genetically human organs inside animals, with non-human primates (henceforth simply "primates") and pigs being the best candidate species. This prospect raises the question of whether creating organs in primates in order to then transplant them into humans would be more (or less) acceptable than using them for research. In this paper, we examine the validity of the purported moral distinction between primates and other animals, and analyze the ethical acceptability of using primates to create organs for human use.

  8. Xenografts of expanded primate olfactory ensheathing glia support transient behavioral recovery that is independent of serotonergic or corticospinal axonal regeneration in nude rats following spinal cord transection.

    PubMed

    Guest, J D; Herrera, L; Margitich, I; Oliveria, M; Marcillo, A; Casas, C E

    2008-08-01

    Transplantation of olfactory ensheathing glial cells (OEG) may improve the outcome from spinal cord injury. Proof-of-principle studies in primates are desirable and the feasibility and efficacy of using in vitro expanded OEG should be tested. An intermediate step between the validation of rodent studies and human clinical trials is to study expanded primate OEG (POEG) xenografts in immunotolerant rodents. In this study the time course to generate purified POEG was evaluated as well as their survival, effect on damaged axons of the corticospinal and serotonergic systems, tissue sparing, and chronic locomotor recovery following transplantation. Fifty-seven nude rats underwent T9/10 spinal cord transection. Thirty-eight rats received POEG, 19 controls were injected with cell medium, and 10 received lentivirally-GFP-transfected POEG. Histological evaluation was conducted at 6 weeks, 8 weeks, 14 weeks and 23-24 weeks. Of these 57 rats, 18 were studied with 5-HT immunostaining, 16 with BDA anterograde CST labeling, and six were used for transmission electron microscopy. In grafted animals, behavioral recovery, sprouting and limited regeneration of 5-HT fibers, and increased numbers of proximal collateral processes but not regeneration of CST fibers was observed. Grafted animals had less cavitation in the spinal cord stumps than controls. Behavioral recovery peaked at three months and then declined. Five POEG-transplanted animals that had shown behavioral recovery underwent retransection and behavioral scores did not change significantly, suggesting that long tract axonal regeneration did not account for the locomotor improvement. At the ultrastructural level presumptive POEG were found to have direct contacts with astrocytes forming the glia limitans, distinct from those formed by Schwann cells. At 6 weeks GFP expression was detected in cells within the lesion site and within nerve roots but did not match the pattern of Hoechst nuclear labeling. At 3.5 months only GFP

  9. Transplantation of Tissue-Engineered Cartilage in an Animal Model (Xenograft and Autograft): Construct Validation.

    PubMed

    Nemoto, Hitoshi; Watson, Deborah; Masuda, Koichi

    2015-01-01

    Tissue engineering holds great promise for cartilage repair with minimal donor-site morbidity. The in vivo maturation of a tissue-engineered construct can be tested in the subcutaneous tissues of the same species for autografts or of immunocompromised animals for allografts or xenografts. This section describes detailed protocols for the surgical transplantation of a tissue-engineered construct into an animal model to assess construct validity.

  10. Survival of pig-to-rhesus corneal xenografts prolonged by prior donor bone marrow transplantation.

    PubMed

    Jie, Ying; Liu, Limin; Pan, Zhiqiang; Wang, Li

    2013-03-01

    The aim of the present study was to explore the survival of pig-rhesus corneal xenografts following donor bone marrow transplantation (BMT). Wuzhishan pigs were used as donors and rhesus monkeys as recipients for corneal xenotransplantation. Twelve rhesus monkeys were divided into two groups. Group 1 received intravenous injection of cyclophosphamide (CP) followed by pig bone marrow cell transplantation, while group 2 was used as a control and only received intravenous CP injection. All xenografts were evaluated using a slit-lamp microscope. The immunological status of the recipients following transplantation, including the formation of chimerism, mixed lymphocyte reaction (MLR) and immunoglobulin and complement in the serum, was analyzed. Two rhesus monkeys in each group were sacrificed for corneal histopathology examination. The mean survival time was 36.0±4.7 days in group 1 and 17.7±3.2 days in group 2. The mean chimerism percentage in group 1 at week 1 was 5.20±1.02%, but decreased with time and was <1% after week 3. MLR demonstrated that immune reactivity to donor spleen cells in group 1 was decreased following surgery. Immunoglobulin and complement levels in the serum revealed a decreasing trend. Histopathological examination demonstrated that the corneal xenografts in group 1 had minimal inflammatory cell infiltration and no eosinophil infiltration. Survival of corneal xenografts may be prolonged by prior BMT, suggesting that immune reactivity to donors is suppressed, and is highly dependent on chimerism formation.

  11. Limited immune diversity in urodela: chronic transplantation responses occur even with family-disparate xenografts.

    PubMed

    Kinefuchi, Kenjiroh; Kushida, Yoshihiro; Touma, Maki; Hosono, Masamichi

    2013-07-01

    Urodele amphibians are thought to have poorer immune responses than evolutionary more ancestral vertebrate classes, such as bony fish. We investigated skin graft rejection and transplantation immunity in Urodele amphibians, Japanese newts, and Asiatic salamanders, and compared these findings to those from transplants in several species of frogs. The skin grafts used in this study were either allogeneic or xenogeneic. The mean survival time of the first set of allografts at 20°C was approximately 60 days for chronic responses in Urodela and 20 days for acute responses in Anura. As the graft survival times of urodeles were significantly longer than those of anurans, even when urodeles were repeatedly grafted from identical donors, there appear to be substantial differences in transplantation immunity between Urodela and Anura. These slow responses in Urodela may not be accompanied by the expansion of cytotoxic T cells, as observed in fish and anuran species, which are known to have functional major histocompatibility complex (MHC)-class I systems. In our study, approximately five histo-incompatible immunogenic components were found to be involved in chronic responses in newts. Similar chronic responses were also observed in xenograft rejection in newts. In contrast, xenografts were rejected in frogs due to an accelerated acute response, possibly involving natural killer cells. Our findings that some anti-allogeneic components appear to be shared with xenogeneic components indicate that the diversification of the acquired immune system is poorly developed in Urodela.

  12. Statistical evaluation and experimental design of a psoriasis xenograft transplantation model treated with cyclosporin A.

    PubMed

    Stenderup, Karin; Rosada, Cecilia; Alifrangis, Lene; Andersen, Søren; Dam, Tomas Norman

    2011-05-01

    Psoriasis xenograft transplantation models where human skin is transplanted onto immune-deficient mice are generally accepted in psoriasis research. Over the last decade, they have been widely employed to screen for new therapeutics with a potential anti-psoriatic effect. However, experimental designs differ in several parameters. Especially, the number of donors and grafts per experimental design varies greatly; numbers that are directly related to the probability of detecting statistically significant drug effects. In this study, we performed a statistical evaluation of the effect of cyclosporine A, a recognized anti-psoriatic drug, to generate a statistical model employable to simulate different scenarios of experimental designs and to calculate the associated statistical study power, defined as the probability of detecting a statistically significant anti-psoriatic drug treatment effect. Results showed that to achieve a study power of 0.8, at least 20 grafts per treatment group and a minimum of five donors should be included in the chosen experimental setting. To our knowledge, this is the first time that study power calculations have been performed to evaluate treatment effects in a psoriasis xenograft transplantation model. This study was based on a defined experimental protocol, thus other parameters such as drug potency, treatment protocol, mouse strain and graft size should, also, be taken into account when designing an experiment. We propose that the results obtained in this study may lend a more quantitative support to the validity of results obtained when exploring new potential anti-psoriatic drug effects.

  13. The emerging technologies of neural xenografting and stem cell transplantation for treating neurodegenerative disorders.

    PubMed

    Harrower, Timothy P; Barker, Roger A

    2004-02-01

    Neural transplantation has normally been considered in the context of the neurodegenerative disorders, Parkinson's and Huntington's disease, which are characterized pathologically by the predominant loss of specific cells in the basal ganglia. This approach has now emerged from the experimental arena into the level of clinical trial, at least with respect to fetal human allografts. However the ethical and practical problems with using such tissue has led to the search for alternative sources of cells of which two of the most promising are cells from another species, such as the pig (xenografts), and stem cells. Neural transplantation using cells derived from the developing pig brain offers many advantages. Firstly, time-mated litters will overcome the issue of donor tissue supply. Secondly, advances in genetic technology have led to the development of pigs which have a reduced rejection potential. Thirdly, xenografted neural fiber outgrowth may be superior to that from neural grafts derived from the same species (allografts) which may increase the potential for circuit reconstruction. Disadvantages with this tissue source include concerns about transmission of zoonotic infections and the immunological rejection of the xenograft. Stem cells are defined as cells capable of division (self-renewal) and differentiation into a range of different cell types (differentiation). A variety of such cells exist including embryonic stem cells, neural stem cells derived from the developing fetal brain (neural progenitor cells), adult neural stem cells and adult stem cells originating from outside of the central nervous system. Each of these different types of stem cell have their own unique benefits but also disadvantages, and access to each type is constrained by a number of limiting factors. All of this means that the translation of these cell therapies into practice is not straightforward and must be done at a pace dictated by laboratory-based research rather than corporate

  14. Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy.

    PubMed

    Kobayashi, T; Taniguchi, S; Neethling, F A; Rose, A G; Hancock, W W; Ye, Y; Niekrasz, M; Kosanke, S; Wright, L J; White, D J; Cooper, D K

    1997-11-15

    This study sought to (i) investigate the efficacy of cobra venom factor (CVF) in preventing hyperacute rejection (HAR) after pig-to-baboon heart transplantation, (ii) examine the effect of additional splenectomy (Spx) and pharmacologic immunosuppression (IS), and (iii) study delayed graft rejection when HAR is avoided by complement depletion. Eleven recipient baboons received heterotopic pig heart transplants. Three received either no therapy or IS (cyclosporine + methylprednisolone +/- cyclophosphamide +/- methotrexate) at clinically well-tolerated doses, with graft survival for only 40, 32, and 15 min, respectively. Two received CVF+/-Spx, which extended survival to 5 and 6 days, respectively. Six underwent Spx + CVF therapy + IS; graft survival was 3 hr (technical complication), 6 days (death from sepsis), 10, 12, and 22 days (vascular rejection), and <25 days (euthanized for viral pneumonia with a functioning graft that showed histopathologic features of vascular rejection). Dense deposition of IgM and, to a lesser extent, IgG and IgA were seen on the endothelial cells within 1 hr of transplantation, but only trace levels of complement deposition were present in CVF-treated recipients. Within approximately 5-12 days, cardiac xenografts showed progressive infiltration by mononuclear cells, consisting primarily of activated macrophages producing tumor necrosis factor-alpha and small numbers of natural killer cells; T and B cells were absent. We conclude that (i) CVF prevents HAR, (ii) the addition of Spx + IS delays rejection, but (iii) the early deposition of antibody leads to progressive graft injury, resulting in (iv) delayed vascular rejection. Our findings indicate that the features of delayed xenograft rejection described in small animal models also occur in the pig-to-baboon model, and that rejection may occur in a complement-independent manner from the effects of antibody and/or host macrophages.

  15. Metabolic Function of a Suboptimal Transplanted Islet Mass in Nonhuman Primates on Rapamycin Monotherapy

    PubMed Central

    Soleimanpour, Scott A.; Hirshberg, Boaz; Bunnell, David J.; Sumner, Anne E.; Ader, Marilyn; Remaley, Alan T.; Rother, Kristina I.; Rickels, Michael R.; Harlan, David M.

    2012-01-01

    Although islet transplantation may restore insulin independence to individuals with type 1 diabetes mellitus, most have abnormal glucose tolerance. We asked whether the defective glucose tolerance is due to inadequate β-cell mass or to impaired insulin sensitivity. We performed metabolic studies on four cynomolgus primates before inducing diabetes with streptozotocin (STZ), then again 2–3 weeks after restoring insulin independence via intrahepatic islet transplantation utilizing a calcineurin inhibitor-free immunosuppressive regimen (induction with rabbit antithymocyte globulin and maintenance therapy with rapamycin). Engrafted β-cell mass was assessed by acute insulin and C-peptide responses to glucose (AIRglu and ACRglu) and arginine (AIRarg and ACRarg). Insulin sensitivity (SI) was determined in naive and transplanted primates from an intravenous glucose tolerance test using the minimal model. α-Cell function was determined by the acute glucagon response to arginine (AGRarg). Glucose tolerance (Kg) decreased from 4.1 ± 0.5%/min in naive primates to 1.8 ± 0.3%/min in transplanted primates (p < 0.01). Following transplantation, AIRglu was 28.7 ± 13.1 μU/ml compared to 169.9 ± 43.1 μU/ml (p < 0.03) in the naive condition, ACRglu was 14.5 ± 6.0 ng/ml compared to 96.5 ± 17.0 ng/ml naive (p < 0.01), AIRarg was 29.1 ± 13.1 μU/ml compared to 91.4 ± 28.2 μU/ml naive (p < 0.05), and ACRarg was 1.11 ± 0.51 ng/ml compared to 2.79 ± 0.77 ng/ml naive (p < 0.05). SI did not differ from naive to posttransplant states. AGRarg was reduced in transplanted primates (349 ± 118 pg/ml) when compared to both naive (827 ± 354 pg/ml) and post-STZ diabetic primates (1020 ± 440 pg/ml) (p < 0.01 for both comparisons). These data suggest that impaired glucose tolerance observed in islet transplant recipients is secondary to low functional β-cell mass and not to insulin resistance shortly after transplant. Furthermore, improved glycemic control achieved via islet

  16. Uterine transplantation in primates: a mini-review of the literature.

    PubMed

    Kisu, I; Banno, K; Mihara, M; Hara, H; Kato, Y; Suganuma, N; Aoki, D

    2014-05-01

    Assisted reproductive technology has improved markedly in recent years, and many infertile patients have had children with the use of this technology. However, women with infertility due to an absent or nonfunctional uterus currently have no option of having a genetically linked child other than gestational surrogacy. Uterus transplantation (UTx) is now a possible approach for women with uterine-factor infertility to deliver a child. UTx studies have been performed in many animals, and accumulation of data from these studies has brought UTx within reach of clinical application. This has led to performance of UTx in humans in Saudi Arabia, Turkey, and Sweden. However, there has yet to be a delivery after allogeneic UTx in primates. More basic studies in primates are needed, and data from research in primates can provide important information for establishment of UTx in humans. In this review, we summarize the literature on UTx studies, with a focus on primates, both human and nonhuman.

  17. Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model.

    PubMed

    Jakobsen, Maria; Stenderup, Karin; Rosada, Cecilia; Moldt, Brian; Kamp, Søren; Dam, Tomas N; Jensen, Thomas G; Mikkelsen, Jacob Giehm

    2009-10-01

    Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-alpha-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference (RNAi) are therapeutically relevant. To test this hypothesis the present study describes first the in vitro functional screening of a panel of short hairpin RNAs (shRNAs) targeting human TNF-alpha mRNA and, next, the transfer of the most potent TNF-alpha shRNA variant, as assessed in vitro, to human skin in the psoriasis xenograft transplantation model by the use of lentiviral vectors. TNF-alpha shRNA treatment leads to amelioration of the psoriasis phentotype in the model, as documented by reduced epidermal thickness, normalization of the skin morphology, and reduced levels of TNF-alpha mRNA as detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-alpha shRNAs in human skin. These findings validate TNF-alpha mRNA as a target molecule for a potential persistent RNA-based treatment of psoriasis and establish the use of small RNA effectors as a novel platform for target validation in psoriasis and other skin disorders.

  18. Structure, growth and cell proliferation of human osteosarcoma and malignant fibrous histiocytoma xenografts in serial transplantation in nude mice.

    PubMed

    Broström, L A; Crnalic, S; Löfvenberg, R; Stenling, R; Boquist, L

    1996-11-01

    Tumour specimens from one patient with osteosarcoma and one with malignant fibrous histiocytoma were transplanted in serial passages in nude mice. Structure, growth and cell kinetics of the xenografts were studied in order to assess the validity of the two tumour models. Cell proliferation was analysed using in vivo labelling with the thymidine analogue iododeoxyuridine (IdUrd) and the IdUrd labelling index (LI) was determined by immunohistochemistry. The DNA index (DI) was examined by flow cytometry. The c-myc oncoprotein expression was studied by immunohistochemistry. More intense proliferation was observed in the peripheral parts of the tumours. There was no correlation between tumour growth and cell proliferation in the two tumour groups. Stability of the tumour models was indicated by low intrapassage and interpassage variations of DI, LI, and volume doubling time, and also by retained histopathological characteristics and c-myc staining patterns of donor patients' tumours during serial transplantation.

  19. Human cytomegalovirus infection leads to elevated levels of transplant arteriosclerosis in a humanized mouse aortic xenograft model.

    PubMed

    Abele-Ohl, S; Leis, M; Wollin, M; Mahmoudian, S; Hoffmann, J; Müller, R; Heim, C; Spriewald, B M; Weyand, M; Stamminger, T; Ensminger, S M

    2012-07-01

    Recent findings emphasized an important role of human cytomegalovirus (HCMV) infection in the development of transplant arteriosclerosis. Therefore, the aim of this study was to develop a human peripheral blood lymphocyte (hu-PBL)/Rag-2(-/-) γc(-/-) mouse-xenograft-model to investigate both immunological as well as viral effector mechanisms in the progression of transplant arteriosclerosis. For this, sidebranches from the internal mammary artery were recovered during coronary artery bypass graft surgery, tissue-typed and infected with HCMV. Then, size-matched sidebranches were implanted into the infrarenal aorta of Rag-2(-/-) γc(-/-) mice. The animals were reconstituted with human peripheral blood mononuclear cells (PBMCs) 7 days after transplantation. HCMV-infection was confirmed by Taqman-PCR and immunofluorescence analyses. Arterial grafts were analyzed by histology on day 40 after transplantation. PBMC-reconstituted Rag-2(-/-) γc(-/-) animals showed splenic chimerism levels ranging from 1-16% human cells. After reconstitution, Rag-2(-/-) γc(-/-) mice developed human leukocyte infiltrates in their grafts and vascular lesions that were significantly elevated after infection. Cellular infiltration revealed significantly increased ICAM-1 and PDGF-R-β expression after HCMV-infection of the graft. Arterial grafts from unreconstituted Rag-2(-/-) γc(-/-) recipients showed no vascular lesions. These data demonstrate a causative relationship between HCMV-infection as an isolated risk factor and the development of transplant-arteriosclerosis in a humanized mouse arterial-transplant-model possibly by elevated ICAM-1 and PDGF-R-β expression.

  20. Uterus transplantation in a non-human primate: long-term follow-up after autologous transplantation.

    PubMed

    Johannesson, L; Enskog, A; Dahm-Kähler, P; Hanafy, A; Chai, D C; Mwenda, J M; Díaz-García, C; Olausson, M; Brännström, M

    2012-06-01

    Uterus transplantation (UTx) may provide the first available treatment for women affected by uterine infertility. The present study aimed to further develop a surgical technique for autologous UTx in a non-human primate species and to assess long-term function. Female baboons (n= 16) underwent autologous transplantation of the uterus with the Fallopian tubes and ovaries, performed with a previously published surgical technique (n= 6, Group 1) or using a modified technique (n= 10; Group 2). The uterine arteries were dissected to the proximal end of the anterior branch (Group 1) or the entire (Group 2) internal iliac artery, and the ovarian veins were dissected to the crossing over the ureter (Group 1) or further cranially to include greater lengths and patches of the cava/renal vein (Group 2). Back-table preparation created common venous and arterial ends with arterial anastomosis either end-to-side to the left external iliac artery (Group 1) or end-to-end to the left internal iliac artery (Group 2). Overall short-time survival of the animals was 88% (66% in Group 1 and 100% in Group 2). Of all the operated animals, 75% (66% in Group 1 and 80% in Group 2) resumed ovarian cyclicity. Regular menstruation after UTx was demonstrated only in Group 2 (60%). Menstruating animals (n= 6) were each exposed to timed mating for ≥5 menstrual cycles, but pregnancy did not occur. Adhesions and tubal blockage were seen in post-mortem analysis. The modified UTx model of Group 2 is a safe procedure and shows resumed long-term uterine function in a majority of the animals, although pregnancy could not be demonstrated.

  1. A xenograft mantle transplantation technique for producing a novel pearl in an akoya oyster host.

    PubMed

    Fukushima, Ei; Iwai, Toshiharu; Miura, Chiemi; Celino, Fritzie T; Urasaki, Shintarou; Miura, Takeshi

    2014-02-01

    The brightness and color of pearls varies among different pearl-producing shellfish and have been a source of human fascination since ancient times. When produced through cultivation, the characteristics and quality of a pearl depend on the kind of shellfish used and also the transplanted mantle graft. This suggests that the Akoya pearl oyster, which is generally used in Japan for pearl culturing, can produce different kinds of pearl through the use of mantles from different species of shellfish. However, a transplanted heterogeneous mantle would be rejected by the immune system of the Akoya oyster. We have therefore developed a new method to suppress the Akoya immune system that archives immune tolerance to other shellfish. It is generally known that small quantities of antigens can be used to produce archived immunological tolerance in a clinical setting. We successfully suppressed the Akoya pearl oyster immune response against a Mabé pearl oyster graft through repeat injections of mantle homogenates. We then transplanted a Mabé pearl oyster mantle graft into the immunologically tolerant Akoya pearl oyster and obtained a Mabé pearl from an Akoya pearl oyster. Our new technique thus makes the production of novel and different pearls in the Akoya possible. We believe that this has significant future potential for the advancement of the pearl industry.

  2. Fetal immune suppression as adjunctive therapy for in utero hematopoietic stem cell transplantation in nonhuman primates.

    PubMed

    Shields, Laurence E; Gaur, Lakshmi; Delio, Patrick; Potter, Jennifer; Sieverkropp, Aimee; Andrews, Robert G

    2004-01-01

    In utero hematopoietic stem cell transplantation could potentially be used to treat many genetic diseases but rarely has been successful except in severe immunodeficiency syndromes. We explored two ways to potentially increase chimerism in a nonhuman primate model: (a) fetal immune suppression at the time of transplantation and (b) postnatal donor stem cell infusion. Fetal Macaca nemestrina treated with a combination of the corticosteroid betamethasone (0.9 mg/kg) and rabbit thymoglobulin (ATG; 50 mg/kg) were given haploidentical, marrow-derived, CD34+ -enriched donor cells. Animals treated postnatally received either donor-derived T cell-depleted or CD34+ -enriched marrow cells. Chimerism was determined by traditional and real-time polymerase chain reaction from marrow, marrow progenitors, peripheral blood, and mature peripheral blood progeny. After birth, the level of chimerism in the progenitor population was higher in the immune-suppressed animals relative to controls (11.3% +/- 2.7% and 5.1% +/- 1.5%, respectively; p = .057). Chimerism remained significantly elevated in both marrow (p = .02) and fluorescence-activated cell sorted and purified CD34+ cells (p = .01) relative to control animals at > or = 14 months of age. Peripheral blood chimerism, both at birth and long term, was similar in immune-suppressed and control animals. In the animals receiving postnatal donor cell infusions, there was an initial increase in progenitor chimerism; however, at 6-month follow-up, the level of chimerism was unchanged from the preinfusion values. Although fetal immune suppression was associated with an increase in the level of progenitor and marrow chimerism, the total contribution to marrow and the levels of mature donor progeny in the peripheral blood remained low. The level of long-term chimerism also was not improved with postnatal donor cell infusion.

  3. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration

    PubMed Central

    Shirai, Hiroshi; Mandai, Michiko; Matsushita, Keizo; Kuwahara, Atsushi; Yonemura, Shigenobu; Nakano, Tokushige; Assawachananont, Juthaporn; Kimura, Toru; Saito, Koichi; Terasaki, Hiroko; Eiraku, Mototsugu; Sasai, Yoshiki; Takahashi, Masayo

    2016-01-01

    Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host–graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications. PMID:26699487

  4. Outcomes of alpha 1,3-GT-knockout porcine heart transplants into a preclinical nonhuman primate model.

    PubMed

    Kim, H; Chee, H K; Yang, J; Hwang, S; Han, K H; Kang, J; Park, J H; Kim, J S; Lee, S J; Ock, S A; Park, M H; Park, K S; Lee, B C; Byeongchun, L; Cho, K; Noh, J; Park, W; Yun, I J; Ahn, C

    2013-10-01

    Solid organ xenotransplantation is a potential solution to current organ shortages in allotransplantation. We performed four heart transplantations from alpha1, 3-galactosyltransferase gene-knockout (GT-KO) pigs to cynomolgus monkeys and monitored immunological parameters before and after transplantation. After blood typing of the cynomolgus monkeys, we assessed the binding activity of immunoglobulin G (IgG) and IgM of monkey serum and serum toxicity toward porcine peripheral blood mononuclear cells (PBMCs) using flow cytometry. Immunosuppressive protocols consisted of anti-thymocyte globulin (25 mg/kg), rituximab (20 mg/kg), anti-CD154mAb (20 mg/kg), cobra venom factor (0.05 mg/kg), tacrolimus, and steroid. Cynomolgus monkeys with A or AB blood type with the lowest antibody binding and serum toxicity activity on porcine PBMCs were selected as recipients. Absolute numbers of CD3(+) T cells, CD20(+) B cells, and CD3(+)CD95(+) memory T cells in the peripheral blood were suppressed upto 24 days after transplantation. Interferon gamma production of T cells in response to porcine antigens were also significantly suppressed. Heart xenografts from GT-KO pigs survived for upto 24 days without pathologic evidence of rejection. We successfully performed 4 heart xenotransplantations using GT-KO pigs. We overcame hyperacute rejection by using GT-KO pigs, and all of the heart xenografts from the GT-KO pigs survived between 11 and 24 days without pathologic evidence of rejection, disseminated intravascular coagulation, or consumptive coagulopathy; however, we need to optimize protocols for immune modulation and postoperative care to attain long-term survival of solid organ xenografts. Copyright © 2013. Published by Elsevier Inc.

  5. Xenograft of microencapsulated Sertoli cells for the cell therapy of type 2 diabetes mellitus in spontaneously diabetic nonhuman primates: preliminary data.

    PubMed

    Luca, G; Cameron, D F; Arato, I; Mancuso, F; Linden, E H; Calvitti, M; Falabella, G; Szekeres, K; Bodo, M; Ricci, G; Hansen, B C; Calafiore, R

    2014-01-01

    Insulin resistance in type 2 diabetes mellitus (T2DM) may be due to a chronic inflammation of the visceral adipose tissue (VAT) leading to local and systemic increases in proinflammatory cytokines. Microencapsulated porcine Sertoli cells (MC-pSC), by provision of immunomodulatory and trophic factors, have been successfully used to reduce such inflammation in rodent animal models of type 1 diabetes with no complications or deleterious side effects. Herein, we have begun to investigate this novel and safe therapeutic approach in the spontaneously obese nonhuman primate with spontaneous, insulin-dependent T2DM. After MC-pSC intraperitoneal injection we have evaluated, throughout a 6-month follow-up period, daily ad libitum fed glucose levels, daily exogenous insulin supplementation, biweekly body weight measurements, periodic fasting blood glucose concentrations, glycated hemoglobin (HbA1c) levels, glucose tolerance tests (GTT), and fluorescence-activated cell sorting cytometry (FACS) assessment of peripheral blood mononuclear cells. Very preliminarily, we have observed a slight reduction in fasting (FPG) and mean nonfasting (NF) plasma glucose levels. We found minimal changes, only in 1 animal, in daily exogenous insulin requirements and HbA1c levels. Flow cytometric analysis was associated with decrease in CD8(+) cells only in 1 recipient with a reduction in mean regulatory T Cells (Treg), whereas interestingly, decrease of B lymphocytes was observed in both animals. These results may suggest that this novel MC-SC-based transplantation protocol might possibly impact the metabolic status of T2DM in higher mammals that are close to humans.

  6. Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1.

    PubMed

    Plege-Fleck, Annegret; Lieke, Thorsten; Römermann, Dorothee; Düvel, Heike; Hundrieser, Joachim; Buermann, Anna; Kraus, Lilli; Klempnauer, Jürgen; Schwinzer, Reinhard

    2014-01-01

    Programmed death-1 (PD-1) costimulation acts as a negative regulator of T-cell responses to allografts. However, the role of the PD-1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T-cell responses to porcine transfectants overexpressing PD-Ligand1 (L23-PD-L1 cells) are remarkably weak. In this report, we asked whether the PD-1/PD-L1 pathway has the potential to diminish xenogeneic immune responses also in vivo. L23-PD-L1 or mock transfected control cells (L23-GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney-infiltrating rat leukocytes and the induction of anti-pig antibodies were monitored in grafted animals. Assessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23-PD-L1 or L23-GFP control cells. However, the level of MHC class-II molecules was reduced on macrophages responding to L23-PD-L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23-PD-L1 cells. In addition, the titers of induced anti-pig antibodies were significantly lower in rats grafted with L23-PD-L1 cells. These data suggest that signals triggered by PD-1-PD-L1 interaction interfere with activation pathways involved in the induction of cellular and antibody-mediated immune responses to xenografts in vivo. Targeting of PD-1 and/or PD-L1 may be a promising approach for immune modulation after xenotransplantation. © 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.

  7. Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

    PubMed Central

    Hantraye, P; Riche, D; Maziere, M; Isacson, O

    1992-01-01

    Huntington disease is a neurological movement disorder involving massive neuronal death in the caudate-putamen region of the brain. Neither preventive nor curative therapy exists for this disease. The implantation of cross-species striatal neural precursor cells into the lesioned striatum of nonhuman primates (baboons) reduced the abnormal movements seen in the disease model. These abnormal movements reappeared after immunological rejection of the implanted striatal cells and were not modified by transplantation with nonstriatal cells. These findings encourage further experimentation toward the use of cell sources other than human fetal cells in a potential clinical application to Huntington disease. Images PMID:1533285

  8. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.

    PubMed

    Mohiuddin, Muhammad M; Singh, Avneesh K; Corcoran, Philip C; Thomas, Marvin L; Clark, Tannia; Lewis, Billeta G; Hoyt, Robert F; Eckhaus, Michael; Pierson, Richard N; Belli, Aaron J; Wolf, Eckhard; Klymiuk, Nikolai; Phelps, Carol; Reimann, Keith A; Ayares, David; Horvath, Keith A

    2016-04-05

    Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications (GTKO.hCD46.hTBM) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days.

  9. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft

    PubMed Central

    Mohiuddin, Muhammad M.; Singh, Avneesh K.; Corcoran, Philip C.; Thomas III, Marvin L.; Clark, Tannia; Lewis, Billeta G.; Hoyt, Robert F.; Eckhaus, Michael; Pierson III, Richard N.; Belli, Aaron J.; Wolf, Eckhard; Klymiuk, Nikolai; Phelps, Carol; Reimann, Keith A.; Ayares, David; Horvath, Keith A.

    2016-01-01

    Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications (GTKO.hCD46.hTBM) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days. PMID:27045379

  10. Transplantation of Human Embryonic Stem Cell-Derived Retinal Cells into the Subretinal Space of a Non-Human Primate

    PubMed Central

    Chao, Jennifer R.; Lamba, Deepak A.; Klesert, Todd R.; Torre, Anna La; Hoshino, Akina; Taylor, Russell J.; Jayabalu, Anu; Engel, Abbi L.; Khuu, Thomas H.; Wang, Ruikang K.; Neitz, Maureen; Neitz, Jay; Reh, Thomas A.

    2017-01-01

    Purpose Previous studies have demonstrated the ability of retinal cells derived from human embryonic stem cells (hESCs) to survive, integrate into the host retina, and mediate light responses in murine mouse models. Our aim is to determine whether these cells can also survive and integrate into the retina of a nonhuman primate, Saimiri sciureus, following transplantation into the subretinal space. Methods hESCs were differentiated toward retinal neuronal fates using our previously published technique and cultured for 60 to 70 days. Differentiated cells were further treated with 20 μM N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) for a period of 5 days immediately prior to subretinal transplantation. Differentiated cells were labeled with a lentivirus expressing GFP. One million cells (10,000 cells/μL) were injected into the submacular space into a squirrel monkey eye, using an ab externo technique. Results RetCam imaging demonstrated the presence and survival of human donor cells 3 months after transplantation in the S. sciureus eye. Injected cells consolidated in the temporal macula. GFP+ axonal projections were observed to emanate from the central consolidation of cells at 1 month, with some projecting into the optic nerve by 3 months after transplantation. Conclusions Human ES cell-derived retinal neurons injected into the submacular space of a squirrel monkey survive at least 3 months postinjection without immunosuppression. Some donor cells appeared to integrate into the host inner retina, and numerous donor axonal projections were noted throughout, with some projecting into the optic nerve. Translational Relevance These data illustrate the feasibility of hESC-derived retinal cell replacement in the nonhuman primate eye. PMID:28516002

  11. Remyelination of the nonhuman primate spinal cord by transplantation of H-transferase transgenic adult pig olfactory ensheathing cells

    PubMed Central

    Radtke, Christine; Akiyama, Yukinori; Brokaw, Jane; Lankford, Karen L.; Wewetzer, Konstantin; Fodor, William L.; Kocsis, Jeffery D.

    2008-01-01

    Olfactory ensheathing cells (OECs) have been shown to mediate remyelination and to stimulate axonal regeneration in a number of in vivo rodent spinal cord studies. However, whether OECs display similar properties in the primate model has not been tested so far. In the present study, we thus transplanted highly-purified OECs isolated from transgenic pigs expressing the α1,2 fucosyltransferase gene (H-transferase or HT) gene into a demyelinated lesion of the African green monkey spinal cord. Four weeks posttransplantation, robust remyelination was found in 62.5% of the lesion sites, whereas there was virtually no remyelination in the nontransplanted controls. This together with the immunohistochemical demonstration of the grafted cells within the lesioned area confirmed that remyelination was indeed achieved by OECs. Additional in vitro assays demonstrated 1) that the applied cell suspension consisted of >98% OECs, 2) that the majority of the cells expressed the transgene, and 3) that expression of the HT gene reduced complement activation more than twofold compared with the nontransgenic control. This is the first demonstration that xenotransplantation of characterized OECs into the primate spinal cord results in remyelination. PMID:14657003

  12. Results of gal-knockout porcine thymokidney xenografts.

    PubMed

    Griesemer, A D; Hirakata, A; Shimizu, A; Moran, S; Tena, A; Iwaki, H; Ishikawa, Y; Schule, P; Arn, J S; Robson, S C; Fishman, J A; Sykes, M; Sachs, D H; Yamada, K

    2009-12-01

    Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous alpha1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys (composite thymus and kidneys) prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a preclinical xenotransplant model. Here, we report the results of seven xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole-body irradiation in all but one recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T-cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early primate thymopoiesis, which in turn may induce T-cell tolerance to solid organ xenografts.

  13. Establishment of a neuroblastoma mouse model by subcutaneous xenograft transplantation and its use to study metastatic neuroblastoma.

    PubMed

    Gao, Q; Chen, C F; Dong, Q; Hou, L; Chen, X; Zhi, Y L; Li, X; Lu, H T; Zhang, H Y

    2015-12-08

    The aim of this study was to establish a metastatic human neuroblastoma (NB) mouse model by xenograft in order to study the metastatic mechanisms of NB. A human NB cell line was obtained from a 5-year-old patient and cultured in vitro. A suspension of these cells was subcutaneously inoculated into nude mice at the right flank next to the forelimb. The biological characteristics of the developed subcutaneous and metastatic tumors were analyzed by hematoxylin and eosin staining. The expression of the tumor marker neuron-specific enolase was determined by immunohistochemistry, and the invasive ability of metastatic tumors was examined by a Matrigel invasion assay. DNA microarray analyses were performed to examine the metastasis-related gene expression. Our results showed that tumors grew in 75% of the mice injected with NB cells and the rate of metastasis was 21%. The xenograft tumors retained the morphological and biological characteristics of the NB specimen from the pediatric patient. Neuron-specific enolase was highly expressed in both subcutaneous and metastatic tumors. The metastatic tumor cells possessed a higher invasive capability than the primary NB cells. The expression of 25 metastasis-related genes was found to be significantly altered in metastatic tumors compared to primary tumors, including RECK, MMP2, VEGF, MMP3, and CXCL12. In conclusion, we successfully established a human NB xenograft model with high tumor-bearing and metastatic rates in nude mice, providing an ideal animal model for the in vivo study of NB.

  14. Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson's disease.

    PubMed

    Wolff, Erin F; Mutlu, Levent; Massasa, Efi E; Elsworth, John D; Eugene Redmond, D; Taylor, Hugh S

    2015-01-01

    Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. Cell-replacement therapies have emerged as a promising strategy to slow down or replace neuronal loss. Compared to other stem cell types, endometrium-derived stem cells (EDSCs) are an attractive source of stem cells for cellular therapies because of their ease of collection and vast differentiation potential. Here we demonstrate that endometrium-derived stem cells may be transplanted into an MPTP exposed monkey model of PD. After injection into the striatum, endometrium-derived stem cells engrafted, exhibited neuron-like morphology, expressed tyrosine hydroxylase (TH) and increased the numbers of TH positive cells on the transplanted side and dopamine metabolite concentrations in vivo. Our results suggest that endometrium-derived stem cells may provide a therapeutic benefit in the primate model of PD and may be used in stem cell based therapies. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  15. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    SciTech Connect

    Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.

    2015-07-10

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

  16. Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation

    SciTech Connect

    Reisner, Y.; Ben-Bassat, I.; Douer, D.; Kaploon, A.; Schwartz, E.; Ramot, B.

    1986-06-01

    The phenomenon of marrow rejection following supralethal radiochemotherapy was explained in the past mainly by non-T-cell mechanisms known to be resistant to high-dose irradiation. In the present study a low but significant number of radiochemoresistant-clonable T cells was found in the peripheral blood and spleen of Rhesus monkeys following the cytoreductive protocol used for treatment of leukemia patients prior to bone marrow transplantation. More than 95% of the clonable cells are concentrated in the spleen 5 days after transplant. The cells possess immune memory as demonstrated by the generation of alloreactive-specific cytotoxicity. The present findings suggest that host-versus-graft activity may be mediated by alloreactive T cells. It is hoped that elimination of such cells prior to bone marrow transplantation will increase the engraftment rate of HLA-nonidentical marrow in leukemia patients.

  17. Transplantation tolerance in primates after total lymphoid irradiation and allogeneic bone marrow injection

    SciTech Connect

    Smit, J.A.; Hill, R.R.H.; Myburgh, J.A.; Browde, S.

    1980-08-01

    After total lymphoid irradiation (TLI), allogeneic bone marrow (BM) injection, and organ transplantation in baboons, there is a prolonged period of reduced lymphocyte proliferative responsiveness to polyclonal mitogens and allogeneic lymphocytes. The effect observed is greater with the use of fractionated TLI than after single doses of irradiation. Suppressor cell activity can be demonstrated in vitro in most animals by inhibition of mixed lymphocyte reactivity (MLR) by mitomycin-treated recipient lymphocytes harvested after TLI, with or without allogeneic BM injection, and organ transplantation. Preliminary data suggest the presence of both donor-specific and nondonor-specific suppression, although other interpretations are possible, and suppressor phenomena may not be responsible for the transplantation tolerance observed.

  18. Accumulation of Intrahepatic Islet Amyloid in a Nonhuman Primate Transplant Model

    PubMed Central

    Liu, Chengyang; Koeberlein, Brigitte; Feldman, Michael D.; Mueller, Rebecca; Wang, Zhonglin; Li, Yanjing; Lane, Kristin; Hoyt, Clifford C.; Tomaszewski, John E.; Naji, Ali

    2012-01-01

    Islet amyloid is hypothesized to play a role in nonimmunologic transplanted islet graft loss. We performed a quantitative histologic analysis of liver biopsies from intrahepatic islet grafts transplanted in streptozotocin-induced diabetic cynomolgus macaques. Seven animals treated with antithymocyte globulin (ATG) and rapamycin or ATG and rituximab experienced islet graft rejection with lymphocytic infiltrates present on islet graft biopsies. Except for one case involving the oldest and largest donor where amyloid was present on initial biopsy 1 month after transplant, none of the six other cases with rejection contained amyloid, including one case biopsied serially to 25 months. In contrast, four out of six animals treated with ATG and rituximab and rapamycin had no evidence of rejection at the time of biopsy (two animals that discontinued rapamycin had mild periislet lymphocytes), and all four cases followed more than 4 months demonstrated amyloid deposition at subsequent time points. Amyloid severity increased with time after transplant (r = 0.68; P < 0.05) and with decreasing islet β-cell area (r = −0.68; P < 0.05). In two islet recipients with no evidence of rejection and still normoglycemic and insulin independent at the first detection of amyloid, β-cell secretory capacity declined over time coincident with increasing amyloid severity and decreasing β-cell area, with both animals eventually becoming hyperglycemic and insulin dependent. Transplanted islet amyloid also developed in autologous islets placed sc. These results indicate that in cynomolgus macaques, transplanted islets may accumulate amyloid over time associated with subsequent decline in β-cell mass and function and support the development of intrahepatic islet amyloid as a potential mechanism for nonimmunologic islet graft loss. PMID:22355065

  19. Accumulation of intrahepatic islet amyloid in a nonhuman primate transplant model.

    PubMed

    Liu, Chengyang; Koeberlein, Brigitte; Feldman, Michael D; Mueller, Rebecca; Wang, Zhonglin; Li, Yanjing; Lane, Kristin; Hoyt, Clifford C; Tomaszewski, John E; Naji, Ali; Rickels, Michael R

    2012-04-01

    Islet amyloid is hypothesized to play a role in nonimmunologic transplanted islet graft loss. We performed a quantitative histologic analysis of liver biopsies from intrahepatic islet grafts transplanted in streptozotocin-induced diabetic cynomolgus macaques. Seven animals treated with antithymocyte globulin (ATG) and rapamycin or ATG and rituximab experienced islet graft rejection with lymphocytic infiltrates present on islet graft biopsies. Except for one case involving the oldest and largest donor where amyloid was present on initial biopsy 1 month after transplant, none of the six other cases with rejection contained amyloid, including one case biopsied serially to 25 months. In contrast, four out of six animals treated with ATG and rituximab and rapamycin had no evidence of rejection at the time of biopsy (two animals that discontinued rapamycin had mild periislet lymphocytes), and all four cases followed more than 4 months demonstrated amyloid deposition at subsequent time points. Amyloid severity increased with time after transplant (r = 0.68; P < 0.05) and with decreasing islet β-cell area (r = -0.68; P < 0.05). In two islet recipients with no evidence of rejection and still normoglycemic and insulin independent at the first detection of amyloid, β-cell secretory capacity declined over time coincident with increasing amyloid severity and decreasing β-cell area, with both animals eventually becoming hyperglycemic and insulin dependent. Transplanted islet amyloid also developed in autologous islets placed sc. These results indicate that in cynomolgus macaques, transplanted islets may accumulate amyloid over time associated with subsequent decline in β-cell mass and function and support the development of intrahepatic islet amyloid as a potential mechanism for nonimmunologic islet graft loss.

  20. Effect of MPTP on primate chromaffin cells in vitro: relevance for adrenal medullary cell transplantation.

    PubMed

    Notter, M F; Kaniuki, M; Felten, S Y; Hansen, J T; Gash, D M

    1991-01-01

    Primate adrenal medullary cells were exposed to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in vitro to examine the effect of this neurotoxic agent on chromaffin cells. Chromaffin cells from monkey and humans were cultured in the presence of 100 ng/ml nerve growth factor for 1 week and then exposed to 150 μM MPTP or its active metabolite methylpyridinium ion (MPP+) for an additional week. Cells which had extended neurites in the presence of NGF showed no morphological effect in response to MPTP or MPP+ at the light microscopic level. However, there was a significant loss in catecholamines as seen by histofluorescence and high performance liquid chromotography (HPLC). Electron microscopy revealed a depletion in dense-core vesicles in chromaffin cells after chronic exposure to MPTP while the mitochondria appeared similar to those observed in control cells. Replacement of MPTP medium with standard medium stimulated restoration of catecholamine histofluorescence after 7 days. An acute 15 min pretreatment of chromaffin cells with MPTP or MPP+ induced secretion of catecholamines over a 1 h pulse, with MPP+ producing the maximum and more rapid secretion as determined by HPLC. These data indicate that MPTP induces a dramatic loss in catecholamines in primate chromaffin cells in vitro after both acute and chronic exposures; however, removal of the toxic agent permits restoration of catecholamines without permanent effect on the integrity of these cells.

  1. Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation

    PubMed Central

    Liu, Congxiao; Chen, Benny J.; DeOliveira, Divinomar; Sempowski, Gregory D.; Chao, Nelson J.

    2010-01-01

    Two critical concerns in clinical cord blood transplantation are the initial time to engraftment and the subsequent restoration of immune function. These studies measured the impact of progenitor cell dose on both the pace and strength of hematopoietic reconstitution by transplanting nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma–null (NSγ) mice with lineage-depleted aldehyde dehydrogenase-bright CD34+ human cord blood progenitors. The progress of each transplant was monitored over an extended time course by repeatedly analyzing the peripheral blood for human hematopoietic cells. In vivo human hematopoietic development was complete. After long-term transplantation assays (≥ 19 weeks), human T-cell development was documented within multiple tissues in 16 of 32 NSγ mice. Human T-cell differentiation was active within NSγ thymuses, as documented by the presence of CD4+ CD8+ T-cell progenitors as well as T-cell receptor excision circles. It is important to note that although myeloid and B-cell engraftment was detected as early as 4 weeks after transplantation, human T-cell development was exclusively late onset. High progenitor cell doses were associated with a robust human hematopoietic chimerism that accelerated both initial time to engraftment and subsequent T-cell development. At lower progenitor cell doses, the chimerism was weak and the human hematopoietic lineage development was frequently incomplete. PMID:20833978

  2. AZ17: a new bispecific drug targeting IL-6 and IL-23 with potential clinical use--improves psoriasis in a human xenograft transplantation model.

    PubMed

    Stenderup, Karin; Rosada, Cecilia; Shanebeck, Kurt; Brady, William; Van Brunt, Michael P; King, Gordon; Marelli, Marcello; Slagle, Paul; Xu, Hengyu; Nairn, Natalie W; Johnson, Jeffrey; Wang, Aijun A; Li, Gary; Thornton, Kenneth C; Dam, Tomas N; Grabstein, Kenneth H

    2015-10-01

    Targeting more than one molecule in multifactorial diseases involving several disease mediators may provide improved therapeutic efficacy. Psoriasis is a multifactorial disease in which interleukin (IL)-6 and IL-23 are important disease mediators because they facilitate development of Th17 cells; widely accepted to be associated with psoriasis. To meet the need for new therapeutics, we aimed to create a clinically relevant bispecific drug, by combining the inhibitory properties of anti-IL-6 and anti-IL-23 antibodies, exhibiting high affinity, high stability and the ability to be produced in high yield. The bispecific molecule AZ17 was created by combining high affinity binding domains originating from monoclonal antibodies targeting human IL-6 and IL-23. To allow for high and efficient production, AZ17 was assembled by site-specific bioconjugation from two individual single chain fragment variables that were synthesized separately in Escherichia coli. To improve stability and extend pharmacokinetics, a flexible poly-ethylene glycol molecule was used as linker. In preclinical psoriasis models, AZ17 reduced IL-23-induced ear inflammation and improved psoriasis in a xenograft transplantation model where psoriasis skin is transplanted onto immune-deficient mice. The data presented here suggest AZ17 to be a promising drug candidate in psoriasis and other inflammatory diseases associated with Th17 cell development.

  3. Preclinical safety evaluation of human mesenchymal stem cell transplantation in cerebrum of nonhuman primates.

    PubMed

    Feng, Ming; Li, Yan; Han, Qin; Bao, Xinjie; Yang, Ming; Zhu, Hua; Li, Qin; Wei, Junji; Ma, Wenbin; Gao, Hong; An, Yihua; Zhao, Robert Chunhua; Qin, Chuan; Wang, Renzhi

    2014-01-01

    The efficacy of stem cell transplantation for promoting recovery of patients with neurological diseases, such as stroke, has been reported in several studies. However, the safety of the intracerebral transplantation of human mesenchymal stem cells (hMSCs) remains unclear. The aim of the study was to evaluate the safety of hMSCs transplanted in cerebrum of Macaca fascicularis and to provide evidence for clinical application. A total of 24 M fascicularis were assigned to 3 groups randomly: low dose (3.0 × 10(5) cells/kg), high dose (2.5 × 10(6) cells/kg), and the control (normal saline [NS]). Human mesenchymal stem cells or NS were injected into each monkey for 2 times, with an interval of 3 weeks. The injection point was located outside of the right putamen, according to a stereotactic map and preoperative magnetic resonance imaging of the monkeys. Animal health, behavior, biophysical and biochemical parameters, and brain neurological function were routinely monitored over a 6-month period posttransplantation, and the histopathologic examinations were also performed. The results showed that local pathologic damage including local tissue necrosis and inflammation was induced after the injection. The damage of low-dose and high-dose groups was greater than that of the control group, yet over time, the damage could be repaired gradually. No major hMSCs-associated changes were induced from other indicators, and the transplantation of hMSCs in monkeys did not affect total immunoglobulin (Ig) M, total IgG, CD3, CD4, or CD8 values. We therefore conclude that transplantation of hMSCs to the cerebrum represents a safe alternative for clinical application of neurological disorders.

  4. Future of liver transplantation: non-human primates for patient-specific organs from induced pluripotent stem cells.

    PubMed

    Sanal, Madhusudana Girija

    2011-08-28

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly.

  5. Future of liver transplantation: Non-human primates for patient-specific organs from induced pluripotent stem cells

    PubMed Central

    Sanal, Madhusudana Girija

    2011-01-01

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient’s genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly. PMID:21990949

  6. Therapeutic regulation of systemic inflammation in xenograft recipients.

    PubMed

    Iwase, Hayato; Liu, Hong; Li, Tao; Zhang, Zhongquiang; Gao, Bingsi; Hara, Hidetaka; Wijkstrom, Martin; Long, Cassandra; Saari, Ryan; Ayares, David; Cooper, David K C; Ezzelarab, Mohamed B

    2017-03-12

    Inflammation is known to preclude tolerance after transplantation. We have previously shown that systemic inflammation in xenograft recipients (SIXR) precedes activation of coagulation in the absence of T cell responses. Accordingly, SIXR may amplify innate and adaptive immune responses against xenografts after pig-to-primate xenotransplantation, even with efficient immunosuppressive therapy. We evaluated the impact of anti-inflammatory agents on pro-inflammatory cytokines and chemokines in pig artery patch and heart xenograft recipients. Baboons received an artery patch (Group1, n=8) or heart (Group2, n=4) from genetically engineered pigs. All baboons received lymphodepletion with thymoglobulin (ATG) and costimulation blockade-based immunosuppression (anti-CD40 and/or CTLA4Ig). In Group1, baboons received either (i) no anti-inflammatory agents (n=2), (ii) cobra venom factor (CVF, n=2), (iii) α1-antitrypsin (AAT, n=2), or (iv) interleukin (IL)-6 receptor antagonist (IL-6RA, n=2). In Group2, all baboon received corticosteroids, either without (n=2) or with (n=2) IL-6RA. Serum IFN-γ, TNF-α, IL-1β, IL-17, IL-6, IL-8, MCP-1, and sCD40L levels were measured by Luminex. Fibrinogen, D-dimers, and C-reactive protein (C-RP) were also measured. Recipient baboon T cell proliferation was evaluated by mixed lymphocyte reaction (MLR) before and after transplantation. Pig and baboon tissue factor (TF) mRNA levels in heart xenografts were measured by RT-PCR. In no recipient was a marked increase in T cell response to pig cells observed after transplantation. In Groups 1 and 2, post-transplantation levels of IFN-γ, TNF-α, IL-1β, and IL-17 remained comparable to or lower than pre-transplant levels, except in one heart recipient that succumbed to CMV infection. In Group1, when no anti-inflammatory agent was administered, post-transplant levels of IL-6, IL-8, and MCP-1 were elevated. After CVF, IL-6, IL-8, and MCP-1 remained low. After IL-6RA, IL-6 and MCP-1 were elevated

  7. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease

    PubMed Central

    Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar; Smith, Gaynor A.; Cooper, Oliver; Osborn, Teresia; Sundberg, Maria; Moore, Michele A.; Perez-Torres, Eduardo; Brownell, Anna-Liisa; Schumacher, James; Spealman, Roger D.; Isacson, Ole

    2015-01-01

    Summary Autologous transplantation of patient-specific iPSC-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility and safety of iPSC-derived dopamine neurons in non human primate models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson's disease (PD) model. In one animal, with the most successful protocol, we found that unilateral engraftment of CM-iPSCs could provide a gradual onset of functional motor improvement contralateral to the side of dopamine neuron transplantation, and increased motor activity, without a need for immunosuppression. Post-mortem analyses demonstrated robust survival of midbrain-like dopaminergic neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD. PMID:25732245

  8. Endothelial induction of fgl2 contributes to thrombosis during acute vascular xenograft rejection.

    PubMed

    Ghanekar, Anand; Mendicino, Michael; Liu, Hao; He, Wei; Liu, Mingfeng; Zhong, Robert; Phillips, M James; Levy, Gary A; Grant, David R

    2004-05-01

    Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-alpha in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2(+/+) and fgl2(+/-) mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2(-/-) mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.

  9. SYSTEMIC INFLAMMATION IN XENOGRAFT RECIPIENTS PRECEDES ACTIVATION OF COAGULATION

    PubMed Central

    Ezzelarab, MB; Ekser, B; Azimzadeh, A; Lin, CC; Zhao, Y; Rodriguez, R; Echeverri, GJ; Iwase, H; Long, C; Hara, H; Ayares, D; Pierson, RN; Thomson, AW; Cooper, DKC

    2014-01-01

    Background Dysregulation of coagulation is considered a major barrier against successful pig organ xenotransplantation in nonhuman primates. Inflammation is known to promote activation of coagulation. The role of pro-inflammatory factors as well as the relationship between inflammation and activation of coagulation in xenograft recipients is poorly understood. Methods Baboons received kidney (n=3), heart (n=4) or artery patch (n=8) xenografts from α1,3-galactosyltransferase gene-knockout (GTKO) pigs or GTKO pigs additionally transgenic for human complement regulatory protein CD46 (GTKO/CD46). Immunosuppression (IS) was based on either CTLA4-Ig or anti-CD154 costimulation blockade. Three artery patch recipients did not receive IS. Pro-inflammatory cytokines, chemokines and coagulation parameters were evaluated in the circulation after transplantation. In artery patch recipients, monocytes and dendritic cells (DC) were monitored in peripheral blood. Expression of tissue factor (TF) and CD40 on monocytes and DC were assessed by flow cytometry. C-reactive protein (C-RP) levels in the blood and C-RP deposition in xenografts as well as native organs were evaluated. Baboon and pig C-RP mRNA in heart and kidney xenografts were evaluated. Results In heart and kidney xenograft recipients, the levels of INFγ, TNF-α, IL-12 and IL-8 were not significantly higher after transplantation. However, MCP-1 and IL-6 levels were significantly higher after transplantation, particularly in kidney recipients. Elevated C-RP levels preceded activation of coagulation in heart and kidney recipients, where high levels of C-RP were maintained until the time of euthanasia in both heart and kidney recipients. In artery patch recipients, INFγ, TNF-α, IL-12, IL-8 and MCP-1 were elevated with no IS, while IL-6 was not. With IS, INFγ, TNF-α, IL-12, IL-8 and MCP-1 were reduced, but IL-6 was elevated. Elevated IL-6 levels were observed as early as 2 weeks in artery patch recipients. While IS was

  10. [Osteostimulating effect of bone xenograft on bone tissue regeneration].

    PubMed

    Balin, V N; Balin, D V; Iordanishvili, A K; Musikin, M I

    2015-01-01

    The aim of experimental case-control study performed in 28 dogs divided in 2 groups was to assess local tissue reactions on bone xenograft transplantation; dynamics of bone remodeling and formation at the site of bone defect wall contacting with bone xenograft; dynamics and mechanisms of xenograft remodeling. Transplantation of xenograft in conventional bone defects did not cause inflammatory of destructive reactions because of high biocompatibility of the material. At transplantation site active fibrous bone trabeculae formation filling the spaces between xenograft participles was observed. On the 90th day newly formed bone showed lammelar structure. Simultaneously from the 42d day the invasion of cell elements from recipient bed into the material was seen leading to xenograft resorption. The observed dynamics may be assessed as gradual substitution of xenograft with newly formed host bone structures.

  11. [Effects of human Livin gene down-regulation by RNA interference on xenograft of transplantation tumor induced by SPC-A1 in nude mice].

    PubMed

    Chen, Yu-Sheng; Li, You-Tang; Li, Hong-Ru; Chen, Xiao-Yan; Lin, Li-Fang

    2011-01-01

    To explore the in vivo inhibitory effect of Livin gene silencing by RNA interference on xenograft of lung adenocarcinoma SPC-A-1 cells in BALB/C nude mice. Three different BALB/C nude mice models were established by subcutaneously inoculating differently treated SPC-A-1 cells into 3 nude mice groups: the blank control group was inoculated with blank SPC-A-1 cells, while the negative group was inoculated with cells transfected with lentivirus-delivered negative shRNA, the experimental group was inoculated with cells with lentivirus-delivered Livin shRNA. Then the growth of tumors was observed, and the volume and weight of the tumors were measured at different time points. The curve of tumor growth was then described, and the inhibition rate was calculated. Livin gene expression in the tumor tissues was determined by RT-PCR and Immunohistochemistry. Cell apoptosis of tumor tissues was detected by TUNEL. Slower tumor growth, smaller tumor volume and lighter tumor weight were observed in the experimental group as compared to the blank and negative groups (F = 70.509, P < 0.01; F = 12.821, P < 0.01). The inhibition rate of tumor volume was (59.5 ± 3.4)%, and the inhibition rate of tumor weight was (71.1 ± 5.6)%. Livinα mRNA and Livinβ mRNA expressions in the experimental group were significantly lower than the 2 control groups [(37.2 ± 1.6)% versus (63.3 ± 3.8)%, (66.1 ± 2.6)%; (29.4 ± 1.1)% versus (53.2 ± 3.4)%, (52.3 ± 3.1)% (F(α) = 45.309, P < 0.01; F(β) = 30.076, P < 0.01)]. Livin protein expression level was also significantly lower than the blank and the negative groups [(15.3 ± 2.8)% versus (51.3 ± 2.1)%, (52.5 ± 2.5)%, F = 78.92, P < 0.01]. The apoptosis rate in the experimental group was significantly higher than that in the 2 control groups [(35.4 ± 3.2)% versus (5.4 ± 1.3)%, (8.6 ± 1.5)%, F = 14.509, P < 0.01]. The lentivirus-delivered Livin shRNA was shown to inhibit the proliferation of transplantation tumor of lung carcinoma effectively

  12. Establishment and Characterization of Baboon Embryonic Stem Cell Lines An Old World Primate Model for Regeneration and Transplantation Research

    PubMed Central

    Simerly, Calvin R.; Navara, Christopher S.; Castro, Carlos A.; Turpin, Janet C.; Redinger, Carrie J.; Mich-Basso, Jocelyn D.; Jacoby, Ethan S.; Grund, Kevin J.; McFarland, David A.; Oliver, Stacie L.; Ben-Yehudah, Ahmi; Carlisle, Diane L.; Frost, Patricia; Penedo, Cecilia; Hewitson, Laura; Schatten, Gerald

    2010-01-01

    Here we have developed protocols using the baboon as a complementary alternative Old World Primate to rhesus and other macaques which have severe limitations in their availability. Baboons are not limited as research resources, they are evolutionarily closer to humans and the multiple generations of pedigreed colonies which display complex human disease phenotypes all support their further optimization an invaluable primate model. Since neither baboon assisted reproductive technologies nor baboon embryonic stem cells (ESCs) have been reported, here we describe the first derivations and characterization of baboon ESC lines from IVF-generated blastocysts. Two ESCs lines (BabESC-4 and BabESC-15) display ESC morphology, express pluripotency markers (Oct-4, hTert, Nanog, Sox-2, Rex-1, TRA1–60, TRA1–81), and maintain stable euploid female karyotypes with parentage confirmed independently. They have been grown continuously for >430 and 290 days, respectively. Teratomas from both lines have all three germ layers. Availabilities of these BabESCs represent another important resource for stem cell biologists. PMID:19393591

  13. Liver xenografts for the treatment of acute liver failure: clinical and experimental experience and remaining immunologic barriers.

    PubMed

    Hara, Hidetaka; Gridelli, Bruno; Lin, Yih Jyh; Marcos, Amadeo; Cooper, David K C

    2008-04-01

    A critical element restricting the application of liver transplantation is the shortage of human deceased donor organs. Xenotransplantation using pig organs might be a solution to this shortage. Although the problems that still require resolution include the immunologic barrier, the potential risk of transferring infectious agents with the transplanted organ, and uncertainty about whether the transplanted organ will function satisfactorily in the human environment, recent progress in the genetic manipulation of pigs has led to the prospect that clinical xenografting, at least as a bridge to allotransplantation, may be possible in the foreseeable future. Experience with clinical auxiliary and orthotopic liver xenotransplantation and experimental liver xenotransplantation in nonhuman primate and other large animal models is reviewed, and the remaining immunologic problems are discussed. Evidence suggests that, in patients with hepatic failure, the pig liver may be less susceptible to antibody-mediated injury than other pig organs, such as the heart or kidney. Pig Kupffer cells and other macrophages will recognize and phagocytose primate red blood cells, but this problem should be overcome by pretransplant depletion of macrophages from the organ-source pig. From the evidence currently available, it does not seem unduly optimistic to anticipate that a liver from an alpha1,3-galactosyltransferase gene-knockout pig would survive at least long enough to function as a successful bridge to allotransplantation. (c) 2008 AASLD.

  14. XENOTRANSPLANTATION – THE FUTURE OF CORNEAL TRANSPLANTATION?

    PubMed Central

    Hara, Hidetaka; Cooper, David K.C.

    2010-01-01

    Although corneal transplantation is readily available in the USA and certain other regions of the developed world, the need for human donor corneas worldwide far exceeds supply. There is currently renewed interest in the possibility of using corneas from other species, especially pigs, for transplantation into humans (xenotransplantation). The biomechanical properties of human and pig corneas are similar. Studies in animal models of corneal xenotransplantation have documented both humoral and cellular immune responses that play roles in xenograft rejection. The results obtained from the Tx of corneas from wild-type (i.e., genetically-unmodified) pigs into nonhuman primates have been surprisingly good and encouraging. Recent progress in the genetic manipulation of pigs has led to the prospect that the remaining immunological barriers will be overcome. There is every reason for optimism that corneal xenoTx will become a clinical reality within the next few years. PMID:21099407

  15. Transplantation tolerance in primates following total lymphoid irradiation and allogeneic bone marrow injection. I. Orthoptic liver allographs

    SciTech Connect

    Myburgh, J.A.; Smit, J.A.; Browde, S.; Hill, R.R.H.

    1980-05-01

    Fractionated total lymphoid irradiation (TLI) and allogeneic bone marrow (BM) injection have been reported to produce stable chimerism without graft-versus-host disease (GVHD) in inbred mice and rats and mongrel dogs, and transplantation tolerance for skin and heart grafts in rodents. This concept has been studied in outbred chacma baboons receiving orthotopic liver allografts with the use of five different irradiation protocols. Eight fractions of 200 rad to the whole torso, followed immediately by allogeneic BM injections, and liver grafts from the BM donors 3 to 4 weeks later resulted in markedly prolonged survivals of 63 to 106 days in four baboons (median survival of untreated controls 19 days). Only one of the four animals died directly from the effects of rejection. BM chimerism was demonstrated in two baboons. There were no clinical or histological signs of GVHD in any of the animals. Two fractions of TLI, totaling 800 rad, 23 hr apart and followed immediately by BM injection and liver grafting resulted in profound thrombocytopenia and death form intraperitoneal hemorrhage in four of five baboons. In one animal BM injection and liver transplantation were delayed for 75 days. The baboon is still alive more than 6 months later. Three groups received single doses of 300, 400, and 500 rad to the whole torso, followed by allogeneic BM injections 1 and 2 weeks later, and liver transplants from their BM donors after an additional 3 to 4 weeks. The four baboons receiving 300 rad survived for 42, 86, 123, and >180 days. Two of the four baboons receiving 400 rad died of septic intraabdominal complications with minimal or no evidence of rejection. Fourh of the five baboons receiving 500 rad died from rejection.

  16. Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates.

    PubMed

    Oura, T; Hotta, K; Lei, J; Markmann, J; Rosales, I; Dehnadi, A; Kawai, K; Ndishabandi, D; Smith, R-N; Cosimi, A B; Kawai, T

    2017-03-01

    The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet-kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti-interleukin-6 receptor mAb and anti-tumor necrosis factor-α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.

  17. Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

    PubMed

    Samy, K P; Anderson, D J; Lo, D J; Mulvihill, M S; Song, M; Farris, A B; Parker, B S; MacDonald, A L; Lu, C; Springer, T A; Kachlany, S C; Reimann, K A; How, T; Leopardi, F V; Franke, K S; Williams, K D; Collins, B H; Kirk, A D

    2017-05-01

    Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  18. Primate cognition.

    PubMed

    Seed, Amanda; Tomasello, Michael

    2010-07-01

    As the cognitive revolution was slow to come to the study of animal behavior, the vast majority of what we know about primate cognition has been discovered in the last 30 years. Building on the recognition that the physical and social worlds of humans and their living primate relatives pose many of the same evolutionary challenges, programs of research have established that the most basic cognitive skills and mental representations that humans use to navigate those worlds are already possessed by other primates. There may be differences between humans and other primates, however, in more complex cognitive skills, such as reasoning about relations, causality, time, and other minds. Of special importance, the human primate seems to possess a species-unique set of adaptations for "cultural intelligence," which are broad reaching in their effects on human cognition.

  19. THE UTILITY OF RIGHT VENTRICULAR ENDOMYOCARDIAL BIOPSY FOR THE DIAGNOSIS OF XENOGRAFT REJECTION AFTER CD46 PIG-TO-BABOON CARDIAC TRANSPLANTATION

    PubMed Central

    Ricci, Davide; Tazelaar, Henry D; Miyagi, Naoto; Rao, Vinay P; Pedersen, Rachel A; Kremers, Walter K; Byrne, Guerard W; McGregor, Christopher G A

    2007-01-01

    Introduction Endomyocardial biopsy (EmBx) is the standard means of establishing cardiac allograft rejection diagnosis. The efficacy of this procedure in xenotransplantation has not been determined. In this study we compare the histology of right ventricular EmBx specimens with the corresponding full cross sections of explanted right ventricle (RV). We also compare RV with the related left ventricle (LV) cross sections. Methods Heterotopic CD46 pig to baboon cardiac xenotransplants (n=64) were studied. RVEmBxs were taken at cardiac explant, using either a standard bioptome (RVEmBxBT; n=24) or by sharp dissection (RVEmBxSD; n=40). Hematoxylin-eosin stained sections of RV and LV cross section and RVEmBxs were compared in a blinded fashion. Characteristics of delayed xenograft rejection (DXR) and a global assessment of ischemia, were scored from 0 to 4 based on the percentage of myocardium involved (0 = 0%, 1=1−25%, 2 = 26−50%, 3 = 51−75%, 4 = 76−100%). Results Median graft survival was 30 days (range 3–137). Linear regression analysis of histology scores demonstrated that both RVEmBxBT and RVEmBxSD equally represented the histology of RV cross section. Global ischemic injury was strongly correlated between RV and RVEmBx (R2=0.84) and between RV and LV cross sections (R2=0.84). Individual characteristics of DXR showed no significant variation between RV and RVEmBx or between RV and LV (p<0.05). Conclusions These results indicate that DXR is a widespread process involving both right and left ventricles similarly. This study shows that histologic assessment of RVEmBx specimens is an effective method for the monitoring of DXR after cardiac xenotransplantation. PMID:17919623

  20. Total lymphoid irradiation and discordant cardiac xenografts

    SciTech Connect

    Kaplan, E.; Dresdale, A.R.; Diehl, J.T.; Katzen, N.A.; Aronovitz, M.J.; Konstam, M.A.; Payne, D.D.; Cleveland, R.J. )

    1990-01-01

    Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival.

  1. Persistence of Indirect but Not Direct T Cell Xenoresponses in Baboon Recipients of Pig Cell and Organ Transplants.

    PubMed

    Buhler, L; Illigens, B M-W; Nadazdin, O; Tena, A; Lee, S; Sachs, D H; Cooper, D K C; Benichou, G

    2016-06-01

    We investigated the contributions of direct and indirect T cell antigen recognition pathways to the immune response to porcine antigens in naïve baboons and baboon recipients of pig xenografts. In naïve baboons, in vitro culture of peripheral blood T cells with intact pig cells (direct xenorecognition pathway) or pig cell sonicates and baboon antigen-presenting cells (indirect xenorecognition pathway) induced the activation and expansion of xenoreactive T cells producing proinflammatory cytokines, interleukin-2 and interferon-γ. Primary indirect xenoresponses were mediated by preexisting memory T cells, whose presence is not typically observed in primary alloresponses. Next, baboons were conditioned with a nonmyeloablative regimen before short-term immunosuppression and transplantation of xenogeneic peripheral blood progenitor cells and a kidney, heart, or pancreatic islets from a miniature swine. All transplants were rejected acutely within 30 days after their placement. Posttransplantation, we observed an inhibition of the direct xenoresponse but a significant expansion of indirectly activated proinflammatory T cells. These results suggest that additional treatment to suppress indirect T cell immunity in primates may be required to achieve tolerance of pig xenografts through hematopoietic chimerism. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  2. Eomesodermin(lo) CTLA4(hi) Alloreactive CD8+ Memory T Cells Are Associated With Prolonged Renal Transplant Survival Induced by Regulatory Dendritic Cell Infusion in CTLA4 Immunoglobulin-Treated Nonhuman Primates.

    PubMed

    Ezzelarab, Mohamed B; Lu, Lien; Guo, Hao; Zahorchak, Alan F; Shufesky, William F; Cooper, David K C; Morelli, Adrian E; Thomson, Angus W

    2016-01-01

    Memory T cells (Tmem), particularly those resistant to costimulation blockade (CB), are a major barrier to transplant tolerance. The transcription factor Eomesodermin (Eomes) is critical for Tmem development and maintenance, but its expression by alloactivated T cells has not been examined in nonhuman primates. We evaluated Eomes and coinhibitory cytotoxic T lymphocyte antigen-4 (CTLA4) expression by alloactivated rhesus monkey T cells in the presence of CTLA4 immunoglobulin, both in vitro and in renal allograft recipients treated with CTLA4Ig, with or without regulatory dendritic cell (DCreg) infusion. In normal monkeys, CD8+ T cells expressed significantly more Eomes than CD4+ T cells. By contrast, CD8+ T cells displayed minimal CTLA4. Among T cell subsets, central Tmem (Tcm) expressed the highest levels of Eomes. Notably, Eomes(lo)CTLA4(hi) cells displayed higher levels of CD25 and Foxp3 than Eomes(hi)CTLA4(lo) CD8+ T cells. After allostimulation, distinct proliferating Eomes(lo)CTLA4(hi) and Eomes(hi)CTLA4(lo) CD8+ T cell populations were identified, with a high proportion of Tcm being Eomes(lo)CTLA4(hi). CB with CTLA4Ig during allostimulation of CD8+ T cells reduced CTLA4 but not Eomes expression, significantly reducing Eomes(lo)CTLA4(hi) cells. After transplantation with CB and rapamycin, donor-reactive Eomes(lo)CTLA4(hi) CD8+ T cells were reduced. However, in monkeys also given DCreg, absolute numbers of these cells were elevated significantly. Low Eomes and high CTLA4 expression by donor-reactive CD8+ Tmem is associated with prolonged renal allograft survival induced by DCreg infusion in CTLA4Ig-treated monkeys. Prolonged allograft survival associated with DCreg infusion may be related to maintenance of donor-reactive Eomes(lo)CTLA4(hi) Tcm.

  3. 1982 Resident's Essay Award: the immunologic effects of lymphoid irradiation in human and non-human primates: cellular changes and the potential for renal transplantation

    SciTech Connect

    Halperin, E.C.; Haas, G.; Dosoretz, D.E.; Gitterman, M.; Barrett, L.; Cosimi, A.B.; Suit, H.D.; Phil, D.

    1983-07-01

    Previous reports have suggested that the immunosuppressive effects of lymphoid irradiation (LI) are related to changes in T cell peripheral blood levels. We prospectively studied 13 patients with Stages I and II Hodgkin's disease before, during, and after a course of LI. Forty to 45Gy delivered to the mantle field in 4-1/2 to 5 weeks was followed by a 3 to 4 week break and 35 to 40 Gy to the paraaortic field. The absolute lymphocyte count prior to LI was 1400 +- 270/mm3. This fell to 597 +- 280/mm3 at the conclusion of LI and returned to 1490 +- 800/mm3 at 7 to 8 months post-LI. Seven previously spleenectomized cynomolgus monkeys received 20Gy of LI in 20 equal daily fractions over a 4 week period through a single anterior field including the cervical, axillary, mediastinal, paraaortic, iliac, and inguinal lymph node chains at a dose rate of 4.6 to 4.8cGy/minute. Renal allografts from unrelated monkey donors were placed following LI. Graft function was monitored by urine output, serum BUN and creatinine, and renal biopsy. Low dose rate LI was well tolerated. The absolute lymphocyte count fell from a pre-LI level of 3080 +- 1227/mm3 to 534 +- 478/mm3 at 1 month post-LI. In 4 animals that received no LI (controls), survival post-transplant was 8 to 11 days prior to death from acute rejection. Five animals received transplants immediately following LI. Four survived 11 to 56 days prior to death of presumed infection. One died at day 45 with rejection. Another group of two animals received transplants 3-1/2 weeks after LI. One died of rejection at day 42. One remains well at day 394 post-transplant.

  4. Organ Perfusion for Uterus Transplantation in Non-Human Primates With Assumed Procurement of a Uterus From a Brain-Dead Donor.

    PubMed

    Kisu, I; Kato, Y; Yamada, Y; Matsubara, K; Obara, H; Emoto, K; Adachi, M; Umene, K; Nogami, Y; Banno, K; Kitagawa, Y; Aoki, D

    2016-05-01

    Clinical studies of uterus transplantation have been performed to treat uterine factor infertility. Because the uterus is a pelvic visceral organ, the method of perfusion for the procurement of vital organs from a brain-dead donor should be modified for removal of the uterus. Herein, we report the results of a preliminary study in cynomolgus monkeys of a new perfusion method for uterus transplantation with assumed procurement of a uterus from a brain-dead donor. Cynomolgus monkeys were used; thoracolaparotomy was performed on the donor. A perfusion catheter was then placed into the unilateral femoral artery and/or external iliac artery. Cross-clamping was performed for the aorta under the diaphragm and the inferior vena cava was divided in the pleural space. The perfusion solution was then administered via the catheter to perfuse all organs in the abdominal cavity, including those in the pelvic cavity. After the perfusion, gross observation and histopathological examination of abdominal organs were conducted. Gross findings showed that all abdominal organs turned white in all specimens, indicating favorable perfusion of the uterus and all other organs in the abdomen. Pathological findings showed that almost no hemocytes were observed in the vessels of each organ. With perfusion via the femoral artery and/or external iliac artery, all organs in the abdominal cavity, including the uterus, could be perfused. It was suggested that this technique could be useful for uterus transplantation assuming the procurement of a uterus from a brain-dead donor. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. A surgical technique using the ovarian vein in non-human primate models of potential living-donor surgery of uterus transplantation.

    PubMed

    Kisu, Iori; Banno, Kouji; Mihara, Makoto; Hara, Hisako; Umene, Kiyoko; Adachi, Masataka; Nogami, Yuya; Aoki, Daisuke

    2015-09-01

    Living donor surgery in organ transplantation should be performed in a minimally invasive manner under conditions that are as safe as possible. The objective of this study is to examine whether the procedure for using the ovarian vein makes donor surgery less invasive in a cynomolgus monkey model of potential living-donor surgery of uterus transplantation. Twenty-two female cynomolgus monkeys aged 6-9 years and with body weights of 3.55 ± 1.28 kg were used in the study. Vessels and tissues surrounding the uterus were dissected while preserving the uterine artery/vein. The deep uterine vein was used as a venous pedicle in four monkeys (Group 1), and the ovarian vein was used instead of the deep uterine vein in 18 monkeys (Group 2). With the uterine artery/vein and deep uterine vein (Group 1) or ovarian vein (Group 2) connected to the uterus, the vaginal canal was cut. The vessels were then clamped to produce a donor surgery model. Surgical time, intraoperative organ and vascular injury were examined in each animal. The average surgical time from laparotomy to clamping of vessels was 230 ± 112 min in all 22 cynomolgus monkeys, and significantly longer in Group 1 (n = 4) than in Group 2 (n = 18) (393 ± 71 vs. 194 ± 84 min, p < 0.05). Surgical time in Group 2 showed a tendency to decrease in animals treated later in the study, with a significantly longer time in the first 10 monkeys compared with the last 8 (253 ± 65 vs. 120 ± 26 min, p < 0.05). All monkeys had no complications, including no injuries to other organs and no unanticipated vascular injury. The procedure using the ovarian vein was less invasive than that using the deep uterine vein in mimicking living-donor surgery in a cynomolgus monkey model of uterus transplantation. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

  6. Xenograft Model for Identifying Chemotherapeutic Agents against Papillomaviruses

    PubMed Central

    Pawellek, A.; Hewlett, G.; Kreuter, J.; Rübsamen-Waigmann, H.; Weber, O.

    2001-01-01

    The report describes the establishment and characterization of a mouse xenograft transplantation model for the study of papillomavirus infection of bovine skin. Calf scrotal skin was inoculated with bovine papillomavirus type 2 before grafting it to the dorsum of severe combined immunodeficient mice. The grafted skin contained epidermis, dermis, and a thin layer of fat. After 5 months the induced warts not only showed histological features of papillomavirus infections but also tested positive for viral DNA and papillomavirus capsid antigen. The formation of infectious virions was demonstrated by inoculation of new transplants with crude extract from the induced warts as well as in a cell culture focus assay. Topical application of bromovinyl-2′-deoxyuridine led to a reduction in viral DNA content in the developing wart. This small-animal xenograft model should be useful for characterizing antiviral compounds and providing an understanding of the regulation of papillomavirus infections. PMID:11257010

  7. Xenotransplantation of solid organs in the pig-to-primate model.

    PubMed

    Ekser, Burcin; Rigotti, Paolo; Gridelli, Bruno; Cooper, David K C

    2009-06-01

    Xenotransplantation using pig organs could solve the significant increasing shortage of donor organs for allotransplantation. In the last two decades, major progress has been made in understanding the xenoimmunobiology of pig-to-nonhuman primate transplantation, and today we are close to clinical trials. The ability to genetically engineer pigs, such as human decay-accelerating factor (hDAF), CD46 (membrane cofactor protein), or alpha1,3-galactosyltransferase gene-knockout (GT-KO), has been a significant step toward the clinical application of xenotransplantation. Using GT-KO pigs and novel immunosuppressant agents, 2 to 6 months' survival of heterotopic heart xenotransplants has been achieved. In life-supporting kidney xenotransplantation, promising survival of close to 3 months has been achieved. However, liver and lung xenotransplantations do not have such encouraging survival as kidney and heart xenotransplantation. Although the introduction of hDAF and GT-KO pigs largely overcame hyperacute rejection, acute humoral xenograft rejection (AHXR) remains a challenge to be overcome if survival is to be increased. In several studies, when classical AHXR was prevented, thrombotic microangiopathy and coagulation dysregulation became more obvious, which make them another hurdle to be overcome. The initiating cause of failure of pig cardiac and renal xenografts may be antibody-mediated injury to the endothelium, leading to the development of microvascular thrombosis. Potential contributing factors toward the development of the thrombotic microangiopathy include: 1) the presence of preformed anti-non-Gal antibodies, 2) the development of very low levels of elicited antibodies to non-Gal antigens, 3) natural killer cell or macrophage activity, and 4) inherent coagulation dysregulation between pigs and primates. The breeding of pigs transgenic for an 'anticoagulant' or 'anti-thrombotic' gene, such as human tissue factor pathway inhibitor, hirudin, or CD39, or lacking the

  8. Phenotypic and Transcriptional Fidelity of Patient-Derived Colon Cancer Xenografts in Immune-Deficient Mice

    PubMed Central

    Chou, Jeffrey; Fitzgibbon, Matthew P.; Mortales, Christie-Lynn L.; Towlerton, Andrea M. H.; Upton, Melissa P.; Yeung, Raymond S.; McIntosh, Martin W.; Warren, Edus H.

    2013-01-01

    Xenografts of human colorectal cancer (CRC) in immune-deficient mice have great potential for accelerating the study of tumor biology and therapy. We evaluated xenografts established in NOD/scid/IL2Rγ-null mice from the primary or metastatic tumors of 27 patients with CRC to estimate their capacity for expanding tumor cells for in vitro studies and to assess how faithfully they recapitulated the transcriptional profile of their parental tumors. RNA-seq analysis of parental human CRC tumors and their derivative xenografts demonstrated that reproducible transcriptional changes characterize the human tumor to murine xenograft transition. In most but not all cases, the human stroma, vasculature, and hematopoietic elements were systematically replaced by murine analogues while the carcinoma component persisted. Once established as xenografts, human CRC cells that could be propagated by serial transplantation remained transcriptionally stable. Three histologically atypical xenografts, established from patients with peritoneal metastases, contained abundant human stromal elements and blood vessels in addition to human tumor cells. The transcriptomes of these mixed tumor/stromal xenografts did not closely resemble those of their parental tumors, and attempts to propagate such xenografts by serial transplantation were unsuccessful. Stable expression of numerous genes previously identified as high priority targets for immunotherapy was observed in most xenograft lineages. Aberrant expression in CRC cells of human genes that are normally only expressed in hematopoietic cells was also observed. Our results suggest that human CRC cells expanded in murine xenografts have great utility for studies of tumor immunobiology and targeted therapies such as immunotherapy but also identify potential limitations. PMID:24278200

  9. Beware of contaminating mouse cells in human xenografts from nude mice.

    PubMed

    Yang, J; Liu, A; Dougherty, C; Chen, X; Guzman, R; Nandi, S

    2000-01-01

    Human tumor xenografts in nude mice are widely utilized model system for the transplantation of human surgical specimens and human established cell lines. Gene expression studies are often carried out in these model systems. With an increasing use of PCR based analyses, the extreme sensitivity of this technique poses a serious challenge with regards to the extent of contaminating host mouse cells in the human tumor xenografts. These xenografts are never free of host cell contamination. We detected mouse estrogen receptor expression in several human tumor xenografts using RT-PCR demonstrating that precaution is necessary when utilizing PCR based analyses in human tumor xenografts. A cytologically based methodology which distinguishes human versus mouse cells will be more suitable for ER expression studies using human xenograft models. Both (1) in situ hybridization using human probe and (2) immunocytochemistry using a monoclonal antibody directed against human cytokeratin have been used successfully to distinguish human cells versus host mouse cells in human xenografts in nude mice. Immunostaining of ER can then be utilized to determine the expression pattern of ER in the transplanted human cells.

  10. Neonatal immune-tolerance in mice does not prevent xenograft rejection

    PubMed Central

    Mattis, Virginia B.; Wakeman, Dustin R.; Tom, Colton; Dodiya, Hemraj B.; Yeung, Sylvia Y.; Tran, Andrew H.; Bernau, Ksenija; Ornelas, Loren; Sahabian, Anais; Reidling, Jack; Sareen, Dhruv; Thompson, Leslie M.; Kordower, Jeffrey H.; Svendsen, Clive N.

    2014-01-01

    Assessing the efficacy of human stem cell transplantation in rodent models is complicated by the significant immune rejection that occurs. Two recent reports have shown conflicting results using neonatal tolerance to xenografts in rats. Here we extend this approach to mice and assess whether neonatal tolerance can prevent the rapid rejection of xenografts. In three strains of neonatal immune-intact mice, using two different brain transplant regimes and three independent stem cell types, we conclusively show that there is rapid rejection of the implanted cells. We also address specific challenges associated with the generation of humanized mouse models of disease. PMID:24440640

  11. Bovine xenograft failures in pediatric foot reconstructive surgery.

    PubMed

    Ledford, Cameron K; Nunley, James A; Viens, Nicholas A; Lark, Robert K

    2013-06-01

    Structural bone grafting serves an important and necessary role during pediatric foot reconstruction. Different bone grafts have been used for such reconstructions including corticocancellous autografts, allografts, and synthetic grafts. Bovine xenografts represent a novel option with multiple potential advantages; however, there are limited clinical data on the efficacy and success of such grafts. This retrospective case series was performed to review the anecdotally recognized high failure rate of bovine xenograft transplantation in pediatric foot reconstruction at a tertiary institution. Ten pediatric patients with 13 feet underwent reconstructive procedures involving implantation of bovine xenografts for various foot deformities. The mean age at time of surgery was 14.1 years with an average clinical follow-up of 21.6 months. All patients received lateral column lengthening with additional various other reconstructive procedures performed by 3 separate orthopaedic surgeons in a similar step-wise manner. Clinical outcomes were obtained through a retrospective chart review of standard preoperative and postoperative clinical and radiographic data. Seven of 13 (53.8%) bovine xenografts implanted resulted in clinical symptoms of failure with corresponding radiographic failed graft incorporation. The most common presenting symptom was foot pain with activity and each failure was easily identified on plain radiographs by lucency surrounding the graft sites. All 7 failures required a subsequent revision surgery to remove the bovine graft followed by placement of human iliac crest allograft. After revision surgery, each patient reported subjective improvement in pain and return to daily activity with radiographic evidence of complete incorporation of the graft. Bovine xenografts used as structural grafts in pediatric foot reconstruction resulted in unacceptably high rates of failure and the need for further revision surgery. For this reason, surgeons should be cautioned

  12. Results of Gal-Knockout porcine thymokidney xenografts

    PubMed Central

    Griesemer, Adam D.; Hirakata, Atsushi; Shimizu, Akira; Moran, Shannon; Tena, Aseda; Iwaki, Hideyuki; Ishikawa, Yoshinori; Schule, Patrick; Arn, J. Scott; Robson, Simon C.; Fishman, Jay A.; Sykes, Megan; Sachs, David H.; Yamada, Kazuhiko

    2009-01-01

    Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous α1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a pre-clinical xenotransplant model. Here, we report the results of 7 xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole body irradiation in all but 1 recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early human thymopoiesis, which in turn may induce T cell tolerance to solid organ xenografts. PMID:19845583

  13. Islet transplantation: immunological perspectives.

    PubMed

    Inverardi, Luca; Kenyon, Norma S; Ricordi, Camillo

    2003-10-01

    Clinical trials of islet transplantation are showing remarkable success, but they require administration of chronic immunosuppression, and are underscoring the large gap that exists between the number of human donors available and the number of patients that could benefit from the procedure. Recent progress has been made in the definition of key immunological mechanisms that are involved in determining islet transplant outcome. Clinical and preclinical studies, and studies in small animal model systems, will all eventually contribute to the definition of efficient and safe protocols for islet transplantation. If the use of xenografts is successful, it might represent a solution to the shortage of human organs.

  14. Next generation patient-derived prostate cancer xenograft models

    PubMed Central

    Lin, Dong; Xue, Hui; Wang, Yuwei; Wu, Rebecca; Watahiki, Akira; Dong, Xin; Cheng, Hongwei; Wyatt, Alexander W; Collins, Colin C; Gout, Peter W; Wang, Yuzhuo

    2014-01-01

    There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients’ tumor tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer. PMID:24589467

  15. Human Immunodeficiency Virus Type 1 Infection of Neural Xenografts

    NASA Astrophysics Data System (ADS)

    Cvetkovich, Therese A.; Lazar, Eliot; Blumberg, Benjamin M.; Saito, Yoshihiro; Eskin, Thomas A.; Reichman, Richard; Baram, David A.; del Cerro, Coca; Gendelman, Howard E.; del Cerro, Manuel; Epstein, Leon G.

    1992-06-01

    Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. To study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11 to 17.5 weeks) human fetal brain or neural retina is transplanted to the anterior chamber of the eye of immunosuppressed adult rats. The human xenografts vascularized, formed a blood-brain barrier, and differentiated, forming neurons and glia. The xenografts were infected with cell-free HIV-1 or with HIV-1-infected human monocytes. Analysis by polymerase chain reaction revealed HIV-1 sequences in DNA from xenograft tissue exposed to HIV-1 virions, and in situ hybridization demonstrated HIV-1 mRNA localized in macrophages and multinucleated giant cells. Pathological damage was observed only in neural xenografts containing HIV-1-infected human monocytes, supporting the hypothesis that these cells mediate neurotoxicity. This small animal model allows the study of direct and indirect effects of HIV-1 infection on developing human fetal neural tissues, and it should prove useful in evaluating antiviral therapies, which must ultimately target HIV-1 infection of the brain.

  16. Xenograft survival in two species combinations using total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Bollinger, R.R.

    1987-02-01

    Total lymphoid irradiation (TLI) has profound immunosuppressive actions and has been applied successfully to allotransplantation but not xenotransplantation. Cyclosporine (CsA) has not generally permitted successful xenotransplantation of organs but has not been used in combination with TLI. TLI and CsA were given alone and in combination to rats that were recipients of hamster or rabbit cardiac xenografts. Combined TLI and CsA prolonged survival of hamster-to-rat cardiac xenografts from three days in untreated controls to greater than 100 days in most recipients. TLI alone significantly prolonged rabbit to rat xenograft survival with doubling of survival time. However, combined treatment did not significantly prolong rabbit-to-rat cardiac xenograft survival compared with TLI alone. The hamster and rat are phylogenetically closely related. Transplants from hamsters to rat are concordant xenografts since the time course of unmodified rejection is similar to first-set rejection of allografts. Although the rabbit-to-rat transplant is also between concordant species (average survival of untreated controls: 3.2 days) the rabbit and rat are more distantly related. These results suggest that TLI is an effective immunosuppressant when applied to cardiac xenotransplants in these animal models; that the choice of species critically affects xenograft survival when TLI and/or CsA are used for immunosuppression; and that the closely related species combination tested has markedly prolonged (greater than 100 days) survival using combined TLI and CsA.

  17. A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-derived Human Breast Cancer Xenograft (PDX) Models

    PubMed Central

    Zhang, Xiaomei; Claerhout, Sofie; Pratt, Aleix; Dobrolecki, Lacey E.; Petrovic, Ivana; Lai, Qing; Landis, Melissa D.; Wiechmann, Lisa; Schiff, Rachel; Giuliano, Mario; Wong, Helen; Fuqua, Suzanne W.; Contreras, Alejandro; Gutierrez, Carolina; Huang, Jian; Mao, Sufeng; Pavlick, Anne C.; Froehlich, Amber M.; Wu, Meng-Fen; Tsimelzon, Anna; Hilsenbeck, Susan G.; Chen, Edward S.; Zuloaga, Pavel; Shaw, Chad A.; Rimawi, Mothaffar F.; Perou, Charles M.; Mills, Gordon B.; Chang, Jenny C.; Lewis, Michael T.

    2013-01-01

    Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2−, one ER+PR+HER2− and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. PMID:23737486

  18. Primate photopigments and primate color vision.

    PubMed Central

    Jacobs, G H

    1996-01-01

    The past 15 years have brought much progress in our understanding of several basic features of primate color vision. There has been particular success in cataloging the spectral properties of the cone photopigments found in retinas of a number of primate species and in elucidating the relationship between cone opsin genes and their photopigment products. Direct studies of color vision show that there are several modal patterns of color vision among groupings of primates: (i) Old World monkeys, apes, and humans all enjoy trichromatic color vision, although the former two groups do not seem prone to the polymorphic variations in color vision that are characteristic of people; (ii) most species of New World monkeys are highly polymorphic, with individual animals having any of several types of dichromatic or trichromatic color vision; (iii) less is known about color vision in prosimians, but evidence suggests that at least some diurnal species have dichromatic color vision; and (iv) some nocturnal primates may lack color vision completely. In many cases the photopigments and photopigment gene arrangements underlying these patterns have been revealed and, as a result, hints are emerging about the evolution of color vision among the primates. PMID:8570598

  19. Immunohistochemical demonstration of epidermal growth factor in human gastric cancer xenografts of nude mice.

    PubMed

    Yoshiyuki, T; Shimizu, Y; Onda, M; Tokunaga, A; Kiyama, T; Nishi, K; Mizutani, T; Matsukura, N; Tanaka, N; Akimoto, M

    1990-02-15

    Thirty-two surgical specimens and three cell lines of human gastric cancers were used for subcutaneous transplantation into nude mice, resulting in the establishment of eight (25%) xenografts from the surgical specimens and two (67%) from the cell lines. The localization of epidermal growth factor (EGF) in the surgical specimens and cell lines of the gastric cancers and their xenografts in nude mice was then investigated immunohistochemically. Epidermal growth factor was stained in the cytoplasm of the cancer cells, being detected in 16 (50%) of the 32 surgical specimens and in all of the cell lines. Seven (44%) of the sixteen EGF-positive surgical specimens and one (6%) of the 16 EGF-negative ones were tumorigenic in nude mice. All of the xenografts in nude mice were positive for EGF. The tumorigenicity of human gastric cancer xenografts in nude mice may, therefore, be correlated with the presence of EGF in cancer cells.

  20. Property in Nonhuman Primates

    ERIC Educational Resources Information Center

    Brosnan, Sarah F.

    2011-01-01

    Property is rare in most nonhuman primates, most likely because their lifestyles are not conducive to it. Nonetheless, just because these species do not frequently maintain property does not mean that they lack the propensity to do so. Primates show respect for possession, as well as behaviors related to property, such as irrational decision…

  1. Property in Nonhuman Primates

    ERIC Educational Resources Information Center

    Brosnan, Sarah F.

    2011-01-01

    Property is rare in most nonhuman primates, most likely because their lifestyles are not conducive to it. Nonetheless, just because these species do not frequently maintain property does not mean that they lack the propensity to do so. Primates show respect for possession, as well as behaviors related to property, such as irrational decision…

  2. Raptors and primate evolution.

    PubMed

    McGraw, W Scott; Berger, Lee R

    2013-01-01

    Most scholars agree that avoiding predators is a central concern of lemurs, monkeys, and apes. However, given uncertainties about the frequency with which primates actually become prey, the selective importance of predation in primate evolution continues to be debated. Some argue that primates are often killed by predators, while others maintain that such events are relatively rare. Some authors have contended that predation's influence on primate sociality has been trivial; others counter that predation need not occur often to be a powerful selective force. Given the challenges of documenting events that can be ephemeral and irregular, we are unlikely ever to amass the volume of systematic, comparative data we have on such topics as feeding, social dynamics, or locomotor behavior. Nevertheless, a steady accumulation of field observations, insight gained from natural experiments, and novel taphonomic analyses have enhanced understanding of how primates interact with several predators, especially raptors, the subject of this review.

  3. Nonhuman primate models in translational regenerative medicine.

    PubMed

    Daadi, Marcel M; Barberi, Tiziano; Shi, Qiang; Lanford, Robert E

    2014-12-01

    Humans and nonhuman primates (NHPs) are similar in size, behavior, physiology, biochemistry, structure and function of organs, and complexity of the immune system. Research on NHPs generates complementary data that bridge translational research from small animal models to humans. NHP models of human disease offer unique opportunities to develop stem cell-based therapeutic interventions that directly address relevant and challenging translational aspects of cell transplantation therapy. These include the use of autologous induced pluripotent stem cell-derived cellular products, issues related to the immune response in autologous and allogeneic setting, pros and cons of delivery techniques in a clinical setting, as well as the safety and efficacy of candidate cell lines. The NHP model allows the assessment of complex physiological, biochemical, behavioral, and imaging end points, with direct relevance to human conditions. At the same time, the value of using primates in scientific research must be carefully evaluated and timed due to expense and the necessity for specialized equipment and highly trained personnel. Often it is more efficient and useful to perform initial proof-of-concept studies for new therapeutics in rodents and/or other species before the pivotal studies in NHPs that may eventually lead to first-in-human trials. In this report, we present how the Southwest National Primate Research Center, one of seven NIH-funded National Primate Research Centers, may help the global community in translating promising technologies to the clinical arena.

  4. Uterus transplantation.

    PubMed

    Brännström, Mats

    2015-12-01

    The recent first live birth after human uterus transplantation (UTx) is a proof-of-concept of UTx as a factual treatment for women with absolute uterine factor infertility. This review summarizes the 15-year-long translational UTx research project, from the beginning in rodents until the first human UTx live birth in 2014. It also gives detailed information about the 11 human UTx cases performed so far. The first live birth after UTx in any species was demonstrated already in 2003, in the syngeneic mouse model. Subsequent studies, in rats, large domestic species, and in nonhuman primates optimized the UTx procedure in regards to surgery, immunosuppression, rejection diagnosis, and pregnancy. Worldwide, only 11 human UTx attempts have been performed. The first two single cases were unsuccessful and performed with no research preparations. The following nine transplantations were completed within a clinical UTx trial in 2013. So far, four healthy babies have been born from this cohort and additional patients are pregnant. Uterus transplantation, still at its early experimental stage, has the potential to become the first true treatment for the around 1.5 million women worldwide that are infertile because of absence of the uterus or presence of a nonfunctional uterus.

  5. Primate taxonomy: species and conservation.

    PubMed

    Rylands, Anthony B; Mittermeier, Russell A

    2014-01-01

    Primatology as a discrete branch of science involving the study of primate behavior and ecology took off in the 1960s after discovery of the importance of primates as models for biomedical research and the realization that primates provide insights into the evolutionary history of humans. Osman Hill's unfortunately incomplete monograph series on the comparative anatomy and taxonomy of the primates(1) and the Napiers' 1967 A Handbook of Living Primates(2) recorded the world's view of primate diversity at this time. This taxonomy remained the baseline for nearly three decades, with the diversity of each genus being represented by some species, but extensively as subspecies. Copyright © 2014 Wiley Periodicals, Inc.

  6. Immunoreactive cytokines within primates.

    PubMed

    Ahne, W; Mayr, A; Wiesner, H

    1996-12-01

    Peripheral blood mononuclear cells of primates (man, orang utan, gorilla, baboon), rodents (mouse, rat), carnivores (cat, dog), artiodactyls (cattle, goat, pig) and perissodactyls (horse) were isolated and stimulated with mitogens (5 micrograms/ml LPS, 5 micrograms/ml PHA) at 37 degrees C. Cytokines immunoreactive to monoclonal antibodies (mAb) directed to human cytokines (TNF-alpha, IL-1 alpha, IL-2, IL-6, IFN-gamma) could be detected by enzyme-linked immunosorbent assay (ELISA) in the case of primates only. The mAb used did not recognize cytokines of the other mammalian species investigated. The results demonstrate the close relationship within the primates from the immunophysiological point of view.

  7. Establishing Prostate Cancer Patient Derived Xenografts: Lessons Learned From Older Studies

    PubMed Central

    Russell, Pamela J; Russell, Peter; Rudduck, Christina; Tse, Brian W-C; Williams, Elizabeth D; Raghavan, Derek

    2015-01-01

    46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), -5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), -22, +r4[cp8]. Conclusions Xenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model. Prostate 75: 628–636, 2015. © The Authors. The Prostate published by Wiley Periodicals, Inc. PMID:25560784

  8. Hands of early primates.

    PubMed

    Boyer, Doug M; Yapuncich, Gabriel S; Chester, Stephen G B; Bloch, Jonathan I; Godinot, Marc

    2013-12-01

    Questions surrounding the origin and early evolution of primates continue to be the subject of debate. Though anatomy of the skull and inferred dietary shifts are often the focus, detailed studies of postcrania and inferred locomotor capabilities can also provide crucial data that advance understanding of transitions in early primate evolution. In particular, the hand skeleton includes characteristics thought to reflect foraging, locomotion, and posture. Here we review what is known about the early evolution of primate hands from a comparative perspective that incorporates data from the fossil record. Additionally, we provide new comparative data and documentation of skeletal morphology for Paleogene plesiadapiforms, notharctines, cercamoniines, adapines, and omomyiforms. Finally, we discuss implications of these data for understanding locomotor transitions during the origin and early evolutionary history of primates. Known plesiadapiform species cannot be differentiated from extant primates based on either intrinsic hand proportions or hand-to-body size proportions. Nonetheless, the presence of claws and a different metacarpophalangeal [corrected] joint form in plesiadapiforms indicate different grasping mechanics. Notharctines and cercamoniines have intrinsic hand proportions with extremely elongated proximal phalanges and digit rays relative to metacarpals, resembling tarsiers and galagos. But their hand-to-body size proportions are typical of many extant primates (unlike those of tarsiers, and possibly Teilhardina, which have extremely large hands). Non-adapine adapiforms and omomyids exhibit additional carpal features suggesting more limited dorsiflexion, greater ulnar deviation, and a more habitually divergent pollex than observed plesiadapiforms. Together, features differentiating adapiforms and omomyiforms from plesiadapiforms indicate increased reliance on vertical prehensile-clinging and grasp-leaping, possibly in combination with predatory behaviors in

  9. Primate wellness exams.

    PubMed

    Weiss, Deborah; Hampshire, Victoria

    2015-09-01

    Non-human primates (NHPs) continue to serve unique animal research needs. Decades of biomedical research have focused on humane restraint and social and environmental enrichment programs necessary to support NHPs, but the housing and care of NHPs remain challenging because of the occupational safety hazards faced by employees who are tasked with the care and use of these valuable animals. Key to obtaining reliable results, providing humane care and ensuring occupational safety when working with NHPs is a sound annual wellness examination. Clinical techniques in veterinary medicine have improved in parallel with efforts to improve psychological well-being, so the timing is opportune to update clinical techniques inside the primate facility.

  10. Exogenous administration of recombinant human FSH does not improve germ cell survival in human prepubertal xenografts.

    PubMed

    Van Saen, Dorien; Goossens, Ellen; Haentjens, Patrick; Baert, Yoni; Tournaye, Herman

    2013-03-01

    In a previous study, meiotic activity was observed in human intratesticular xenografts from peripubertal patients. However, full spermatogenesis could not be established. The present study aimed to evaluate whether the administration of recombinant human FSH could improve the spermatogonial survival and the establishment of full spermatogenesis in intratesticular human xenografts. Human testicular tissue was obtained from six boys (aged 2.5-12.5years). The testicular biopsy was fragmented and one fragment of 1.5-3.0mm(3) was transplanted to the testis of immunodeficient nude mice. Transplanted mice were assigned to different experimental groups to enable evaluation of the effects of FSH administration and freezing. The structural integrity of the seminiferous tubules, the spermatogonial survival and the presence of differentiated cells were evaluated by histology and immunohistochemistry. Freezing or administration of FSH did not influence tubule integrity and germ cell survival in human xenografts. Meiotic germ cells were observed in the xenografts. More tubules containing only Sertoli cells were observed in frozen-thawed grafts, and more tubules with meiotic cells were present in fresh grafts. There was no clear influence of FSH treatment on meiotic differentiation. Administration of FSH did not improve the establishment of full spermatogenesis after intratesticular tissue grafting. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  11. Liver transplant

    MedlinePlus

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  12. Update: nonhuman primate importation.

    PubMed

    1991-10-11

    Beginning in November 1989, a number of cynomolgus monkeys (Macaca fascicularis) imported into the United States were found to have been infected with a previously unrecognized Ebola-like filovirus. This report summarizes findings of surveillance and serologic testing of nonhuman primates imported under special permits from June 1990 through September 1991.

  13. Glenohumeral mobility in primates.

    PubMed

    Chan, Lap Ki

    2007-01-01

    This study refutes the traditional idea that the glenohumeral joint of hominoids is more mobile than that of other primates, a belief that forms a basis for the two prominent theories of hominoid evolution. According to the brachiation theory, many anatomical features of the hominoid shoulder (including those of the glenohumeral joint) increase shoulder mobility and are interpreted as adaptations for brachiation. The slow climbing theory explains the same set of features as adaptations for slow climbing. The slow-climbing primates should therefore also possess these features, and their glenohumeral mobility should be the same as that of hominoids and be higher than that of other primates. This study presents three-dimensional glenohumeral mobility data, measured using a single video camera method on fresh specimens. The results show that the hominoid glenohumeral joint is actually less mobile than those of non-hominoid primates, including the habitually slow-climbing lorines, but it is characterized by a smooth excursion in the scapulocranial direction. Copyright (c) 2007 S. Karger AG, Basel.

  14. Nonhuman Primate Ocular Biometry

    PubMed Central

    Augusteyn, Robert C.; Maceo Heilman, Bianca; Ho, Arthur; Parel, Jean-Marie

    2016-01-01

    Purpose To examine ocular growth in nonhuman primates (NHPs) from measurements on ex vivo eyes. Methods We obtained NHP eyes from animals that had been killed as part of other studies or because of health-related issues. Digital calipers were used to measure the horizontal, vertical, and anteroposterior globe diameters as well as corneal horizontal and vertical diameters of excised globes from 98 hamadryas baboons, 551 cynomolgus monkeys, and 112 rhesus monkeys, at ages ranging from 23 to 360 months. Isolated lens sagittal thickness and equatorial diameter were measured by shadowphotogrammetry. Wet and fixed dry weights were obtained for lenses. Results Nonhuman primate globe growth continues throughout life, slowing toward an asymptotic maximum. The final globe size scales with negative allometry to adult body size. Corneal growth ceases at around 20 months. Lens diameter increases but thickness decreases with increasing age. Nonhuman primate lens wet and dry weight accumulation is monophasic, continuing throughout life toward asymptotic maxima. The dry/wet weight ratio reaches a maximum of 0.33. Conclusions Nonhuman primate ocular globe and lens growth differ in several respects from those in humans. Although age-related losses of lens power and accommodative amplitude are similar, lens growth and properties are different indicating care should be taken in extrapolating NHP observations to the study of human accommodation. PMID:26780314

  15. What Is a Primate?

    ERIC Educational Resources Information Center

    McGee, Elizabeth

    2003-01-01

    Describes a series of hands-on experiments that engage students in hypothesis testing and promotes active learning of the concepts of evolution and adaptation. Laboratory exercises demonstrate how features of the hands and eyes distinguish primates from other mammals. (SOE)

  16. What Is a Primate?

    ERIC Educational Resources Information Center

    McGee, Elizabeth

    2003-01-01

    Describes a series of hands-on experiments that engage students in hypothesis testing and promotes active learning of the concepts of evolution and adaptation. Laboratory exercises demonstrate how features of the hands and eyes distinguish primates from other mammals. (SOE)

  17. The perspectives for porcine-to-human xenografts.

    PubMed

    Petersen, Bjoern; Carnwath, Joseph W; Niemann, Heiner

    2009-03-01

    The shortage of donated human organs for transplantation continues to be a life threatening problem for patients suffering from complete organ failure. Although this gap is increasing due to the demographic changes in aging Western populations, it is generally accepted that international trading in human organ is not an ethical solution. Alternatives to the use of human organs for transplantation must be developed and these alternatives include stem cell therapy, artificial organs and organs from other species, i.e. xenografts. For practical reasons but most importantly because of its physiological similarity with humans, the pig is generally accepted as the species of choice for xenotransplantation. Nevertheless, before porcine organs can be used in human xenotransplantation, it is necessary to make a series of precise genetic modifications to the porcine genome, including the addition of genes for factors which suppress the rejection of transplanted porcine tissues and the inactivation or removal of undesirable genes which can only be accomplished at this time by targeted recombination and somatic nuclear transfer. This review will give an insight into the advances in transgenic manipulation and cloning in pigs--in the context of porcine-to-human xenotransplantation.

  18. Uterus transplant: evidence and ethics.

    PubMed

    Nair, Anjana; Stega, Jeanetta; Smith, J Richard; Del Priore, Giuseppe

    2008-04-01

    Absolute uterine infertility affects millions of women in the United States and more throughout the world. For instance, each year in the United States about 5,000 hysterectomies are performed in women under the age of 24. In total, nearly 9 million women of reproductive age have had a hysterectomy. Based on fecundity rates, thousands of these women may be candidates for uterus transplantation. An ongoing study enrolling some of these potential recipients onto a uterus transplant "waiting list" has revealed that most of these women have Rokitansky syndrome, hysterectomy secondary to endometriosis, cervical cancer, or compelling personal accounts justifying their candidacy. Fertility restoration by uterus transplantation was derived from fertility preservation research, including the development of the radical trachelectomy, oxygenation and perfusion of the in situ uterus, and work with organ donor networks. A decade of modern animal research set the foundation for this human work. Ongoing experiments include stable, long-term large animal allografts for investigating immunosuppression regimens and other transplantation details. Each of the animal models has contributed to the current knowledge base. Recently, nonhuman primates have been used to further investigate the possibility of human uterus transplantation. Nonhuman primate anatomy is analogous to that of humans with notable exceptions. The first human uterus transplant surgery took place in 2000, but it did not result in a pregnancy. However, taken in total, the magnitude of the intervening work from multiple groups throughout the world has made uterus transplantation a topic for discussion. It may also soon be a reality.

  19. Impending extinction crisis of the world's primates: Why primates matter.

    PubMed

    Estrada, Alejandro; Garber, Paul A; Rylands, Anthony B; Roos, Christian; Fernandez-Duque, Eduardo; Di Fiore, Anthony; Nekaris, K Anne-Isola; Nijman, Vincent; Heymann, Eckhard W; Lambert, Joanna E; Rovero, Francesco; Barelli, Claudia; Setchell, Joanna M; Gillespie, Thomas R; Mittermeier, Russell A; Arregoitia, Luis Verde; de Guinea, Miguel; Gouveia, Sidney; Dobrovolski, Ricardo; Shanee, Sam; Shanee, Noga; Boyle, Sarah A; Fuentes, Agustin; MacKinnon, Katherine C; Amato, Katherine R; Meyer, Andreas L S; Wich, Serge; Sussman, Robert W; Pan, Ruliang; Kone, Inza; Li, Baoguo

    2017-01-01

    Nonhuman primates, our closest biological relatives, play important roles in the livelihoods, cultures, and religions of many societies and offer unique insights into human evolution, biology, behavior, and the threat of emerging diseases. They are an essential component of tropical biodiversity, contributing to forest regeneration and ecosystem health. Current information shows the existence of 504 species in 79 genera distributed in the Neotropics, mainland Africa, Madagascar, and Asia. Alarmingly, ~60% of primate species are now threatened with extinction and ~75% have declining populations. This situation is the result of escalating anthropogenic pressures on primates and their habitats-mainly global and local market demands, leading to extensive habitat loss through the expansion of industrial agriculture, large-scale cattle ranching, logging, oil and gas drilling, mining, dam building, and the construction of new road networks in primate range regions. Other important drivers are increased bushmeat hunting and the illegal trade of primates as pets and primate body parts, along with emerging threats, such as climate change and anthroponotic diseases. Often, these pressures act in synergy, exacerbating primate population declines. Given that primate range regions overlap extensively with a large, and rapidly growing, human population characterized by high levels of poverty, global attention is needed immediately to reverse the looming risk of primate extinctions and to attend to local human needs in sustainable ways. Raising global scientific and public awareness of the plight of the world's primates and the costs of their loss to ecosystem health and human society is imperative.

  20. Bone marrow transplant

    MedlinePlus

    Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; ...

  1. Effects of complement suppression on xenograft survival in hyperacute rejection.

    PubMed

    Mukai, S; Orihashi, K; Sueda, T; Kajihara, H; Matsuura, Y

    1999-03-01

    To examine the significance of complement in discordant cardiac xenograft rejection, morphological changes in the rejection reaction were investigated following administration of FUT-175 (FUT), an anticomplement reagent. Guinea pigs were the cardiac donors, and Wistar rats were the recipients. Four groups of rats were constituted as follows: Group 0 was the control group. FUT of 40 mg/kg was injected intraperitoneally in group I. It was followed by continuous intravenous infusion (20 and 40 mg/kg/hr) in groups II and III. In one series, the effects of FUT on complement suppression was examined. In the FUT groups of rats (groups I to III), the serum levels of CH50 and ACH50 were measured at 0, 1, 2 and 4 hr following injection of FUT. In the second series of rats with identical treatments, the graft heart beating time following cardiac transplantation was measured. Cardiac transplantation into untreated rats was also performed as a control (group 0). In another series, the graft hearts in the FUT groups were extracted after 15, 30, 60 and 90 min of coronary reperfusion for morphological examination with scanning electron microscopy. The complement levels decreased significantly in the FUT-treated rats in a dose-dependent manner. Although the graft heart beating times in the FUT-treated groups were significantly longer than in group 0 (103, 106, and 112 min versus 14.7 min, p < 0.01), there was no significant difference in the graft heart beating time or in the morphological changes among the three FUT groups. Our results suggest the presence of factors other than complements contribute to the cardiac xenograft rejection.

  2. [Effects of baicalin on HL-60 cell xenografts in nude mice and its mechanism].

    PubMed

    Zheng, Jing; Hu, Jian-Da; Huang, Yi; Chen, Ying-Yu; Li, Jing; Chen, Bu-Yuan

    2012-10-01

    This study was aimed to investigate the effects of baicalin on HL-60 cell xenografts in nude mice in vivo and explore its mechanism. Xenograft tumor model of HL-60 cells in nude mice was established, which was divided randomly into 6 groups: negative control group (injection of 5% NaHCO(3)), 25, 50 and 100 mg/kg baicalin groups, combination group (50 mg/kg baicalin + 2 mg/kg VP16) and positive control group (VP16 4 mg/kg). The nude mice with HL-60 cell xenografts were treated with drugs via intraperitoneal injection daily. After treatment for 14 days average weigh and inhibitory rate of transplanted tumor stripped from 5 nude mice in each group were calculated, and the ultrastructure change of xenografts cells were tested by transmission electron microscopy. Histopathologic examination was used to observed the change of main organs in nude mice. The expression of signaling molecular PI3K/Akt proteins extracted from xenografts was detected by Western blot. The effects of baicalin on overall survival time in nude mice with HL-60 cell xenografts were evaluated. The results showed that baicalin could inhibit the growth of transplanted tumors in dose-dependent manner. There were more necrotic and apoptotic cells in mice of baicalin-treated groups and combination group than that in mice of negative control group. Baicalin could inhibit the proliferation of HL-60 cells in vivo by down-regulating the PI3K/Akt/mTOR signal pathway, where the expressions of p-Akt, mTOR and p-mTOR proteins decreased compared with negative control group, and no significant difference of Akt expression was found between different groups. Compared with negative control group, the median survival time of mice in combination group was more prolongated (P < 0.05). It is concluded that baicalin can inhibit growth and induce apoptosis of HL-60 cell xenografts in nude mice, and prolong median survival time of nude mice. The possible mechanisms may be related to inhibition of Akt activity and down

  3. Preventing T cell rejection of pig xenografts.

    PubMed

    Higginbotham, Laura; Ford, Mandy L; Newell, Kenneth A; Adams, Andrew B

    2015-11-01

    Xenotransplantation is a potential solution to the limited supply of donor organs. While early barriers to xenograft acceptance, such as hyperacute rejection, are now largely avoided through genetic engineering, the next frontier in successful xenograft survival will require prevention of T cell-mediated rejection. Most successful immunosuppressive regimens in xenotransplantation utilize T cell depletion with antibody therapy. Additionally, the use of T cell costimulatory blockade - specifically blockade of the CD40-CD154 pathway - shows promise with several reports of long-term xenograft survival. Additional therapies, such as transgenic expression of T cell coinhibitory molecules or transfer of immunomodulatory cells to promote tolerance, may be necessary to achieve reliable long-term xenograft acceptance. Further studies in pre-clinical models are essential in order to optimize these regimens prior to trials in patients. Copyright © 2015. Published by Elsevier Ltd.

  4. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.

    PubMed

    Bhadury, Joydeep; Einarsdottir, Berglind O; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; Dávila López, Marcela; Nilsson, Jonas A

    2016-04-26

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.

  5. Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts

    PubMed Central

    Bhadury, Joydeep; Einarsdottir, Berglind O.; Podraza, Agnieszka; Bagge, Roger Olofsson; Stierner, Ulrika; Ny, Lars; López, Marcela Dávila; Nilsson, Jonas A.

    2016-01-01

    Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors. PMID:27009863

  6. Embryonic stem cell lines of nonhuman primates.

    PubMed

    Nakatsuji, Norio; Suemori, Hirofumi

    2002-06-26

    Human embryonic stem (ES) cell lines have opened great potential and expectation for cell therapy and regenerative medicine. Monkey and human ES cell lines, which are very similar to each other, have been established from monkey blastocysts and surplus human blastocysts from fertility clinics. Nonhuman primate ES cell lines provide important research tools for basic and applicative research. Firstly, they provide wider aspects of investigation of the regulative mechanisms of stem cells and cell differentiation among primate species. Secondly, their usage does not need clearance or permission from the regulative rules in many countries that are associated with the ethical aspects of human ES cells, although human and nonhuman embryos and fetuses are very similar to each other. Lastly and most importantly, they are indispensable for animal models of cell therapy to test effectiveness, safety, and immunological reaction of the allogenic transplantation in a setting similar to the treatment of human diseases. So far, ES cell lines have been established from rhesus monkey (Macaca mulatta), common marmoset (Callithrix jacchus), and cynomolgus monkey (Macaca fascicularis), using blastocysts produced naturally or by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). These cell lines seem to have very similar characteristics. They express alkaline phosphatase activity and stage-specific embryonic antigen (SSEA)-4 and, in most cases, SSEA-3. Their pluripotency was confirmed by the formation of embryoid bodies and differentiation into various cell types in culture and also by the formation of teratomas that contained many types of differentiated tissues including derivatives of three germ layers after transplantation into the severe combined immunodeficiency (SCID) mice. The noneffectiveness of the leukemia inhibitory factor (LIF) signal makes culture of primate and human ES cell lines prone to undergo spontaneous differentiation and thus it is

  7. Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy.

    PubMed Central

    Turner, J. H.; Rose, A. H.; Glancy, R. J.; Penhale, W. J.

    1998-01-01

    Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy. Images Figure 1 Figure 2 Figure 3 PMID:9716032

  8. Meiotic activity in orthotopic xenografts derived from human postpubertal testicular tissue.

    PubMed

    Van Saen, D; Goossens, E; Bourgain, C; Ferster, A; Tournaye, H

    2011-02-01

    Grafting of frozen-thawed testicular tissue has been suggested as a novel fertility preservation method for patients undergoing gonadotoxic treatments. However, this technique still needs further optimization before any clinical application. So far, grafting of human testicular tissue has only been performed to the back skin of nude mice and has shown spermatogonial stem-cell survival and occasionally differentiation up to primary spermatocytes. In this study, orthotopic grafting to mouse testes was evaluated as an alternative, and the effect of freezing and the donor's age was studied. Human testicular tissue was obtained from two prepubertal (aged 3 and 5) and two postpubertal (aged 12 and 13) boys. Both fresh and frozen-thawed testicular tissue was grafted to the testis of immuno-deficient nude mice. Four and nine months after transplantation, testes were analyzed by histology and immunohistochemistry. Four and nine months after transplantation, spermatogonial stem cells were observed in all tissue grafts. Germ cell survival was found to be higher in xenografts from the older boys when compared with that from younger donors. Furthermore, no differentiation was observed in the xenografts from younger patients, but the grafts of two older donors showed differentiation up to the primary spermatocyte level, with the presence of secondary spermatocytes in the oldest donor 9 months after transplantation. This xenografting study shows that intratesticular grafting results in high germ cell survival. In grafts derived from the older boys, meiotic activity was maintained in the xenografts for at least 9 months. Although difficult to conduct due to the scarcity of the tissue, more comparative research is needed to elucidate an optimal grafting strategy.

  9. Heart transplantation in perspective.

    PubMed

    Keon, W J

    1999-01-01

    Heart disease remains one of the leading causes of death in the western world. In the 35 years since the first human heart transplants, cardiac transplantation has become established as the therapeutic option of choice in the management of terminal cardiac failure. Since 1981, the introduction of cyclosporin for immunosuppression has dramatically increased cardiac transplantation. However, several obstacles limit further utilization, including limited availability of donor hearts, limited ischemic time tolerated by donor hearts, and chronic rejection. Research is underway into donor heart preservation and new immunosuppressant drugs in an effort to increase donor organ availability. Due to these constraints, alternative therapies are under development. More than 2,000 circulatory assist devices have been implanted with >25% used as a bridge to heart transplantation. The University of Ottawa Heart Institute began the first Canadian implantation of circulatory assist devices in 1986 and has implanted 23 total artificial hearts and 23 ventricular assist devices. The Heart Institute is also developing a totally implantable electrohydraulic ventricular assist device (EVAD) for long-term mechanical support outside the hospital. Another alternative being evaluated for clinical use is xenotransplantation. The major obstacle for widespread use of clinical xenotransplantation remains graft rejection, and fundamental research is ongoing to address hyperacute and delayed xenograft rejection. While cardiac transplantation is the most effective treatment of terminal heart failure, limited donor hearts compel us to rely on alternatives. In the future, the research underway on xenotransplantation and mechanical circulatory assist devices will provide new options for the clinical treatment of terminal cardiac failure.

  10. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts.

    PubMed

    Valoti, G; Nicoletti, M I; Pellegrino, A; Jimeno, J; Hendriks, H; D'Incalci, M; Faircloth, G; Giavazzi, R

    1998-08-01

    The antitumor activity of ecteinascidin (ET)-743, a novel marine natural product, was evaluated against a panel of human ovarian carcinoma xenografts characterized by different malignant behaviors and drug responsiveness in nude mice. These tumor models included three xenografts transplanted s.c. (HOC18, HOC22-S, and MNB-PTX-1) into nude mice, representing different levels of sensitivity to cisplatinum (DDP), which was used as reference drug for ovarian carcinoma, and two other xenografts (HOC22 and HOC8), which are highly malignant in the peritoneal cavity of nude mice, representing the growth pattern of this neoplasm. At the maximum tolerated dose of 0.2 mg/kg using an intermittent schedule of one i.v. injection every 4 days, ET-743 was highly active against HOC22-S (sensitive to DDP), inducing long-lasting, complete regressions, and against HOC18 (marginally sensitive to DDP), inducing partial tumor regressions. Moreover, significant growth delay was observed in mice bearing late-stage HOC18 tumor (400-mg tumor weight; nonresponsive to DDP). ET-743, however, was not active against MNB-PTX-1, a tumor that is highly resistant to chemotherapy, including DDP. In the i.p. ovarian carcinoma xenograft model, ET-743 at the maximum tolerated dose induced complete tumor remissions in all mice bearing HOC22 tumor, with 25% histopathologically confirmed cures, and produced marginal tumor growth delay against HOC8. These results indicate that ET-743 is a potent drug against ovarian carcinoma xenografts, being equally as active or more efficacious than DDP in the same tumor line. Our findings with human ovarian carcinoma xenografts justify clinical assessment of this drug with this tumor target.

  11. Suppression of T cells results in long-term survival of mouse heart xenografts in C6-deficient rats.

    PubMed

    Wu, G; Korsgren, O; van Rooijen, N; Tibell, A

    2001-11-01

    The present study aimed to investigate the role of cellular immune response in the absence of membrane attack complex (MAC) formation in the concordant mouse-to-rat heart xenografting. Hearts from BALB/c mice were transplanted into the neck vessels of C6-competent (C6(+)) and C6-deficient (C6(-)) PVG rats. Liposome-encapsulated dichloro-methylene diphosphonate (Lip-Cl2MDP) was administered at a dose of 10 ml/kg 2 days before transplantation and every 5 days thereafter. Cyclosporine (CsA) was administered intramuscularly (i.m.) at a dose of 15 mg/kg per day. The heart xenografts were harvested for immuno-histological analysis at the time of rejection and the functioning grafts were removed at 70 days after transplantation. In untreated C6(+) rats, xeno-grafts survived for 2.3 +/- 0.5 days. Treatment with CsA or Lip-Cl(2)MDP in C6(+) rats did not significantly affect graft survival (2.5 +/- 0.6 and 2.3 +/- 0.4 days, respectively). In untreated C6(-) rats, xenografts survived for 5.0 +/- 0.6 days. However, Lip-Cl(2)MDP in C6(-) rats resulted in a prolongation of graft survival to 11 +/- 2.3 days (P < 0.05 vs. untreated C6(-) rats), while treatment with CsA alone in these rats led to more than 70 days' survival in four out of six grafts (61 +/- 16 days). In untreated C6(+) rats, immunohistology showed a severe myocardial necrosis and thrombosis with a scarce cellular infiltrate in the rejected xenografts. By contrast, in untreated C6(-) rats, xenografts were heavily infiltrated by macrophages and T cells. The number of macrophages, but not T cells, was markedly reduced in Lip-Cl(2)MDP-treated rats. In CsA-treated C6(-) rats, the grafts harvested at 70 days after transplantation had a normal morphology, with a minimal cellular infiltrate. Our data indicate that MAC-mediated injury plays an essential role in concordant xenograft rejection. Once this mechanism has been prevented, suppression of T cells allows for long-term xenograft survival.

  12. Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts.

    PubMed

    Hoffman, Robert M

    2015-08-01

    The majority of human solid tumours do not metastasize when grown subcutaneously in immunocompromised mice; this includes patient-derived xenograft (PDX) models. However, orthotopic implantation of intact tumour tissue can lead to metastasis that mimics that seen in patients. These patient-derived orthotopic xenograft (PDOX) models have a long history and might better recapitulate human tumours than PDX models.

  13. Update on Islet Transplantation

    PubMed Central

    McCall, Michael; James Shapiro, A.M.

    2012-01-01

    Clinical islet transplantation has progressed considerably over the past 12 years, and >750 patients with type 1 diabetes have received islet transplants internationally over this time. Many countries are beginning to accept the transition from research to accepted and funded clinical care, especially for patients with brittle control that cannot be stabilized by more conventional means. Major challenges remain, including the need for more than one donor, and the requirement for potent, chronic immunosuppression. Combining immunological tolerance both to allo- and autoantigens, and a limitless expandable source of stem cell- or xenograft-derived insulin-secreting cells represent remaining hurdles in moving this effective treatment to a potential cure for all those with type 1 or 2 diabetes. PMID:22762022

  14. Organ transplantation: a Sunni Islamic perspective.

    PubMed

    Albar, Mohammed

    2012-07-01

    This paper reviews the standpoints of Muslim jurists within the Sunni tradition on organ transplantation. Muslim jurists allowed different forms of bone grafts (autograft, allograft and xenograft) for widely broken bones. Ibn Sina in 1037 discussed this subject in Al-Kanoon 1000 years ago. In 1959, the Muftis of Egypt and Tunisia allowed, under specific conditions, corneal transplants from dead persons. Thereafter, many fatwas (jurisprudence) on organ trans-plantation have been issued from different parts of the Muslim world. In Amman, Jordan, the International Islamic Jurist Council recognized brain-death as a recognized sign of death in Islam in October 1986. This paved the way for organ transplantation from brain-dead persons, which started immediately in Saudi Arabia. In 1990 and 2003, the International Islamic Fiqh Academy (IIFA) and the Islamic Fiqh Academy (IFA) issued important fatwas on organ transplantation. By the end of 2008, more than 3600 organs were transplanted from brain-dead persons in Saudi Arabia.

  15. Uterus transplantation and beyond.

    PubMed

    Brännström, Mats

    2017-05-01

    Uterus transplantation is today the only available treatment for absolute uterine factor infertility which is caused by either congenital/surgical uterine absence or that a present uterus is non-functioning. Structured animal-based research, from rodents to nonhuman primates, was the scientific basis for a successful introduction of uterus transplantation as a clinical procedure. The patient groups for uterus transplantation, the preclinical research and data from the published human cases will be covered herein. During recent years the concept of bioengineering of organs and tissues has emerged. Creation of a bioengineered uterus is in the initial research state, with experiments performed in rodents. The research that has been performed to create a bioengineered uterus will be summarized. In conclusion, uterus transplantation is now a clinical experimental procedure for treatment of uterine factor infertility. In parallel to the establishment of this combined assisted reproduction technique and transplantation procedure as a routine clinical procedure, we predict that uterus bioengineering will develop further towards introduction within the human setting, but that this process will take several years.

  16. Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

    PubMed Central

    Poglio, Sandrine; Lewandowski, Daniel; Calvo, Julien; Caye, Aurélie; Gros, Audrey; Laharanne, Elodie; Leblanc, Thierry; Landman-Parker, Judith; Baruchel, André; Soulier, Jean; Ballerini, Paola; Clappier, Emmanuelle; Pflumio, Françoise

    2016-01-01

    T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7+/CD34+ leukemic cell transplantations. Here we investigated the genetic characteristics of CD7+/CD34+ and CD7+/CD34− cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7+/CD34+ or CD7+/CD34− T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7+/CD34+ or CD7+/CD34− cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments. PMID:27191650

  17. Bone marrow transplant - discharge

    MedlinePlus

    Transplant - bone marrow - discharge; Stem cell transplant - discharge; Hematopoietic stem cell transplant - discharge; Reduced intensity; Non-myeloablative transplant - discharge; Mini transplant - discharge; Allogenic bone marrow transplant - ...

  18. Visual influences on primate encephalization.

    PubMed

    Kirk, E Christopher

    2006-07-01

    Primates differ from most other mammals in having relatively large brains. As a result, numerous comparative studies have attempted to identify the selective variables influencing primate encephalization. However, none have examined the effect of the total amount of visual input on relative brain size. According to Jerison's principle of proper mass, functional areas of the brain devoted primarily to processing visual information should exhibit increases in size when the amount of visual input to those areas increases. As a result, the total amount of visual input to the brain could exert a large influence on encephalization because visual areas comprise a large proportion of total brain mass in primates. The goal of this analysis is to test the expectation of a direct relationship between visual input and encephalization using optic foramen size and optic nerve size as proxies for total visual input. Data were collected for a large comparative sample of primates and carnivorans, and three primary analyses were undertaken. First, the relationship between relative proxies for visual input and relative endocranial volume were examined using partial correlations and phylogenetic comparative methods. Second, to examine the generality of the results derived for extant primates, a parallel series of partial correlation and comparative analyses were undertaken using data for carnivorans. Third, data for various Eocene and Oligocene primates were compared with those for living primates in order to determine whether the fossil taxa demonstrate a similar relationship between relative brain size and visual input. All three analyses confirm the expectations of proper mass and favor the conclusion that the amount of visual input has been a major influence on the evolution of relative brain size in both primates and carnivorans. Furthermore, this study suggests that differences in visual input may partly explain (1) the high encephalization of primates relative to the primitive

  19. Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection

    PubMed Central

    Byrne, Guerard W; Azimzadeh, Agnes M; Ezzelarab, Mohamed; Tazelaar, Henry D; Ekser, Burcin; Pierson, Richard N; Robson, Simon C; Cooper, David K C; McGregor, Christopher G A

    2013-01-01

    The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics. These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation. This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection. PMID:25098626

  20. Determining epithelial contribution to in vivo mesenchymal tumour expression signature using species-specific microarray profiling analysis of xenografts.

    PubMed

    Purdom, E; Restall, C; Busuttil, R A; Schluter, H; Boussioutas, A; Thompson, E W; Anderson, R L; Speed, T P; Haviv, I

    2013-02-01

    Gene expression profiling using microarrays and xenograft transplants of human cancer cell lines are both popular tools to investigate human cancer. However, the undefined degree of cross hybridization between the mouse and human genomes hinders the use of microarrays to characterize gene expression of both the host and the cancer cell within the xenograft. Since an increasingly recognized aspect of cancer is the host response (or cancer-stroma interaction), we describe here a bioinformatic manipulation of the Affymetrix profiling that allows interrogation of the gene expression of both the mouse host and the human tumour. Evidence of microenvironmental regulation of epithelial mesenchymal transition of the tumour component in vivo is resolved against a background of mesenchymal gene expression. This tool could allow deeper insight to the mechanism of action of anti-cancer drugs, as typically novel drug efficacy is being tested in xenograft systems.

  1. Modeling of Chronic Myeloid Leukemia: An Overview of In Vivo Murine and Human Xenograft Models

    PubMed Central

    Vellenga, Edo

    2016-01-01

    Over the past years, a wide variety of in vivo mouse models have been generated in order to unravel the molecular pathology of Chronic Myeloid Leukemia (CML) and to develop and improve therapeutic approaches. These models range from (conditional) transgenic models, knock-in models, and murine bone marrow retroviral transduction models followed by transplantation. With the advancement of immunodeficient xenograft models, it has become possible to use human stem/progenitor cells for in vivo studies as well as cells directly derived from CML patients. These models not only mimic CML but also have been instrumental in uncovering various fundamental mechanisms of CML disease progression and tyrosine kinase inhibitor (TKI) resistance. With the availability of iPSC technology, it has become feasible to derive, maintain, and expand CML subclones that are at least genetically identical to those in patients. The following review provides an overview of all murine as well as human xenograft models for CML established till date. PMID:27642303

  2. [Potential role of patient-derived tumor xenografts (PDTXs) in the selection of optimal therapeutic strategy].

    PubMed

    Tóvári, József

    2015-12-01

    The rapid selection of the efficient anticancer therapy may decrease the unwanted burden to patients and has financial consequences. Tumor models including xenografts in mice were used previously mostly in the development of new anticancer drugs. Nowadays xenografts from direct patient-derived tumor tissues (PDTT) in immune deficient mice yield better models than experimental tumors originating from cell cultures. The new method enables researchers to observe heterogeneous tumor cells with their surrounding tissue elements and matrices representing the clinical situation in humans much better. The cells in PDTT tumors are alive and functionally active through several generations after serial transplantation. Therefore using these models we may investigate tumor response to different therapies, the selection of resistant cell populations and the formation of metastasis predicting the outcomes in the personalized therapy.

  3. Ethics of primate use

    NASA Astrophysics Data System (ADS)

    Prescott, M. J.

    2010-11-01

    This article provides an overview of the ethical issues raised by the use of non-human primates (NHPs) in research involving scientific procedures which may cause pain, suffering, distress or lasting harm. It is not an exhaustive review of the literature and views on this subject, and it does not present any conclusions about the moral acceptability or otherwise of NHP research. Rather the aim has been to identify the ethical issues involved and to provide guidance on how these might be addressed, in particular by carefully examining the scientific rationale for NHP use, implementing fully the 3Rs principle of Russell and Burch (1959) and applying a robust "harm-benefit assessment" to research proposals involving NHPs.

  4. Brains, Genes and Primates

    PubMed Central

    Belmonte, Juan Carlos Izpisua; Callaway, Edward M.; Churchland, Patricia; Caddick, Sarah J.; Feng, Guoping; Homanics, Gregg E.; Lee, Kuo-Fen; Leopold, David A.; Miller, Cory T.; Mitchell, Jude F.; Mitalipov, Shoukhrat; Moutri, Alysson R.; Movshon, J. Anthony; Okano, Hideyuki; Reynolds, John H.; Ringach, Dario; Sejnowski, Terrence J.; Silva, Afonso C.; Strick, Peter L.; Wu, Jun; Zhang, Feng

    2015-01-01

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. PMID:25950631

  5. Brains, genes, and primates.

    PubMed

    Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J; Churchland, Patricia; Feng, Guoping; Homanics, Gregg E; Lee, Kuo-Fen; Leopold, David A; Miller, Cory T; Mitchell, Jude F; Mitalipov, Shoukhrat; Moutri, Alysson R; Movshon, J Anthony; Okano, Hideyuki; Reynolds, John H; Ringach, Dario; Sejnowski, Terrence J; Silva, Afonso C; Strick, Peter L; Wu, Jun; Zhang, Feng

    2015-05-06

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. History of Clinical Transplantation

    PubMed Central

    Starzl, Thomas E.

    2010-01-01

    The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations in surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipients had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts. PMID:10833242

  7. Serum immune response of pearl oyster Pinctada fucata to xenografts and allografts.

    PubMed

    Wei, Jinfen; Liu, Baosuo; Fan, Sigang; Zhang, Bo; Su, Jiaqi; Yu, Dahui

    2017-03-01

    The mantle piece from the donor pearl oyster would be rejected by the immune system of recipient oyster in pearl culture practice, especially in the case that the donor and receptor are different species. Thus, investigation of the immune response of recipient oyster to grafted mantle pieces, particularly to xenografts, is of importance in creating xenograft transplantation technology for pearl culture industry. The humoral immune responses of P. fucata to allograft (mantle piece of P. fucata) and xenografts (mantle pieces of P. maxima and P. margaritifera, respectively) were studied in this paper. The oysters receiving no transplantations were served as the control group. The serum was collected from recipient P. fucata at 1 d, 2 d, 3 d, 4 d, 5 d, 7 d, 9 d, 11 d, 13 d, and 15 d, respectively after transplantation, and the serum antibacterial activity, lysozyme activity (LZM), alkaline phosphatase (AKP), acid phosphatase (ACP), total antioxidant capacity (TAC), and agglutination to rabbit red blood cells were investigated. The result indicated that serum of both the experimental groups and the control group can agglutinate rabbit red blood cells, with variation between groups and between time points, respectively. The antibacterial activity in the experimental group was significantly higher than that in the control group at 2-4 d, but lower at 5-11 d and returned back to normal at 15 d, with significant differences among experimental groups (P < 0.05). The LZM in the experimental group was significantly higher than that in the control group at 3-7 d, with significant differences in bacteriolytic activity among various groups (P < 0.05). Both the ACP and AKP activity levels in the experimental groups were higher than those in the control group at 2-9 d, with significant differences among various groups at 3-9 d (P < 0.05). The TAC level in the experimental groups was higher than that in the control group at 1-7 d, with significant

  8. Kidney Transplant

    MedlinePlus

    Kidney transplant Overview By Mayo Clinic Staff A kidney transplant is a surgical procedure to place a healthy kidney ... bloodstream via a machine (dialysis) or a kidney transplant to stay alive. Mayo Clinic's approach . Mayo Clinic ...

  9. Lung Transplant

    MedlinePlus

    Lung transplant Overview By Mayo Clinic Staff A lung transplant is a surgical procedure to replace a diseased or ... lung, usually from a deceased donor. A lung transplant is reserved for people who have tried other ...

  10. Kidney transplant

    MedlinePlus

    Renal transplant; Transplant - kidney ... Barry JM, Conlin MJ. In: Renal transplantation. Wein AJ, ed. Campbell-Walsh Urology . 10th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 44. Kidney Disease: Improving Global Outcomes ( ...

  11. Decomplementation with cobra venom factor prolongs survival of xenografted islets in a rat to mouse model

    PubMed Central

    OBERHOLZER, J; YU, D; TRIPONEZ, F; CRETIN, N; ANDEREGGEN, E; MENTHA, G; WHITE, D; BUEHLER, L; MOREL, P; LOU, J

    1999-01-01

    Although the involvement of complement in hyperacute rejection of xenotransplants is well recognized, its role in rejection of devascularized xenografts, such as pancreatic islets, is not completely understood. In this study, we investigated whether complement participates in the immunopathology of xeno-islet transplantation in a concordant rat to mouse model. Rat pancreatic islets were implanted under the kidney capsule of normal and cobra venom factor (CVF)-decomplementized diabetic C57BL/6 mice. Graft survival was monitored by blood glucose levels. Deposition of IgM and C3 on grafted islets in vivo or on isolated islets in vitro (after incubation with normal and decomplementized mouse serum), as well as CD4- and CD8-positive leucocyte infiltration of grafts, was checked by immunohistochemistry. In addition, complement-mediated cytotoxicity on rat islet cells was evaluated by a 3-(4,5-dimethythiazolyl)-2.5-diphenyl-2H-tetrazolium-bromide (MTT) assay. A significant C3 deposition was found on grafted islets from the first day after transplantation in vivo, as well as on isolated islets after incubation with mouse serum in vitro. By MTT assay, complement-mediated cytotoxicity for islet cells was found. Decomplementation by CVF decreased C3 deposition on either isolated or grafted islets, delayed CD4- and CD8-positive leucocyte infiltration, led to significant inhibition of complement-mediated cytotoxicity for islet cells, and prolonged graft survival (mean survival time 21·3 versus 8·5 days; P <0·01). Our results indicate that decomplementation can prolong the survival time of devascularized xenografts across concordant species. The deposition of complement on transplanted islets may contribute to xenograft rejection by direct cytotoxicity and by promoting leucocyte infiltration. PMID:10447729

  12. Captivity humanizes the primate microbiome

    PubMed Central

    Vangay, Pajau; Huang, Hu; Ward, Tonya; Hillmann, Benjamin M.; Al-Ghalith, Gabriel A.; Travis, Dominic A.; Long, Ha Thang; Tuan, Bui Van; Minh, Vo Van; Cabana, Francis; Nadler, Tilo; Toddes, Barbara; Murphy, Tami; Glander, Kenneth E.; Johnson, Timothy J.; Knights, Dan

    2016-01-01

    The primate gastrointestinal tract is home to trillions of bacteria, whose composition is associated with numerous metabolic, autoimmune, and infectious human diseases. Although there is increasing evidence that modern and Westernized societies are associated with dramatic loss of natural human gut microbiome diversity, the causes and consequences of such loss are challenging to study. Here we use nonhuman primates (NHPs) as a model system for studying the effects of emigration and lifestyle disruption on the human gut microbiome. Using 16S rRNA gene sequencing in two model NHP species, we show that although different primate species have distinctive signature microbiota in the wild, in captivity they lose their native microbes and become colonized with Prevotella and Bacteroides, the dominant genera in the modern human gut microbiome. We confirm that captive individuals from eight other NHP species in a different zoo show the same pattern of convergence, and that semicaptive primates housed in a sanctuary represent an intermediate microbiome state between wild and captive. Using deep shotgun sequencing, chemical dietary analysis, and chloroplast relative abundance, we show that decreasing dietary fiber and plant content are associated with the captive primate microbiome. Finally, in a meta-analysis including published human data, we show that captivity has a parallel effect on the NHP gut microbiome to that of Westernization in humans. These results demonstrate that captivity and lifestyle disruption cause primates to lose native microbiota and converge along an axis toward the modern human microbiome. PMID:27573830

  13. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates

    PubMed Central

    Blin, Guillaume; Nury, David; Stefanovic, Sonia; Neri, Tui; Guillevic, Oriane; Brinon, Benjamin; Bellamy, Valérie; Rücker-Martin, Catherine; Barbry, Pascal; Bel, Alain; Bruneval, Patrick; Cowan, Chad; Pouly, Julia; Mitalipov, Shoukhrat; Gouadon, Elodie; Binder, Patrice; Hagège, Albert; Desnos, Michel; Renaud, Jean-François; Menasché, Philippe; Pucéat, Michel

    2010-01-01

    Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has had only marginal positive benefits in clinical trials, perhaps because adult stem cells have limited plasticity. The identification, among human pluripotent stem cells, of early cardiovascular cell progenitors required for the development of the first cardiac lineage would shed light on human cardiogenesis and might pave the way for cell therapy for cardiac degenerative diseases. Here, we report the isolation of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (SSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. This progenitor population was multipotential and able to generate cardiomyocytes as well as smooth muscle and endothelial cells. When transplanted into the infarcted myocardium of immunosuppressed nonhuman primates, an SSEA-1+ progenitor population derived from Rhesus embryonic stem cells differentiated into ventricular myocytes and reconstituted 20% of the scar tissue. Notably, primates transplanted with an unpurified population of cardiac-committed cells, which included SSEA-1– cells, developed teratomas in the scar tissue, whereas those transplanted with purified SSEA-1+ cells did not. We therefore believe that the SSEA-1+ progenitors that we have described here have the potential to be used in cardiac regenerative medicine. PMID:20335662

  14. T Cell-Mediated Rejection of Human CD34(+) Cells Is Prevented by Costimulatory Blockade in a Xenograft Model.

    PubMed

    Oh, Annie L; Mahmud, Dolores; Nicolini, Benedetta; Mahmud, Nadim; Senyuk, Vitalyi; Patel, Pritesh R; Bonetti, Elisa; Arpinati, Mario; Ferrara, James L M; Rondelli, Damiano

    2017-08-14

    A xenograft model of stem cell rejection was developed by co-transplantating human CD34(+) and allogeneic CD3(+) T cells into NOD-scid ɣ-chain(null) mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34(+) cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34(+) cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day -1 to +27 (group A), from day -1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34(+) cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34(+) cells may be facilitated by treatment with abatacept and late stem cell boost. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  15. Breast cancer in intraductal carcinogen-treated non-human primates.

    PubMed

    Lillie, Madeline A; Ambrus, Clara M; Pickren, John W; Akhter, Selina; Islam, Abul; Ambrus, Julian L

    2004-01-01

    Eight female Macaca arctoides monkeys were given dimethylbenzanthracene (DMBA) directly into the milk ducts. During a 4-year observation period, ending with euthanasia and autopsy, no mammary cancers were noticed. However, one animal developed a superficial localized squamous cell carcinoma. DMBA is highly carcinogenic in rodents, e.g. producing a high incidence of breast cancer in C3H mice. It was concluded that carcinogenicity testing should be extended beyond testing in rodents to non-human primates in order to distinguish "primary rodent carcinogens" from those highly active in primates as well. Studies are in progress to study carcinogens in human cell lines transplanted into nu/nu mice.

  16. Novel enhanced green fluorescent protein-expressing NOG mouse for analyzing the microenvironment of xenograft tissues.

    PubMed

    Higuchi, Yuichiro; Kawai, Kenji; Yamamoto, Masafumi; Kuronuma, Miyuki; Ando, Yasuhiko; Katano, Ikumi; Nakamura, Masato; Suemizu, Hiroshi

    2014-01-01

    The interaction between transplanted cells and host tissues is important for the growth and maintenance of transplanted cells. To analyze the mechanisms of these interactions, a systemic fluorescent protein-expressing mouse is a useful recipient. In this study, we generated a novel NOG strain, which strongly expresses enhanced green fluorescent protein (EGFP; PgkEGFP-NOG), especially in the liver, kidney, gastrointestinal tract, and testis. Because the host tissues expressed EGFP, xenotransplanted human cancer cells were clearly identified as EGFP-negative colonies in PgkEGFP-NOG mice. Immunohistochemical analysis revealed that EGFP-expressing stromal tissues formed a complicated tumor microenvironment within xenograft tissues. Moreover, a similar microenvironment was observed in human iPS cell-derived teratomas. Collectively, these results indicated that a suitable microenvironment is essential for the growth and maintenance of xenotransplanted cells and that PgkEGFP-NOG mice represent a useful animal model for analyzing the mechanisms of microenvironment formation.

  17. Establishment of a human B-CLL xenograft model: utility as a preclinical therapeutic model.

    PubMed

    Mohammad, R M; Mohamed, A N; Hamdan, M Y; Vo, T; Chen, B; Katato, K; Abubakr, Y A; Dugan, M C; al-Katib, A

    1996-01-01

    Chronic lymphocytic leukemia (CLL), a proliferative disease of mature looking B lymphocytes, is the commonest leukemia in western countries. It remains incurable by available treatment modalities. We report on the establishment of a permanent, EBV-negative, B-CLL line (WSU-CLL) from the peripheral blood of a patient with CLL. The cells grow as suspension in liquid culture, express IgG lambda and other B cell markers and show lg heavy and light gene rearrangements. Karyotypic analysis shows 45,X,del(3)(p14;p24),t(4;12;12) (q31;q22;p13), t(5;12) (q31;p13), add(16)(q24)X2, t(18;21) (q12;p12). WSU-CLL forms colonies when grown on soft agar. A xenograft model was established by injecting the WSU-CLL cells subcutaneously (s.c.) in severe combined immune deficient (SCID) mice. When the s.c. tumor was transplanted in vivo to other SCID mice, the success rate was 100% with a doubling time of 7.3 days. The CLL-SCID xenograft model was used to test the efficacy of selected standard chemotherapy drugs and new therapeutic agents against WSU-CLL. The cell line and the xenograft described can be used as a model to facilitate the development of new therapeutic agents against CLL in man.

  18. Human skeletal muscle xenograft as a new preclinical model for muscle disorders

    PubMed Central

    Zhang, Yuanfan; King, Oliver D.; Rahimov, Fedik; Jones, Takako I.; Ward, Christopher W.; Kerr, Jaclyn P.; Liu, Naili; Emerson, Charles P.; Kunkel, Louis M.; Partridge, Terence A.; Wagner, Kathryn R.

    2014-01-01

    Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metabolic fidelity of the normal tissue in vivo. Herein, we demonstrate the feasibility and validity of human to mouse xenografts as a preclinical model of myopathy. Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1null IL2rγnull immunodeficient host mice regenerate new vascularized and innervated myofibers from human myogenic precursor cells. The grafts exhibit contractile and calcium release behavior, characteristic of functional muscle tissue. The validity of the human graft as a model of facioscapulohumeral muscular dystrophy is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the fresh donor biopsies. These findings illustrate the value of a new experimental model of muscle disease, the human muscle xenograft in mice, as a feasible and valid preclinical tool to better investigate the pathogenesis of human genetic myopathies and to more accurately predict their response to novel therapeutics. PMID:24452336

  19. A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-κB signaling in chordoma biology.

    PubMed

    Trucco, Matteo M; Awad, Ola; Wilky, Breelyn A; Goldstein, Seth D; Huang, Ruili; Walker, Robert L; Shah, Preeti; Katuri, Varalakshmi; Gul, Naheed; Zhu, Yuelin J; McCarthy, Edward F; Paz-Priel, Ido; Meltzer, Paul S; Austin, Christopher P; Xia, Menghang; Loeb, David M

    2013-01-01

    Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.

  20. The malignant primate?

    PubMed

    de Grouchy, J

    1991-01-01

    Speciation and carcinogenesis result from genomic instability at the gametic or at the somatic levels. After an infinity of trials they occur, by chromosome rearrangements, in single individuals or in single cells and evolve by similar chromosomal or clonal evolutions. Loss of heterozygosity for the first event is essential in both processes: in evolution, a chromosomal rearrangement, a pericentric inversion or a Robertsonian fusion, must become homozygous to ensure a reproductive barrier for a new species; Knudson's two-event sequence is a similar situation in cancer. Position effect is equally important: we have shown overexpression of the SOD1 gene in the orangutan phylum probably by an intrachromosomal rearrangement; the t(9;22) in CML acts by typical position effect. Parental imprinting underlies the evolution of genome function and the unset of certain cancers. Evolution and malignancy are interweaved by viruses and oncogenes since the dawn of life. Cancer uses its intelligence to expand and to destroy the other tissues, using subtle metabolic pathways and a variety of tricks to metastasize other cells. It always wins but saws the branch on which it sits. Mankind also grows exponentially, killing thousands of other species, poisoning the oceans and soft waters, polluting the atmosphere, all for his egoistic needs. Man also travels and metastasizes other Earths. He modifies his genome or that of other species, and develops new technologies for his reproduction. He can destroy the planet in an eyeblink. To be or not to be the malignant primate, that will be the dilemma for the 21st Century.

  1. Hand transplantation.

    PubMed

    Amer, Hatem; Carlsen, Brian T; Dusso, Jennifer L; Edwards, Brooks S; Moran, Steven L

    2011-05-01

    The first successful hand transplant was performed in 1998, opening up a new possibility for patients who have suffered mutilating hand injuries. Since then, more than 60 such procedures have been performed throughout the world. This article describes the evolution of hand transplantation, outcomes of patients listed in the International Registry of Hand and Composite Tissue Transplantation, and ethical issues involved in hand transplantation. It also describes the hand transplantation program at Mayo Clinic, which was established in 2010.

  2. A Molecular Phylogeny of Living Primates

    PubMed Central

    Perelman, Polina; Johnson, Warren E.; Roos, Christian; Seuánez, Hector N.; Horvath, Julie E.; Moreira, Miguel A. M.; Kessing, Bailey; Pontius, Joan; Roelke, Melody; Rumpler, Yves; Schneider, Maria Paula C.; Silva, Artur; O'Brien, Stephen J.; Pecon-Slattery, Jill

    2011-01-01

    Comparative genomic analyses of primates offer considerable potential to define and understand the processes that mold, shape, and transform the human genome. However, primate taxonomy is both complex and controversial, with marginal unifying consensus of the evolutionary hierarchy of extant primate species. Here we provide new genomic sequence (∼8 Mb) from 186 primates representing 61 (∼90%) of the described genera, and we include outgroup species from Dermoptera, Scandentia, and Lagomorpha. The resultant phylogeny is exceptionally robust and illuminates events in primate evolution from ancient to recent, clarifying numerous taxonomic controversies and providing new data on human evolution. Ongoing speciation, reticulate evolution, ancient relic lineages, unequal rates of evolution, and disparate distributions of insertions/deletions among the reconstructed primate lineages are uncovered. Our resolution of the primate phylogeny provides an essential evolutionary framework with far-reaching applications including: human selection and adaptation, global emergence of zoonotic diseases, mammalian comparative genomics, primate taxonomy, and conservation of endangered species. PMID:21436896

  3. Effects of gene transfer CTLA4Ig and anti-CD40L monoclonal antibody on islet xenograft rejection in mice.

    PubMed

    Zhang, J; Li, H; Jiang, N; Zhang, Q; Wang, G-S; Yi, H-M; Fu, B-S; Wang, G-Y; Yang, Y; Chen, G-H

    2010-06-01

    Blockade of a costimulatory pathway by adenovirus-mediated cytotoxic T lymphocyte associated antigen 4 immunoglobulin (CTLA4-Ig) gene transfer and anti-CD40L mAb(MR1) have been reported to enhance graft survival in several experimental transplantation models. In this study, we investigated the effects of gene transfer of CTLA4Ig and MR1 on islet xenograft rejection in mice. Recombinant adenovirus AdCTLA4Ig was constructed to express CTLA4Ig. Islet grafts from adult male DA rats transferred with AdCTLA4Ig were transplanted to streptozocin-induced diabetic Balb/c mice. The diabetic mice were treated with MR1 after transplantation. We evaluated the islet xenograft mean survival time as well as changes in interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) levels in transplanted mice. The mean survival of islet xenografts in the MR1 treatment group was 34.9 +/- 5.62 days, in the AdCTLA4Ig treatment group it was 56.5 +/- 10.64 days, and in the AdCTLA4Ig plus MR1 treatment group it was 112.9 +/- 19.26 days, all significantly prolonged compared with an untreated group (8.1 +/- 0.83 days). Within 1 week after transplantation the levels of IL-2 and TNF-alpha showed sharp increases in the untreated group, being significantly higher than those observed prior to transplantation. In conclusion, using both AdCTLA4Ig and MR1 can improve the islet xenograft survival. The beneficial effects of the combined use of the 2 reagents were superior to either 1 alone, possibly related to down-regulated expression of Th1 cell-related cytokines.

  4. 42 CFR 71.53 - Nonhuman primates.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Nonhuman primates. 71.53 Section 71.53 Public... FOREIGN QUARANTINE Importations § 71.53 Nonhuman primates. (a) Definitions. As used in this section the... nonhuman primates from a foreign country within a period of 31 days, beginning with the importation date...

  5. 42 CFR 71.53 - Nonhuman primates.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Nonhuman primates. 71.53 Section 71.53 Public... FOREIGN QUARANTINE Importations § 71.53 Nonhuman primates. (a) Definitions. As used in this section the... nonhuman primates from a foreign country within a period of 31 days, beginning with the importation date...

  6. 42 CFR 71.53 - Nonhuman primates.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Nonhuman primates. 71.53 Section 71.53 Public... FOREIGN QUARANTINE Importations § 71.53 Nonhuman primates. (a) Definitions. As used in this section the... nonhuman primates from a foreign country within a period of 31 days, beginning with the importation date...

  7. Orthotopic xenografts of RCC retain histological, immunophenotypic and genetic features of tumors in patients

    PubMed Central

    Grisanzio, Chiara; Seeley, Apryle; Chang, Michelle; Collins, Michael; Di Napoli, Arianna; Cheng, Su-Chun; Percy, Andrew; Beroukhim, Rameen; Signoretti, Sabina

    2013-01-01

    Renal cell carcinoma (RCC) is an aggressive malignancy with limited responsiveness to existing treatments. In vivo models of human cancer, including RCC, are critical for developing more effective therapies. Unfortunately, current RCC models do not accurately represent relevant properties of the human disease. The goal of this study was to develop clinically relevant animal models of RCC for preclinical investigations. We transplanted intact human tumor tissue fragments orthotopically in immunodeficient mice. The xenografts were validated by comparing the morphologic, phenotypic, and genetic characteristics of the kidney tumor tissues before and after implantation. Twenty kidney tumors were transplanted into mice. Successful tumor growth was detected in 19 cases (95%). The histopathologic and immunophenotypic features of the xenografts and those of the original tumors largely overlapped in all the cases. Evaluation of genetic alterations in a subset of 10 cases demonstrated that the grafts largely retained the genetic features of the pre-implantation RCC tissues. Indeed, primary tumors and corresponding grafts displayed identical VHL mutations. Moreover, an identical pattern of DNA copy amplification or loss was observed in 6 of 10 cases (60%). In summary, orthotopic engrafting of RCC tissue fragments can be successfully used to generate animal models that closely resemble RCC in patients. These models will be invaluable for in vivo preclinical drug testing, and for deeper understanding of kidney carcinogenesis. PMID:21710693

  8. pO{sub 2} Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts

    SciTech Connect

    Ellingsen, Christine; Ovrebo, Kirsti Marie; Galappathi, Kanthi; Mathiesen, Berit; Rofstad, Einar K.

    2012-07-15

    Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (pO{sub 2}) and tissue regions showing cycling hypoxia. In this study, we investigated whether the pO{sub 2} fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels. Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue pO{sub 2} was measured simultaneously in two positions in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia. Results: The proportion of tumor regions showing pO{sub 2} fluctuations, the pO{sub 2} fluctuation frequency in these regions, and the relative amplitude of the pO{sub 2} fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts. Conclusions: Temporal heterogeneity in blood flow and tissue pO{sub 2} in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and pO{sub 2} and, thus, protect tumor tissue from cycling hypoxia.

  9. Cooperation and deception in primates.

    PubMed

    Hall, Katie; Brosnan, Sarah F

    2017-08-01

    Though competition and cooperation are often considered opposing forces in an arms race driving natural selection, many animals, including humans, cooperate in order to mitigate competition with others. Understanding others' psychological states, such as seeing and knowing, others' goals and intentions, and coordinating actions are all important for complex cooperation-as well as for predicting behavior in order to take advantage of others through tactical deception, a form of competition. We outline evidence of primates' understanding of how others perceive the world, and then consider how the evidence from both deception and cooperation fits this framework to give us a more complete understanding of the evolution of complex social cognition in primates. In experimental food competitions, primates flexibly manipulate group-mates' behavior to tactically deceive them. Deception can infiltrate cooperative interactions, such as when one takes an unfair share of meat after a coordinated hunt. In order to counter competition of this sort, primates maintain cooperation through partner choice, partner control, and third party punishment. Yet humans appear to stand alone in their ability to understand others' beliefs, which allows us not only to deceive others with the explicit intent to create a false belief, but it also allows us to put ourselves in others' shoes to determine when cheaters need to be punished, even if we are not directly disadvantaged by the cheater. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Viral infections of nonhuman primates.

    PubMed

    Kalter, S S; Heberling, R L; Cooke, A W; Barry, J D; Tian, P Y; Northam, W J

    1997-10-01

    Approximately 53,000 serologic tests and viral isolation studies were performed on 1,700 nonhuman primate specimens for evidence of past and/or current viral infection. Information, other than the requested test, generally was not provided with the specimen. This lack of information does not permit any attempt at interpretation of results. Requested testing included a large number of diverse viral agents in approximately 40 primate species. The resulting data are in keeping with those of previous studies and offer an insight into the needs of colony management, as well as some general information on the overall frequency of infection with the indicated viruses. Inasmuch as the results represent testing of single specimens, they are not to be construed as "diagnostic," and simply indicate past infection as represented by the presence of antibody in the test animal. Viral isolation results are listed, and the number of positive results versus the number of animals tested emphasizes the limitations of the procedure. Investigations such as these continue to assist in the maintenance of healthy nonhuman primate colonies. This information also supports continued use of nonhuman primates for research in human viral infections and may be helpful in terms of animal selection for use in xenotransplants.

  11. Neuroethology of primate social behavior

    PubMed Central

    Chang, Steve W. C.; Brent, Lauren J. N.; Adams, Geoffrey K.; Klein, Jeffrey T.; Pearson, John M.; Watson, Karli K.; Platt, Michael L.

    2013-01-01

    A neuroethological approach to human and nonhuman primate behavior and cognition predicts biological specializations for social life. Evidence reviewed here indicates that ancestral mechanisms are often duplicated, repurposed, and differentially regulated to support social behavior. Focusing on recent research from nonhuman primates, we describe how the primate brain might implement social functions by coopting and extending preexisting mechanisms that previously supported nonsocial functions. This approach reveals that highly specialized mechanisms have evolved to decipher the immediate social context, and parallel circuits have evolved to translate social perceptual signals and nonsocial perceptual signals into partially integrated social and nonsocial motivational signals, which together inform general-purpose mechanisms that command behavior. Differences in social behavior between species, as well as between individuals within a species, result in part from neuromodulatory regulation of these neural circuits, which itself appears to be under partial genetic control. Ultimately, intraspecific variation in social behavior has differential fitness consequences, providing fundamental building blocks of natural selection. Our review suggests that the neuroethological approach to primate behavior may provide unique insights into human psychopathology. PMID:23754410

  12. Pathogenesis of varicelloviruses in primates.

    PubMed

    Ouwendijk, Werner J D; Verjans, Georges M G M

    2015-01-01

    Varicelloviruses in primates comprise the prototypic human varicella-zoster virus (VZV) and its non-human primate homologue, simian varicella virus (SVV). Both viruses cause varicella as a primary infection, establish latency in ganglionic neurons and reactivate later in life to cause herpes zoster in their respective hosts. VZV is endemic worldwide and, although varicella is usually a benign disease in childhood, VZV reactivation is a significant cause of neurological disease in the elderly and in immunocompromised individuals. The pathogenesis of VZV infection remains ill-defined, mostly due to the species restriction of VZV that impedes studies in experimental animal models. SVV infection of non-human primates parallels virological, clinical, pathological and immunological features of human VZV infection, thereby providing an excellent model to study the pathogenesis of varicella and herpes zoster in its natural host. In this review, we discuss recent studies that provided novel insight in both the virus and host factors involved in the three elementary stages of Varicellovirus infection in primates: primary infection, latency and reactivation.

  13. Radiation responses of human bladder cancer assessed in vitro or as xenografts in immune-deprived mice

    SciTech Connect

    Tannock, I.; Choo, B.; Buick, R.

    1984-10-01

    The response to radiation of cells derived from transitional cell carcinoma (TCC) of the human bladder has been studied. In vitro radiation survival curves for two established cell lines, RT-4 and MGH-U1, and for a cell line HB-10 derived recently from biopsy of a metastatic lymph node were characterized by values of D/sub 0/ and anti n in the range of 1.1-1.5 Gy and 2-7 respectively. The oxygen enhancement ratio of HB-10 cells was 2.8. Xenografts derived from the line HB-10 were irradiated in vivo under both aerobic and hypoxic conditions and cell survival was assessed in agar. Both aerobic and hypoxic survival curves were similar to that obtained for irradiation of hypoxic HB-10 cells in culture. Another tumor line, HB-15, derived from a cystoscopic biopsy of primary TCC, was maintained by transplantation of xenografts. Regrowth curves for HB-15 xenografts after radiation doses of 10 or 20 Gy were parallel to the growth curve for untreated controls but with volume reduced by factors of about 5 and 20 respectively. Cells derived from TCC of the human bladder exhibit parameters of radiation survival similar to those of other mammalian cells, and that xenografts derived from such cells contain a high proportion of hypoxic cells.

  14. Comparison of the Gene Expression Profiles of Human Hematopoietic Stem Cells between Humans and a Humanized Xenograft Model.

    PubMed

    Matsuzawa, Hideyuki; Matsushita, Hiromichi; Yahata, Takashi; Tanaka, Masayuki; Ando, Kiyoshi

    2017-04-20

    The aim of this study is to evaluate the feasibility of NOD/Shi-scid-IL2Rγ(null)(NOG) mice transplanted with human CD34(+)/CD38(-)/Lin(-/low) hematopoietic cells from cord blood (CB) as an experimental model of the gene expression in human hematopoiesis. We compared the gene expressions of human CD34(+)/CD38(-)/Lin(-/low) cells from human bone marrow (BM) and in xenograft models. The microarray data revealed that 25 KEGG pathways were extracted from the comparison of human CD34(+)/CD38(-)/Lin(-/low) HSCs between CB and BM, and that 17 of them--which were mostly related to cellular survival, RNA metabolism and lymphoid development--were shared with the xenograft model. When the probes that were commonly altered in CD34(+)/CD38(-)/Lin(-/low) cells from both human and xenograft BM were analyzed, most of them, including the genes related hypoxia, hematopoietic differentiation, epigenetic modification, translation initiation, and RNA degradation, were downregulated. These alterations of gene expression suggest a reduced differentiation capacity and likely include key alterations of gene expression for settlement of CB CD34(+)/CD38(-)/Lin(-/low) cells in BM. Our findings demonstrate that the xenograft model of human CB CD34(+)/CD38(-)/Lin(-/low) cells using NOG mice was useful, at least in part, for the evaluation of the gene expression profile of human hematopoietic stem cells.

  15. Lung Transplantation

    MedlinePlus

    ... who have severe COPD Cystic fibrosis Idiopathic pulmonary fibrosis Alpha-1 antitrypsin deficiency Pulmonary hypertension Complications of lung transplantation include rejection of the transplanted lung and infection. NIH: National Heart, Lung, and Blood Institute

  16. Liver Transplant

    MedlinePlus

    ... Home > Your Liver > Liver Disease Information > Liver Transplant Liver Transplant Explore this section to learn more about ... resource. www.paulcox.com.au Why is the liver important? The liver is the second largest organ ...

  17. Cornea Transplant

    MedlinePlus

    ... who had several conditions, such as certain central nervous system conditions, infections, and prior eye surgery or eye conditions, or from people who died from an unknown cause. During your cornea transplant On the day of your cornea transplant, you' ...

  18. Intestine Transplant

    MedlinePlus

    ... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Intestine Transplant Although it is possible for a living donor to donate an intestine segment, most intestine transplants involve a whole organ ...

  19. Hair transplant

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/007205.htm Hair transplant To use the sharing features on this page, please enable JavaScript. A hair transplant is a surgical procedure to improve baldness. Description ...

  20. Pancreas transplant

    MedlinePlus

    ... In: Cameron JL, Cameron AM, eds. Current Surgical Therapy . 11th ed. Philadelphia, PA: Elsevier Saunders; 2014:511-5. Gruessner AC, Gruessner RWG. Pancreas and kidney transplantation for diabetic nephropathy. In: Morris PJ, Knechtle SJ, eds. Kidney Transplantation: ...

  1. Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models.

    PubMed

    Guan, Xin; Qin, Meng; Zhang, Yu; Wang, Yanan; Shen, Bin; Ren, Zhihua; Ding, Xinxin; Dai, Wei; Jiang, Yongping

    2017-03-01

    Because of a lack of platelet supply and a U.S. Food and Drug Administration-approved platelet growth factor, megakaryocytes have emerged as an effective substitute for alleviating thrombocytopenia. Here, we report the development of an efficient two-stage culture system that is free of stroma, animal components, and genetic manipulations for the production of functional megakaryocytes from hematopoietic stem cells. Safety and functional studies were performed in murine and nonhuman primate models. One human cryopreserved cord blood CD34(+) cell could be induced ex vivo to produce up to 1.0 × 10(4) megakaryocytes that included CD41a(+) and CD42b(+) cells at 82.4% ± 6.1% and 73.3% ± 8.5% (mean ± SD), respectively, yielding approximately 650-fold higher cell numbers than reported previously. Induced human megakaryocytic cells were capable of engrafting and producing functional platelets in the murine xenotransplantation model. In the nonhuman primate model, transplantation of primate megakaryocytic progenitors increased platelet count nadir and enhanced hemostatic function with no adverse effects. In addition, primate platelets were released in vivo as early as 3 hours after transplantation with autologous or allogeneic mature megakaryocytes and lasted for more than 48 hours. These results strongly suggest that large-scale induction of functional megakaryocytic cells is applicable for treating thrombocytopenic blood diseases in the clinic. Stem Cells Translational Medicine 2017;6:897-909.

  2. [Emergency Keratoplasty with Porcine Xenografts in Necrotizing Keratitis].

    PubMed

    Drozhzhyna, Galyna I; Gaidamaka, Tetiana B; Cursiefen, Claus; Bachmann, Björn O; Ivanovska, Olena V; Ostashevsky, Viktor L; Kogan, Boris M; Usov, Volodymyr J; Pasyechnikova, Natalija V

    2017-07-06

    Background The great shortage of donor material in Ukraine makes it necessary to find additional sources of transplant material. A possible suitable material are the porcine corneas, as they are similar in structure and biomechanical parameters to the human cornea. The purpose of our study was to analyze the results of therapeutic keratoplasty (KP) with keratoxenotransplants from cryolyophilized porcine corneas in patients with severe necrotizing keratitis. Methods A retrospective analysis of 32 xenotransplantations patients with severe necrotizing keratitis (17 lamellar, 6 stepped perforating, 4 perforating, 5 "biological coverage" according to Puchkovskaya) was completed. Results All eyes could be preserved, but the graft was rejected in all eyes. A semitransparent xenograft (XG) was achieved in 9 patients (33.3%). The best results were obtained after lamellar XKP with an XT diameter of 3.5 - 6.5 mm. Lamellar XTs with larger diameters (7.0 - 10.0 mm) were opaque. Postoperatively, the intensity of the inflammatory response after stepped XKP was slightly lower than that of the classical perforating XKP. A new KP with human corneas had to be performed in 5 patients, in one case combined with an antiglaucomatous operation and in another case with cataract extraction. Antiglaucomatous surgery had to be performed in 5 patients (15.6%). Conclusion In the absence of human donor corneas, a porcine keratoxenoimplant can be used as temporary therapeutic keratoplasty in case of emergency stop the inflammation process and to save the eye. In cases of keratoxenoimplant, a poor visual outcome is expected. Georg Thieme Verlag KG Stuttgart · New York.

  3. Uterus transplantation.

    PubMed

    Altchek, Albert

    2003-05-01

    Until recently, only life and death situations warranted organ transplantation. Nonvital transplantation, to further a patient s wishes and goals, was not considered justified. It can be argued, however, that this distinction is not morally significant. Patients with kidney failure, for example, can be kept alive by dialysis. But their quality of life would be greatly enhanced by kidney transplant, which is thus considered a justified procedure. So a spectrum of rationales may justify transplantation. Transplantation of the uterus would relieve the anguish of women who greatly desire to conceive a child. Some women do not have a uterus. In some cases this is due to a congenital absence (Rokitansky s syndrome). In other cases, surgical removal of the uterus was required to repair an obstetrical rupture. With a transplanted uterus, many of these women could have the opportunity to become pregnant as a result of nonvital organ transplant. While other organ transplant donations most often come from cadavers and less often from living donors (kidney or partial liver), the donor source for a uterus may be an otherwise healthy living patient who requires uterus removal as a standard care procedure. Furthermore, it should be possible to remove the transplanted uterus from the recipient after successful pregnancies, so the patient would not be subjected to lifelong antirejection medications. Since animal uterus transplantation has been done successfully, human uterus transplantation might be considered for select cases. One such case has been reported.

  4. Nonhuman primates are relevant models for research in hematology, immunology and virology.

    PubMed

    Hérodin, F; Thullier, P; Garin, D; Drouet, M

    2005-06-01

    Nonhuman primates have been used for biomedical research for several decades. They have proved to be models that are relevant to humans because of the high level of gene homology which underlies physiological and biochemical similarities. The similarity of monkeys to humans has been used to investigate pathophysiological mechanisms in hematology, immunology and virology. New therapeutic procedures can be assessed in primates by using materials, in particular pharmacological reagents, and methods designed for humans. The relevance of these models also relies on the use of species-specific pathogens and the availability of recombinant, homologous cytokines. The introduction of more and more sophisticated cell and gene therapy protocols in hematopoietic cell transplantation and immunotherapy requires the development of preclinical trials similar to clinical settings. For several decades now, baboons and cynomolgus/rhesus monkeys have been the most useful primate models in experimental hematology, and this has contributed to numerous therapeutic advances. Primate models of AIDS have been developed to study the pathogenesis, transmission and immune responses to infection, and to test vaccines and drugs. Primate research should be restricted in quantity, and mainly designed with the aim of removing uncertainty as to the safety and clinical benefit to the patient, of new biomedical protocols.

  5. Pancreas Transplantation

    PubMed Central

    Sutherland, David ER

    2010-01-01

    Diabetes mellitus is generally treated with oral diabetic drugs and/or insulin. However, the morbidity and mortality associated with this condition increases over time, even in patients receiving intensive insulin treatment, and this is largely attributable to diabetic complications or the insulin therapy itself. Pancreas transplantation in humans was first conducted in 1966, since when there has been much debate regarding the legitimacy of this procedure. Technical refinements and the development of better immunosuppressants and better postoperative care have brought about marked improvements in patient and graft survival and a reduction in postoperative morbidity. Consequently, pancreas transplantation has become the curative treatment modality for diabetes, particularly for type I diabetes. An overview of pancreas transplantation is provided herein, covering the history of pancreas transplantation, indications for transplantation, cadaveric and living donors, surgical techniques, immunosuppressants, and outcome following pancreas transplantation. The impact of successful pancreas transplantation on the complications of diabetes will also be reviewed briefly. PMID:21253293

  6. Rejection of wild-type and genetically engineered major histocompatibility complex-deficient glial cell xenografts in the central nervous system results in bystander demyelination and Wallerian degeneration.

    PubMed

    O'Leary, M T; Bujdoso, R; Blakemore, W F

    1998-07-01

    Mixed glial cell cultures prepared from neonatal wild type and mutant male mice lacking either major histocompatibility complex class I, class II or both class I and II molecules (major histocompatibility complex class I(o/o)II(o/o)), and from syngeneic male rats were transplanted into female rat spinal cord white matter. Graft survival was monitored using DNA probes specific to the Y chromosome. Survival of major histocompatibility complex class-deficient grafts was not prolonged compared to wild-type grafts and in most cases grafts could not be detected at 28 days post-transplantation, at which time syngeneic grafts were still present. However, rejection of xenografts resulted in significant bystander damage to host tissue. In recipients of wild-type and major histocompatibility complex class I(o/o) xenografts the predominant pathology was demyelination. Demyelination was also observed in recipients of major histocompatibility complex class II(o/o) and major histocompatibility complex class I(o/o)II(o/o) xenografts, however in addition there was marked collagen deposition and meningeal cell invasion. Significantly more axons had undergone Wallerian degeneration in recipients of major histocompatibility complex class II(o/o) and major histocompatibility complex class I(o/o)II(o/o) xenografts than recipients of wild-type and major histocompatibility complex class I(o/o) xenografts. These findings were interpreted as evidence of a more destructive immune response associated with rejection of grafts lacking major histocompatibility complex class II molecules. It was proposed that the difference in the severity of bystander damage may be related to the previously demonstrated ability of xenogeneic major histocompatibility complex class II molecules to activate host T cells directly, whereas xenografts lacking major histocompatibility complex class II molecules were capable of activating host T cells only by the indirect pathway.

  7. Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice.

    PubMed

    Martínez, Allyson K; Jensen, Kendal; Hall, Chad; O'Brien, April; Ehrlich, Laurent; White, Tori; Meng, Fanyin; Zhou, Tianhao; Greene, John; Bernuzzi, Francesca; Invernizzi, Pietro; Dostal, David E; Lairmore, Terry; Alpini, Gianfranco; Glaser, Shannon S

    2017-05-01

    Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures.

    PubMed

    Kabos, Peter; Finlay-Schultz, Jessica; Li, Chunling; Kline, Enos; Finlayson, Christina; Wisell, Joshua; Manuel, Christopher A; Edgerton, Susan M; Harrell, J Chuck; Elias, Anthony; Sartorius, Carol A

    2012-09-01

    Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved

  9. Underground hibernation in a primate.

    PubMed

    Blanco, Marina B; Dausmann, Kathrin H; Ranaivoarisoa, Jean F; Yoder, Anne D

    2013-01-01

    Hibernation in mammals is a remarkable state of heterothermy wherein metabolic rates are reduced, core body temperatures reach ambient levels, and key physiological functions are suspended. Typically, hibernation is observed in cold-adapted mammals, though it has also been documented in tropical species and even primates, such as the dwarf lemurs of Madagascar. Western fat-tailed dwarf lemurs are known to hibernate for seven months per year inside tree holes. Here, we report for the first time the observation that eastern dwarf lemurs also hibernate, though in self-made underground hibernacula. Hence, we show evidence that a clawless primate is able to bury itself below ground. Our findings that dwarf lemurs can hibernate underground in tropical forests draw unforeseen parallels to mammalian temperate hibernation. We expect that this work will illuminate fundamental information about the influence of temperature, resource limitation and use of insulated hibernacula on the evolution of hibernation.

  10. Optogenetics in the nonhuman primate

    PubMed Central

    Han, Xue

    2013-01-01

    The nonhuman primate brain, the model system closest to the human brain, plays a critical role in our understanding of neural computation, cognition, and behavior. The continued quest to crack the neural codes in the monkey brain would be greatly enhanced with new tools and technologies that can rapidly and reversibly control the activities of desired cells at precise times during specific behavioral states. Recent advances in adapting optogenetic technologies to monkeys have enabled precise control of specific cells or brain regions at the millisecond timescale, allowing for the investigation of the causal role of these neural circuits in this model system. Validation of optogenetic technologies in monkeys also represents a critical preclinical step on the translational path of new generation cell-type-specific neural modulation therapies. Here, I discuss the current state of the application of optogenetics in the nonhuman primate model system, highlighting the available genetic, optical and electrical technologies, and their limitations and potentials. PMID:22341328

  11. Underground hibernation in a primate

    PubMed Central

    Blanco, Marina B.; Dausmann, Kathrin H.; Ranaivoarisoa, Jean F.; Yoder, Anne D.

    2013-01-01

    Hibernation in mammals is a remarkable state of heterothermy wherein metabolic rates are reduced, core body temperatures reach ambient levels, and key physiological functions are suspended. Typically, hibernation is observed in cold-adapted mammals, though it has also been documented in tropical species and even primates, such as the dwarf lemurs of Madagascar. Western fat-tailed dwarf lemurs are known to hibernate for seven months per year inside tree holes. Here, we report for the first time the observation that eastern dwarf lemurs also hibernate, though in self-made underground hibernacula. Hence, we show evidence that a clawless primate is able to bury itself below ground. Our findings that dwarf lemurs can hibernate underground in tropical forests draw unforeseen parallels to mammalian temperate hibernation. We expect that this work will illuminate fundamental information about the influence of temperature, resource limitation and use of insulated hibernacula on the evolution of hibernation. PMID:23636180

  12. In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models.

    PubMed

    Asadzadeh, Fatemeh; Ferrucci, Veronica; DE Antonellis, Pasqualino; Zollo, Massimo

    2017-03-01

    Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub

  13. Primate Experiments on SLS-1

    NASA Technical Reports Server (NTRS)

    Aochi, J.

    1985-01-01

    Experiments to study how certain body systems are affected by the space environment are described. These experiments are to be conducted on space shuttle flights. How weightlessness affects two body systems of primates are the prime concern. Thermoregulation and fluid and electrolyte homeostasis are the two systems concerned. The thermoregulation project will provide data on how body temperature and circadian rhythms are affected in a weightlessness environment and the homeostasis in fluids and electrolyte levels will address the problem of body fluid shifts.

  14. Primate Experiments on SLS-1

    NASA Technical Reports Server (NTRS)

    Aochi, J.

    1985-01-01

    Experiments to study how certain body systems are affected by the space environment are described. These experiments are to be conducted on space shuttle flights. How weightlessness affects two body systems of primates are the prime concern. Thermoregulation and fluid and electrolyte homeostasis are the two systems concerned. The thermoregulation project will provide data on how body temperature and circadian rhythms are affected in a weightlessness environment and the homeostasis in fluids and electrolyte levels will address the problem of body fluid shifts.

  15. Soils, time, and primate paleoenvironments

    USGS Publications Warehouse

    Bown, T.M.; Kraus, M.J.

    1993-01-01

    Soils are the skin of the earth. From both poles to the equator, wherever rocks or sediment are exposed at the surface, soils are forming through the physical and chemical action of climate and living organisms. The physical attributes (color, texture, thickness) and chemical makeup of soils vary considerably, depending on the composition of the parent material and other variables: temperature, rainfall and soil moisture, vegetation, soil fauna, and the length of time that soil-forming processes have been at work. United States soil scientists1 have classified modern soils into ten major groups and numerous subgroups, each reflecting the composition and architecture of the soils and, to some extent, the processes that led to their formation. The physical and chemical processes of soil formation have been active throughout geologic time; the organic processes have been active at least since the Ordovician.2 Consequently, nearly all sedimentary rocks that were deposited in nonmarine settings and exposed to the elements contain a record of ancient, buried soils or paleosols. A sequence of these rocks, such as most ancient fluvial (stream) deposits, provides a record of soil paleoenvironments through time. Paleosols are also repositories of the fossils of organisms (body fossils) and the traces of those organisms burrowing, food-seeking, and dwelling activities (ichnofossils). Indeed, most fossil primates are found in paleosols. Careful study of ancient soils gives new, valuable insights into the correct temporal reconstruction of the primate fossil record and the nature of primate paleoenvironments. ?? 1993 Wiley-Liss, Inc.

  16. Assessing Anxiety in Nonhuman Primates

    PubMed Central

    Coleman, Kristine; Pierre, Peter J.

    2014-01-01

    Anxiety can be broadly described as a psychological state in which normally innocuous environmental stimuli trigger negative emotional expectations. Human anxiety disorders are multidimensional and may be organic or acquired, situational or pervasive. The broad ranging nature of the anxiety phenotype speaks to the need for models that identify its various components and root causes to develop effective clinical treatments. The cross-species comparative approach to modeling anxiety disorders in animals aims to understand mechanisms that both contribute to and modulate anxiety. Nonhuman primate models provide an important bridge from nonprimate model systems because of the complexity of nonhuman primates’ biobehavioral capacities and their commonalities with human emotion. The broad goal of this review is to provide an overview of various procedures available to study anxiety in the nonhuman primate, with a focus on the behavioral aspects of anxiety. Commonly used methods covered in this review include assessing animals in their home environment or in response to an ethologically relevant threat, associative conditioning and startle response tests, and cognitive bias tests. We also discuss how these procedures can help veterinarians and researchers care for captive nonhuman primates. PMID:25225310

  17. Molecular immunology profiles of monkeys following xenografting with the islets and heart of α-1,3-galactosyltransferase knockout pigs.

    PubMed

    Ock, Sun A; Lee, Jungkyu; Oh, Keon Bong; Hwang, Seongsoo; Yun, Ik Jin; Ahn, Curie; Chee, Hyun Keun; Kim, Hwajung; Park, Jae Berm; Kim, Sung Joo; Kim, Youngim; Im, Gi-Sun; Park, EungWoo

    2016-09-01

    Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system-related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α-1,3-galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old). The immunosuppressive regimen included administration of cobra venom factor, anti-thymocyte globulin, rituximab, and anti-CD154 monoclonal antibodies to recipients before and after grafting. Islets were xenografted into the portal vein in type 1 diabetic monkeys, and the heart was xenografted by heterotopic abdominal heart transplantation. Genes from recipient blood were analyzed using RT(2) profiler PCR arrays and the web-based RT(2) profiler PCR array software v.3.5. Recipients treated with immunosuppressive agents without grafting showed significant downregulation of CCL5, CCR4, CCR6, CD4, CD40LG, CXCR3, FASLG, CXCR3, FOXP3, GATA3, IGNG, L10, IL23A, TRAF6, MAPK8, MIF, STAT4, TBX21, TLR3, TLR7, and TYK2 and upregulation of IFNGR1; thus, genes involved in protection against viral and bacterial infection were downregulated, confirming the risk of infection. Notably, C3-level control resulted in xenograft failure within 2 days because of a 7- to 11-fold increase in all xenotransplanted models. Islet grafting using single GalT-KO pigs resulted in upregulation of CXCL10 and MX1, early inflammation, and acute rejection-associated signals at 2 days after xenografting. We observed at least 5-fold upregulation in recipients transplanted with islets grafts from single (MX1) or double (C3, CCR8, IL6, IL13, IRF6, CXCL10, and MX1) GalT-KO pigs after 77 days; single GalT-KO incurred early losses owing to immune attacks. Our

  18. Growth patterns and cell kinetics of human osteosarcoma xenografts in serial passages in nude mice analyzed by in vivo labelling with iododeoxyuridine.

    PubMed

    Broström, L A; Crnalic, S; Löfvenberg, R; Boquist, L; Stenling, R

    1996-01-01

    A human osteoblastic osteosarcoma was transplanted in nude mice and followed in seven serial passages. Tumor cell kinetics was analyzed by in vivo labelling with the thymidine analogue iododeoxyuridine (IdUrd). Immunohistochemistry was used to measure the IdUrd labelling index. Duration of S phase (ts) was estimated by flow cytometry. From these two parameters potential doubling time (tpot) was calculated. Cell kinetic parameters showed low variations between passages and also between xenografts in same passage. Smaller variations of ts compared to labelling index and tpot were found. tpot was generally short with an interpassageal mean of 1.3 days and CV=14.8%. All xenografts showed DNA aneuploidy (mean DNA index --1.6). Homogeneous tumor growth was indicated by low variations of volume doubling time and lag time. There was no correlation between tumor growth and cell proliferation. Histopathological characteristics of the donor patients tumor were retained during serial transplantation.

  19. Lung transplantation

    PubMed Central

    Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

    2015-01-01

    ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550

  20. Thoracic transplantation.

    PubMed

    Shumway, N E

    2000-07-01

    Experimental orthotopic transplantation of the heart was accomplished in 1959. Long-term survival was achieved in 1965 with a chemical immunosuppression protocol substantially different from that used for renal and hepatic transplants. Performance characteristics of the transplanted denervated heart were found to differ only slightly from normal. It appeared by the time of the Clinical Congress of the American College of Surgeons in October 1967 that clinical heart transplantation might be justified if the concept of brain death could be legally recognized. The Stanford program in clinical heart transplantation was inaugurated on January 6, 1968 and has been in continuous operation. To date, more than 1000 patients have undergone transplantation of the heart with the 5-year survival at 75%. The first long-term success in lung transplantation occurred at Stanford in 1981, with transplantation of the heart and both lungs. In 1990 the concept of living pulmonary lobar donors was introduced and is slowly finding its clinical role. The steroid-sparing capability of cyclosporine made possible both successful lung and pediatric heart transplantation. Only the donor shortage remains as a substantial barrier to widespread thoracic transplantation. Xenotransplantation is under intense scrutiny, with some encouraging experimental results. Development of the artificial heart continues to offer some relief for patients with end-stage heart disease.

  1. Interstitial Fluid Pressure and Vascularity of Intradermal and Intramuscular Human Tumor Xenografts

    SciTech Connect

    Gulliksrud, Kristine; Galappathi, Kanthi; Rofstad, Einar K.

    2011-05-01

    Purpose: High interstitial fluid pressure (IFP) in tumors has been shown to be associated with poor prognosis. Mechanisms underlying the intertumor heterogeneity in IFP were investigated in this study. Methods and Materials: A-07 melanoma xenografts were transplanted intradermally or intramuscularly in BALB/c nu/nu mice. IFP was measured in the center of the tumors with a Millar catheter. Tumor blood perfusion and extracellular volume fraction were assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The necrotic fraction, vascular density, and vessel diameters of the tumors were determined by image analysis of histological preparations. Results: Significant intertumor heterogeneity in IFP, blood perfusion, and microvascular morphology was observed whether the tumors were transplanted intradermally or intramuscularly. High IFP was mainly a consequence of high resistance to blood flow caused by low vessel diameters in either transplantation site. IFP decreased with increasing blood perfusion in intradermal tumors and increased with increasing blood perfusion in intramuscular tumors, mainly because the morphology of the tumor microvasculature differed systematically between the two tumor models. Conclusion: The potential of DCE-MRI as a noninvasive method for assessing the IFP of tumors may be limited because any relationship between IFP and blood perfusion may differ with the tumor growth site.

  2. Ecology and evolution of primate colour vision.

    PubMed

    Vorobyev, Misha

    2004-07-01

    More than one hundred years ago, Grant Allen suggested that colour vision in primates, birds and insects evolved as an adaptation for foraging on colourful advertisements of plants--fruits and flowers. Recent studies have shown that well developed colour vision appeared long before fruits and flowers evolved. Thus, colour vision is generally beneficial for many animals, not only for those eating colourful food. Primates are the only placental mammals that have trichromatic colour vision. This may indicate either that trichromacy is particularly useful for primates or that primates are unique among placental mammals in their ability to utilise the signals of three spectrally distinct types of cones or both. Because fruits are an important component of the primate diet, primate trichromacy could have evolved as a specific adaptation for foraging on fruits. Alternatively, primate trichromacy could have evolved as an adaptation for many visual tasks. Comparative studies of mammalian eyes indicate that primates are the only placental mammals that have in their retina a pre-existing neural machinery capable of utilising the signals of an additional spectral type of cone. Thus, the failure of non-primate placental mammals to evolve trichromacy can be explained by constraints imposed on the wiring of retinal neurones.

  3. Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model

    PubMed Central

    Bissig-Choisat, Beatrice; Wang, Lili; Legras, Xavier; Saha, Pradip K.; Chen, Leon; Bell, Peter; Pankowicz, Francis P.; Hill, Matthew C.; Barzi, Mercedes; Leyton, Claudia Kettlun; Leung, Hon-Chiu Eastwood; Kruse, Robert L.; Himes, Ryan W.; Goss, John A.; Wilson, James M.; Chan, Lawrence; Lagor, William R.; Bissig, Karl-Dimiter

    2015-01-01

    Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR). Like familial hypercholesterolaemia patients, our familial hypercholesterolaemia liver chimeric mice develop hypercholesterolaemia and a 'humanized‘ serum profile, including expression of the emerging drug targets cholesteryl ester transfer protein and apolipoprotein (a), for which no genes exist in mice. We go on to replace the missing LDLR in familial hypercholesterolaemia liver chimeric mice using an adeno-associated virus 9-based gene therapy and restore normal lipoprotein profiles after administration of a single dose. Our study marks the first time a human metabolic disease is induced in an experimental animal model by human hepatocyte transplantation and treated by gene therapy. Such xenograft platforms offer the ability to validate human experimental therapies and may foster their rapid translation into the clinic. PMID:26081744

  4. Establishment of patient-derived cancer xenografts in immunodeficient NOG mice.

    PubMed

    Chijiwa, Tsuyoshi; Kawai, Kenji; Noguchi, Akira; Sato, Hidemitsu; Hayashi, Akimune; Cho, Haruhiko; Shiozawa, Manabu; Kishida, Takeshi; Morinaga, Soichiro; Yokose, Tomoyuki; Katayama, Makoto; Takenaka, Nobuo; Suemizu, Hiroshi; Yamada, Roppei; Nakamura, Yoshiyasu; Ohtsu, Takashi; Takano, Yasuo; Imai, Kohzoh; Miyagi, Yohei; Nakamura, Masato

    2015-07-01

    Viable and stable human cancer cell lines and animal models combined with adequate clinical information are essential for future advances in cancer research and patient care. Conventional in vitro cancer cell lines are commonly available; however, they lack detailed information on the patient from which they originate, including disease phenotype and drug sensitivity. Patient-derived xenografts (PDX) with clinical information (so-called 'cancer xenopatients') are a promising advance that may accelerate the development of anticancer therapies. We established 61 PDX lines from 116 surgically removed tumor tissues inoculated subcutaneously into NOG mice (53% success rate). PDX lines were established from various types of epithelial tumors and also from sarcomas, including gastrointestinal stromal tumors and Ewing/PNET sarcomas. The metastatic tumors yielded PDX lines more effectively (65%) than the primary tumors (27%, P<0.001). In our PDX models, morphological characteristics, gene expression profiles, and genetic alteration patterns were all well preserved. In eight cases (7%), the transplantable xenografts for several generations were composed of large monotonous nonepithelial cells of human origin, revealed to be Epstein-Barr virus infection-associated lympho-proliferative lesions. Despite this, PDX linked with clinical information offer many advantages for preclinical studies investigating new anticancer drugs. The fast and efficient establishment of individual PDX may also contribute to future personalized anticancer therapies.

  5. A zebrafish xenograft model for studying human cancer stem cells in distant metastasis and therapy response.

    PubMed

    Chen, L; Groenewoud, A; Tulotta, C; Zoni, E; Kruithof-de Julio, M; van der Horst, G; van der Pluijm, G; Ewa Snaar-Jagalska, B

    2017-01-01

    Lethal and incurable bone metastasis is one of the main causes of death in multiple types of cancer. A small subpopulation of cancer stem/progenitor-like cells (CSCs), also known as tumor-initiating cells from heterogenetic cancer is considered to mediate bone metastasis. Although over the past decades numerous studies have been performed in different types of cancer, it is still difficult to track small numbers of CSCs during the onset of metastasis. With use of noninvasive high-resolution imaging, transparent zebrafish embryos can be employed to dynamically visualize cancer progression and reciprocal interaction with stroma in a living organism. Recently we established a zebrafish CSC-xenograft model to visually and functionally analyze the role of CSCs and their interactions with the microenvironment at the onset of metastasis. Given the highly conserved human and zebrafish genome, transplanted human cancer cells are able to respond to zebrafish cytokines, modulate the zebrafish microenvironment, and take advantage of the zebrafish stroma during cancer progression. This chapter delineates the zebrafish CSC-xenograft model as a useful tool for both CSC biological study and anticancer drug screening. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Human polyethylene granuloma tissues inhibit bone healing in a novel xenograft animal model.

    PubMed

    Esposito, Christina I; Oliver, Rema A; Campbell, Patricia A; Yu, Yan; Walter, William L; Walter, William K; Walsh, William R

    2014-06-01

    During revision of a conventional polyethylene joint replacement, surgeons usually remove the source of osteolysis (polyethylene) but cannot always remove all of the polyethylene granuloma tissues. We developed a human/rat xenograft model to investigate the effects of polyethylene granuloma tissues on bone healing. Human osteoarthritic and periprosthetic tissues collected during primary and revision hip arthroplasty surgeries were transplanted into the distal femora of athymic nude rats. After 3 weeks in vivo, there was a significant difference in the bone volume fraction (Vf ) between empty, primary, and revision defects (p = 0.02), with a lower Vf in defects with revision granuloma tissues compared to defects with primary osteoarthritic tissues. Polyethylene granuloma tissues in trabecular bone defects inhibited bone healing. Therefore, debridement around a metal-on-polyethylene hip replacement may shorten the time it takes to achieve secondary stability around a revision hip replacement. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  7. Primate-Specific Regulation of Natural Killer Cells

    PubMed Central

    Parham, Peter; Abi-Rached, Laurent; Matevosyan, Lilit; Moesta, Achim K.; Norman, Paul J.; Aguilar, Anastazia M. Older; Guethlein, Lisbeth A.

    2010-01-01

    Summary Natural killer (NK) cells are circulating lymphocytes that function in innate immunity and placental reproduction. Regulating both development and function of NK cells is an array of variable and conserved receptors that interact with major histocompatibility complex (MHC) class I molecules. Families of lectin-like and immunoglobulin-like receptors are determined by genes in the natural killer (NKC) and leukocyte receptor (LRC) complexes, respectively. As a consequence of the strong, varying pressures on the immune and reproductive systems, NK cell receptors and their MHC class I ligands evolve rapidly, are highly diverse, and exhibit dramatic species-specific differences. The variable, polymorphic family of killer cell immunoglobulin-like receptors (KIR) that regulate human NK cell development and function evolved recently, from a single-copy gene during the evolution of simian primates. Our studies of KIR and MHC class I genes in representative species show how these two unlinked but functionally intertwined genetic complexes have co-evolved. In humans, combinations of KIR and HLA class I factors are associated with infectious diseases, including HIV/AIDS, autoimmunity, reproductive success and the outcome of therapeutic transplantation. The extraordinary, and unanticipated, divergence of human NK cell receptors and MHC class I ligands from their mouse counterparts can in part explain the difficulties experienced in finding informative mouse models for human diseases. Non-human primate models have far greater potential, but to realize their promise will first require more complete definition of the genetics and function of KIR and MHC variation in non-human primate species, at a level comparable to that achieved for the human species. PMID:20618586

  8. Bion 11 mission: primate experiments

    NASA Technical Reports Server (NTRS)

    Ilyin, E. A.; Korolkov, V. I.; Skidmore, M. G.; Viso, M.; Kozlovskaya, I. B.; Grindeland, R. E.; Lapin, B. A.; Gordeev, Y. V.; Krotov, V. P.; Fanton, J. W.; Bielitzki, J. T.; Golov, V. K.; Magedov, V. S.; Hines, J. W.

    2000-01-01

    A summary is provided of the major operations required to conduct the wide range of primate experiments on the Bion 11 mission, which flew for 14 days beginning December 24, 1996. Information is given on preflight preparations, including flight candidate selection and training; attachment and implantation of bioinstrumentation; flight and ground experiment designs; onboard life support and test systems; ground and flight health monitoring; flight monkey selection and transport to the launch site; inflight procedures and data collection; postflight examinations and experiments; and assessment of results.

  9. Patient-Derived Xenografts as a Model System for Radiation Research

    PubMed Central

    Willey, Christopher D.; Gilbert, Ashley; Anderson, Joshua C.; Gillespie, G. Yancey

    2015-01-01

    The cancer literature is filled with promising preclinical studies demonstrating impressive efficacy for new therapeutics, yet translation of these approaches into clinical successes has been rare, indicating that current methods used to predict efficacy are sub-optimal. The most likely reason for the limitation of these studies is the disconnect between preclinical models and cancers treated in the clinic. Specifically, most preclinical models are poor representations of human disease. Immortalized cancer cell lines that dominate the cancer literature may be, in a sense, “paper tigers” that have been selected by decades of culture to be artificially driven by highly targetable proteins. Thus, although effective in treating these cell lines either in vitro or as artificial tumors transplanted from culture into experimental animals as xenografts, the identified therapies will likely underperform in a clinical setting. This inherent limitation not only applies to drug testing, but also to experiments with radiation therapy. Indeed, traditional radiobiology methods rely on monolayer culture systems, with emphasis on colony formation and DNA damage assessment that may have limited clinical translation. As such, there has been keen interest in developing tumor explant systems in which patient tumors are directly transplanted into, and solely maintained in vivo, using immunocompromised mice. These so-called Patient-Derived Xenografts (PDX) represent a robust model system that has been garnering support in academia and industry as a superior preclinical approach to drug testing. Likewise, PDX models have the potential to improve radiation research. In this review, we describe how PDX models are currently being used for both drug and radiation testing and how they can be incorporated into a translational research program. PMID:26384275

  10. Influenza Virus Infection in Nonhuman Primates

    PubMed Central

    Karlsson, Erik A.; Engel, Gregory A.; Feeroz, M.M.; San, Sorn; Rompis, Aida; Lee, Benjamin P. Y.-H.; Shaw, Eric; Oh, Gunwha; Schillaci, Michael A.; Grant, Richard; Heidrich, John; Schultz-Cherry, Stacey

    2012-01-01

    To determine whether nonhuman primates are infected with influenza viruses in nature, we conducted serologic and swab studies among macaques from several parts of the world. Our detection of influenza virus and antibodies to influenza virus raises questions about the role of nonhuman primates in the ecology of influenza. PMID:23017256

  11. The evolution of neocortex in primates.

    PubMed

    Kaas, Jon H

    2012-01-01

    We can learn about the evolution of neocortex in primates through comparative studies of cortical organization in primates and those mammals that are the closest living relatives of primates, in conjunction with brain features revealed by the skull endocasts of fossil archaic primates. Such studies suggest that early primates had acquired a number of features of neocortex that now distinguish modern primates. Most notably, early primates had an array of new visual areas, and those visual areas widely shared with other mammals had been modified. Posterior parietal cortex was greatly expanded with sensorimotor modules for reaching, grasping, and personal defense. Motor cortex had become more specialized for hand use, and the functions of primary motor cortex were enhanced by the addition and development of premotor and cingulate motor areas. Cortical architecture became more varied, and cortical neuron populations became denser overall than in nonprimate ancestors. Primary visual cortex had the densest population of neurons, and this became more pronounced in the anthropoid radiation. Within the primate clade, considerable variability in cortical size, numbers of areas, and architecture evolved.

  12. A mitogenomic phylogeny of living primates.

    PubMed

    Finstermeier, Knut; Zinner, Dietmar; Brameier, Markus; Meyer, Matthias; Kreuz, Eva; Hofreiter, Michael; Roos, Christian

    2013-01-01

    Primates, the mammalian order including our own species, comprise 480 species in 78 genera. Thus, they represent the third largest of the 18 orders of eutherian mammals. Although recent phylogenetic studies on primates are increasingly built on molecular datasets, most of these studies have focused on taxonomic subgroups within the order. Complete mitochondrial (mt) genomes have proven to be extremely useful in deciphering within-order relationships even up to deep nodes. Using 454 sequencing, we sequenced 32 new complete mt genomes adding 20 previously not represented genera to the phylogenetic reconstruction of the primate tree. With 13 new sequences, the number of complete mt genomes within the parvorder Platyrrhini was widely extended, resulting in a largely resolved branching pattern among New World monkey families. We added 10 new Strepsirrhini mt genomes to the 15 previously available ones, thus almost doubling the number of mt genomes within this clade. Our data allow precise date estimates of all nodes and offer new insights into primate evolution. One major result is a relatively young date for the most recent common ancestor of all living primates which was estimated to 66-69 million years ago, suggesting that the divergence of extant primates started close to the K/T-boundary. Although some relationships remain unclear, the large number of mt genomes used allowed us to reconstruct a robust primate phylogeny which is largely in agreement with previous publications. Finally, we show that mt genomes are a useful tool for resolving primate phylogenetic relationships on various taxonomic levels.

  13. Modeling Olfactory Bulb Evolution through Primate Phylogeny

    PubMed Central

    Heritage, Steven

    2014-01-01

    Adaptive characterizations of primates have usually included a reduction in olfactory sensitivity. However, this inference of derivation and directionality assumes an ancestral state of olfaction, usually by comparison to a group of extant non-primate mammals. Thus, the accuracy of the inference depends on the assumed ancestral state. Here I present a phylogenetic model of continuous trait evolution that reconstructs olfactory bulb volumes for ancestral nodes of primates and mammal outgroups. Parent-daughter comparisons suggest that, relative to the ancestral euarchontan, the crown-primate node is plesiomorphic and that derived reduction in olfactory sensitivity is an attribute of the haplorhine lineage. The model also suggests a derived increase in olfactory sensitivity at the strepsirrhine node. This oppositional diversification of the strepsirrhine and haplorhine lineages from an intermediate and non-derived ancestor is inconsistent with a characterization of graded reduction through primate evolution. PMID:25426851

  14. Undifferentiated primate spermatogonia and their endocrine control.

    PubMed

    Plant, Tony M

    2010-08-01

    The biology of spermatogonial stem cells is currently an area of intensive research and contemporary studies in primates are emerging. Quantitative regulation of sperm output by the primate testis seems to be exerted primarily on the transition from undifferentiated to differentiating spermatogonia. This review examines recent advances in our understanding of the mechanisms governing spermatogonial renewal and early differentiation in male primates, with a focus on the monkey. Emerging revisions to the classic view of dark and pale type A spermatogonia as reserve and renewing spermatogonial stem cells, respectively, are critically evaluated and essential features of endocrine control of undifferentiated spermatogonia throughout postnatal primate development are discussed. Obstacles in gaining a more complete understanding of primate spermatogonia are also identified.

  15. Comprehensive analysis of leukocytes, vascularization and matrix metalloproteinases in human menstrual xenograft model.

    PubMed

    Guo, Yong; He, Bin; Xu, Xiangbo; Wang, Jiedong

    2011-02-17

    In our previous study, menstrual-like changes in mouse were provoked through the pharmacologic withdrawal of progesterone with mifepristone following induction of decidualization. However, mouse is not a natural menstruation animal, and the menstruation model using external stimuli may not truly reflect the occurrence and development of the human menstrual process. Therefore, we established a model of menstruation based on human endometrial xenotransplantation. In this model, human endometrial tissues were transplanted subcutaneously into SCID mice that were ovarectomized and supplemented with estrogen and progestogen by silastic implants with a scheme imitating the endocrinological milieu of human menstrual cycle. Morphology, hormone levels, and expression of vimentin and cytokeratin markers were evaluated to confirm the menstrual-like changes in this model. With 28 days of hormone treatment, transplanted human endometrium survived and underwent proliferation, differentiation and disintegration, similar to human endometrium in vivo. Human CD45+ cells showed a peak of increase 28 days post-transplantation. Three days after progesterone withdrawal, mouse CD45+ cells increased rapidly in number and were significantly greater than human CD45+ cell counts. Mouse CD31+ blood vascular-like structures were detected in both transplanted and host tissues. After progesterone withdrawal, the expression levels of matrix metalloproteinases (MMP) 1, 2, and 9 were increased. In summary, we successfully established a human endometrial xenotransplantation model in SCID mice, based on the results of menstrual-like changes in which MMP-1, 2 and 9 are involved. We showed that leukocytes are originated from in situ proliferation in human xenografts and involved in the occurrence of menstruation. This model will help to further understand the occurrence, growth, and differentiation of the endometrium and the underlying mechanisms of menstruation.

  16. [Hormones and parturition in primates].

    PubMed

    Germain, G; Ferre, F

    1987-01-01

    In primates, the endocrine signals which correlate with the end of gestation, i.e. account for fetal maturity, and initiate the parturition, i.e. trigger the myometrium contractility, remain unknown. Direct and indirect evidence supports the view that, as with domestic mammals, progesterone (or the estrogen/-progesterone ratio) plays a prominent role in inhibiting the contractility of the pregnant uterus. In the past few years an increasing number of endocrine factors have been identified in the placenta. They may contribute to the control of local or systemic steroid production but their effects are extraordinarily intermingled and it is impossible today to state whether any of them are relevant to the mechanism of parturition. The trophoblast and the myometrium establish close contact in the primate pregnancy. This is evidenced by histological studies and also by the influence of the proximity of the placenta on tissue steroid concentrations and the mechanisms of hormone coupling in the myometrium. Specific types or subtypes of myometrium hormone receptors are now well identified (e.g. to oxytocin, to catecholamines) and this now permits a better understanding of the role of their endogenous agonists in the course of parturition. However, such data are still lacking for other factors (e.g. prostanoids, VIP, relaxin...) involved to varying degrees in this process.

  17. The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets†

    PubMed Central

    Pode-Shakked, Naomi; Shukrun, Rachel; Mark-Danieli, Michal; Tsvetkov, Peter; Bahar, Sarit; Pri-Chen, Sara; Goldstein, Ronald S; Rom-Gross, Eithan; Mor, Yoram; Fridman, Edward; Meir, Karen; Simon, Amos; Magister, Marcus; Kaminski, Naftali; Goldmacher, Victor S; Harari-Steinberg, Orit; Dekel, Benjamin

    2013-01-01

    There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated – NCAM1 expressing – “blastema” phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets. PMID:23239665

  18. The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets.

    PubMed

    Pode-Shakked, Naomi; Shukrun, Rachel; Mark-Danieli, Michal; Tsvetkov, Peter; Bahar, Sarit; Pri-Chen, Sara; Goldstein, Ronald S; Rom-Gross, Eithan; Mor, Yoram; Fridman, Edward; Meir, Karen; Simon, Amos; Magister, Marcus; Kaminski, Naftali; Goldmacher, Victor S; Harari-Steinberg, Orit; Dekel, Benjamin

    2013-01-01

    There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated-NCAM1 expressing-"blastema" phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets.

  19. Resistance of established porcine islet xenografts to humoral rejection by hyperimmune sera.

    PubMed

    Gourlay, W A; O'Neil, J J; Hancock, W W; Monaco, A P; Maki, T

    1999-09-27

    Although preformed natural antibodies cause hyperacute rejection of primarily vascularized xenografts, tissue grafts such as skin or islets are revascularized by in-growth of host capillaries and therefore might be resistant to circulating antibodies. We examined the effect of hyperimmune serum and primed T cells on the survival of long-term porcine islet xenografts in diabetic nude mice. Porcine islets were transplanted beneath the kidney capsule of streptozotocin-induced diabetic BALB/c athymic mice. Hyperimmune serum and sensitized splenocytes were prepared by repeated immunization of BALB/c mice with porcine lymph node cells. Splenic T cells were enriched by nylon wool column separation. Tissues were examined by immunohistology using murine- and porcine-specific monoclonal antibodies. Porcine islets survived in nude mice for > 100 days with high levels of circulating porcine C-peptide and maintenance of normoglycemia. Injection of the hyperimmune sera (IgG) into normoglycemic nude mice bearing porcine islets for > 70 days failed to induce rejection despite the continued presence of circulating anti-porcine cytotoxic antibody. Injection of sensitized T cells caused acute rejection of long-term (>140 days) porcine islets, whereas injection of naive T cells had no effect. Histologically, porcine islets removed from mice treated with hyperimmune serum showed no staining for IgG. Long-surviving porcine islet grafts showed strong staining for interleukin (IL)-10 and a lesser amount of IL-4 but no staining for IL-2 or interferon-gamma. Although fresh porcine islets were positive for swine leukocyte antigen class 1 antigen and intercellular adhesion molecule (ICAM)-1 but negative for mouse platelet endothelial cell adhesion molecule and ICAM-2, long-surviving porcine islets showed positive endothelial staining for mouse platelet endothelial cell adhesion molecule and ICAM-2. Established islet xenografts are resistant to hyperimmune serum as a result of a lack of target

  20. Laparoscopic Rectopexy with Urinary Bladder Xenograft Reinforcement

    PubMed Central

    Mehta, Aradhana; Afshar, Rami; Gardner, Amy; Ackerman, Ellen; Brandt, Jared; Sasse, Kent C.

    2017-01-01

    Background and Objectives: Rectal prolapse is often repaired laparoscopically, frequently with the use of reinforcement material. Both synthetic and biologically derived materials reduce recurrence rate compared to primary suture repair. Synthetic mesh introduces potential complications such as mesh erosion, fibrosis, and infection. Urinary bladder matrix (UBM) represents a biologically derived material for reinforcement of rectal prolapse repair with the potential to improve durability without risks of synthetic materials. The objective of the study is to evaluate the effectiveness, durability, and functional result of laparoscopic rectopexy using urinary bladder matrix xenograft reinforcement at three years follow up. Methods: The 20 cases presented describe rectal prolapse repair by means of laparoscopic rectopexy with presacral UBM reinforcement. Patients were followed up for an average of 3 years and assessed with interviews, physical examination, manometry, and the fecal incontinence severity index (FISI). Results: Each repair was completed laparoscopically. UBM exhibited favorable handling characteristics when sutured to the sacrum and the lateral rectal walls. One patient underwent laparoscopic drainage of a postoperative abscess; no other complications occurred. In 3 years of follow-up, there have been no full-thickness recurrences, erosions, reoperations, or long-term complications. Two patients exhibited a small degree of mucosal prolapse on follow-up physical examination that did not require surgery. Three-year FISI scores averaged 8 (range, 0–33 of a possible 61), indicating low fecal incontinence symptomatology. Follow-up anorectal manometry was performed in 9 patients, showing mixed results. Conclusion: Surgeons may safely use laparoscopic rectopexy with UBM reinforcement for repair of rectal prolapses. In this series, repairs with UBM grafts have been durable at 3-year follow-up and may be an alternative to synthetic mesh reinforcement of rectal

  1. Assessment of Tumor Stiffness With Shear Wave Elastography in a Human Prostate Cancer Xenograft Implantation Model.

    PubMed

    Wang, Yiru; Yao, Binwei; Li, Hongfei; Zhang, Yan; Gao, Hanjing; Gao, Yabin; Peng, Ruiyun; Tang, Jie

    2017-05-01

    To investigate the stiffness of human prostate cancer in a xenograft implantation model using shear wave elastography and compare the pathologic features of tumors with varying elasticity. Human prostate cancer DU-145 cells were injected into 24 nude male mice. The mice were divided into 3 groups according to the time of transplantation (6, 8, and 10 weeks). The volume, elasticity, and Young modulus of tumors were recorded by 2-dimensional sonography and shear wave elastography. The tumors were collected for pathologic analyses: hematoxylin-eosin staining, Ponceau S, and aniline staining were used to stain collagen and elastic fibers, and picric acid-sirius red staining was used to indicate type I and III collagen. The area ratios of collagen I/III were calculated. The correlation between the Young modulus of the tumor and area ratio of collagen I/III were evaluated. Immunohistochemistry of vimentin and α-smooth muscle actin was performed. Nineteen tumors in 3 groups were collected. The volume and mean Young modulus increased with the time of transplantation. There were more collagen fibers in the stiff tumors, and there were significant differences in the area ratios of collagen I/III between groups 1 (mean ± SD, 0.50 ± 0.17) and 3 (1.97 ± 0.56; P < .01). The Young modulus of the tumors showed a very significant correlation with the area ratios of collagen I/III (r = 0.968; P < .05). The expression level of α-smooth muscle actin protein was higher in group 3 than in the other groups, but differences in vimentin expression were barely seen. Shear wave elastography is a novel useful technology for showing the elasticity of human prostate cancer xenograft implantation tumors. Collagen fibers, especially collagen type I, play a crucial role in the elasticity in the human prostate cancer xenograft implantation model. © 2017 by the American Institute of Ultrasound in Medicine.

  2. Multi-Chemotherapeutic Schedules Containing the pan-FGFR Inhibitor ARQ 087 are Safe and Show Antitumor Activity in Different Xenograft Models.

    PubMed

    Chilà, Rosaria; Hall G, Terence; Abbadessa, Giovanni; Broggini, Massimo; Damia, Giovanna

    2017-02-02

    ARQ 087 is a multi-tyrosine kinase inhibitor with potent activity against the FGFR receptor family, currently in Phase I clinical studies for the treatment of advanced solid tumors. The compound has a very safe profile and induces tumor regressions in FGFR-driven models. The feasibility of combining ARQ 087 with chemotherapy was investigated in FGFR deregulated human xenografts. Nude mice were transplanted subcutaneously with H1581, and when tumor masses reached 150 mg, were randomized to receive vehicle, ARQ 087, paclitaxel, carboplatin as single agents or in combination. Similar experimental conditions were applied in nude mice bearing SNU16 and MFE296 xenografts, with the inclusion of capecitabine in the former xenograft model. In the different xenograft models, the drugs given as single agents ranged from very active to partially active. The double combinations were more active than the single ones, but the triple combinations were the most active. In particular, the combination of ARQ 087 + paclitaxel + carboplatin in H1581 bearing mice was able to induce tumor regression in all the mice, with 6/8 mice tumor free at day 140 after tumor transplant. Of note, no toxic deaths nor premature stopping or delaying of drug administration were observed. The data herein reported demonstrated the feasibility of using xenografts models for poli-chemotherapeutic trials mimicking the best standard of care in treatment of specific tumor type and that ARQ 087, a new pan-FGFR inhibitor, can be safely combined with standard cytotoxic chemotherapeutic drugs with apparently no sign of cumulative toxicity and an associated increased antitumor effect.

  3. Impending extinction crisis of the world’s primates: Why primates matter

    PubMed Central

    Estrada, Alejandro; Garber, Paul A.; Rylands, Anthony B.; Roos, Christian; Fernandez-Duque, Eduardo; Di Fiore, Anthony; Nekaris, K. Anne-Isola; Nijman, Vincent; Heymann, Eckhard W.; Lambert, Joanna E.; Rovero, Francesco; Barelli, Claudia; Setchell, Joanna M.; Gillespie, Thomas R.; Mittermeier, Russell A.; Arregoitia, Luis Verde; de Guinea, Miguel; Gouveia, Sidney; Dobrovolski, Ricardo; Shanee, Sam; Shanee, Noga; Boyle, Sarah A.; Fuentes, Agustin; MacKinnon, Katherine C.; Amato, Katherine R.; Meyer, Andreas L. S.; Wich, Serge; Sussman, Robert W.; Pan, Ruliang; Kone, Inza; Li, Baoguo

    2017-01-01

    Nonhuman primates, our closest biological relatives, play important roles in the livelihoods, cultures, and religions of many societies and offer unique insights into human evolution, biology, behavior, and the threat of emerging diseases. They are an essential component of tropical biodiversity, contributing to forest regeneration and ecosystem health. Current information shows the existence of 504 species in 79 genera distributed in the Neotropics, mainland Africa, Madagascar, and Asia. Alarmingly, ~60% of primate species are now threatened with extinction and ~75% have declining populations. This situation is the result of escalating anthropogenic pressures on primates and their habitats—mainly global and local market demands, leading to extensive habitat loss through the expansion of industrial agriculture, large-scale cattle ranching, logging, oil and gas drilling, mining, dam building, and the construction of new road networks in primate range regions. Other important drivers are increased bushmeat hunting and the illegal trade of primates as pets and primate body parts, along with emerging threats, such as climate change and anthroponotic diseases. Often, these pressures act in synergy, exacerbating primate population declines. Given that primate range regions overlap extensively with a large, and rapidly growing, human population characterized by high levels of poverty, global attention is needed immediately to reverse the looming risk of primate extinctions and to attend to local human needs in sustainable ways. Raising global scientific and public awareness of the plight of the world’s primates and the costs of their loss to ecosystem health and human society is imperative. PMID:28116351

  4. A brief history of cross-species organ transplantation

    PubMed Central

    2012-01-01

    Cross-species transplantation (xenotransplantation) offers the prospect of an unlimited supply of organs and cells for clinical transplantation, thus resolving the critical shortage of human tissues that currently prohibits a majority of patients on the waiting list from receiving transplants. Between the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff advocated the transplantation of slices of chimpanzee testis into aged men whose “zest for life” was deteriorating, believing that the hormones produced by the testis would rejuvenate his patients. Following the pioneering surgical work of Carrel, who developed the technique of blood vessel anastomosis, numerous attempts at nonhuman primate organ transplantation in patients were carried out in the 20th century. In 1963–1964, when human organs were not available and chronic dialysis was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost 9 months before suddenly dying from what was believed to be an electrolyte disturbance. The first heart transplant in a human ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient died within 2 hours. Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992, he obtained patient survival for 70 days following a baboon liver transplant. With the advent of genetic engineering and cloning technologies, pigs are currently available with a number of different manipulations that protect their tissues from the human immune response, resulting in increasing pig graft survival in nonhuman primate models. Genetically modified pigs offer hope of a limitless supply of organs and cells for those in need of a transplant. PMID:22275786

  5. Effects of transplantation sites on tumour growth, pulmonary metastasis and ezrin expression of canine osteosarcoma cell lines in nude mice.

    PubMed

    Jaroensong, T; Endo, Y; Lee, S-J; Kamida, A; Mochizuki, M; Nishimura, R; Sasaki, N; Nakagawa, T

    2012-12-01

    To determine the influence of the transplantation site of canine osteosarcoma (OS) cell lines on tumour growth and pulmonary metastasis, three OS cell lines were transplanted into nude mice via subcutaneous (SC), intratibial (IT) or intravenous (IV) injection. IT-xenografts exhibited greater potential for developing primary masses and pulmonary metastasis than SC-xenografts. In IT and IV xenografts, lung micrometastases along with phosphorylated ezrin-radixin-moesin (p-ERM) overexpression were found in mice xenografted with HMPOS and OOS cells after 1 week and metastasis was found with decreased p-ERM expression at later time points. The expression of ezrin and p-ERM in the primary tumours of IT-xenografted mice was higher than those in SC-xenografted mice with HMPOS and OOS cells. The results suggest that the orthotopic transplantation site plays an important role in the spontaneous metastasis of canine OS and that ezrin phosphorylation may be involved in the early metastatic mechanism of canine OS cells. © 2011 Blackwell Publishing Ltd.

  6. Eliciting hyperacute xenograft response to treat human cancer: alpha(1,3) galactosyltransferase gene therapy.

    PubMed

    Link, C J; Seregina, T; Atchison, R; Hall, A; Muldoon, R; Levy, J P

    1998-01-01

    Xenograft hyperacute rejection in humans occurs as a secondary response to a cellular glycosylation incompatibility with most non-human mammalian species. A key component of hyperacute rejection, alpha(1,3)galactosyl (agal) epitopes present on the surface of most non-human mammal cells, is bound by host anti-agal IgG antibodies leading to the activation of complement and, cellular lysis (1). The enzyme causing specific glycosylation patterns, alpha(1,3)galactosyltransferase [alpha(1,3)GT], directs the addition of agal to N-acetyl glucosamine residues in the trans Golgi apparatus in most mammalian species including Mus musculus, but not old world primates, apes or humans. In this report, we cloned both a truncated and full length murine alpha(1,3)GT gene into a retroviral vector backbone in order to transfer alpha(1,3)galactosyl epitopes into human A375 melanoma cells. Expression of agal epitopes on A375 cells after alpha(1,3)GT gene transfer was demonstrated using FITC-labeled ligand and FACS analysis. These cells were exposed to human serum for 30 minutes and > 90% of the agal expressing cells were killed by this treatment. These pretreated cells failed to establish tumors after implantation into athymic nude mice. This is the first report of retroviral vector transfer of the alpha(1,3)GT gene into human tumor cells in an attempt to elicit hyperacute rejection as a novel anti-cancer gene therapy strategy.

  7. Diversity components of impending primate extinctions.

    PubMed

    Jernvall, J; Wright, P C

    1998-09-15

    Many extant species are at risk to go extinct. This impending loss of species is likely to cause changes in future ecosystem functions. Ecological components of diversity, such as dietary or habitat specializations, can be used to estimate the impact of extinctions on ecosystem functions. As an approach to estimate the impact of future extinctions, we tested interdependency between ecological and taxonomic change based on current predictions of extinction rates in primates. We analyzed the ecological characteristics of extant primate faunas having species in various categories of endangerment of extinction and forecasted the future primate faunas as if they were paleontological faunas. Predicting future faunas combines the wealth of ecological information on living primates with large, fossil record-like changes in diversity. Predicted extinction patterns of living primates in Africa, Asia, Madagascar, and South America show that changes in ecology differ among the regions in ways that are not reducible to taxonomic measures. The ecological effects of primate extinctions are initially least severe in South America and larger in Asia and Africa. Disproportionately larger ecological changes are projected for Madagascar. The use of taxonomy as a proxy for ecology can mislead when estimating competence of future primate ecosystems.

  8. Comparing primate crania: The importance of fossils.

    PubMed

    Fleagle, John G; Gilbert, Christopher C; Baden, Andrea L

    2016-10-01

    Extant primate crania represent a small subset of primate crania that have existed. The main objective here is to examine how the inclusion of fossil crania changes our understanding of primate cranial diversity relative to analyses of extant primates. We hypothesize that fossil taxa will change the major axes of cranial shape, occupy new areas of morphospace, change the relative diversity of major primate clades, and fill in notable gaps separating major primate taxa/clades. Eighteen 3D landmarks were collected on 157 extant and fossil crania representing 90 genera. Data were subjected to a Generalized Procrustes Analysis then principal components analysis. Relative diversity between clades was assessed using an F-statistic. Fossil taxa do not significantly alter major axes of cranial shape, but they do occupy unique areas of morphospace, change the relative diversity between clades, and fill in notable gaps in primate cranial evolution. Strepsirrhines remain significantly less diverse than anthropoids. Fossil hominins fill the gap in cranial morphospace between extant great apes and modern humans. The morphospace outlined by living primates largely includes that occupied by fossil taxa, suggesting that the cranial diversity of living primates generally encompasses the total diversity that has evolved in this Order. The evolution of the anthropoid cranium was a significant event allowing anthropoids to achieve significantly greater cranial diversity compared to strepsirrhines. Fossil taxa fill in notable gaps within and between clades, highlighting their transitional nature and eliminating the appearance of large morphological distances between extant taxa, particularly in the case of extant hominids. © 2016 Wiley Periodicals, Inc.

  9. Special issue: Comparative biogeography of Neotropical primates.

    PubMed

    Lynch Alfaro, Jessica W; Cortés-Ortiz, Liliana; Di Fiore, Anthony; Boubli, Jean P

    2015-01-01

    New research presented in this special issue of Molecular Phylogenetics and Evolution on the "Phylogeny and Biogeography of Neotropical Primates" greatly improves our understanding of the evolutionary history of the New World monkeys and provides insights into the multiple platyrrhine radiations, diversifications, extinctions, and recolonizations that have taken place over time and over space in the Neotropics. Here, we synthesize genetic and biogeographic research from the past several years to construct an overarching hypothesis for platyrrhine evolution. We also highlight continuing controversies in Neotropical primate biogeography, such as whether the location of origin of platyrrhines was Africa or Asia; whether Patagonian fossil primates are stem or crown platyrrhines; and whether cis- and trans-Andean Neotropical primates were subject to vicariance through Andes mountain building, or instead diversified through isolation in mountain valleys after skirting around the Andes on the northwestern coast of South America. We also consider the role of the Amazon River and its major tributaries in shaping platyrrhine biodiversity, and how and when primates from the Amazon reached the Atlantic Forest. A key focus is on primate colonizations and extirpations in Central America, the Andes, and the seasonally dry tropical forests and savannas (such as the Llanos, Caatinga, and Cerrado habitats), all ecosystems that have been understudied up until now for primates. We suggest that most primates currently inhabiting drier open habitats are relatively recent arrivals, having expanded from rainforest habitats in the Pleistocene. We point to the Pitheciidae as the taxonomic group most in need of further phylogenetic and biogeographic research. Additionally, genomic studies on the Platyrrhini are deeply needed and are expected to bring new surprises and insights to the field of Neotropical primate biogeography. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Workshop summary: neotropical primates in biomedical research.

    PubMed

    Tardif, Suzette D; Abee, Christian R; Mansfield, Keith G

    2011-01-01

    This report summarizes presentations and discussions at an NIH-sponsored workshop on Neotropical Primates in Biomedical Research, held in September 2010. Neotropical primates (New World monkeys), with their smaller size, faster maturation, and shorter lifespans than Old World monkeys, are efficient models and present unique opportunities for studying human health and disease. After overviews of the most commonly used neotropical species-squirrel monkeys, marmosets, and owl monkeys-speakers described the use of neotropical primates in specific areas of immunology, infectious disease, neuroscience, and physiology research. Presentations addressed the development of new research tools: immune-based reagents, fMRI technologies suited to these small primates, sequencing of the marmoset genome, the first germline transgenic monkey, and neotropical primate induced pluripotent stem cells. In the discussions after the presentations, participants identified challenges to both continued use and development of new uses of neotropical primates in research and suggested the following actions to address the challenges: (1) mechanisms to support breeding colonies of some neotropical species to ensure a well-characterized domestic source; (2) resources for the continuing development of critical research tools to improve the immunological and hormonal characterization of neotropical primates; (3) improved opportunities for networking among investigators who use neotropical primates, training and other measures to improve colony and veterinary management, and continued research on neotropical primate management and veterinary care issues; (4) support for development activities to produce models that are more affordable and more efficient for moving research "from benchside to bedside"; and (5) establishment of a small program that would fund "orphan" species.

  11. PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel

    PubMed Central

    Yang, Lin; Clarke, Michelle J.; Carlson, Brett L.; Mladek, Ann C.; Schroeder, Mark A.; Decker, Paul; Wu, Wenting; Kitange, Gaspar J.; Grogan, Patrick T.; Goble, Jennie M.; Uhm, Joon; Galanis, Evanthia; Giannini, Caterina; Lane, Heidi A.; James, C. David; Sarkaria, Jann N.

    2014-01-01

    Purpose Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus). Experimental Design To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN. Results Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy. Conclusion These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme. PMID:18559622

  12. Primates in 21st century ecosystems: does primate conservation promote ecosystem conservation?

    PubMed

    Norconk, Marilyn A; Boinski, Sue; Forget, Pierre-Michel

    2011-01-01

    Contributors to this issue of the American Journal of Primatology were among the participants in an invited symposium at the 2008 Association for Tropical Biology and Conservation meeting in Paramaribo, Suriname. They were asked to assess how essential primates are to tropical ecosystems and, given their research interests, discuss how primate research contributes to the broader understanding about how ecosystems function. This introduction to the issue is divided into three parts: a review of the roles that nonhuman primates play in tropical ecosystems; the implementation of large-scale landscape methods used to identify primate densities; and concerns about the increasingly porous boundaries between humans, nonhuman primates, and pathogens. Although 20th century primate research created a rich database on individual species, including both theoretical and descriptive approaches, the dual effects of high human population densities and widespread habitat destruction should warn us that creative, interdisciplinary and human-related research is needed to solve 21st century problems.

  13. The Automated Primate Research Laboratory (APRL)

    NASA Technical Reports Server (NTRS)

    Pace, N.; Smith, G. D.

    1972-01-01

    A description is given of a self-contained automated primate research laboratory to study the effects of weightlessness on subhuman primates. Physiological parameters such as hemodynamics, respiration, blood constituents, waste, and diet and nutrition are analyzed for abnormalities in the simulated space environment. The Southeast Asian pig-tailed monkey (Macaca nemistrina) was selected for the experiments owing to its relative intelligence and learning capacity. The objective of the program is to demonstrate the feasibility of a man-tended primate space flight experiment.

  14. Pulmonary pneumocystosis in nonhuman primates.

    PubMed

    Chandler, F W; McClure, H M; Campbell, W G; Watts, J C

    1976-03-01

    Pulmonary infection with Pneumocystis carinii was detected in two aged owl monkeys (Aotus trivirgatus) and two young chimpanzees (Pan troglodytes). The clinical histories of the owl monkeys were similar and included progressive weight loss, anorexia, failure to thrive, and death. One of the owl monkeys had no concurrent disease, whereas the other had been experimentally inoculated with Treponema pallidum 44 months before death. In both chimpanzees, an underlying myeloproliferative malignant neoplasm was associated with Pneumocystis infection. Pneumocystis organisms were found in alveolar spaces and alveolar lining cells by light and electron microscopy. Pathologic features of these untreated cases and a case in a chimpanzee treated with pentamidine isethionate were similar to those described in humans. To our knowledge, this is the first report of pulmonary pneumocystosis associated with death in nonhuman primates.

  15. Transplant services

    MedlinePlus

    ... that you may have. References Herman M, Keaveny AP. Organ transplantation. In: Walsh D, Caraceni AT, Fainsinger ... Support Get email updates Subscribe to RSS Follow us Disclaimers Copyright Privacy Accessibility Quality Guidelines Viewers & Players ...

  16. Pancreas Transplantation

    MedlinePlus

    The pancreas is a gland behind your stomach and in front of your spine. It produces the juices that ... hormones that help control blood sugar levels. A pancreas transplant is surgery to place a healthy pancreas ...

  17. Pancreas Transplantation

    MedlinePlus

    ... for Association Events Messaging Tools Recruiting Advocates Local Market Planning Training Webinars News & Events Advocacy News Call ... risky. Each person needs to carefully weigh the potential benefits and risks. Benefits of Pancreas Transplants You ...

  18. Heart transplant

    MedlinePlus

    ... will reject it. You are put into a deep sleep with general anesthesia , and a cut is ... Bleeding Infection Risks of transplant include: Blood clots ( deep venous thrombosis ) Damage to the kidneys, liver, or ...

  19. Lung transplant

    MedlinePlus

    ... diseases that may require a lung transplant are: Cystic fibrosis Damage to the arteries of the lung because ... BC; Clinical Practice Guidelines for Pulmonary Therapies Committee; ... Therapies Committee. Cystic fibrosis pulmonary guidelines: ...

  20. Liver Transplant

    MedlinePlus

    ... Trials Porphyria Primary Biliary Cholangitis Definition & Facts Symptoms & Causes Diagnosis Treatment Eating, Diet, & Nutrition Clinical Trials Primary Sclerosing Cholangitis Wilson Disease Liver Disease A-Z Liver Transplant View or ...

  1. Lung Transplant

    MedlinePlus

    ... will recover in the hospital’s intensive care unit (ICU) before moving to a hospital room for one to three weeks. Your doctor may recommend pulmonary rehabilitation after your lung transplant surgery to help you ...

  2. Heart Transplant

    MedlinePlus

    ... of this information Order our Heart Transplant brochure Video: Preparing For Your Surgery Find helpful tips from ... how to plan and prepare for your surgery. Video: Recovering From Your Surgery Find helpful tips from ...

  3. Patient-derived xenograft (PDX) models in basic and translational breast cancer research.

    PubMed

    Dobrolecki, Lacey E; Airhart, Susie D; Alferez, Denis G; Aparicio, Samuel; Behbod, Fariba; Bentires-Alj, Mohamed; Brisken, Cathrin; Bult, Carol J; Cai, Shirong; Clarke, Robert B; Dowst, Heidi; Ellis, Matthew J; Gonzalez-Suarez, Eva; Iggo, Richard D; Kabos, Peter; Li, Shunqiang; Lindeman, Geoffrey J; Marangoni, Elisabetta; McCoy, Aaron; Meric-Bernstam, Funda; Piwnica-Worms, Helen; Poupon, Marie-France; Reis-Filho, Jorge; Sartorius, Carol A; Scabia, Valentina; Sflomos, George; Tu, Yizheng; Vaillant, François; Visvader, Jane E; Welm, Alana; Wicha, Max S; Lewis, Michael T

    2016-12-01

    Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.

  4. Development of Patient Derived Xenograft Models of Overt Spontaneous Breast Cancer Metastasis: A Cautionary Note

    PubMed Central

    Paez-Ribes, Marta; Man, Shan; Xu, Ping; Kerbel, Robert S.

    2016-01-01

    Several approaches are being evaluated to improve the historically limited value of studying transplanted primary tumors derived by injection of cells from established cell lines for predicting subsequent cancer therapy outcomes in patients and clinical trials. These approaches include use of genetically engineered mouse models (GEMMs) of spontaneous tumors, or patient tumor tissue derived xenografts (PDXs). Almost all such therapy studies utilizing such models involve treatment of established primary tumors. An alternative approach we have developed involves transplanted human tumor xenografts derived from established cell lines to treat mice with overt visceral metastases after primary tumor resection. The rationale is to mimic the more challenging circumstance of treating patients with late stage metastatic disease. These metastatic models entail prior in vivo selection of heritable, phenotypically stable variants with increased aggressiveness for spontaneous metastasis; they were derived by orthotopic injection of tumor cells followed by primary tumor resection and serial selection of distant spontaneous metastases, from which variant cell lines having a more aggressive heritable metastatic phenotype were established. We attempted to adopt this strategy for breast cancer PDXs. We studied five breast cancer PDXs, with the emphasis on two, called HCI-001 and HCI-002, both derived from triple negative breast cancer patients. However significant technical obstacles were encountered. These include the inherent slow growth rates of PDXs, the rarity of overt spontaneous metastases (detected in only 3 of 144 mice), very high rates of tumor regrowths at the primary tumor resection site, the failure of the few human PDX metastases isolated to manifest a more aggressive metastatic phenotype upon re-transplantation into new hosts, and the formation of metastases which were derived from de novo mouse thymomas arising in aged SCID mice that we used for the experiments. We

  5. The future of human uterus transplantation.

    PubMed

    Johannesson, Liza; Dahm-Kähler, Pernilla; Eklind, Saskia; Brännström, Mats

    2014-07-01

    The only untreatable subgroup of female infertility is absolute uterine factor infertility (AUFI), which is due to congenital or surgical absence of a uterus or presence of a nonfunctional uterus. The solitary option for a woman with AUFI to become a biological mother today is through a gestational surrogate mother, a procedure that is prohibited in Sweden and large parts of the world. Uterus transplantation (UTx) is a potential future treatment of AUFI. After extensive animal research, also involving non-human primates, a small number of human UTx cases have recently been performed. Here, we summarize the primate UTx experiments that have paved the way for the human UTx cases, which are described and analyzed in more detail. We also estimate how many women of fertile age are affected by AUFI and describe the causes. The ethics around UTx is complex and is also addressed.

  6. Zebrafish Xenograft: An Evolutionary Experiment in Tumour Biology.

    PubMed

    Wyatt, Rachael A; Trieu, Nhu P V; Crawford, Bryan D

    2017-09-05

    Though the cancer research community has used mouse xenografts for decades more than zebrafish xenografts, zebrafish have much to offer: they are cheap, easy to work with, and the embryonic model is relatively easy to use in high-throughput assays. Zebrafish can be imaged live, allowing us to observe cellular and molecular processes in vivo in real time. Opponents dismiss the zebrafish model due to the evolutionary distance between zebrafish and humans, as compared to mice, but proponents argue for the zebrafish xenograft's superiority to cell culture systems and its advantages in imaging. This review places the zebrafish xenograft in the context of current views on cancer and gives an overview of how several aspects of this evolutionary disease can be addressed in the zebrafish model. Zebrafish are missing homologs of some human proteins and (of particular interest) several members of the matrix metalloproteinase (MMP) family of proteases, which are known for their importance in tumour biology. This review draws attention to the implicit evolutionary experiment taking place when the molecular ecology of the xenograft host is significantly different than that of the donor.

  7. Xenograft model for therapeutic drug testing in recurrent respiratory papillomatosis.

    PubMed

    Ahn, Julie; Bishop, Justin A; Akpeng, Belinda; Pai, Sara I; Best, Simon R A

    2015-02-01

    Identifying effective treatment for papillomatosis is limited by a lack of animal models, and there is currently no preclinical model for testing potential therapeutic agents. We hypothesized that xenografting of papilloma may facilitate in vivo drug testing to identify novel treatment options. A biopsy of fresh tracheal papilloma was xenografted into a NOD-scid-IL2Rgamma(null) (NSG) mouse. The xenograft began growing after 5 weeks and was serially passaged over multiple generations. Each generation showed a consistent log-growth pattern, and in all xenografts, the presence of the human papillomavirus (HPV) genome was confirmed by polymerase chain reaction (PCR). Histopathologic analysis demonstrated that the squamous architecture of the original papilloma was maintained in each generation. In vivo drug testing with bevacizumab (5 mg/kg i.p. twice weekly for 3 weeks) showed a dramatic therapeutic response compared to saline control. We report here the first successful case of serial xenografting of a tracheal papilloma in vivo with a therapeutic response observed with drug testing. In severely immunocompromised mice, the HPV genome and squamous differentiation of the papilloma can be maintained for multiple generations. This is a feasible approach to identify therapeutic agents in the treatment of recurrent respiratory papillomatosis. © The Author(s) 2014.

  8. Stem Cell Transplant

    MedlinePlus

    ... transplant is a procedure that infuses healthy blood stem cells into your body to replace your damaged or ... A bone marrow transplant is also called a stem cell transplant. A bone marrow transplant may be necessary ...

  9. International Transplant Nurses Society

    MedlinePlus

    ... the Transplant Nursing Symposium. Register for the Transplant Nursing Symposium Registration is now open for the Transplant ... to non-members. Purchase your copy today! Transplant Nursing Scope & Standards of Practice, 2nd Edition Click the ...

  10. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma.

    PubMed

    Jiang, Zhiwu; Jiang, Xiaofeng; Chen, Suimin; Lai, Yunxin; Wei, Xinru; Li, Baiheng; Lin, Simiao; Wang, Suna; Wu, Qiting; Liang, Qiubin; Liu, Qifa; Peng, Muyun; Yu, Fenglei; Weng, Jianyu; Du, Xin; Pei, Duanqing; Liu, Pentao; Yao, Yao; Xue, Ping; Li, Peng

    2016-01-01

    The lack of a general clinic-relevant model for human cancer is a major impediment to the acceleration of novel therapeutic approaches for clinical use. We propose to establish and characterize primary human hepatocellular carcinoma (HCC) xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR) T cells and accelerate the clinical translation of CAR T cells used in HCC. Primary HCCs were used to establish the xenografts. The morphology, immunological markers, and gene expression characteristics of xenografts were detected and compared to those of the corresponding primary tumors. CAR T cells were adoptively transplanted into patient-derived xenograft (PDX) models of HCC. The cytotoxicity of CAR T cells in vivo was evaluated. PDX1, PDX2, and PDX3 were established using primary tumors from three individual HCC patients. All three PDXs maintained original tumor characteristics in their morphology, immunological markers, and gene expression. Tumors in PDX1 grew relatively slower than that in PDX2 and PDX3. Glypican 3 (GPC3)-CAR T cells efficiently suppressed tumor growth in PDX3 and impressively eradicated tumor cells from PDX1 and PDX2, in which GPC3 proteins were highly expressed. GPC3-CAR T cells were capable of effectively eliminating tumors in PDX model of HCC. Therefore, GPC3-CAR T cell therapy is a promising candidate for HCC treatment.

  11. The use of nonhuman primates in space

    NASA Technical Reports Server (NTRS)

    Simmonds, R. C. (Editor); Bourne, G. H. (Editor)

    1977-01-01

    Space related biomedical research involving nonhuman primates is reviewed. The scientific assets of various species and the instruments used for monitoring physiological processes during long duration experimentations are described.

  12. Biokinetics of Plutonium in Nonhuman Primates.

    PubMed

    Poudel, Deepesh; Guilmette, Raymond A; Gesell, Thomas F; Harris, Jason T; Brey, Richard R

    2016-10-01

    A major source of data on metabolism, excretion and retention of plutonium comes from experimental animal studies. Although old world monkeys are one of the closest living relatives to humans, certain physiological differences do exist between these nonhuman primates and humans. The objective of this paper was to describe the metabolism of plutonium in nonhuman primates using the bioassay and retention data obtained from macaque monkeys injected with plutonium citrate. A biokinetic model for nonhuman primates was developed by adapting the basic model structure and adapting the transfer rates described for metabolism of plutonium in adult humans. Significant changes to the parameters were necessary to explain the shorter retention of plutonium in liver and skeleton of the nonhuman primates, differences in liver to bone partitioning ratio, and significantly higher excretion of plutonium in feces compared to that in humans.

  13. A Mitogenomic Phylogeny of Living Primates

    PubMed Central

    Finstermeier, Knut; Zinner, Dietmar; Brameier, Markus; Meyer, Matthias; Kreuz, Eva; Hofreiter, Michael; Roos, Christian

    2013-01-01

    Primates, the mammalian order including our own species, comprise 480 species in 78 genera. Thus, they represent the third largest of the 18 orders of eutherian mammals. Although recent phylogenetic studies on primates are increasingly built on molecular datasets, most of these studies have focused on taxonomic subgroups within the order. Complete mitochondrial (mt) genomes have proven to be extremely useful in deciphering within-order relationships even up to deep nodes. Using 454 sequencing, we sequenced 32 new complete mt genomes adding 20 previously not represented genera to the phylogenetic reconstruction of the primate tree. With 13 new sequences, the number of complete mt genomes within the parvorder Platyrrhini was widely extended, resulting in a largely resolved branching pattern among New World monkey families. We added 10 new Strepsirrhini mt genomes to the 15 previously available ones, thus almost doubling the number of mt genomes within this clade. Our data allow precise date estimates of all nodes and offer new insights into primate evolution. One major result is a relatively young date for the most recent common ancestor of all living primates which was estimated to 66-69 million years ago, suggesting that the divergence of extant primates started close to the K/T-boundary. Although some relationships remain unclear, the large number of mt genomes used allowed us to reconstruct a robust primate phylogeny which is largely in agreement with previous publications. Finally, we show that mt genomes are a useful tool for resolving primate phylogenetic relationships on various taxonomic levels. PMID:23874967

  14. The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts

    PubMed Central

    Dore-Savard, Louis; Lee, Esak; Kakkad, Samata; Popel, Aleksander S.; Bhujwalla, Zaver M.

    2016-01-01

    The plasticity of cancer cells and the fluidity of the tumor microenvironment continue to present major challenges in the comprehensive understanding of cancer that is essential to design effective treatments. The tumor interstitial fluid (TIF) encompasses the secretome and holds the key to several of the phenotypic characteristics of cancer. Difficulties in sampling this fluid have resulted in limited characterization of its components. Here we have sampled TIF from triple negative and estrogen receptor (ER)-positive human breast tumor xenografts with or without VEGF overexpression. Angiogenesis-related factors were characterized in the TIF and plasma, to understand the relationship between the TIF and plasma secretomes. Clear differences were observed between the TIF and plasma angiogenic secretomes in triple negative MDA-MB-231 breast cancer xenografts compared to ER-positive MCF-7 xenografts with or without VEGF overexpression that provide new insights into TIF components and the role of VEGF in modifying the angiogenic secretome. PMID:27995973

  15. Concerns about human hand transplantation in the 21st century.

    PubMed

    Jones, Neil F

    2002-09-01

    The decision to perform a human hand transplant was justified perhaps on less than an ideal scientific basis-only approximately 60 rat limb transplants and 2 primate limb transplants have survived for longer than 200 days and only 8 of 19 pig limb osteomyocutaneous transplants showed no signs of rejection at 90 days. It seems unlikely that the survival of a human hand transplant will be any better than the survival of a kidney transplant, which has a half-life of approximately 7.5 to 9.5 years. Fourteen hand transplants, however, have now been performed in 11 humans with the skin component of 1 remaining viable up to 3 years after surgery. Intermittent episodes of acute rejection seem to have been relatively simple to reverse by temporarily increasing the dose of immunosuppressive agents and steroids. Chronic rejection has occurred in 1 patient, necessitating re-amputation of the transplanted hand. Active range of motion of the digits has been surprisingly better than would have been expected based on previous results of replantation, but return of sensibility has been less than optimal. The immunosuppression has been well tolerated without any major medical problems or life-threatening episodes, but some patients have developed chronic viral and fungal infections and several have developed posttransplant diabetes. Extrapolating from the previous experience of solid-organ transplants, chronic immunosuppression may predispose a hand transplant patient to an 80% chance of developing an infection, a 20% potential risk of developing posttransplant diabetes, and a 4% to 18% potential risk of developing a malignancy. Even though there is universal agreement that composite tissue allograft transplantation will become the ultimate reconstructive option, no one can predict the eventual role of hand transplantation in the future, but perhaps an international database of these hand transplant patients should be established so that independent reviewers can more objectively

  16. Contextualising primate origins--an ecomorphological framework.

    PubMed

    Soligo, Christophe; Smaers, Jeroen B

    2016-04-01

    Ecomorphology - the characterisation of the adaptive relationship between an organism's morphology and its ecological role - has long been central to theories of the origin and early evolution of the primate order. This is exemplified by two of the most influential theories of primate origins: Matt Cartmill's Visual Predation Hypothesis, and Bob Sussman's Angiosperm Co-Evolution Hypothesis. However, the study of primate origins is constrained by the absence of data directly documenting the events under investigation, and has to rely instead on a fragmentary fossil record and the methodological assumptions inherent in phylogenetic comparative analyses of extant species. These constraints introduce particular challenges for inferring the ecomorphology of primate origins, as morphology and environmental context must first be inferred before the relationship between the two can be considered. Fossils can be integrated in comparative analyses and observations of extant model species and laboratory experiments of form-function relationships are critical for the functional interpretation of the morphology of extinct species. Recent developments have led to important advancements, including phylogenetic comparative methods based on more realistic models of evolution, and improved methods for the inference of clade divergence times, as well as an improved fossil record. This contribution will review current perspectives on the origin and early evolution of primates, paying particular attention to their phylogenetic (including cladistic relationships and character evolution) and environmental (including chronology, geography, and physical environments) contextualisation, before attempting an up-to-date ecomorphological synthesis of primate origins. © 2016 Anatomical Society.

  17. Ontogeny of the nasopalatine duct in primates.

    PubMed

    Shimp, Kristin L; Bhatnagar, Kunwar P; Bonar, Christopher J; Smith, Timothy D

    2003-09-01

    Ecological explanations have been put forward to account for the precocious or delayed development of patency in ducts leading to the vomeronasal organ (VNO) in certain mammals. Perinatal function may be related, in part, to the patency or fusion of the vomeronasal and nasopalatine (NPD) ducts. However, few studies have focused on NPD development in primates, which generally have a prolonged period of dependence during infancy. In this study we examined 24 prenatal primates and 13 neonatal primates, and a comparative sample of fetal mice and insectivores. In embryonic and early fetal Microcebus murinus, the NPD was completely fused, whereas in fetuses of later stages the duct was partially fused or completely patent. M. myoxinus of all stages demonstrated some degree of NPD fusion. In all other prenatal primates, the NPD was fused to some extent. Four prenatal insectivores (Tenrec ecaudatus) showed some degree of NPD fusion. In Mus musculus at 19 days gestation, the NPD was patent, although the anatomically separate VNO duct was fused. T. ecaudatus and most of the neonatal primates revealed complete NPD patency. An exception was Saguinus geoffroyi, which exhibited fusion of the NPD near the VNO opening. These observations may relate to differences in perinatal VNO function. The differences noted in our study suggest that M. murinus and M. myoxinus may differ in perinatal VNO functionality and perhaps in related behavior. Observations of neonatal primates suggest that NPD patency may be relatively common at birth and could serve other purposes in addition to being an access route for VNO stimuli.

  18. A xenograft animal model of human arteriovenous malformations

    PubMed Central

    2013-01-01

    Background Arteriovenous malformations (AVMs) are a type of high-flow vascular malformations that most commonly occurs in the head and neck. They are present at birth but are usually clinically asymptomatic until later in life. The pathogenesis of AVMs remains unclear and therapeutic approaches to AVMs are unsatisfied. In order to provide a tool for studying the pathogenesis and therapies of this disease, we established and studied a xenograft animal model of human AVMs. Methods Fresh human AVMs specimens harvested from 4 patients were sectioned (5x5x5 mm) and xenografted subcutaneously in 5 immunologically naïve nude mice (Athymic Nude-Foxn1nu). Each mouse had four pieces specimens in four quadrants along the back. The grafts were observed weekly for volume, color and texture. The grafts were harvested at every 30 days intervals for histologic examination. All grafts (n = 20) were sectioned and stained for hematoxylin and eosin (H&E). Comparative pathologic evaluation of the grafts and native AVMs were performed by two blinded pathologists. Immunohistochemical examination of human-specific nuclear antigen, vascular endothelial growth factor receptor-2 (VEGFR-2) and Ki-67 was performed. Results Clinical characteristics and pathologic diagnosis of native human derived AVMs were confirmed. 85% (n = 17) of AVM xenografts survived although the sizes decreased after implantation. Histological examination demonstrated numerous small and medium-size vessels and revealed structural characteristics matching the native AVMs tissue.76.5% (n = 13) of the surviving xenografts were positive for Ki-67 and human-specific nuclear antigen suggesting survival of the human derived tissue, 52.9% (n = 9) were positive for VEGFR-2. Conclusions This preliminary xenograft animal model suggests that AVMs can survive in the nude mouse. The presence of human-specific nuclear antigen, VEGFR-2, and Ki-67 demonstrates the stability of native tissue qualities within the

  19. Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors.

    PubMed

    Bondarenko, Gennadiy; Ugolkov, Andrey; Rohan, Stephen; Kulesza, Piotr; Dubrovskyi, Oleksii; Gursel, Demirkan; Mathews, Jeremy; O'Halloran, Thomas V; Wei, Jian J; Mazar, Andrew P

    2015-09-01

    Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients' personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients' samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Follicular development in cryopreserved Common Wombat ovarian tissue xenografted to Nude rats.

    PubMed

    Wolvekamp, M C; Cleary, M L; Cox, S L; Shaw, J M; Jenkin, G; Trounson, A O

    2001-01-31

    The Northern Hairy-nosed Wombat (Lasiorhinus krefftii) is a highly endangered marsupial species and every possible option for sustaining the species needs to be explored. One important approach may be the development of assisted reproductive technologies in the non-endangered Common Wombat (Vombatus ursinus) and Southern Hairy-nosed Wombat (Lasiorhinus latifrons) for application in breeding the Northern Hairy-nosed Wombat. In this study, it was examined whether cryopreserved Wombat ovarian tissue would develop following xenografting to immunologically deficient rats. Ovarian tissue was collected from Common Wombats (n = 3) and cryopreserved as small cortical pieces. After thawing the cortical pieces were grafted underneath the kidney capsule of Nude rats (n = 16). The grafts were recovered at 2, 4, and 10 weeks after transplantation and their gross and histological appearance investigated. Two weeks after grafting (n = 2), the tissue was revascularized and healthy primordial follicles were present. At week 4 (n = 2), some follicular development was present. At week 10, six rats received human chorionic gonadotrophin (hCG) to trigger follicle and oocyte maturation while another six rats were not given any treatment. The administration of hCG did not induce preovulatory follicles and oocyte maturation although type 5 follicles were present in ovarian tissue collected 10 weeks posttransplantation in both treated and untreated groups. This study demonstrates for the first time that Wombat ovarian tissue can survive and function when grafted into immunocompromized rats and that Wombat ovarian follicles can be recruited to growth and development in an ovarian xenograft. This model system has the potential to produce mature oocytes from endangered species for use in assisted reproductive technologies such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and mature oocytes from non-endangered species for nuclear transfer which may be necessary for

  1. Comparative oncological studies of feline bronchioloalveolar lung carcinoma, its derived cell line and xenograft.

    PubMed

    Grossman, Deborah A; Hiti, Alan L; McNiel, Elizabeth A; Ye, Yin; Alpaugh, Mary L; Barsky, Sanford H

    2002-07-01

    Although certain neoplasms are unique to man, others occur across species. One such neoplasm is bronchioloalveolar lung carcinoma (BAC), a neoplasm of the Type II pneumocyte that affects humans, sheep, and small animals (dogs and cats). Human BAC occurs largely in nonsmokers. Sheep BAC is caused by the jaagsiekte retrovirus and is endemic and contagious. Feline BAC is neither endemic nor contagious and occurs sporadically and spontaneously in older purebred cats. In these respects, feline BAC is more closely similar to human BAC than sheep BAC (jaagsiekte) is. To study feline BAC further, we established the first immortal cell line (SPARKY) and transplantable scid mouse xenograft (Sparky-X) from a malignant pleural effusion of a 12-year-old Persian male with autopsy-confirmed BAC. SPARKY exhibited a Type II pneumocyte phenotype characterized by surfactant and thyroid-transcription factor-1 immunoreactivities and lamellar bodies. SPARKY's karyotype was aneuploid (66 chromosomes: 38, normal cat) and showed evidence of genomic instability analogous to human lung cancers. p53 showed a homozygous G to T transversion at codon 167, the feline equivalent of human codon 175, one of the many hot spots mutated in the lung cancers of smokers. H-ras and K-ras were not altered. By reverse transcription-PCR, SPARKY lacked expression of retroviral JSRVgag transcripts that were present in the lungs of sheep BAC (jaagsiekte). Unlike human BAC xenografts, SPARKY-X retained its unique lepidic BAC growth pattern even though it was grown in murine s.c. tissues. This property may be related to the ability of SPARKY-X to up-regulate its surfactant genes (SP-A, SP-B, and SP-D). These studies of feline BAC may allow insights into the human disease that are not possible by studying human BAC directly.

  2. Voice discrimination in four primates.

    PubMed

    Candiotti, Agnès; Zuberbühler, Klaus; Lemasson, Alban

    2013-10-01

    One accepted function of vocalisations is to convey information about the signaller, such as its age-sex class, motivation, or relationship with the recipient. Yet, in natural habitats individuals not only interact with conspecifics but also with members of other species. This is well documented for African forest monkeys, which form semi-permanent mixed-species groups that can persist for decades. Although members of such groups interact with each other on a daily basis, both physically and vocally, it is currently unknown whether they can discriminate familiar and unfamiliar voices of heterospecific group members. We addressed this question with playbacks on monkey species known to form polyspecific associations in the wild: red-capped mangabeys, Campbell's monkeys and Guereza colobus monkeys. We tested subjects' discrimination abilities of contact calls of familiar and unfamiliar female De Brazza monkeys. When pooling all species, subjects looked more often towards the speaker when hearing contact calls of unfamiliar than familiar callers. When testing De Brazza monkeys with their own calls, we found the same effect with the longest gaze durations after hearing unfamiliar voices. This suggests that primates can discriminate, not only between familiar and unfamiliar voices of conspecifics, but also between familiar and unfamiliar voices of heterospecifics living within a close proximity.

  3. Social knowledge and signals in primates.

    PubMed

    Bergman, Thore J; Sheehan, Michael J

    2013-07-01

    Primates are notable for having a rich and detailed understanding of their social environment and there has been great interest in the evolution and function of social knowledge in primates. Indeed, primates have been shown to have impressive understandings of not only other group members but also the complex relationships among them. To be useful, however, social knowledge requires memories from previous encounters and observations about individual traits that are stable. Here, we argue that social systems or traits that make social knowledge more costly or less accurate will favor signals that either supplement or replace social knowledge. Thus, the relationship between signals and social knowledge can be complementary or antagonistic depending on the type of signal. Our goal in this review is to elucidate the relationships between signals and social knowledge in primates. We categorize signals into three types, each with different relationships to social knowledge. (1) Identity signals directly facilitate social knowledge, (2) current-state signals supplement information gained through social knowledge, and (3) badges of status replace social knowledge. Primates rely extensively on identity information, but it remains to be determined to what extent this is based on receiver perception of individual variation or senders using identity signals. Primates frequently utilize current-state signals including signals of intent to augment their interactions with familiar individuals. Badges of status are rare in primates, and the cases where they are used point to a functional and evolutionary trade-off between badges of status and social knowledge. However, the nature of this relationship needs further exploration.

  4. 184AA3: a xenograft model of ER+ breast adenocarcinoma

    SciTech Connect

    Hines, William C.; Kuhn, Irene; Thi, Kate; Chu, Berbie; Stanford-Moore, Gaelen; Sampayo, Rocío; Garbe, James C.; Stampfer, Martha; Borowsky, Alexander D.; Bissell, Mina J.

    2015-12-12

    Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER+) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Xenografts of one cell line, 184AA3, consistently formed ER+ adenocarcinomas that had a high proliferative rate and other features consistent with “luminal B” intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44High subpopulation was discovered, yet their tumor forming ability was far less than CD44Low cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture, and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER+ cancers. This model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development.

  5. Development of human neural transplantation.

    PubMed

    Madrazo, I; Franco-Bourland, R; Aguilera, M; Ostrosky-Solis, F; Cuevas, C; Castrejón, H; Magallón, E; Madrazo, M

    1991-08-01

    The possibility of altering the course of Parkinson's disease by brain grafting is slowly becoming a reality through the efforts of many research groups worldwide. It has been shown that this procedure, as performed in high-level medical research centers, usually produces no permanent adverse effects and can effectively ameliorate parkinsonian signs in certain patients. This progress has served to reinforce our commitment to develop neural transplantation into an effective therapy to treat such a devastating neurodegenerative disease. We have summarized the most important events that have shaped the initial phase of this research. In the course of the last 4 years, considerable knowledge has been gained in the clinical neurosciences regarding the real potential of various brain grafting procedures in treating Parkinson's disease, their shortcomings, and their usefulness in carefully selected patients. There is still no consensus regarding the various fundamental aspects of human brain grafting in Parkinson's disease. Questions concerning surgical technique, candidate selection, the optimal brain regions for implantation, the optimal tissue for implantation, and the real usefulness of brain grafting must be addressed. The importance of the quality of adrenal medulla fragments for grafting, the requirement for immunosuppressors in fetal brain grafting, and the optimal fetal age and the amount of donor tissue for effective grafting are additional areas of concern. The potential of xenografting, preserved tissues, and genetically engineered cells for human brain grafting remain unanswered. The development of human neural transplantation is the responsibility and privilege of neurosurgery.

  6. Transplant production

    USDA-ARS?s Scientific Manuscript database

    For field pepper (Capsicum spp.) production, plants can be established from direct seed or transplants depending on the location and cultural practices for the specific pepper type grown. Direct seeding can result in slow, variable, and reduced plant stands due to variations in soil temperature, wat...

  7. Heart Transplantation

    MedlinePlus

    A heart transplant removes a damaged or diseased heart and replaces it with a healthy one. The healthy heart comes from a donor who has died. It is the last resort for people with heart failure when all other treatments have failed. The ...

  8. A brief history of corneal transplantation: From ancient to modern.

    PubMed

    Crawford, Alexandra Z; Patel, Dipika V; McGhee, Charles Nj

    2013-09-01

    This review highlights many of the fundamental concepts and events in the development of corneal transplantation - from ancient times to modern. Tales of eye, limb, and even heart transplantation appear in ancient and medieval texts; however, in the scientific sense, the original concepts of corneal surgery date back to the Greek physician Galen (130-200 AD). Although proposals to provide improved corneal clarity by surgical interventions, including keratoprostheses, were better developed by the 17(th) and 18(th) centuries, true scientific and surgical experimentation in this field did not begin until the 19(th) century. Indeed, the success of contemporary corneal transplantation is largely the result of a culmination of pivotal ideas, experimentation, and perseverance by inspired individuals over the last 200 years. Franz Reisinger initiated experimental animal corneal transplantation in 1818, coining the term "keratoplasty". Subsequently, Wilhelmus Thorne created the term corneal transplant and 3 years later Samuel Bigger, 1837, reported successful corneal transplantation in a gazelle. The first recorded therapeutic corneal xenograft on a human was reported shortly thereafter in 1838-unsurprisingly this was unsuccessful. Further progress in corneal transplantation was significantly hindered by limited understanding of antiseptic principles, anesthesiology, surgical technique, and immunology. There ensued an extremely prolonged period of debate and experimentation upon the utility of animal compared to human tissue, and lamellar versus penetrating keratoplasty. Indeed, the first successful human corneal transplant was not performed by Eduard Zirm until 1905. Since that first successful corneal transplant, innumerable ophthalmologists have contributed to the development and refinement of corneal transplantation aided by the development of surgical microscopes, refined suture materials, the development of eye banks, and the introduction of corticosteroids. Recent

  9. A brief history of corneal transplantation: From ancient to modern

    PubMed Central

    Crawford, Alexandra Z; Patel, Dipika V; McGhee, Charles NJ

    2013-01-01

    This review highlights many of the fundamental concepts and events in the development of corneal transplantation – from ancient times to modern. Tales of eye, limb, and even heart transplantation appear in ancient and medieval texts; however, in the scientific sense, the original concepts of corneal surgery date back to the Greek physician Galen (130-200 AD). Although proposals to provide improved corneal clarity by surgical interventions, including keratoprostheses, were better developed by the 17th and 18th centuries, true scientific and surgical experimentation in this field did not begin until the 19th century. Indeed, the success of contemporary corneal transplantation is largely the result of a culmination of pivotal ideas, experimentation, and perseverance by inspired individuals over the last 200 years. Franz Reisinger initiated experimental animal corneal transplantation in 1818, coining the term “keratoplasty”. Subsequently, Wilhelmus Thorne created the term corneal transplant and 3 years later Samuel Bigger, 1837, reported successful corneal transplantation in a gazelle. The first recorded therapeutic corneal xenograft on a human was reported shortly thereafter in 1838—unsurprisingly this was unsuccessful. Further progress in corneal transplantation was significantly hindered by limited understanding of antiseptic principles, anesthesiology, surgical technique, and immunology. There ensued an extremely prolonged period of debate and experimentation upon the utility of animal compared to human tissue, and lamellar versus penetrating keratoplasty. Indeed, the first successful human corneal transplant was not performed by Eduard Zirm until 1905. Since that first successful corneal transplant, innumerable ophthalmologists have contributed to the development and refinement of corneal transplantation aided by the development of surgical microscopes, refined suture materials, the development of eye banks, and the introduction of corticosteroids. Recent

  10. Sperm Morphology Assessment in Captive Neotropical Primates.

    PubMed

    Swanson, W F; Valle, R R; Carvalho, F M; Arakaki, P R; Rodas-Martínez, A Z; Muniz, Japc; García-Herreros, M

    2016-08-01

    The main objective of this study was to evaluate sperm morphology in four neotropical primate species to compare the sperm morphological traits and the sperm morphometric parameters as a basis for establishing normative sperm standards for each species. Data from 80 ejaculates collected from four primate species, Callithrix jacchus, Callimico goeldii, Alouatta caraya and Ateles geoffroyi, were analysed for detection of sperm morphological alterations using subjective World Health Organization (WHO-2010) standards and Sperm Deformity Index (SDI) criteria, objective computer-assisted sperm morphometry analysis (CASMA) and subpopulation sperm determination (SSD) methods. There were multiple differences (p < 0.01) observed among primate species in values obtained from WHO-2010, SDI, CASMA and SSD sperm analysis methods. In addition, multiple significant positive and negative correlations were observed between the sperm morphological traits (SDI, Sperm Deformity Index Head Defects, Sperm Deformity Index Midpiece Defects, Sperm Deformity Index Tail Defects, Normal Sperm, Head Defects, Midpiece Defects and Tail Defects) and the sperm morphometric parameters (SSD, Area (A), Perimeter (P), Length (L), Width (W), Ellipticity, Elongation and Rugosity) (p ≤ 0.046). In conclusion, our findings using different evaluation methods indicate that pronounced sperm morphological variation exists among these four neotropical primate species. Because of the strong relationship observed among morphological and morphometric parameters, these results suggest that application of objective analysis methods could substantially improve the reliability of comparative studies and help to establish valid normative sperm values for neotropical primates.

  11. How primates (including us!) respond to inequity.

    PubMed

    Brosnan, Sarah F

    2008-01-01

    Responding negatively to inequity is not a uniquely human trait. Some of our closest evolutionary ancestors respond negatively when treated less well than a conspecific. Comparative work between humans and other primates can help elucidate the evolutionary underpinnings of humans' social preferences. Results from studies of nonhuman primates, in particular chimpanzees and capuchin monkeys, are presented in comparison to human results that have been collected during economic game studies in humans, such as in the Ultimatum Game or Impunity Game. Among nonhuman primates, a frequent behavioral reaction to inequity is to refuse to continue the interaction. While in some cases this response appears to be caused by the inequitable distribution, in others, it seems to be caused by another individual's inequitable behavior. While these reactions are similar to those of humans, this reaction does not appear to be a sense of fairness in the way that we think of it in humans. Neither nonhuman primate species alters their behavior when they are the benefited individual, and in an experimental situation, chimpanzees do not alter their behavior to obtain food for their partner as well as for themselves. Although there are differences between human and nonhuman primate responses, such studies allow us to better understand the evolution of our own responses to inequity. Given the strong behavioral reactions that even monkeys show to inequitable treatment, it is not surprising that humans are concerned with equity. Such comparisons increase understanding of issues such as healthcare disparities in humans.

  12. Endocrine function after immunosuppression of pancreatic allograft by ionizing irradiation in the primate

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Laker, L.; Els, D.; Weideman, A.; Wolfe-Coote, S.; Du Toit, L.B.

    1986-05-01

    The object of this preliminary study was to evaluate the endocrine function after heterotopic intraperitoneal segmental pancreatic allotransplantation with unligated duct in irradiated, totally pancreatectomized primates. All allograft recipients received, pre- and peroperative donor-specific blood transfusions and peroperative external irradiation from a linear accelerator; 200 rads was administered weekly and increased to a total dose of 1,500 rads. Pancreatic transplantation was performed between 2 and 6 weeks after completion of irradiation and preoperative blood transfusions. As previously reported, only minimal pancreatic allograft survival was achieved following preoperative irradiation. One recipient remained normoglycaemic for greater than 100 days after transplantation, the longest surviving pancreatic allograft recipient reported from this laboratory. Intravenous glucose tolerance test results in this recipient revealed normoglycaemia, reduced K-value, hypoinsulinaemia, normal glucagon response, reduced C-peptide values, and moderate glucose intolerance. Aortography and electron-microscopic examination of allograft biopsy tissue confirmed the presence of a functioning allograft.

  13. Operant nociception in nonhuman primates.

    PubMed

    Kangas, Brian D; Bergman, Jack

    2014-09-01

    The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.

  14. Convergent evolution in primates and an insectivore

    SciTech Connect

    Boffelli, Dario; Cheng, Jan-Fang; Rubin, Edward M.

    2003-04-16

    The cardiovascular risk factor apolipoprotein(a) (apo(a)) has a puzzling distribution among mammals, its presence being limited to a subset of primates and a member of the insectivore lineage, the hedgehog. To explore the evolutionary history of apo(a), we performed extensive genomic sequence comparisons of multiple species with and without an apo(a) gene product, such as human, baboon, hedgehog, lemurand mouse. This analysis indicated that apo(a) arose independently in a subset of primates, including baboon and human, and an insectivore, the hedgehog, and was not simply lost by species lacking it. The similar structural domains shared by the hedgehog and primate apo(a) indicate that they were formed by a unique molecular mechanism involving the convergent evolution of paralogous genes in these distantspecies.

  15. Genetic correlates of the evolving primate brain

    PubMed Central

    Vallender, Eric J.

    2012-01-01

    The tremendous shifts in the size, structure, and function of the brain during primate evolution are ultimately caused by changes at the genetic level. Understanding what these changes are and how they effect the phenotypic changes observed lies at the heart of understanding evolutionary change. This chapter focuses on understanding the genetic basis of primate brain evolution, considering the substrates and mechanisms through which genetic change occurs. It also discusses the implications that our current understandings and tools have for what we have already discovered and where our studies will head in the future. While genetic and genomic studies have identified many regions undergoing positive selection during primate evolution, the findings are certainly not exhaustive and functional relevance remains to be confirmed. Nevertheless, a strong foundation has been built upon which future studies will emerge. PMID:22230621

  16. The ecology of primate material culture

    PubMed Central

    Koops, Kathelijne; Visalberghi, Elisabetta; van Schaik, Carel P.

    2014-01-01

    Tool use in extant primates may inform our understanding of the conditions that favoured the expansion of hominin technology and material culture. The ‘method of exclusion’ has, arguably, confirmed the presence of culture in wild animal populations by excluding ecological and genetic explanations for geographical variation in behaviour. However, this method neglects ecological influences on culture, which, ironically, may be critical for understanding technology and thus material culture. We review all the current evidence for the role of ecology in shaping material culture in three habitual tool-using non-human primates: chimpanzees, orangutans and capuchin monkeys. We show that environmental opportunity, rather than necessity, is the main driver. We argue that a better understanding of primate technology requires explicit investigation of the role of ecological conditions. We propose a model in which three sets of factors, namely environment, sociality and cognition, influence invention, transmission and retention of material culture. PMID:25392310

  17. The social nature of primate cognition

    PubMed Central

    Barrett, Louise; Henzi, Peter

    2005-01-01

    The hypothesis that the enlarged brain size of the primates was selected for by social, rather than purely ecological, factors has been strongly influential in studies of primate cognition and behaviour over the past two decades. However, the Machiavellian intelligence hypothesis, also known as the social brain hypothesis, tends to emphasize certain traits and behaviours, like exploitation and deception, at the expense of others, such as tolerance and behavioural coordination, and therefore presents only one view of how social life may shape cognition. This review outlines work from other relevant disciplines, including evolutionary economics, cognitive science and neurophysiology, to illustrate how these can be used to build a more general theoretical framework, incorporating notions of embodied and distributed cognition, in which to situate questions concerning the evolution of primate social cognition. PMID:16191591

  18. Recent advances in primate nutritional ecology.

    PubMed

    Righini, Nicoletta

    2017-04-01

    Nutritional ecology seeks to explain, in an ecological and evolutionary context, how individuals choose, acquire, and process food to satisfy their nutritional requirements. Historically, studies of primate feeding ecology have focused on characterizing diets in terms of the botanical composition of the plants consumed. Further, dietary studies have demonstrated how patch and food choice in relation to time spent foraging and feeding are influenced by the spatial and temporal distribution of resources and by social factors such as feeding competition, dominance, or partner preferences. From a nutritional perspective, several theories including energy and protein-to-fiber maximization, nutrient mixing, and toxin avoidance, have been proposed to explain the food choices of non-human primates. However, more recently, analytical frameworks such as nutritional geometry have been incorporated into primatology to explore, using a multivariate approach, the synergistic effects of multiple nutrients, secondary metabolites, and energy requirements on primate food choice. Dietary strategies associated with nutrient balancing highlight the tradeoffs that primates face in bypassing or selecting particular feeding sites and food items. In this Special Issue, the authors bring together a set of studies focusing on the nutritional ecology of a diverse set of primate taxa characterized by marked differences in dietary emphasis. The authors present, compare, and discuss the diversity of strategies used by primates in diet selection, and how species differences in ecology, physiology, anatomy, and phylogeny can affect patterns of nutrient choice and nutrient balancing. The use of a nutritionally explicit analytical framework is fundamental to identify the nutritional requirements of different individuals of a given species, and through its application, direct conservation efforts can be applied to regenerate and protect specific foods and food patches that offer the opportunity of a

  19. Asian Primate Species Richness Correlates with Rainfall

    PubMed Central

    Wang, Yi-Chen; Srivathsan, Amrita; Feng, Chen-Chieh; Salim, Agus; Shekelle, Myron

    2013-01-01

    Previous studies of meta-analyses found significantly positive correlations between primate species richness and rainfall for Africa, Madagascar and the Neotropics, with the exception of Asia, leaving the open question whether that anomaly is the result of sampling bias, biogeography, or some other factor. This study re-examines the question using modelled data, with primate species richness data from the Southeast Asian Mammals Databank and rainfall data from the Climatic Research Unit. Data processing with Geographical Information Systems resulted in 390 sample points. Reduced major axis and ordinary least squares regressions were employed to examine the relationship for six regions, including the whole study area of Southeast Asia, and the subareas of Huxley West, Huxley East, Mainland Southeast Asia, Borneo, and Sumatra. The results showed a significant positive relationship between primate species richness and mean annual rainfall for Southeast Asia (r = 0.26, P<0.001). Comparing the results for the large islands and Mainland Southeast Asia showed that Sumatra had the highest correlation (r = 0.58; P<0.05). After controlling for the major biogeographic effect associated with Huxley’s Line, our results showed that primate species richness is positively associated with mean annual rainfall in Southeast Asia. Our findings contrast to prior studies of meta-analyses that showed no relationship between rainfall and primate species richness in Asia, and thereby bring Asia into agreement with results showing significant positive correlations between rainfall and primate species richness everywhere else in the world. The inference is that previous anomalous results for Asia were result of sampling bias in the meta-analysis. PMID:23383023

  20. AAV9-mediated engineering of autotransplanted kidney of non-human primates.

    PubMed

    Tomasoni, S; Trionfini, P; Azzollini, N; Zentilin, L; Giacca, M; Aiello, S; Longaretti, L; Cozzi, E; Baldan, N; Remuzzi, G; Benigni, A

    2017-05-01

    Ex vivo gene transfer to the graft before transplantation is an attractive option for circumventing systemic side effects of chronic antirejection therapy. Gene delivery of the immunomodulatory protein cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) prevented chronic kidney rejection in a rat model of allotransplantation without the need for systemic immunosuppression. Here we generated adeno-associated virus type 2 (AAV2) and AAV9 vectors encoding for LEA29Y, an optimized version of CTLA4-Ig. Both LEA29Y vectors were equally efficient for reducing T-cell proliferation in vitro. Serotype 9 was chosen for in vivo experiments owing to a lower frequency of preformed antibodies against the AAV9 capsid in 16 non-human primate tested sera. AAV9-LEA29Y was able to transduce the kidney of non-human primates in an autotransplantation model. Expression of LEA29Y mRNA by renal cells translated into the production of the corresponding protein, which was confined to the graft but not detected in serum. Results in non-human primates represent a step forward in maintaining the portability of this strategy into clinics.

  1. Human CD55 Expression Blocks Hyperacute Rejection and Restricts Complement Activation in Gal Knockout Cardiac Xenografts

    PubMed Central

    McGregor, Christopher G.A.; Ricci, Davide; Miyagi, Naoto; Stalboerger, Paul G.; Du, Zeji; Oehler, Elise A.; Tazelaar, Henry D.; Byrne, Guerard W.

    2012-01-01

    Background Transgenic expression of human complement regulatory proteins (hCRPs) reduces the frequency of hyperacute rejection (HAR) in Gal-positive cardiac xenotransplantation. In this study we examine the impact of human CD55 (hCD55) expression on a Gal knock-out (GTKO) background using pig-to-primate heterotopic cardiac xenotransplantation. Methods Cardiac xenotransplantation was performed with GTKO (Group 1; n=6) and GTKO.hCD55 (Group 2; n=5) donor pigs using similar immunosuppression. Cardiac biopsies were obtained 30 minutes after organ reperfusion. Rejection was characterized by histology and immunohistology. Intragraft gene expression, serum non-Gal antibody and antibody recovered from rejected hearts were analyzed. Results HAR of a GTKO heart was observed. Remaining grafts developed delayed xenograft rejection. Median survival was 21 and 28 days for Groups 1 and 2 respectively. Vascular antibody deposition was uniformly detected 30 minutes after organ reperfusion and at explant. A higher frequency of vascular C5b deposition was seen in GTKO organs at explant. Serum non-Gal antibody, antibody recovered from the graft and intragraft gene expression were similar between the groups. Conclusion HAR of GTKO hearts without hCD55 may occur. Expression of hCD55 appeared to restrict local complement activation, but did not improve graft survival. Chronic vascular antibody deposition with evidence of protracted endothelial cell activation was seen. These observations suggest that non-Gal antibody-induced chronic endothelial cell activation coupled to possible haemostatic incompatibilities may be the primary stimulus for DXR of GTKO hearts. To avoid possible HAR, future clinical studies should employ donors expressing hCRPs in the GTKO background. PMID:22391577

  2. Learning about primates' learning, language, and cognition

    NASA Technical Reports Server (NTRS)

    Rumbaugh, Duane M.

    1992-01-01

    Results are presented of many years of research on the methods of teaching primates the language and cognitive skills which were long considered to be unteachable to particular species of primates. It was found that chimpanzee subjects could not only learn a number of 'stock sentences' but to use them in variations and several combinations for the purpose of solving various problems. Apes placed in different rooms could be taught to communicate via computer, and collaborate with each other on doing specific tasks. Contrary to expectations, young rhesus monkeys proved to be able to learn as much as the chimpanzee species.

  3. Scaling of rotational inertia of primate mandibles.

    PubMed

    Ross, Callum F; Iriarte-Diaz, Jose; Platts, Ellen; Walsh, Treva; Heins, Liam; Gerstner, Geoffrey E; Taylor, Andrea B

    2017-05-01

    The relative importance of pendulum mechanics and muscle mechanics in chewing dynamics has implications for understanding the optimality criteria driving the evolution of primate feeding systems. The Spring Model (Ross et al., 2009b), which modeled the primate chewing system as a forced mass-spring system, predicted that chew cycle time would increase faster than was actually observed. We hypothesized that if mandibular momentum plays an important role in chewing dynamics, more accurate estimates of the rotational inertia of the mandible would improve the accuracy with which the Spring Model predicts the scaling of primate chew cycle period. However, if mass-related momentum effects are of negligible importance in the scaling of primate chew cycle period, this hypothesis would be falsified. We also predicted that greater "robusticity" of anthropoid mandibles compared with prosimians would be associated with higher moments of inertia. From computed tomography scans, we estimated the scaling of the moment of inertia (Ij) of the mandibles of thirty-one species of primates, including 22 anthropoid and nine prosimian species, separating Ij into the moment about a transverse axis through the center of mass (Ixx) and the moment of the center of mass about plausible axes of rotation. We found that across primates Ij increases with positive allometry relative to jaw length, primarily due to positive allometry of jaw mass and Ixx, and that anthropoid mandibles have greater rotational inertia compared with prosimian mandibles of similar length. Positive allometry of Ij of primate mandibles actually lowers the predictive ability of the Spring Model, suggesting that scaling of primate chew cycle period, and chewing dynamics in general, are more strongly influenced by factors other than scaling of inertial properties of the mandible, such as the dynamic properties of the jaw muscles and neural control. Differences in cycle period scaling between chewing and locomotion systems

  4. The primate semicircular canal system and locomotion

    PubMed Central

    Spoor, Fred; Garland, Theodore; Krovitz, Gail; Ryan, Timothy M.; Silcox, Mary T.; Walker, Alan

    2007-01-01

    The semicircular canal system of vertebrates helps coordinate body movements, including stabilization of gaze during locomotion. Quantitative phylogenetically informed analysis of the radius of curvature of the three semicircular canals in 91 extant and recently extinct primate species and 119 other mammalian taxa provide support for the hypothesis that canal size varies in relation to the jerkiness of head motion during locomotion. Primate and other mammalian species studied here that are agile and have fast, jerky locomotion have significantly larger canals relative to body mass than those that move more cautiously. PMID:17576932

  5. Effective primate conservation education: gaps and opportunities.

    PubMed

    Jacobson, Susan K

    2010-05-01

    Conservation education goals generally include influencing people's conservation awareness, attitudes, and behaviors. Effective programs can help foster sustainable behavior, improve public support for conservation, reduce vandalism and poaching in protected areas, improve compliance with conservation regulations, increase recreation carrying capacities, and influence policies and decisions that affect the environment. Primate conservation problems cut across many disciplines, and primate conservation education must likewise address cross-disciplinary issues. Conservation educators must incorporate both theoretical and practical knowledge and skills to develop effective programs, and the skill set must stretch beyond pedagogy. Expertise needed comes from the areas of planning, collaboration, psychology, entertainment, and evaluation. Integration of these elements can lead to greater program success.

  6. Learning about primates' learning, language, and cognition

    NASA Technical Reports Server (NTRS)

    Rumbaugh, Duane M.

    1992-01-01

    Results are presented of many years of research on the methods of teaching primates the language and cognitive skills which were long considered to be unteachable to particular species of primates. It was found that chimpanzee subjects could not only learn a number of 'stock sentences' but to use them in variations and several combinations for the purpose of solving various problems. Apes placed in different rooms could be taught to communicate via computer, and collaborate with each other on doing specific tasks. Contrary to expectations, young rhesus monkeys proved to be able to learn as much as the chimpanzee species.

  7. Primate feedstock for the evolution of consonants.

    PubMed

    Lameira, Adriano R; Maddieson, Ian; Zuberbühler, Klaus

    2014-02-01

    The evolution of speech remains an elusive scientific problem. A widespread notion is that vocal learning, underlined by vocal-fold control, is a key prerequisite for speech evolution. Although present in birds and non-primate mammals, vocal learning is ostensibly absent in non-human primates. Here we argue that the main road to speech evolution has been through controlling the supralaryngeal vocal tract, for which we find evidence for evolutionary continuity within the great apes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Labeling of breast cancer patient-derived xenografts with traceable reporters for tumor growth and metastasis studies

    PubMed Central

    Hanna, Colton; Kwok, Letty; Finlay-Schultz, Jessica; Sartorius, Carol A; Cittelly, Diana M

    2017-01-01

    We describe a method for stable labeling of patient-derived xenografts (PDXs) with lentiviral particles expressing green-fluorescent protein and luciferase reporters. This method allows for tracking the growth of PDXs at the primary site, as well as detecting spontaneous and experimental metastases using in vivo imaging systems. The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many transgenic mouse models, often fail to recapitulate the key aspects of human malignancies. Thus, alternative models that better represent the heterogeneity of patients’ tumors and their metastases are being developed. Patient-derived xenograft (PDX) models in which surgically resected tumor samples are engrafted into immunocompromised mice have become an attractive alternative as they can be transplanted through multiple generations, and more efficiently reflect tumor heterogeneity than xenografts derived from human cancer cell lines. A limitation to the use of PDXs is that they are difficult to transfect or transduce to introduce traceable reporters or to manipulate gene expression. The current protocol describes methods to transduce dissociated tumor cells from PDXs with high transduction efficiency, and the use of labeled PDXs for experimental models of breast cancer metastases. The protocol also demonstrates the use of labeled PDXs in experimental metastasis models to study the organ-colonization process of the metastatic cascade. Metastases to different organs can be easily visualized and quantified using bioluminescent imaging in live animals, or GFP expression during dissection and in excised organs. These methods provide a powerful tool to extend the use of multiple types of PDXs to metastasis research. PMID:27929464

  9. Coinfection of human foreskin fragments with multiple human papillomavirus types (HPV-11, -40, and -LVX82/MM7) produces regionally separate HPV infections within the same athymic mouse xenograft.

    PubMed Central

    Christensen, N D; Koltun, W A; Cladel, N M; Budgeon, L R; Reed, C A; Kreider, J W; Welsh, P A; Patrick, S D; Yang, H

    1997-01-01

    The athymic mouse xenograft system was used to prepare infectious stocks of two additional anogenital tissue-targeting human papillomaviruses (HPVs) in a manner similar to that for the development of infectious stocks of HPV-11. An anal condyloma from a transplant patient was used as material for extraction of infectious virus, and human foreskin fragments were incubated with the virus suspension and transplanted subrenally into athymic mice. Partial viral sequencing indicated that two rare HPV types (HPV-40 and HPVLVX82/MM7) were concurrently present in both the patient condyloma and the foreskin xenografts, and passage of both types was achieved as a mixed infection with HPV-40 predominating. Xenografts that developed from simultaneous infection of human foreskin fragments with HPV-11, -40, and -LVX82/MM7 virions produced regionally separate areas of HPV-11 and -40 infection as determined by in situ hybridization. In addition, in situ hybridization with HPV-40 and HPVLVX82/MM7 DNA probes demonstrated that both of these HPV types were present as adjacent but separate infections within the same anal condyloma of the transplant patient. These studies indicate that multiple HPV types can simultaneously infect genital tissue and that each HPV type predominantly maintains regional separation within the same papilloma. PMID:9311811

  10. Transplant Ethics.

    PubMed

    Altınörs, Nur; Haberal, Mehmet

    2016-11-01

    The aim of this study was to review and discuss the great variety of ethical issues related to organ donation, organ procurement, transplant activities, and new ethical problems created as a result of technologic and scientific developments. An extensive literature survey was made, and expert opinions were obtained. The gap between demand and supply of organs for transplant has yielded to organ trafficking, organ tourism, and commercialism. This problem seems to be the most important issue, and naturally there are ethical dilemmas related to it. A wide number of ideas have been expressed on the subject, and different solutions have been proposed. The struggle against organ trafficking and commercialism should include legislation, efforts to increase deceased-donor donations, and international cooperation. China's policy to procure organs from prisoners sentenced to death is unethical, and the international community should exert more pressure on the Chinese government to cease this practice. Each particular ethical dilemma should be taken separately and managed.

  11. Scaffold-integrated microchips for end-to-end in vitro tumor cell attachment and xenograft formation

    PubMed Central

    Lee, Jungwoo; Kohl, Nathaniel; Shanbhang, Sachin; Parekkadan, Biju

    2015-01-01

    Microfluidic technologies have substantially advanced cancer research by enabling the isolation of rare circulating tumor cells (CTCs) for diagnostic and prognostic purposes. The characterization of isolated CTCs has been limited due to the difficulty in recovering and growing isolated cells with high fidelity. Here, we present a strategy that uses a 3D scaffold, integrated into a microfludic device, as a transferable substrate that can be readily isolated after device operation for serial use in vivo as a transplanted tissue bed. Hydrogel scaffolds were incorporated into a PDMS fluidic chamber prior to bonding and were rehydrated in the chamber after fluid contact. The hydrogel matrix completely filled the fluid chamber, significantly increasing the surface area to volume ratio, and could be directly visualized under a microscope. Computational modeling defined different flow and pressure regimes that guided the conditions used to operate the chip. As a proof of concept using a model cell line, we confirmed human prostate tumor cell attachment in the microfluidic scaffold chip, retrieval of the scaffold en masse, and serial implantation of the scaffold to a mouse model with preserved xenograft development. With further improvement in capture efficiency, this approach can offer an end-to-end platform for the continuous study of isolated cancer cells from a biological fluid to a xenograft in mice. PMID:26709385

  12. Scaffold-integrated microchips for end-to-end in vitro tumor cell attachment and xenograft formation.

    PubMed

    Lee, Jungwoo; Kohl, Nathaniel; Shanbhang, Sachin; Parekkadan, Biju

    2015-12-01

    Microfluidic technologies have substantially advanced cancer research by enabling the isolation of rare circulating tumor cells (CTCs) for diagnostic and prognostic purposes. The characterization of isolated CTCs has been limited due to the difficulty in recovering and growing isolated cells with high fidelity. Here, we present a strategy that uses a 3D scaffold, integrated into a microfludic device, as a transferable substrate that can be readily isolated after device operation for serial use in vivo as a transplanted tissue bed. Hydrogel scaffolds were incorporated into a PDMS fluidic chamber prior to bonding and were rehydrated in the chamber after fluid contact. The hydrogel matrix completely filled the fluid chamber, significantly increasing the surface area to volume ratio, and could be directly visualized under a microscope. Computational modeling defined different flow and pressure regimes that guided the conditions used to operate the chip. As a proof of concept using a model cell line, we confirmed human prostate tumor cell attachment in the microfluidic scaffold chip, retrieval of the scaffold en masse, and serial implantation of the scaffold to a mouse model with preserved xenograft development. With further improvement in capture efficiency, this approach can offer an end-to-end platform for the continuous study of isolated cancer cells from a biological fluid to a xenograft in mice.

  13. [Kidney transplantation].

    PubMed

    Talbot-Wright, R; Alcaraz, A; Carretero, P; Alvarez, R; Vilardell, J; Ictech, S; Quiroga, G

    1990-01-01

    In a consecutive series of 639 Renal Transplants (RT) performed between January 1st 1978 and December 31st 1988, 75 Renal Transplanctectomies (RTX) were carried out. Of those, fifty-seven (76%) were due to immunological causes, 10 (13.3%) to vascular complications, 7 (9.3%) to urological problems and 1 (1.3%) to deep infection. The time elapsed between RTX and RT was as follows: 25 were performed earlier than 6 weeks, 17 between 6 weeks to 6 months, and 33 after 6 months. The higher number of complications did not happened, as it is frequently described, in the first group; on the contrary, it fell in the group that had been transplanted longer. There were 13 immunologically caused renal rhexis, 5 of which were RTX, another 5 were operated on and diagnosed at perioperation, and immediately received the appropriate treatment so they were able to keep their kidney, and finally, 3 patients were diagnosed a rejection with renal rhexis, ecographically confirmed. These patients were given only medical treatment, which was enough to allow jugulation of the picture. RTX techniques used were: extracapsular in 28 cases and intracapsular in 47. Surgical approach, except for 2 cases of simultaneous kidney and pancreas transplantation, was extraperitoneal.

  14. Fine-tuning patient-derived xenograft models for precision medicine approaches in leukemia.

    PubMed

    Francis, Olivia L; Milford, Terry-Ann M; Beldiman, Cornelia; Payne, Kimberly J

    2016-03-01

    Many leukemias are characterized by well-known mutations that drive oncogenesis. Mice engineered with these mutations provide a foundation for understanding leukemogenesis and identifying therapies. However, data from whole genome studies provide evidence that malignancies are characterized by multiple genetic alterations that vary between patients, as well as inherited genetic variation that can also contribute to oncogenesis. Improved outcomes will require precision medicine approaches-targeted therapies tailored to malignancies in each patient. Preclinical models that reflect the range of mutations and the genetic background present in patient populations are required to develop and test the combinations of therapies that will be used to provide precision medicine therapeutic strategies. Patient-derived xenografts (PDX) produced by transplanting leukemia cells from patients into immune deficient mice provide preclinical models where disease mechanisms and therapeutic efficacy can be studied in vivo in context of the genetic variability present in patient tumors. PDX models are possible because many elements in the bone marrow microenvironment show cross-species activity between mice and humans. However, several cytokines likely to impact leukemia cells are species-specific with limited activity on transplanted human leukemia cells. In this review we discuss the importance of PDX models for developing precision medicine approaches to leukemia treatment. We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.

  15. Biosafety in Ex Vivo Gene Therapy and Conditional Ablation of Lentivirally Transduced Hepatocytes in Nonhuman Primates

    PubMed Central

    Menzel, Olivier; Birraux, Jacques; Wildhaber, Barbara E; Jond, Caty; Lasne, Françoise; Habre, Walid; Trono, Didier; Nguyen, Tuan H; Chardot, Christophe

    2009-01-01

    Ex vivo gene therapy is an interesting alternative to orthotopic liver transplantation (OLT) for treating metabolic liver diseases. In this study, we investigated its efficacy and biosafety in nonhuman primates. Hepatocytes isolated from liver lobectomy were transduced in suspension with a bicistronic liver-specific lentiviral vector and immediately autotransplanted (SLIT) into three cynomolgus monkeys. The vector encoded cynomolgus erythropoietin (EPO) and the conditional suicide gene herpes simplex virus-thymidine kinase (HSV-TK). Survival of transduced hepatocytes and vector dissemination were evaluated by detecting transgene expression and vector DNA. SLIT was safely performed within a day in all three subjects. Serum EPO and hematocrit rapidly increased post-SLIT and their values returned to baseline within about 1 month. Isoforms of EPO detected in monkeys' sera differed from the physiological renal EPO. In liver biopsies at months 8 and 15, we detected EPO protein, vector mRNA and DNA, demonstrating long-term survival and functionality of transplanted lentivirally transduced hepatocytes. Valganciclovir administration resulted in complete ablation of the transduced hepatocytes. We demonstrated the feasibility and biosafety of SLIT, and the long term (>1 year) functionality of lentivirally transduced hepatocytes in nonhuman primates. The HSV-TK/valganciclovir suicide strategy can increase the biosafety of liver gene therapy protocols by safely and completely ablating transduced hepatocytes on demand. PMID:19568222

  16. Prolonged cardiac xenograft survival in guinea pig-to-rat model by a highly active cobra venom factor.

    PubMed

    Sun, Qian-Yun; Chen, Gang; Guo, Hui; Chen, Shi; Wang, Wan-Yu; Xiong, Yu-Liang

    2003-09-01

    A highly active cobra venom factor (CVF) was isolated from the venom of Naja kaouthia by sequential column chromatography. It displays strong anticomplementary activity, and has 1515 U of anticomplementary activity per mg protein. A single dose of 0.1 mg/kg CVF given i.v. to rats completely abrogated complement activity for nearly 5 days. Given 0.02 mg/kg of CVF, the complement activity of rats was reduced by more than 96.5% in 6 h. In guinea pig-to-rat heart transplant model, rats treated with a single dose of 0.05 mg/kg CVF had significantly prolonged xenograft survival (56.12+/-6.27 h in CVF-treated rats vs. 0.19+/-0.07 h in control rats, P<0.001).

  17. Meniscal allograft transplantation

    MedlinePlus

    Meniscus transplant; Surgery - knee - meniscus transplant; Surgery - knee - cartilage; Arthroscopy - knee - meniscus transplant ... the lab for any diseases and infection. Other surgeries, such as ligament or cartilage repairs, may be ...

  18. Exclusion of Complex Paraannular Aortic Abscess With the Freestyle Xenograft.

    PubMed

    Guihaire, Julien; Kloeckner, Martin; Deleuze, Philippe

    2016-10-01

    Destructive aortic valve endocarditis is a serious condition that can result in aortoventricular disjunction. The appropriate surgical approach for severe excavating lesions remains a matter of debate. Homografts, prosthetic valves associated with a pericardial patch for annulus repair, and prosthetic valve conduits can be used. We report the technical issue of subcoronary inclusion of the full root Freestyle xenograft for complicated aortic endocarditis extending to the left ventricular outflow tract.

  19. 184AA3: a xenograft model of ER+ breast adenocarcinoma

    DOE PAGES

    Hines, William C.; Kuhn, Irene; Thi, Kate; ...

    2015-12-12

    Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER+) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Xenografts of one cell line, 184AA3, consistently formed ER+ adenocarcinomas that had a high proliferative rate and other features consistent withmore » “luminal B” intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44High subpopulation was discovered, yet their tumor forming ability was far less than CD44Low cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture, and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER+ cancers. This model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development.« less

  20. 184AA3: A Xenograft Model of ER+ Breast Adenocarcinoma

    PubMed Central

    Hines, William C.; Kuhn, Irene; Thi, Kate; Chu, Berbie; Stanford-Moore, Gaelen; Sampayo, Rocío; Garbe, James C.; Stampfer, Martha; Borowsky, Alexander D.; Bissell, Mina

    2015-01-01

    Purpose Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER+) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development, and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Methods Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Results Xenografts of one cell line, 184AA3, consistently formed ER+ adenocarcinomas that had a high proliferative rate and other features consistent with “luminal B” intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44High subpopulation was discovered, yet their tumor forming ability was far less than CD44Low cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture, and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER+ cancers. Conclusions This model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing and drug development. PMID:26661596

  1. Nuclear microprobe study of TiO 2-penetration in the epidermis of human skin xenografts

    NASA Astrophysics Data System (ADS)

    Kertész, Zs.; Szikszai, Z.; Gontier, E.; Moretto, P.; Surlève-Bazeille, J.-E.; Kiss, B.; Juhász, I.; Hunyadi, J.; Kiss, Á. Z.

    2005-04-01

    Titanium-dioxide is a widely used physical photoprotective component of various cosmetic products. However, very few experiments have been carried out on its penetration through the human epidermal barrier and its possible biological effects in vivo and in vitro. In the frame of the NANODERM EU5 project, the penetration of TiO2-nanoparticles through the epidermis of human foreskin grafts transplanted into SCID mice was investigated in the Debrecen and Bordeaux nuclear microprobe laboratories using combined IBA techniques. Transmission electron microscope studies of the same samples were also carried out in the DMPFCS laboratory. The skin grafts were treated with a hydrophobic emulsion containing micronised TiO2-nanoparticles in occlusion, for different time periods. Quantitative elemental concentrations and distributions have been determined in 14-16 μm thick freeze-dried sections obtained from quick frozen punch biopsies using STIM, PIXE and RBS analytical methods. Using both microscopic methods, we have observed nanoparticles having penetrated into the corneocyte layers of stratum corneum by direct visualisation in TEM and via their chemical fingerprint in PIXE. The human skin xenograft has proved to be a model particularly well adapted to such penetration studies.

  2. Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies

    PubMed Central

    Hayashi, Tetsutaro; Janssen, Claudia; Awrey, Shannon; Wyatt, Alexander W.; Anderson, Shawn; Moskalev, Igor; Haegert, Anne; Alshalalfa, Mohammed; Erho, Nicholas; Davicioni, Elai; Fazli, Ladan; Li, Estelle; Collins, Colin; Wang, Yuzhuo; Black, Peter C.

    2015-01-01

    Optimal animal models of muscle invasive bladder cancer (MIBC) are necessary to overcome the current lack of novel targeted therapies for this malignancy. Here we report on the establishment and characterization of patient-derived primary xenografts (PDX). Patient tumors were grafted under the renal capsule of mice and subsequently transplanted over multiple generations. Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC). One PDX harbouring an FGFR3 mutation was treated with an inhibitory monoclonal antibody targeting FGFR3. Five PDX were successfully established. Tumor doubling time ranged from 5 to 11 days. Array CGH revealed shared chromosomal aberrations in the patient tumors and PDX. Gene expression microarray and IHC confirmed that PDXs maintain similar patterns to the parental tumors. Tumor growth in the PDX with an FGFR3 mutation was inhibited by the FGFR3 inhibitor. PDXs recapitulate the tumor biology of the patients' primary tumors from which they are derived. Investigations related to tumor biology and drug testing in these models are therefore more likely to be relevant to the disease state in patients. They represent a valuable tool for developing precision therapy in MIBC. PMID:26041878

  3. Radiocurability Is Associated with Interstitial Fluid Pressure in Human Tumor Xenografts1

    PubMed Central

    Rofstad, Einar K; Gaustad, Jon-Vidar; Brurberg, Kjetil G; Mathiesen, Berit; Galappathi, Kanthi; Simonsen, Trude G

    2009-01-01

    Interstitial fluid pressure (IFP) has been shown to be an independent prognostic parameter for disease-free survival in cervical carcinoma patients treated with radiation therapy. However, the underlying mechanisms are not fully understood. The main aims of this study were to investigate whether tumor radiocurability may be associated with IFP and, if so, to identify possible mechanisms. Human melanoma xenografts transplanted intradermally or in window chamber preparations in BALB/c nu/nu mice were used as preclinical tumor models. Radiation dose resulting in 50% local tumor control was higher by a factor of 1.19 ± 0.06 in tumors with IFP ≥ 9 mm Hg than in tumors with IFP ≤ 7 mm Hg. Tumor IFP was positively correlated to vessel segment length and vessel tortuosity and was inversely correlated to vessel density. Compared with tumors with low IFP, tumors with high IFP showed high resistance to blood flow, high frequency of Po2 fluctuations, and high fractions of acutely hypoxic cells, whereas the fraction of radiobiologically hypoxic cells and the fraction of chronically hypoxic cells did not differ between tumors with high and tumors with low IFP. IFP showed a significant correlation to the fraction of acutely hypoxic cells, probably because both parameters were determined primarily by the microvascular resistance to blood flow. Therefore, the observed association between tumor radiocurability and IFP was most likely an indirect consequence of a strong relationship between IFP and the fraction of acutely hypoxic cells. PMID:19881960

  4. Generation and molecular characterization of pancreatic cancer patient-derived xenografts reveals their heterologous nature

    PubMed Central

    Seol, Hyang Sook; Choi, Yeon Sook; Kim, Eunji; Lee, Eun Ji; Rhee, Je-Keun; Singh, Shree Ram; Jun, Eun Sung; Han, Buhm; Hong, Seung Mo; Kim, Song Cheol; Chang, Suhwan

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the most challenging type of cancer to treat, with a 5-year survival rate of <10%. Furthermore, because of the large portion of the inoperable cases, it is difficult to obtain specimens to study the biology of the tumors. Therefore, a patient-derived xenograft (PDX) model is an attractive option for preserving and expanding these tumors for translational research. Here we report the generation and characterization of 20 PDX models of PDAC. The success rate of the initial graft was 74% and most tumors were re-transplantable. Histological analysis of the PDXs and primary tumors revealed a conserved expression pattern of p53 and SMAD4; an exome single nucleotide polymorphism (SNP) array and Comprehensive Cancer Panel showed that PDXs retained over 94% of cancer-associated variants. In addition, Polyphen2 and the Sorting Intolerant from Tolerant (SIFT) prediction identified 623 variants among the functional SNPs, highlighting the heterologous nature of pancreatic PDXs; an analysis of 409 tumor suppressor genes and oncogenes in Comprehensive Cancer Panel revealed heterologous cancer gene mutation profiles for each PDX-primary tumor pair. Altogether, we expect these PDX models are a promising platform for screening novel therapeutic agents and diagnostic markers for the detection and eradication of PDAC. PMID:27613834

  5. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

    PubMed Central

    Hooper, Jody E.; Cantor, Emma L.; Ehlen, Macgregor S.; Banerjee, Avirup; Malempati, Suman; Stenzel, Peter; Woltjer, Randy L.; Gandour-Edwards, Regina; Goodwin, Neal C.; Yang, Yan; Kaur, Pali; Bult, Carol J.; Airhart, Susan D.; Keller, Charles

    2015-01-01

    Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study. PMID:26696773

  6. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies.

    PubMed

    Hooper, Jody E; Cantor, Emma L; Ehlen, Macgregor S; Banerjee, Avirup; Malempati, Suman; Stenzel, Peter; Woltjer, Randy L; Gandour-Edwards, Regina; Goodwin, Neal C; Yang, Yan; Kaur, Pali; Bult, Carol J; Airhart, Susan D; Keller, Charles

    2015-01-01

    Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

  7. Improved Method for Ex Ovo-Cultivation of Developing Chicken Embryos for Human Stem Cell Xenografts

    PubMed Central

    Schomann, Timo; Qunneis, Firas; Widera, Darius; Kaltschmidt, Christian; Kaltschmidt, Barbara

    2013-01-01

    The characterization of human stem cells for the usability in regenerative medicine is particularly based on investigations regarding their differentiation potential in vivo. In this regard, the chicken embryo model represents an ideal model organism. However, the access to the chicken embryo is only achievable by windowing the eggshell resulting in limited visibility and accessibility in subsequent experiments. On the contrary, ex ovo-culture systems avoid such negative side effects. Here, we present an improved ex ovo-cultivation method enabling the embryos to survive 13 days in vitro. Optimized cultivation of chicken embryos resulted in a normal development regarding their size and weight. Our ex ovo-approach closely resembles the development of chicken embryos in ovo, as demonstrated by properly developed nervous system, bones, and cartilage at expected time points. Finally, we investigated the usability of our method for trans-species transplantation of adult stem cells by injecting human neural crest-derived stem cells into late Hamburger and Hamilton stages (HH26–HH28/E5—E6) of ex ovo-incubated embryos. We demonstrated the integration of human cells allowing experimentally easy investigation of the differentiation potential in the proper developmental context. Taken together, this ex ovo-method supports the prolonged cultivation of properly developing chicken embryos enabling integration studies of xenografted mammalian stem cells at late developmental stages. PMID:23554818

  8. Improved method for ex ovo-cultivation of developing chicken embryos for human stem cell xenografts.

    PubMed

    Schomann, Timo; Qunneis, Firas; Widera, Darius; Kaltschmidt, Christian; Kaltschmidt, Barbara

    2013-01-01

    The characterization of human stem cells for the usability in regenerative medicine is particularly based on investigations regarding their differentiation potential in vivo. In this regard, the chicken embryo model represents an ideal model organism. However, the access to the chicken embryo is only achievable by windowing the eggshell resulting in limited visibility and accessibility in subsequent experiments. On the contrary, ex ovo-culture systems avoid such negative side effects. Here, we present an improved ex ovo-cultivation method enabling the embryos to survive 13 days in vitro. Optimized cultivation of chicken embryos resulted in a normal development regarding their size and weight. Our ex ovo-approach closely resembles the development of chicken embryos in ovo, as demonstrated by properly developed nervous system, bones, and cartilage at expected time points. Finally, we investigated the usability of our method for trans-species transplantation of adult stem cells by injecting human neural crest-derived stem cells into late Hamburger and Hamilton stages (HH26-HH28/E5-E6) of ex ovo-incubated embryos. We demonstrated the integration of human cells allowing experimentally easy investigation of the differentiation potential in the proper developmental context. Taken together, this ex ovo-method supports the prolonged cultivation of properly developing chicken embryos enabling integration studies of xenografted mammalian stem cells at late developmental stages.

  9. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.

    PubMed

    Kemper, Kristel; Krijgsman, Oscar; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; Song, Ji-Ying; Kuilman, Thomas; Vis, Daniel J; Wessels, Lodewyk F; Voest, Emile E; Schumacher, Ton Nm; Blank, Christian U; Adams, David J; Haanen, John B; Peeper, Daniel S

    2015-09-01

    The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma.

  10. Nutritional contributions of insects to primate diets: implications for primate evolution.

    PubMed

    Rothman, Jessica M; Raubenheimer, David; Bryer, Margaret A H; Takahashi, Maressa; Gilbert, Christopher C

    2014-06-01

    Insects and other invertebrates form a portion of many living and extinct primate diets. We review the nutritional profiles of insects in comparison with other dietary items, and discuss insect nutrients in relation to the nutritional needs of living primates. We find that insects are incorporated into some primate diets as staple foods whereby they are the majority of food intake. They can also be incorporated as complements to other foods in the diet, providing protein in a diet otherwise dominated by gums and/or fruits, or be incorporated as supplements to likely provide an essential nutrient that is not available in the typical diet. During times when they are very abundant, such as in insect outbreaks, insects can serve as replacements to the usual foods eaten by primates. Nutritionally, insects are high in protein and fat compared with typical dietary items like fruit and vegetation. However, insects are small in size and for larger primates (>1 kg) it is usually nutritionally profitable only to consume insects when they are available in large quantities. In small quantities, they may serve to provide important vitamins and fatty acids typically unavailable in primate diets. In a brief analysis, we found that soft-bodied insects are higher in fat though similar in chitin and protein than hard-bodied insects. In the fossil record, primates can be defined as soft- or hard-bodied insect feeders based on dental morphology. The differences in the nutritional composition of insects may have implications for understanding early primate evolution and ecology. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Disproportional representation of primates in the ecological literature.

    PubMed

    Heymann, Eckhard W; Zinner, Dietmar; Ganzhorn, Jörg U

    2013-01-01

    We address the question why papers dealing with the ecology of primates are so sparsely represented in the general ecological literature. A literature analyses based on entries in Web of Science and PrimateLit reveals that despite a large number of papers published on primates in general and on the ecology of primates, only a very small fraction of these papers is published in high-ranking international ecological journals. We discuss a number of potential reasons for the disproportion and highlight the problems associated with experimental research on wild primates and constraints on sample size as major issues.

  12. Pathology of Human Pheochromocytoma and Paraganglioma Xenografts in NSG Mice

    PubMed Central

    Powers, James F.; Pacak, Karel; Tischler, Arthur S.

    2016-01-01

    A major impediment to the development of effective treatments for metastatic or unresectable pheochromocytomas and paragangliomas has been the absence of valid models for pre-clinical testing. Attempts to establish cell lines or xenografts from human pheochromocytomas and paragangliomas have previously been unsuccessful. NOD-scid gamma (NSG) mice are a recently developed strain lacking functional B-cells, T-cells and NK cells. We report here that xenografts of primary human paragangliomas will take in NSG mice while maintaining their architectural and immunophenotypic characteristics as expressed in the patients. In contrast to grafts of cell lines and of most common types of primary tumors, the growth rate of grafted paragangliomas is very slow, accurately representing the growth rate of most pheochromocytomas and paragangliomas even in metastases in humans. Although the model is therefore technically challenging, primary patient derived xenografts of paragangliomas in NSG mice provide a potentially valuable new tool that could prove especially valuable for testing treatments aimed at eradicating the small tumor deposits that are often numerous in patients with metastatic paraganglioma. PMID:27709415

  13. Remarkable ancient divergences amongst neglected lorisiform primates

    PubMed Central

    Nekaris, K. Anne‐Isola; Perkin, Andrew; Bearder, Simon K.; Pimley, Elizabeth R.; Schulze, Helga; Streicher, Ulrike; Nadler, Tilo; Kitchener, Andrew; Zischler, Hans; Zinner, Dietmar; Roos, Christian

    2015-01-01

    Lorisiform primates (Primates: Strepsirrhini: Lorisiformes) represent almost 10% of the living primate species and are widely distributed in sub‐Saharan Africa and South/South‐East Asia; however, their taxonomy, evolutionary history, and biogeography are still poorly understood. In this study we report the largest molecular phylogeny in terms of the number of represented taxa. We sequenced the complete mitochondrial cytochrome b gene for 86 lorisiform specimens, including ∼80% of all the species currently recognized. Our results support the monophyly of the Galagidae, but a common ancestry of the Lorisinae and Perodicticinae (family Lorisidae) was not recovered. These three lineages have early origins, with the Galagidae and the Lorisinae diverging in the Oligocene at about 30 Mya and the Perodicticinae emerging in the early Miocene. Our mitochondrial phylogeny agrees with recent studies based on nuclear data, and supports Euoticus as the oldest galagid lineage and the polyphyletic status of Galagoides. Moreover, we have elucidated phylogenetic relationships for several species never included before in a molecular phylogeny. The results obtained in this study suggest that lorisiform diversity remains substantially underestimated and that previously unnoticed cryptic diversity might be present within many lineages, thus urgently requiring a comprehensive taxonomic revision of this primate group. © 2015 The Linnean Society of London PMID:26900177

  14. Homeostasis in primates in hyperacceleration fields

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.

    1984-01-01

    Various homeostatic responses of a nonhuman primate, the squirrel monkey (Saimiri sciureus) to acute changes in the acceleration environment were examined. When these animals were exposed to a hyperdynamic field the body temperature was consistently depressed and the animals showed behavioral indications of increased drowsiness. Further, time of day played a significant role in influencing these responses.

  15. [Experimental whooping cough of nonhuman primate].

    PubMed

    Kubrava, D T; Medkova, A Iu; Siniashina, L N; Shevtsova, Z V; Matua, A Z; Kondzharia, I G; Barkaia, V S; Elistratova, Zh V; Karataev, G I; Mikvabia, Z Ia; Gintsburg, A L

    2013-01-01

    Despite considerable success in study of Bordetella pertussis virulence factors, pathogenesis of whooping cough, duration of B. pertussis bacteria persistence, types and mechanisms of immune response are still keep underinvestigated. It can be explained by the absence ofadequate experimental animal model for pertussis study. Our study estimates clinical and laboratory parameters of whooping cough in non-human primates of the Old World in the process of intranasan infection by virulent B. pertussis bacteria. Also the duration of B. pertussis bacteria persistence in animals was investigated. 14 animal units of 4 species of non-human primates of the Old World were used for intranasal infection. The examination of infect animals included: visual exploration of nasopharynx, thermometry, clinical and biochemical blood analyses, identification ofB. pertussis, using microbiologic and molecular genetic analyses, estimation of innate and adoptive immune factors. The development of infectious process was accompanied by generation of B. pertussis bacteria, catarrhal inflammation of nasopharyngeal mucosa, leucocytosis, hypoglycemia specific for pertussis, and activation of innate and adaptive immunity for all primates regardless of specie were seen. While repeated experimental infection in primates single bacterial colonies were registered during only first week after challenge. It occurs like the absence of inflammation of nasopharyngeal mucosa and the lack of laboratory marks of whooping cough, recorded after first challenge. The evident booster effect of humoral immunity was observed. As a model for investigation of B. pertussis bacteria persistence and immune response against whooping cough we suggest the usage of rhesus macaque as more available to experiments.

  16. Chronic wasting disease agents in nonhuman primates.

    PubMed

    Race, Brent; Meade-White, Kimberly D; Phillips, Katie; Striebel, James; Race, Richard; Chesebro, Bruce

    2014-05-01

    Chronic wasting disease is a prion disease of cervids. Assessment of its zoonotic potential is critical. To evaluate primate susceptibility, we tested monkeys from 2 genera. We found that 100% of intracerebrally inoculated and 92% of orally inoculated squirrel monkeys were susceptible, but cynomolgus macaques were not, suggesting possible low risk for humans.

  17. Optogenetics Advances in Primate Visual Pathway.

    PubMed

    Jazayeri, Mehrdad; Remington, Evan

    2016-04-06

    In this issue of Neuron, Klein et al. (2016) used cell-type-specific optogenetics and electrical microstimulation to characterize the koniocellular geniculocortical projections in nonhuman primates. Their work offers a powerful platform for refining our understanding of the mechanisms of visual information processing in the lateral geniculate nucleus and primary visual cortex.

  18. Primate molecular phylogenetics in a genomic era.

    PubMed

    Ting, Nelson; Sterner, Kirstin N

    2013-02-01

    A primary objective of molecular phylogenetics is to use molecular data to elucidate the evolutionary history of living organisms. Dr. Morris Goodman founded the journal Molecular Phylogenetics and Evolution as a forum where scientists could further our knowledge about the tree of life, and he recognized that the inference of species trees is a first and fundamental step to addressing many important evolutionary questions. In particular, Dr. Goodman was interested in obtaining a complete picture of the primate species tree in order to provide an evolutionary context for the study of human adaptations. A number of recent studies use multi-locus datasets to infer well-resolved and well-supported primate phylogenetic trees using consensus approaches (e.g., supermatrices). It is therefore tempting to assume that we have a complete picture of the primate tree, especially above the species level. However, recent theoretical and empirical work in the field of molecular phylogenetics demonstrates that consensus methods might provide a false sense of support at certain nodes. In this brief review we discuss the current state of primate molecular phylogenetics and highlight the importance of exploring the use of coalescent-based analyses that have the potential to better utilize information contained in multi-locus data.

  19. Nonhuman primate models of focal cerebral ischemia

    PubMed Central

    Fan, Jingjing; Li, Yi; Fu, Xinyu; Li, Lijuan; Hao, Xiaoting; Li, Shasha

    2017-01-01

    Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model. PMID:28400817

  20. Processing Of Visual Information In Primate Brains

    NASA Technical Reports Server (NTRS)

    Anderson, Charles H.; Van Essen, David C.

    1991-01-01

    Report reviews and analyzes information-processing strategies and pathways in primate retina and visual cortex. Of interest both in biological fields and in such related computational fields as artificial neural networks. Focuses on data from macaque, which has superb visual system similar to that of humans. Authors stress concept of "good engineering" in understanding visual system.

  1. Homeostasis in primates in hyperacceleration fields

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.

    1984-01-01

    Various homeostatic responses of a nonhuman primate, the squirrel monkey (Saimiri sciureus) to acute changes in the acceleration environment were examined. When these animals were exposed to a hyperdynamic field the body temperature was consistently depressed and the animals showed behavioral indications of increased drowsiness. Further, time of day played a significant role in influencing these responses.

  2. Quantification of neocortical ratios in stem primates.

    PubMed

    Long, Adam; Bloch, Jonathan I; Silcox, Mary T

    2015-07-01

    Extant euprimates (=crown primates) have a characteristically expanded neocortical region of the brain relative to that of other mammals, but the timing of that expansion in their evolutionary history is poorly resolved. Examination of anatomical landmarks on fossil endocasts of Eocene euprimates suggests that significant neocortical expansion relative to contemporaneous mammals was already underway. Here, we provide quantitative estimates of neocorticalization in stem primates (plesiadapiforms) relevant to the question of whether relative neocortical expansion was uniquely characteristic of the crown primate radiation. Ratios of neocortex to endocast surface areas were calculated for plesiadapiforms using measurements from virtual endocasts of the paromomyid Ignacius graybullianus (early Eocene, Wyoming) and the microsyopid Microsyops annectens (middle Eocene, Wyoming). These data are similar to a published estimate for the plesiadapid, Plesiadapis tricuspidens, but contrast with those calculated for early Tertiary euprimates in being within the 95% confidence intervals for archaic mammals generally. Interpretation of these values is complicated by the paucity of sampled endocasts for older stem primates and euarchontogliran outgroups, as well as by a combination of effects related to temporal trends, allometry, and taxon-unique specializations. Regardless, these results are consistent with the hypothesis that a shift in brain organization occurred in the first euprimates, likely in association with elaborations to the visual system.

  3. Processing Of Visual Information In Primate Brains

    NASA Technical Reports Server (NTRS)

    Anderson, Charles H.; Van Essen, David C.

    1991-01-01

    Report reviews and analyzes information-processing strategies and pathways in primate retina and visual cortex. Of interest both in biological fields and in such related computational fields as artificial neural networks. Focuses on data from macaque, which has superb visual system similar to that of humans. Authors stress concept of "good engineering" in understanding visual system.

  4. The Neuroendocrinology of Primate Maternal Behavior

    PubMed Central

    Saltzman, Wendy; Maestripieri, Dario

    2010-01-01

    In nonhuman primates and humans, similar to other mammals, hormones are not strictly necessary for the expression of maternal behavior, but nevertheless influence variation in maternal responsiveness and parental behavior both within and between individuals. A growing number of correlational and experimental studies have indicated that high circulating estrogen concentrations during pregnancy increase maternal motivation and responsiveness to infant stimuli, while effects of prepartum or postpartum estrogens and progestogens on maternal behavior are less clear. Prolactin is thought to play a role in promoting paternal and alloparental care in primates, but little is known about the relationship between this hormone and maternal behavior. High circulating cortisol levels appear to enhance arousal and responsiveness to infant stimuli in young, relatively inexperienced female primates, but interfere with the expression of maternal behavior in older and more experienced mothers. Among neuropeptides and neurotransmitters, preliminary evidence indicates that oxytocin and endogenous opioids affect maternal attachment to infants, including maintenance of contact, grooming, and responses to separation. Brain serotonin affects anxiety and impulsivity, which in turn may affect maternal behaviors such as infant retrieval or rejection of infants’ attempts to make contact with the mother. Although our understanding of the neuroendocrine correlates of primate maternal behavior has grown substantially in the last two decades, very little is known about the mechanisms underlying these effects, e.g., the extent to which these mechanisms may involve changes in perception, emotion, or cognition. PMID:20888383

  5. Tropical warming and the dynamics of endangered primates.

    PubMed

    Wiederholt, Ruscena; Post, Eric

    2010-04-23

    Many primate species are severely threatened, but little is known about the effects of global warming and the associated intensification of El Niño events on primate populations. Here, we document the influences of the El Niño southern oscillation (ENSO) and hemispheric climatic variability on the population dynamics of four genera of ateline (neotropical, large-bodied) primates. All ateline genera experienced either an immediate or a lagged negative effect of El Niño events. ENSO events were also found to influence primate resource levels through neotropical arboreal phenology. Furthermore, frugivorous primates showed a high degree of interspecific population synchrony over large scales across Central and South America attributable to the recent trends in large-scale climate. These results highlight the role of large-scale climatic variation and trends in ateline primate population dynamics, and emphasize that global warming could pose additional threats to the persistence of multiple species of endangered primates.

  6. Occurrence and distribution of Indian primates

    USGS Publications Warehouse

    Karanth, K.K.; Nichols, J.D.; Hines, J.E.

    2010-01-01

    Global and regional species conservation efforts are hindered by poor distribution data and range maps. Many Indian primates face extinction, but assessments of population status are hindered by lack of reliable distribution data. We estimated the current occurrence and distribution of 15 Indian primates by applying occupancy models to field data from a country-wide survey of local experts. We modeled species occurrence in relation to ecological and social covariates (protected areas, landscape characteristics, and human influences), which we believe are critical to determining species occurrence in India. We found evidence that protected areas positively influence occurrence of seven species and for some species are their only refuge. We found evergreen forests to be more critical for some primates along with temperate and deciduous forests. Elevation negatively influenced occurrence of three species. Lower human population density was positively associated with occurrence of five species, and higher cultural tolerance was positively associated with occurrence of three species. We find that 11 primates occupy less than 15% of the total land area of India. Vulnerable primates with restricted ranges are Golden langur, Arunachal macaque, Pig-tailed macaque, stump-tailed macaque, Phayre's leaf monkey, Nilgiri langur and Lion-tailed macaque. Only Hanuman langur and rhesus macaque are widely distributed. We find occupancy modeling to be useful in determining species ranges, and in agreement with current species ranking and IUCN status. In landscapes where monitoring efforts require optimizing cost, effort and time, we used ecological and social covariates to reliably estimate species occurrence and focus species conservation efforts. ?? Elsevier Ltd.

  7. Variation in the molecular clock of primates

    PubMed Central

    Moorjani, Priya; Amorim, Carlos Eduardo G.; Arndt, Peter F.; Przeworski, Molly

    2016-01-01

    Events in primate evolution are often dated by assuming a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life history traits, suggesting it should also be found among primates. Motivated by these considerations, we analyze whole genomes from 10 primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs), and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are up to 64% higher in lineages leading from the hominoid–NWM ancestor to NWMs than to apes. Within apes, rates are ∼2% higher in chimpanzees and ∼7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however; in particular, transitions at CpG sites exhibit a more clocklike behavior than do other types, presumably because of their nonreplicative origin. Thus, not only the total rate, but also the mutational spectrum, varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate the human and chimpanzee divergence time is 12.1 million years,​ and the human and gorilla divergence time is 15.1 million years​. PMID:27601674

  8. The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice.

    PubMed

    Fujii, Etsuko; Kato, Atsuhiko; Chen, Yu Jau; Matsubara, Koichi; Ohnishi, Yasuyuki; Suzuki, Masami

    2015-01-01

    Patient-derived xenografts (PDXs) of tumors are increasingly becoming important tools for translational research in oncology. The NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic (NOG) mouse is an efficient host for PDXs. Thus as a basis for future development of methods to obtain PDXs from various disease types, we have studied the factors that affect the outcome of transplantation of human colorectal cancer in NOG mice. Of the original donor cases examined, 73% had successful engraftment. The outcome of donor-matched tissues was consistent in most cases, and was thought to show that the condition of the host did not affect engraftment. Next we analyzed the tumor aggressiveness in terms of histology grade of the original tumor and found that they were related to engraftment. Detailed histopathological examination of the transplanted tissues strongly indicated that lymphocytes engrafted with the tumor cells affect engraftment. As a factor related to transplantation of lymphocytes, we studied the human IgG concentration in the serum of tumor-bearing mice, but there was no tendency for higher concentrations to result in unsuccessful engraftment. Finally, we studied the type, density and location of T cells in the original donor tissue to determine the immune contexture and found that the unsuccessful engraftment cases tended to have an adequate or coordinated immune contexture compared to successful engraftment cases. From these results, we concluded that the aggressiveness and the T cell infiltration of the original tumor affect the outcome of transplantation in the NOG mouse.

  9. Evidence for a convergent slowdown in primate molecular rates and its implications for the timing of early primate evolution

    PubMed Central

    Steiper, Michael E.; Seiffert, Erik R.

    2012-01-01

    A long-standing problem in primate evolution is the discord between paleontological and molecular clock estimates for the time of crown primate origins: the earliest crown primate fossils are ∼56 million y (Ma) old, whereas molecular estimates for the haplorhine-strepsirrhine split are often deep in the Late Cretaceous. One explanation for this phenomenon is that crown primates existed in the Cretaceous but that their fossil remains have not yet been found. Here we provide strong evidence that this discordance is better-explained by a convergent molecular rate slowdown in early primate evolution. We show that molecular rates in primates are strongly and inversely related to three life-history correlates: body size (BS), absolute endocranial volume (EV), and relative endocranial volume (REV). Critically, these traits can be reconstructed from fossils, allowing molecular rates to be predicted for extinct primates. To this end, we modeled the evolutionary history of BS, EV, and REV using data from both extinct and extant primates. We show that the primate last common ancestor had a very small BS, EV, and REV. There has been a subsequent convergent increase in BS, EV, and REV, indicating that there has also been a convergent molecular rate slowdown over primate evolution. We generated a unique timescale for primates by predicting molecular rates from the reconstructed phenotypic values for a large phylogeny of living and extinct primates. This analysis suggests that crown primates originated close to the K–Pg boundary and possibly in the Paleocene, largely reconciling the molecular and fossil timescales of primate evolution. PMID:22474376

  10. Evidence for a convergent slowdown in primate molecular rates and its implications for the timing of early primate evolution.

    PubMed

    Steiper, Michael E; Seiffert, Erik R

    2012-04-17

    A long-standing problem in primate evolution is the discord between paleontological and molecular clock estimates for the time of crown primate origins: the earliest crown primate fossils are ~56 million y (Ma) old, whereas molecular estimates for the haplorhine-strepsirrhine split are often deep in the Late Cretaceous. One explanation for this phenomenon is that crown primates existed in the Cretaceous but that their fossil remains have not yet been found. Here we provide strong evidence that this discordance is better-explained by a convergent molecular rate slowdown in early primate evolution. We show that molecular rates in primates are strongly and inversely related to three life-history correlates: body size (BS), absolute endocranial volume (EV), and relative endocranial volume (REV). Critically, these traits can be reconstructed from fossils, allowing molecular rates to be predicted for extinct primates. To this end, we modeled the evolutionary history of BS, EV, and REV using data from both extinct and extant primates. We show that the primate last common ancestor had a very small BS, EV, and REV. There has been a subsequent convergent increase in BS, EV, and REV, indicating that there has also been a convergent molecular rate slowdown over primate evolution. We generated a unique timescale for primates by predicting molecular rates from the reconstructed phenotypic values for a large phylogeny of living and extinct primates. This analysis suggests that crown primates originated close to the K-Pg boundary and possibly in the Paleocene, largely reconciling the molecular and fossil timescales of primate evolution.

  11. Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance

    PubMed Central

    Chen, Yi-Bin; Kawai, Tatsuo; Spitzer, Thomas R.

    2016-01-01

    The induction of specific tolerance, in order to avoid the detrimental effects of lifelong systemic immunosuppressive therapy after organ transplantation, has been considered the “Holy Grail” of transplantation. Experimentally, tolerance has been achieved through clonal deletion, through costimulatory blockade, through the induction or infusion of regulatory T-cells, and through the establishment of hematopoietic chimerism following donor bone marrow transplantation. The focus of this review is how tolerance has been achieved following combined bone marrow and kidney transplantation. Preclinical models of combined bone marrow and kidney transplantation have shown that tolerance can be achieved through either transient or sustained hematopoietic chimerism. Combined transplants for patients with multiple myeloma have shown that organ tolerance and prolonged disease remissions can be accomplished with such an approach. Similarly, multiple clinical strategies for achieving tolerance in patients without an underlying malignancy have been described, in the context of either transient or durable mixed chimerism or sustained full donor hematopoiesis. To expand the chimerism approach to deceased donor transplants, a delayed tolerance approach, which will involve organ transplantation with conventional immunosuppression followed months later by bone marrow transplantation, has been successful in a primate model. As combined bone marrow and organ transplantation become safer and increasingly successful, the achievement of specific tolerance may become more widely applicable. PMID:27239198

  12. Establishment of a patient-derived orthotopic Xenograft (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern.

    PubMed

    Hiroshima, Yukihiko; Zhang, Yong; Zhang, Nan; Maawy, Ali; Mii, Sumiyuki; Yamamoto, Mako; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Murakami, Takashi; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Murata, Takuya; Endo, Itaru; Hoffman, Robert M

    2015-01-01

    Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2-positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient's cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient's cervical tumors resulted in primary growth but not metastasis.

  13. Establishment of a Patient-Derived Orthotopic Xenograft (PDOX) Model of HER-2-Positive Cervical Cancer Expressing the Clinical Metastatic Pattern

    PubMed Central

    Hiroshima, Yukihiko; Zhang, Yong; Zhang, Nan; Maawy, Ali; Mii, Sumiyuki; Yamamoto, Mako; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Murakami, Takashi; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Murata, Takuya; Endo, Itaru; Hoffman, Robert M.

    2015-01-01

    Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2-positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient’s cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient’s cervical tumors resulted in primary growth but not metastasis. PMID:25689852

  14. As2 O3 combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model.

    PubMed

    Jiao, Zhi-Xing; Leng, Yun; Xia, Jun-Jie; Wu, Hai-Qiao; Jin, Ning; Fu, Jia-Zhao; Cheng, Lian-Na; Wang, Jin-Hua; Ni, Shao-Bin; Qi, Zhong-Quan

    2016-05-01

    Xenotransplantation remits the severe shortage of human organs and tissues for transplantation, which is a problem that severely limits the application of transplantation to the treatment of human disease. However, severe immune rejection significantly limits the efficacy of xenotransplantation. In this study, we systematically investigated the immunosuppressive effect and mechanism of action of As2 O3 and leflunomide using a hamster-to-rat heart xenotransplantation model. We initially examined heart xenograft survival following As2 O3 and leflunomide treatment alone or combined treatment. We found that treatment with As2 O3 combined with leflunomide can significantly prolong the survival of heart xenograft by inhibiting Th1 and Th2 differentiation and reducing the production of IgG and IgM. Interestingly, As2 O3 and leflunomide showed low toxicity to the organs of the recipient. Taken together, these observations indicate that treatment with As2 O3 combined with leflunomide may be a promising immunosuppressive schedule for xenotransplantation.

  15. Taxonomy and conservation of Vietnam's primates: a review.

    PubMed

    Blair, Mary E; Sterling, Eleanor J; Hurley, Martha M

    2011-11-01

    Vietnam has the highest number of primate taxa overall (24-27) and the highest number of globally threatened primate taxa (minimum 20) in Mainland Southeast Asia. Conservation management of these species depends in part on resolving taxonomic uncertainties, which remain numerous among the Asian primates. Recent research on genetic, morphological, and acoustic diversity in Vietnam's primates has clarified some of these uncertainties, although a number of significant classification issues still remain. Herein, we summarize and compare the major current taxonomic classifications of Vietnam's primates, discuss recent advances in the context of these taxonomies, and suggest key areas for additional research to best inform conservation efforts in a region crucial to global primate diversity. Among the most important next steps for the conservation of Vietnam's primates is a new consensus list of Asian primates that resolves current differences between major taxonomies, incorporates recent research advances, and recognizes units of diversity at scales below the species-level, whether termed populations, morphs, or subspecies. Priority should be placed on recognizing distinct populations, regardless of the species concept in use, in order to foster the evolutionary processes necessary for primate populations to cope with inevitable environmental changes. The long-term conservation of Vietnam's primates depends not only on an accepted and accurate taxonomy but also on funding for on-the-ground conservation activities, including training, and the continued dedication and leadership of Vietnamese researchers and managers.

  16. Canine size, shape, and bending strength in primates and carnivores.

    PubMed

    Plavcan, J Michael; Ruff, Christopher B

    2008-05-01

    Anthropoid primates are well known for their highly sexually dimorphic canine teeth, with males possessing canines that are up to 400% taller than those of females. Primate canine dimorphism has been extensively documented, with a consensus that large male primate canines serve as weapons for intrasexual competition, and some evidence that large female canines in some species may likewise function as weapons. However, apart from speculation that very tall male canines may be relatively weak and that seed predators have strong canines, the functional significance of primate canine shape has not been explored. Because carnivore canine shape and size are associated with killing style, this group provides a useful comparative baseline for primates. We evaluate primate maxillary canine tooth size, shape and relative bending strength against body size, skull size, and behavioral and demographic measures of male competition and sexual selection, and compare them to those of carnivores. We demonstrate that, relative to skull length and body mass, primate male canines are on average as large as or larger than those of similar sized carnivores. The range of primate female canine sizes embraces that of carnivores. Male and female primate canines are generally as strong as or stronger than those of carnivores. Although we find that seed-eating primates have relatively strong canines, we find no clear relationship between male primate canine strength and demographic or behavioral estimates of male competition or sexual selection, in spite of a strong relationship between these measures and canine crown height. This suggests either that most primate canines are selected to be very strong regardless of variation in behavior, or that primate canine shape is inherently strong enough to accommodate changes in crown height without compromising canine function.

  17. Beneficial effects of the transgenic expression of human sTNF-αR-Fc and HO-1 on pig-to-mouse islet xenograft survival.

    PubMed

    Yan, Ji-Jing; Yeom, Hye-Jeong; Jeong, Jong Cheol; Lee, Jae-Ghi; Lee, Eun Won; Cho, Bumrae; Lee, Han Sin; Kim, Su Jin; Hwang, Jong-Ik; Kim, Sung Joo; Lee, Byeong-Chun; Ahn, Curie; Yang, Jaeseok

    2016-02-01

    Both human soluble tumor necrosis factor-α receptor-Fc (sTNF-αR-Fc) and heme oxygenase-1 (HO-1) transgenic pigs have been generated previously for xenotransplantation. Here, we investigated whether overexpression of sTNF-αR-Fc or HO-1 in pig islets prolongs islet xenograft survival. Adult porcine islets were isolated from human sTNF-αR-Fc or HO-1 transgenic and wild type pigs, and were transplanted into diabetic nude mice. Effects of the expression of both genes on islet apoptosis, chemokine expression, cellular infiltration, antibody production, and islet xenograft survival were analyzed. Human sTNF-αR-Fc transgenic pigs successfully expressed sTNF-αR-Fc in the islets; human HO-1 transgenic pigs expressed significant levels of HO-1 in the islets. Pig-to-mouse islet xenograft survival was significantly prolonged in both the sTNF-αR-Fc and HO-1 groups compared with that in the wild type group. Both the sTNF-αR-Fc and HO-1 groups exhibited suppressed intragraft expression of monocyte chemoattractant protein-1 (MCP-1) and decreased perigraft infiltration of immune cells. However, there was no difference in the anti-pig antibody levels between the groups. Apoptosis of islet cells during the early engraftment was suppressed only in the HO-1 group. Porcine islets from both sTNF-αR-Fc and HO-1 transgenic pigs prolonged xenograft survival by suppressing islet cell apoptosis or secondary inflammatory responses following islet death, indicating that these transgenic pigs might have applications in successful islet xenotransplantation. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Analysis of the Lipidome of Xenografts Using MALDI-IMS and UHPLC-ESI-QTOF

    NASA Astrophysics Data System (ADS)

    Fernández, Roberto; Lage, Sergio; Abad-García, Beatriz; Barceló-Coblijn, Gwendolyn; Terés, Silvia; López, Daniel H.; Guardiola-Serrano, Francisca; Martín, M. Laura; Escribá, Pablo V.; Fernández, José A.

    2014-07-01

    Human tumor xenografts in immunodeficient mice are a very popular model to study the development of cancer and to test new drug candidates. Among the parameters analyzed are the variations in the lipid composition, as they are good indicators of changes in the cellular metabolism. Here, we present a study on the distribution of lipids in xenografts of NCI-H1975 human lung cancer cells, using MALDI imaging mass spectrometry and UHPLC-ESI-QTOF. The identification of lipids directly from the tissue by MALDI was aided by the comparison with identification using ESI ionization in lipid extracts from the same xenografts. Lipids belonging to PCs, PIs, SMs, DAG, TAG, PS, PA, and PG classes were identified and their distribution over the xenograft was determined. Three areas were identified in the xenograft, corresponding to cells in different metabolic stages and to a layer of adipose tissue that covers the xenograft.

  19. Analysis of the lipidome of xenografts using MALDI-IMS and UHPLC-ESI-QTOF.

    PubMed

    Fernández, Roberto; Lage, Sergio; Abad-García, Beatriz; Barceló-Coblijn, Gwendolyn; Terés, Silvia; López, Daniel H; Guardiola-Serrano, Francisca; Martín, M Laura; Escribá, Pablo V; Fernández, José A

    2014-07-01

    Human tumor xenografts in immunodeficient mice are a very popular model to study the development of cancer and to test new drug candidates. Among the parameters analyzed are the variations in the lipid composition, as they are good indicators of changes in the cellular metabolism. Here, we present a study on the distribution of lipids in xenografts of NCI-H1975 human lung cancer cells, using MALDI imaging mass spectrometry and UHPLC-ESI-QTOF. The identification of lipids directly from the tissue by MALDI was aided by the comparison with identification using ESI ionization in lipid extracts from the same xenografts. Lipids belonging to PCs, PIs, SMs, DAG, TAG, PS, PA, and PG classes were identified and their distribution over the xenograft was determined. Three areas were identified in the xenograft, corresponding to cells in different metabolic stages and to a layer of adipose tissue that covers the xenograft.

  20. Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts.

    PubMed

    Sudha, Thangirala; Bharali, Dhruba J; Sell, Stewart; Darwish, Noureldien H E; Davis, Paul J; Mousa, Shaker A

    2017-04-10

    Thyroid hormone as L-thyroxine (T4) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.

  1. Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies

    SciTech Connect

    Williams, J.A.; Wessels, B.W.; Wharam, M.D.; Order, S.E.; Wanek, P.M.; Poggenburg, J.K.; Klein, J.L. )

    1990-06-01

    Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively.

  2. Establishment of Patient-Derived Keloid Xenograft Model.

    PubMed

    Park, Tae Hwan; Rah, Dong Kyun; Chang, Choong Hyun; Kim, Sung Young

    2016-10-01

    Recent advances on preclinical model based on patient-derived tumor xenografts have new insight into many clinical fields. According to our literature review, many authors believe that immunodeficient animals such as athymic rats and mice should be used to prevent tissue loss caused by acute rejection to establish patient-derived tumor xenografts models.However, recent advances showed that the microenvironment has gained attention as an important factor responsible for disease progression. Additionally, researchers attempt to come up with novel findings in chemotherapy drugs and immune modulator to control development of keloid. For these reasons, establishment of reliable animal model of keloids is very important.In this new model using an immunocompetent animal as a humanized-xenografts model, human keloid scar has been maintained for as long as 4 months. Results of migration assay have demonstrated that typical morphology of keloid fibroblast was preserved based on multiple time point observations despite its aging change. Quantitative real time polymerase chain reaction findings suggested that after implantation, there has been significant increase of vascular endothelial growth factor, CD34, and transforming growth factor beta 1 expression despite insignificant changes of hypoxia inducible factor 1 an matrix metallopeptidase 1, and matrix metallopeptidase 9 gene expression. These findings suggested that implantation of keloids within the immunocompetent animals yields is very useful experimental model in terms of fibrosis.In summary, the authors have successfully established and propagated patient-derived keloid model using the immunocompetent animals. This model could be used to test novel materials as well as combination therapies and is superior to the conventional cell line experiment models. In addition, the biology of the keloids can easily be assessed to identify predictive markers for responses to treatment regimens that are currently actively under

  3. Experimental evidence that primate trichromacy is well suited for detecting primate social colour signals

    PubMed Central

    Higham, James P.

    2017-01-01

    Primate trichromatic colour vision has been hypothesized to be well tuned for detecting variation in facial coloration, which could be due to selection on either signal wavelengths or the sensitivities of the photoreceptors themselves. We provide one of the first empirical tests of this idea by asking whether, when compared with other visual systems, the information obtained through primate trichromatic vision confers an improved ability to detect the changes in facial colour that female macaque monkeys exhibit when they are proceptive. We presented pairs of digital images of faces of the same monkey to human observers and asked them to select the proceptive face. We tested images that simulated what would be seen by common catarrhine trichromatic vision, two additional trichromatic conditions and three dichromatic conditions. Performance under conditions of common catarrhine trichromacy, and trichromacy with narrowly separated LM cone pigments (common in female platyrrhines), was better than for evenly spaced trichromacy or for any of the dichromatic conditions. These results suggest that primate trichromatic colour vision confers excellent ability to detect meaningful variation in primate face colour. This is consistent with the hypothesis that social information detection has acted on either primate signal spectral reflectance or photoreceptor spectral tuning, or both. PMID:28615496

  4. Nonhuman primate dermatology: a literature review

    PubMed Central

    Bernstein, Joseph A.; Didier, Peter J.

    2015-01-01

    In general, veterinary dermatologists do not have extensive clinical experience of nonhuman primate (NHP) dermatoses. The bulk of the published literature does not provide an organized evidence-based approach to the NHP dermatologic case. The veterinary dermatologist is left to extract information from both human and veterinary dermatology, an approach that can be problematic as it forces the clinician to make diagnostic and therapeutic decisions based on two very disparate bodies of literature. A more cohesive approach to NHP dermatology – without relying on assumptions that NHP pathology most commonly behaves similarly to other veterinary and human disease – is required. This review of the dermatology of NHP species includes discussions of primary dermatoses, as well as diseases where dermatologic signs represent a significant secondary component, provides a first step towards encouraging the veterinary community to study and report the dermatologic diseases of nonhuman primates. PMID:19490576

  5. [Ecotourism disturbances to non-human primates].

    PubMed

    Fan, Peng-Lai; Xiang, Zuo-Fu

    2013-02-01

    In tandem with economic growth and rising living conditions, ecotourism has increasingly gained popularity among the Chinese public. Non-human primates, as charismatic animals and the closest relatives of human beings, have shown a strong affinity in attracting the general public and raising money, and for that reason a variety of monkey parks, valleys, and islands are becoming increasingly popular in China. Though successful in raising a substantial sum of money for the managing agency of a nature reserve, there may be negative impacts on monkey groups used in ecotourism. Here, to establish effective guards for non-human primates involved in ecotourism, we present a review on tourism disturbance and summarize the negative impacts on behavioral patterns, reproduction, and health condition of animals.

  6. Evolution of alkaline phosphatases in primates.

    PubMed Central

    Goldstein, D J; Rogers, C; Harris, H

    1982-01-01

    Alkaline phosphatase [orthophosphoric-monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1] in placenta, intestine, liver, kidney, bone, and lung from a variety of primate species has been characterized by quantitative inhibition, thermostability, and immunological studies. Characteristic human placental-type alkaline phosphatase occurs in placentas of great apes (chimpanzee and orangutan) but not in placentas of other primates, including gibbon. It is also present in trace amounts in human lung but not in lung or other tissues of various Old and New World monkeys. However, a distinctive alkaline phosphatase resembling it occurs in substantial amounts in lungs from Old World monkeys but not New World monkeys. It appears that duplication of alkaline phosphatase genes and mutations of genetic elements controlling their tissue expression have occurred relatively recently in mammalian evolution. Images PMID:6950431

  7. Optogenetics in primates: a shining future?

    PubMed

    Gerits, Annelies; Vanduffel, Wim

    2013-07-01

    To understand the functional role of specific neurons in micro- and macro-brain circuitry, health, and disease, it is critical to control their activity precisely. This ambitious goal was first achieved by optogenetics, allowing researchers to increase or decrease neural activity artificially with high temporal and spatial precision. In contrast to the revolution optogenetics engendered in invertebrate and rodent research, only a few studies have reported optogenetic-induced neuronal and behavioral effects in primates. Such studies are nonetheless critical before optogenetics can be applied in a clinical setting. Here, we review the state-of-the-art tools for performing optogenetics in mammals, emphasizing recent neuronal and behavioral results obtained in nonhuman primates. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Induced Pluripotent Stem Cells from Nonhuman Primates.

    PubMed

    Mishra, Anuja; Qiu, Zhifang; Farnsworth, Steven L; Hemmi, Jacob J; Li, Miao; Pickering, Alexander V; Hornsby, Peter J

    2016-01-01

    Induced pluripotent stem cells from nonhuman primates (NHPs) have unique roles in cell biology and regenerative medicine. Because of the relatedness of NHPs to humans, NHP iPS cells can serve as a source of differentiated derivatives that can be used to address important questions in the comparative biology of primates. Additionally, when used as a source of cells for regenerative medicine, NHP iPS cells serve an invaluable role in translational experiments in cell therapy. Reprogramming of NHP somatic cells requires the same conditions as previously established for human cells. However, throughout the process, a variety of modifications to the human cell protocols must be made to accommodate significant species differences.

  9. PLATELET AGGREGATION IN HUMANS AND NONHUMAN PRIMATES: RELEVANCE TO XENOTRANSPLANTATION

    PubMed Central

    Iwase, Hayato; Ekser, Burcin; Zhou, Hao; Dons, Eefje M; Cooper, David K.C.; Ezzelarab, Mohamed B

    2012-01-01

    Introduction Platelet activation/aggregation plays a key role in the dysregulation of coagulation and the development of thrombotic microangiopathy in nonhuman primate recipients of pig xenografts. As a preliminary to the study of anti-platelet therapy in vitro and in vivo, the present study aimed to compare platelet aggregation in whole blood from humans, baboons, and cynomolgus monkeys. Methods Using ‘Chrono-log’ technology (two-sample four-channel Chrono-log Whole Blood Aggregometer), we studied aggregation of platelets in healthy humans (n=8), baboons (n=5), and monkeys (n=8). Whole blood (blood) samples were collected, and platelet aggregation was assessed using three different volumes of blood (1, 0.5, and 0.25 mL). Platelet activation was induced using collagen (at 3 and 5 µg/mL), ristocetin (at 0.5 and 1.0 mg/ml), adenosine diphosphate (ADP; at 10, 20, and 40 µM), or thrombin (at 1 and 5 IU/ml). Inhibition of agonist-induced platelet aggregation by heparin and low molecular weight heparin (LMWH) (at 1, 10, and 100 IU/mL) was evaluated. Results Mean platelet counts were 222.1, 263.2, and 276.1 (x103/ul) in humans, baboons, and monkeys, respectively. In all 3 species, platelet aggregation was induced by collagen, ristocetin, ADP, or thrombin in a dose-dependent manner. A blood volume of 0.5mL provided the most consistent results with all agonists in all 3 species. Dilution studies indicated that there was a significant positive correlation between platelet count and percent aggregation of platelets (p<0.05). Collagen (3 and 5µg/mL), ADP (10, 20 and 40 µM) and thrombin (1 and 5 IU/ml) induced significantly greater platelet aggregation in humans than in baboons. ADP (20 and 40 µM) and thrombin (1 and 5 IU/ml) induced significantly greater platelet aggregation in monkeys than in baboons. There was no species difference with ristocetin (0.5 or 1.0 mg/ml). In all species, thrombin (1 or 5 IU) induced greater platelet aggregation than any of the other

  10. Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

    PubMed Central

    Li, Shunqiang; Shen, Dong; Shao, Jieya; Crowder, Robert; Liu, Wenbin; Prat, Aleix; He, Xiaping; Liu, Shuying; Hoog, Jeremy; Lu, Charles; Ding, Li; Griffith, Obi L.; Miller, Christopher; Larson, Dave; Fulton, Robert S.; Harrison, Michelle; Mooney, Tom; McMichael, Joshua F.; Luo, Jingqin; Tao, Yu; Goncalves, Rodrigo; Schlosberg, Christopher; Hiken, Jeffrey F.; Saied, Laila; Sanchez, Cesar; Giuntoli, Therese; Bumb, Caroline; Cooper, Crystal; Kitchens, Robert T.; Lin, Austin; Phommaly, Chanpheng; Davies, Sherri R.; Zhang, Jin; Kavuri, Megha Shyam; McEachern, Donna; Dong, Yi Yu; Ma, Cynthia; Pluard, Timothy; Naughton, Michael; Bose, Ron; Suresh, Rama; McDowell, Reida; Michel, Loren; Aft, Rebecca; Gillanders, William; DeSchryver, Katherine; Wilson, Richard K.; Wang, Shaomeng; Mills, Gordon B.; Gonzalez-Angulo, Ana; Edwards, John R.; Maher, Christopher; Perou, Charles M.; Mardis, Elaine R.; Ellis, Matthew J.

    2013-01-01

    SUMMARY To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation. PMID:24055055

  11. Cognitive consequences of cooperative breeding in primates?

    PubMed

    Burkart, Judith Maria; van Schaik, Carel P

    2010-01-01

    Several hypotheses propose that cooperative breeding leads to increased cognitive performance, in both nonhuman and human primates, but systematic evidence for such a relationship is missing. A causal link might exist because motivational and cognitive processes necessary for the execution and coordination of helping behaviors could also favor cognitive performance in contexts not directly related to caregiving. In callitrichids, which among primates rely most strongly on cooperative breeding, these motivational and cognitive processes include attentional biases toward monitoring others, the ability to coordinate actions spatially and temporally, increased social tolerance, increased responsiveness to others' signals, and spontaneous prosociality. These processes are likely to enhance performance particularly in socio-cognitive contexts. Therefore, cooperatively breeding primates are expected to outperform their independently breeding sister taxa in socio-cognitive tasks. We evaluate this prediction by reviewing the literature and comparing cognitive performance in callitrichids with that of their sister taxa, i.e. squirrel monkeys, which are independent breeders, and capuchin monkeys, which show an intermediate breeding system. Consistent with our prediction, this review reveals that callitrichids systematically and significantly outperform their sister taxa in the socio-cognitive, but not in the non-social domain. This comparison is complemented with more qualitative evaluations of prosociality and cognitive performance in non-primate cooperative breeders, which suggest that among mammals, cooperative breeding generally produces conditions conducive to socio-cognitive performance. In the hominid lineage, however, the adoption of extensive allomaternal care presumably resulted in more pervasive cognitive consequences, because the motivational consequences of cooperative breeding was added to an ape-level cognitive system already capable of understanding simple

  12. Endoscopy and Endosurgery in Nonhuman Primates.

    PubMed

    Chai, Norin

    2015-09-01

    Endoscopy in nonhuman primates (NHPs) has resulted in improvements in research and clinical care for more than 4 decades. The indications and procedures are the same as in humans and the approach is similar to that in dogs, cats, and humans. Selected procedures are discussed including rhinoscopy, tracheobronchoscopy, upper gastrointestinal endoscopy, laparoscopy, and endoscopic salpingectomy. This short overview provides practitioners with pragmatic elements for safe and effective endoscopy in NHPs.

  13. Relaxin and the control of primate parturition.

    PubMed

    Weiss, Gerson

    2013-01-01

    In primate pregnancy, circulating relaxin, solely a product of the corpus luteum, peaks in the first trimester of pregnancy then declines and levels off for the remainder of pregnancy. Relaxin actions in pregnancy include increasing cervical pro-MMP-1 and pro-MMP-3 and decreasing TIMP-1, changes which soften the cervix. Relaxin, from early pregnancy, increases endometrial natural killer cells, macrophages and neutrophils, blood flow and arterial number. Hyperrelaxinemia correlates with preterm birth.

  14. Molecular evolution of prolactin in primates.

    PubMed

    Wallis, O Caryl; Mac-Kwashie, Akofa O; Makri, Georgia; Wallis, Michael

    2005-05-01

    Pituitary prolactin, like growth hormone (GH) and several other protein hormones, shows an episodic pattern of molecular evolution in which sustained bursts of rapid change contrast with long periods of slow evolution. A period of rapid change occurred in the evolution of prolactin in primates, leading to marked sequence differences between human prolactin and that of nonprimate mammals. We have defined this burst more precisely by sequencing the coding regions of prolactin genes for a prosimian, the slow loris (Nycticebus pygmaeus), and a New World monkey, the marmoset (Callithrix jacchus). Slow loris prolactin is very similar in sequence to pig prolactin, so the episode of rapid change occurred during primate evolution, after the separation of lines leading to prosimians and higher primates. Marmoset prolactin is similar in sequence to human prolactin, so the accelerated evolution occurred before divergence of New World monkeys and Old World monkeys/apes. The burst of change was confined largely to coding sequence (nonsynonymous sites) for mature prolactin and is not marked in other components of the gene sequence. This and the observations that (1) there was no apparent loss of function during the episode of rapid evolution, (2) the rate of evolution slowed toward the basal rate after this burst, and (3) the distribution of substitutions in the prolactin molecule is very uneven support the idea that this episode of rapid change was due to positive adaptive selection. In the slow loris and marmoset there is no evidence for duplication of the prolactin gene, and evidence from another New World monkey (Cebus albifrons) and from the chimpanzee and human genome sequences, suggests that this is the general position in primates, contrasting with the situation for GH genes. The chimpanzee prolactin sequence differs from that of human at two residues and comparison of human and chimpanzee prolactin gene sequences suggests that noncoding regions associated with regulating

  15. Transplantation in Turkey.

    PubMed

    Haberal, Mehmet

    2013-01-01

    The cornerstone events of transplantation history in Turkey are summarized herein. In 1975, we performed the first living-related renal transplant in Turkey. We followed this in 1978 with the first deceased donor kidney transplantation, using an organ supplied by Eurotransplant. In 1979, the law on harvesting, storage, grafting, and transplantation of organs and tissues was enacted; later that year, the first local deceased donor kidney transplantation was performed by our team. In 1988, another groundbreaking event in Turkey was successfully achieved: the first cadaveric liver transplantation. In 1990, the first pediatric living-related segmental liver transplantation in Turkey, the region, and Europe was performed by our team. One month later, an adult-to-adult living-related liver transplantation was successfully performed. In May 1992, we performed the first combined liver-kidney transplantation from a living-related donor, which was the first operation of its kind. To date, we have performed 2,084 kidney and, since 1988, 439 liver transplantations. During 29 years of solid organ transplantation history in Turkey, 20,794 kidney transplants have been performed nationwide in 62 different centers, as well as 6,565 liver, 621 heart, and 168 pancreas transplants. In 2001, the Ministry of Health established the National Coordination Center as an umbrella organization to promote transplantation activities, especially for deceased donor organ procurement. Transplantation activities are accelerating daily throughout the country, but deceased donors are still far below the desired rates.

  16. Theory of Auditory Thresholds in Primates

    NASA Astrophysics Data System (ADS)

    Harrison, Michael J.

    2001-03-01

    The influence of thermal pressure fluctuations at the tympanic membrane has been previously investigated as a possible determinant of the threshold of hearing in humans (L.J. Sivian and S.D. White, J. Acoust. Soc. Am. IV, 4;288(1933).). More recent work has focussed more precisely on the relation between statistical mechanics and sensory signal processing by biological means in creatures' brains (W. Bialek, in ``Physics of Biological Systems: from molecules to species'', H. Flyvberg et al, (Eds), p. 252; Springer 1997.). Clinical data on the frequency dependence of hearing thresholds in humans and other primates (W.C. Stebbins, ``The Acoustic Sense of Animals'', Harvard 1983.) has long been available. I have derived an expression for the frequency dependence of hearing thresholds in primates, including humans, by first calculating the frequency dependence of thermal pressure fluctuations at eardrums from damped normal modes excited in model ear canals of given simple geometry. I then show that most of the features of the clinical data are directly related to the frequency dependence of the ratio of thermal noise pressure arising from without to that arising from within the masking bandwidth which signals must dominate in order to be sensed. The higher intensity of threshold signals in primates smaller than humans, which is clinically observed over much but not all of the human auditory spectrum is shown to arise from their smaller meatus dimensions. note

  17. Emotions, stress, and maternal motivation in primates.

    PubMed

    Maestripieri, Dario

    2011-06-01

    Recent research conducted with nonhuman primates confirms that adaptive emotional processes, such as maternal attraction arousability and maternal anxiety arousability, enhance and sustain female motivation to interact with infants, invest in them, and protect them during the postpartum period. Changes in these emotional processes, and concomitant changes in maternal motivation, facilitate the reduction and eventual termination of maternal investment associated with infant weaning. Although laboratory studies of rodents and socially deprived rhesus monkeys have suggested that nulliparous females are neophobic and find infant stimuli aversive, recent primate research indicates that neophobia or aversion to infant stimuli do not occur in females with normal developmental experience. Furthermore, although some rodent and human studies have shown that lactation is accompanied by physiological hyporesponsiveness to stress, other studies of rodents, nonhuman primates, and humans indicate that mothers are highly vulnerable to stress and that stress-induced dysregulation of emotions can interfere with maternal motivation and parenting behavior. It is possible that some aspects of the emotional and experiential regulation of maternal motivation and parental behavior are different in different mammalian species. However, variation in the environments in which subjects are tested and in their developmental experience may also be responsible for the some discrepancies between the results of different studies.

  18. The ecology of primate material culture.

    PubMed

    Koops, Kathelijne; Visalberghi, Elisabetta; van Schaik, Carel P

    2014-11-01

    Tool use in extant primates may inform our understanding of the conditions that favoured the expansion of hominin technology and material culture. The 'method of exclusion' has, arguably, confirmed the presence of culture in wild animal populations by excluding ecological and genetic explanations for geographical variation in behaviour. However, this method neglects ecological influences on culture, which, ironically, may be critical for understanding technology and thus material culture. We review all the current evidence for the role of ecology in shaping material culture in three habitual tool-using non-human primates: chimpanzees, orangutans and capuchin monkeys. We show that environmental opportunity, rather than necessity, is the main driver. We argue that a better understanding of primate technology requires explicit investigation of the role of ecological conditions. We propose a model in which three sets of factors, namely environment, sociality and cognition, influence invention, transmission and retention of material culture. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  19. The appropriation of glucose through primate neurodevelopment.

    PubMed

    Bauernfeind, Amy L; Babbitt, Courtney C

    2014-12-01

    The human brain is considerably larger and more energetically costly than that of other primate species. As such, discovering how human ancestors were able to provide sufficient energy to their brains is a central theme in the study of hominin evolution. However, many discussions of metabolism frequently omit the different ways in which energy, primarily glucose, is used once made available to the brain. In this review, we discuss two glucose metabolic pathways, oxidative phosphorylation and aerobic glycolysis, and their respective contributions to the energetic and anabolic budgets of the brain. While oxidative phosphorylation is a more efficient producer of energy, aerobic glycolysis contributes essential molecules for the growth of the brain and maintaining the structure of its cells. Although both pathways occur in the brain throughout the lifetime, aerobic glycolysis is a critical pathway during development, and oxidative phosphorylation is highest during adulthood. We outline how elevated levels of aerobic glycolysis may support the protracted neurodevelopmental sequence of humans compared with other primates. Finally, we review the genetic evidence for differences in metabolic function in the brains of primates and explore genes that may provide insight into how glucose metabolism may differ across species.

  20. Visual specialization and brain evolution in primates.

    PubMed Central

    Barton, R A

    1998-01-01

    Several theories have been proposed to explain the evolution of species differences in brain size, but no consensus has emerged. One unresolved question is whether brain size differences are a result of neural specializations or of biological constraints affecting the whole brain. Here I show that, among primates, brain size variation is associated with visual specialization. Primates with large brains for their body size have relatively expanded visual brain areas, including the primary visual cortex and lateral geniculate nucleus. Within the visual system, it is, in particular, one functionally specialized pathway upon which selection has acted: evolutionary changes in the number of neurons in parvocellular, but not magnocellular, layers of the lateral geniculate nucleus are correlated with changes in both brain size and ecological variables (diet and social group size). Given the known functions of the parvocellular pathway, these results suggest that the relatively large brains of frugivorous species are products of selection on the ability to perceive and select fruits using specific visual cues such as colour. The separate correlation between group size and visual brain evolution, on the other hand, may indicate the visual basis of social information processing in the primate brain. PMID:9821360

  1. Dietary quality and encephalization in platyrrhine primates

    PubMed Central

    Allen, Kari L.; Kay, Richard F.

    2012-01-01

    The high energetic costs of building and maintaining large brains are thought to constrain encephalization. The ‘expensive-tissue hypothesis’ (ETH) proposes that primates (especially humans) overcame this constraint through reduction of another metabolically expensive tissue, the gastrointestinal tract. Small guts characterize animals specializing on easily digestible diets. Thus, the hypothesis may be tested via the relationship between brain size and diet quality. Platyrrhine primates present an interesting test case, as they are more variably encephalized than other extant primate clades (excluding Hominoidea). We find a high degree of phylogenetic signal in the data for diet quality, endocranial volume and body size. Controlling for phylogenetic effects, we find no significant correlation between relative diet quality and relative endocranial volume. Thus, diet quality fails to account for differences in platyrrhine encephalization. One taxon, in particular, Brachyteles, violates predictions made by ETH in having a large brain and low-quality diet. Dietary reconstructions of stem platyrrhines further indicate that a relatively high-quality diet was probably in place prior to increases in encephalization. Therefore, it is unlikely that a shift in diet quality was a primary constraint release for encephalization in platyrrhines and, by extrapolation, humans. PMID:21831898

  2. THE KINEMATICS OF PRIMATE MIDFOOT FLEXIBILITY

    PubMed Central

    Greiner, Thomas M.; Ball, Kevin A.

    2015-01-01

    This study describes a unique assessment of primate intrinsic foot joint kinematics based upon bone pin rigid cluster tracking. It challenges the assumption that human evolution resulted in a reduction of midfoot flexibility, which has been identified in other primates as the “midtarsal break.” Rigid cluster pins were inserted into the foot bones of human, chimpanzee, baboon and macaque cadavers. The positions of these bone pins were monitored during a plantarflexion-dorsiflexion movement cycle. Analysis resolved flexion-extension movement patterns and the associated orientation of rotational axes for the talonavicular, calcaneocuboid and lateral cubometatarsal joints. Results show that midfoot flexibility occurs primarily at the talonavicular and cubometatarsal joints. The rotational magnitudes are roughly similar between humans and chimps. There is also a similarity among evaluated primates in the observed rotations of the lateral cubometatarsal joint, but there was much greater rotation observed for the talonavicular joint, which may serve to differentiate monkeys from the hominines. It appears that the capability for a midtarsal break is present within the human foot. A consideration of the joint axes shows that the medial and lateral joints have opposing orientations, which has been associated with a rigid locking mechanism in the human foot. However, the potential for this same mechanism also appears in the chimpanzee foot. These findings demonstrate a functional similarity within the midfoot of the hominines. Therefore, the kinematic capabilities and restrictions for the skeletal linkages of the human foot may not be as unique as has been previously suggested. PMID:25234343

  3. Phylogenomics of primates and their ancestral populations

    PubMed Central

    Siepel, Adam

    2009-01-01

    Genome assemblies are now available for nine primate species, and large-scale sequencing projects are underway or approved for six others. An explicitly evolutionary and phylogenetic approach to comparative genomics, called phylogenomics, will be essential in unlocking the valuable information about evolutionary history and genomic function that is contained within these genomes. However, most phylogenomic analyses so far have ignored the effects of variation in ancestral populations on patterns of sequence divergence. These effects can be pronounced in the primates, owing to large ancestral effective population sizes relative to the intervals between speciation events. In particular, local genealogies can vary considerably across loci, which can produce biases and diminished power in many phylogenomic analyses of interest, including phylogeny reconstruction, the identification of functional elements, and the detection of natural selection. At the same time, this variation in genealogies can be exploited to gain insight into the nature of ancestral populations. In this Perspective, I explore this area of intersection between phylogenetics and population genetics, and its implications for primate phylogenomics. I begin by “lifting the hood” on the conventional tree-like representation of the phylogenetic relationships between species, to expose the population-genetic processes that operate along its branches. Next, I briefly review an emerging literature that makes use of the complex relationships among coalescence, recombination, and speciation to produce inferences about evolutionary histories, ancestral populations, and natural selection. Finally, I discuss remaining challenges and future prospects at this nexus of phylogenetics, population genetics, and genomics. PMID:19801602

  4. Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates.

    PubMed

    Dugan, Laura L; Tian, LinLin; Quick, Kevin L; Hardt, Josh I; Karimi, Morvarid; Brown, Chris; Loftin, Susan; Flores, Hugh; Moerlein, Stephen M; Polich, John; Tabbal, Samer D; Mink, Jonathan W; Perlmutter, Joel S

    2014-09-01

    We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C3 (n = 8) or placebo (n = 7) for 2 months starting 1 week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated nonhuman primate rating scale, kinematic analyses of peak upper extremity velocity, positron emission tomography imaging of 6-[(18) F]fluorodopa (FD; reflects dopa decarboxylase) and [(11) C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), ex vivo quantification of striatal dopamine, and stereologic counts of tyrosine hydroxylase-immunostained neurons in substantia nigra. After 2 months, C3 -treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 -treated animals developed any toxicity. Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for Parkinson disease. © 2014 American Neurological Association.

  5. Testosterone and reproductive effort in male primates.

    PubMed

    Muller, Martin N

    2016-09-08

    Considerable evidence suggests that the steroid hormone testosterone mediates major life-history trade-offs in vertebrates, promoting mating effort at the expense of parenting effort or survival. Observations from a range of wild primates support the "Challenge Hypothesis," which posits that variation in male testosterone is more closely associated with aggressive mating competition than with reproductive physiology. In both seasonally and non-seasonally breeding species, males increase testosterone production primarily when competing for fecund females. In species where males compete to maintain long-term access to females, testosterone increases when males are threatened with losing access to females, rather than during mating periods. And when male status is linked to mating success, and dependent on aggression, high-ranking males normally maintain higher testosterone levels than subordinates, particularly when dominance hierarchies are unstable. Trade-offs between parenting effort and mating effort appear to be weak in most primates, because direct investment in the form of infant transport and provisioning is rare. Instead, infant protection is the primary form of paternal investment in the order. Testosterone does not inhibit this form of investment, which relies on male aggression. Testosterone has a wide range of effects in primates that plausibly function to support male competitive behavior. These include psychological effects related to dominance striving, analgesic effects, and effects on the development and maintenance of the armaments and adornments that males employ in mating competition.

  6. The oldest known primate skeleton and early haplorhine evolution.

    PubMed

    Ni, Xijun; Gebo, Daniel L; Dagosto, Marian; Meng, Jin; Tafforeau, Paul; Flynn, John J; Beard, K Christopher

    2013-06-06

    Reconstructing the earliest phases of primate evolution has been impeded by gaps in the fossil record, so that disagreements persist regarding the palaeobiology and phylogenetic relationships of the earliest primates. Here we report the discovery of a nearly complete and partly articulated skeleton of a primitive haplorhine primate from the early Eocene of China, about 55 million years ago, the oldest fossil primate of this quality ever recovered. Coupled with detailed morphological examination using propagation phase contrast X-ray synchrotron microtomography, our phylogenetic analysis based on total available evidence indicates that this fossil is the most basal known member of the tarsiiform clade. In addition to providing further support for an early dichotomy between the strepsirrhine and haplorhine clades, this new primate further constrains the age of divergence between tarsiiforms and anthropoids. It also strengthens the hypothesis that the earliest primates were probably diurnal, arboreal and primarily insectivorous mammals the size of modern pygmy mouse lemurs.

  7. Efficient and Targeted Transduction of Nonhuman Primate Liver With Systemically Delivered Optimized AAV3B Vectors.

    PubMed

    Li, Shaoyong; Ling, Chen; Zhong, Li; Li, Mengxin; Su, Qin; He, Ran; Tang, Qiushi; Greiner, Dale L; Shultz, Leonard D; Brehm, Michael A; Flotte, Terence R; Mueller, Christian; Srivastava, Arun; Gao, Guangping

    2015-12-01

    Recombinant adeno-associated virus serotype 3B (rAAV3B) can transduce cultured human liver cancer cells and primary human hepatocytes efficiently. Serine (S)- and threonine (T)-directed capsid modifications further augment its transduction efficiency. Systemically delivered capsid-optimized rAAV3B vectors can specifically target cancer cells in a human liver cancer xenograft model, suggesting their potential use for human liver-directed gene therapy. Here, we compared transduction efficiencies of AAV3B and AAV8 vectors in cultured primary human hepatocytes and cancer cells as well as in human and mouse hepatocytes in a human liver xenograft NSG-PiZ mouse model. We also examined the safety and transduction efficacy of wild-type (WT) and capsid-optimized rAAV3B in the livers of nonhuman primates (NHPs). Intravenously delivered S663V+T492V (ST)-modified self-complementary (sc) AAV3B-EGFP vectors led to liver-targeted robust enhanced green fluorescence protein (EGFP) expression in NHPs without apparent hepatotoxicity. Intravenous injections of both WT and ST-modified rAAV3B.ST-rhCG vectors also generated stable super-physiological levels of rhesus chorionic gonadotropin (rhCG) in NHPs. The vector genome predominantly targeted the liver. Clinical chemistry and histopathology examinations showed no apparent vector-related toxicity. Our studies should be important and informative for clinical development of optimized AAV3B vectors for human liver-directed gene therapy.

  8. Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells

    PubMed Central

    Lee, Soyoung; Yamada, Yohei; Tonsho, Makoto; Boskovic, Svjetlan; Nadazdin, Ognjenka; Schoenfeld, David; Cappetta, Kate; Atif, Muhammad; Smith, Rex-Neal; Cosimi, A. Benedict; Benichou, Gilles; Kawai, Tatsuo

    2014-01-01

    Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow (DBM) transplantation. To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel conditioning regimen, the “delayed protocol” in which DBM is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8+ memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2highCD8+ effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2high cells including CD8+ TEM while sparing naïve CD8+ T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2high T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach. PMID:24165326

  9. A comparative psychophysical approach to visual perception in primates.

    PubMed

    Matsuno, Toyomi; Fujita, Kazuo

    2009-04-01

    Studies on the visual processing of primates, which have well developed visual systems, provide essential information about the perceptual bases of their higher-order cognitive abilities. Although the mechanisms underlying visual processing are largely shared between human and nonhuman primates, differences have also been reported. In this article, we review psychophysical investigations comparing the basic visual processing that operates in human and nonhuman species, and discuss the future contributions potentially deriving from such comparative psychophysical approaches to primate minds.

  10. Agroecosystems and primate conservation in the tropics: a review.

    PubMed

    Estrada, Alejandro; Raboy, Becky E; Oliveira, Leonardo C

    2012-08-01

    Agroecosystems cover more than one quarter of the global land area (ca. 50 million km(2) ) as highly simplified (e.g. pasturelands) or more complex systems (e.g. polycultures and agroforestry systems) with the capacity to support higher biodiversity. Increasingly more information has been published about primates in agroecosystems but a general synthesis of the diversity of agroecosystems that primates use or which primate taxa are able to persist in these anthropogenic components of the landscapes is still lacking. Because of the continued extensive transformation of primate habitat into human-modified landscapes, it is important to explore the extent to which agroecosystems are used by primates. In this article, we reviewed published information on the use of agroecosystems by primates in habitat countries and also discuss the potential costs and benefits to human and nonhuman primates of primate use of agroecosystems. The review showed that 57 primate taxa from four regions: Mesoamerica, South America, Sub-Saharan Africa (including Madagascar), and South East Asia, used 38 types of agroecosystems as temporary or permanent habitats. Fifty-one percent of the taxa recorded in agroecosystems were classified as least concern in the IUCN Red List, but the rest were classified as endangered (20%), vulnerable (18%), near threatened (9%), or critically endangered (2%). The large proportion of threatened primates in agroecosystems suggests that agroecosystems may play an important role in landscape approaches to primate conservation. We conclude by discussing the value of agroecosystems for primate conservation at a broad scale and highlight priorities for future research. © 2012 Wiley Periodicals, Inc.

  11. Predictors of orbital convergence in primates: a test of the snake detection hypothesis of primate evolution.

    PubMed

    Wheeler, Brandon C; Bradley, Brenda J; Kamilar, Jason M

    2011-09-01

    Traditional explanations for the evolution of high orbital convergence and stereoscopic vision in primates have focused on how stereopsis might have aided early primates in foraging or locomoting in an arboreal environment. It has recently been suggested that predation risk by constricting snakes was the selective force that favored the evolution of orbital convergence in early primates, and that later exposure to venomous snakes favored further degrees of convergence in anthropoid primates. Our study tests this snake detection hypothesis (SDH) by examining whether orbital convergence among extant primates is indeed associated with the shared evolutionary history with snakes or the risk that snakes pose for a given species. We predicted that orbital convergence would be higher in species that: 1) have a longer history of sympatry with venomous snakes, 2) are likely to encounter snakes more frequently, 3) are less able to detect or deter snakes due to group size effects, and 4) are more likely to be preyed upon by snakes. Results based on phylogenetically independent contrasts do not support the SDH. Orbital convergence shows no relationship to the shared history with venomous snakes, likelihood of encountering snakes, or group size. Moreover, those species less likely to be targeted as prey by snakes show significantly higher values of orbital convergence. Although an improved ability to detect camouflaged snakes, along with other cryptic stimuli, is likely a consequence of increased orbital convergence, this was unlikely to have been the primary selective force favoring the evolution of stereoscopic vision in primates. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Toll-like receptors (TLRs) in transplantation

    PubMed Central

    Alegre, Maria-Luisa; Chong, Anita

    2015-01-01

    TLRs have been extensively studied over the past decade for their ability to recognize microbial molecular patterns and activate innate immune cells to fight infections. They have also been described to provide a link between innate and adaptive immunity, as TLR signals also enhance the antigen presenting capacity of innate immune cells to T cells. In recent years, a contribution of TLR pathways to immune responses elicited by ischemia/reperfusion injury (IRI), allografts and xenografts has been uncovered, although the ligands that bind TLRs in these settings remain to be revealed. Such research has the potential to identify novel therapeutic targets that may facilitate allograft acceptance. In this review, we will summarize the results published to date on the role of TLRs in experimental and clinical transplantation. PMID:19482622

  13. Transplantation of the heart and both lungs

    PubMed Central

    Longmore, D. B.; Cooper, D. K. C.; Hall, R. W.; Sekabunga, J.; Welch, W.

    1969-01-01

    It is estimated that an unknown, yet possibly large, number of patients would benefit from transplantation of the heart and both lungs if technically, physiologically, and immunologically feasible. In this paper we attempt to explore the main non-immunological areas in which we feel that cardiopulmonary transplantation requires further evaluation. A technique is described by which the heart and lungs, as one unit, can be removed from a donor animal, and viability of these organs can be maintained for several hours by autoperfusion (circulation being through the coronary and pulmonary vessels) with positive pressure ventilation via the trachea. This simple heart-lung preparation preserves the organs concerned for sufficient time to allow preparation of the recipient, transport of the donor organs, and tissue typing to be carried out. Our technique of implanting these donor organs into the recipient is also described. We have carried out this operation on approximately 100 dogs and have been impressed by the good cardiac function obtained, but spontaneous respiratory function has been either absent or inadequate to sustain life for more than a few hours. It would appear that dogs cannot tolerate bilateral pulmonary denervation, and our findings are discussed in the light of other work on this subject. Work on primates suggests that man would be able to undergo this procedure successfully. The organizational and ethical problems involved in cardiac and cardiopulmonary transplantation are briefly discussed. Images PMID:4894051

  14. Patient-derived xenografts as preclinical neuroblastoma models.

    PubMed

    Braekeveldt, Noémie; Bexell, Daniel

    2017-09-19

    The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing.

  15. Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

    PubMed Central

    Huang, Kuan-lin; Li, Shunqiang; Mertins, Philipp; Cao, Song; Gunawardena, Harsha P.; Ruggles, Kelly V.; Mani, D. R.; Clauser, Karl R.; Tanioka, Maki; Usary, Jerry; Kavuri, Shyam M.; Xie, Ling; Yoon, Christopher; Qiao, Jana W; Wrobel, John; Wyczalkowski, Matthew A.; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Hoog, Jeremy; Singh, Purba; Niu, Beifung; Guo, Zhanfang; Sun, Sam Qiancheng; Sanati, Souzan; Kawaler, Emily; Wang, Xuya; Scott, Adam; Ye, Kai; McLellan, Michael D.; Wendl, Michael C.; Malovannaya, Anna; Held, Jason M.; Gillette, Michael A.; Fenyö, David; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Davies, Sherri R.; Perou, Charles M.; Ma, Cynthia; Reid Townsend, R.; Chen, Xian; Carr, Steven A.; Ellis, Matthew J.; Ding, Li

    2017-01-01

    Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. PMID:28348404

  16. Mifepristone improves chemo-radiation response in glioblastoma xenografts

    PubMed Central

    2013-01-01

    Background We have investigated the ability of Mifepristone, an anti-progestin and anti-glucocorticoid drug, to modulate the antitumor effect of current standard clinical treatment in glioblastoma xenografts. Methods The effect of radiation alone or combined with Mifepristone and Temozolamide was evaluated on tumor growth in glioblastoma xenografts, both in terms of preferentially triggering tumor cell death and inhibiting angiogenesis. Tumor size was measured once a week using a caliper and tumor metabolic-activity was carried out by molecular imaging using a microPET/CT scanner. The effect of Mifepristone on the expression of angiogenic factors after concomitant radio-chemotherapy was determined using a quantitative real-time PCR analysis of VEGF gene expression. Results The analysis of the data shows a significant antitumoral effect by the simultaneous administration of radiation-Mifepristone-Temozolamide in comparison with radiation alone or radiation-Temozolamide. Conclusion Our results suggest that Mifepristone could improve the efficacy of chemo-radiotherapy in Glioblastoma. The addition of Mifepristone to standard radiation-Temozolamide therapy represents a potential approach as a chemo-radio-sensitizer in treating GBMs, which have very limited treatment options. PMID:23530939

  17. Reproducibility of Differential Proteomic Technologies in CPTAC Fractionated Xenografts

    SciTech Connect

    Tabb, David L.; Wang, Xia; Carr, Steven A.; Clauser, Karl R.; Mertins, Philipp; Chambers, Matthew C.; Holman, Jerry D.; Wang, Jing; Zhang, Bing; Zimmerman, Lisa J.; Chen, Xian; Gunawardena, Harsha P.; Davies, Sherri R.; Ellis, Matthew J. C.; Li, Shunqiang; Townsend, R. Reid; Boja, Emily S.; Ketchum, Karen A.; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Liu, Tao; Kim, Sangtae; McDermott, Jason E.; Payne, Samuel H.; Petyuk, Vladislav A.; Rodland, Karin D.; Smith, Richard D.; Yang, Feng; Chan, Daniel W.; Zhang, Bai; Zhang, Hui; Zhang, Zhen; Zhou, Jian-Ying; Liebler, Daniel C.

    2016-03-04

    The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC-MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows. We evaluated iTRAQ reporter ions, label-free spectral counts, and label-free extracted ion chromatograms as strategies for data interpretation. From these assessments we found that differential genes from a single replicate were confirmed by other replicates on the same instrument from 61-93% of the time. When comparing across different instruments and quantitative technologies, differential genes were reproduced by other data sets from 67-99% of the time. Projecting gene differences to biological pathways and networks increased the similarities. These overlaps send an encouraging message about the maturity of technologies for proteomic differentiation.

  18. Integrated Analysis of Transcriptome in Cancer Patient-Derived Xenografts

    PubMed Central

    Li, Hong; Zhu, Yinjie; Tang, Xiaoyan; Li, Junyi; Li, Yuanyuan; Zhong, Zhaomin; Ding, Guohui; Li, Yixue

    2015-01-01

    Patient-derived xenograft (PDX) tumor model is a powerful technology in evaluating anti-cancer drugs and facilitating personalized medicines. Multiple research centers and commercial companies have put huge efforts into building PDX mouse models. However, PDX models have not been widely available and their molecular features have not been systematically characterized. In this study, we provided a comprehensive survey of PDX transcriptome by integrating analysis of 58 patients involving 8 different tumors. The median correlation coefficient between patients and xenografts is 0.94, which is higher than that between patients and cell line panel or between patients with the same tumor. Major differential gene expressions in PDX occur in the engraftment of human tumor tissue into mice, while gene expressions are relatively stable over passages. 48 genes are frequently differentially expressed in PDX mice of multiple cancers. They are enriched in extracellular matrix and immune response, and some are reported as targets for anticancer drugs. A simulation study showed that expression change between PDX and patient tumor (6%) would result in acceptable change in drug sensitivity (3%). Our findings demonstrate that PDX mice represent the gene-expression and drug-response features of primary tumors effectively, and it is recommended to monitoring the overall expression profiles and drug target genes in clinical application. PMID:25951608

  19. Reproducibility of Differential Proteomic Technologies in CPTAC Fractionated Xenografts

    PubMed Central

    2015-01-01

    The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC–MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows. We evaluated iTRAQ reporter ions, label-free spectral counts, and label-free extracted ion chromatograms as strategies for data interpretation (source code is available from http://homepages.uc.edu/~wang2x7/Research.htm). From these assessments, we found that differential genes from a single replicate were confirmed by other replicates on the same instrument from 61 to 93% of the time. When comparing across different instruments and quantitative technologies, using multiple replicates, differential genes were reproduced by other data sets from 67 to 99% of the time. Projecting gene differences to biological pathways and networks increased the degree of similarity. These overlaps send an encouraging message about the maturity of technologies for proteomic differentiation. PMID:26653538

  20. Regression of prostate cancer xenografts by RLIP76 depletion

    PubMed Central

    Singhal, Sharad S.; Roth, Cherice; Leake, Kathryn; Singhal, Jyotsana; Yadav, Sushma; Awasthi, Sanjay

    2009-01-01

    RLIP76 plays a central role in radiation and chemotherapy resistance through its activity as a multi-specific ATP-dependent transporter which is over-expressed in a number of types of cancers. RLIP76 appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that depletion or inhibition of RLIP76 causes selective toxicity in malignant cells. RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GS-E. The results of our in vivo studies demonstrate that administration of RLIP76 antibodies, siRNA or anti-sense to mice bearing xenografts of PC-3 prostate cancer cells leads to near complete regression of established subcutaneous xenografts with no apparent toxic effects. Since anti-RLIP76 IgG (which inhibit RLIP76- mediated transport), siRNA and antisense (which deplete RLIP76) showed similar tumor regressing activities, our results indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. These studies indicate that RLIP76 serves a key effector function for the survival of prostate cancer cells and that it is a valid target for cancer therapy. PMID:19073149

  1. Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia

    PubMed Central

    Delitto, Andrea E.; Nosacka, Rachel L.; Rocha, Fernanda G.; DiVita, Bayli B.; Gerber, Michael H.; George, Thomas J.; Behrns, Kevin E.; Hughes, Steven J.; Wallet, Shannon M.; Judge, Andrew R.; Trevino, Jose G.

    2017-01-01

    Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome. PMID:27901481

  2. Native MAG-1 antibody almost destroys human breast cancer xenografts.

    PubMed

    North, William G; Pang, Roy H L; Gao, Guohong; Memoli, Vincent A; Cole, Bernard F

    2011-06-01

    A native form of mouse monoclonal IgG1 antibody called MAG-1, which recognizes an epitope on provasopressin, has been found to shrink and produce extensive necrosis of human breast tumor xenografts in nu/nu mice. We examined the ability of (90)Yttrium-labeled and native MAG-1 to affect the growth in nu/nu mice of cancer xenografts that were estrogen-responsive (from MCF-7 cells) and triple-negative (from MDA-MB231 cells). The growth rates of treated cells were compared to those receiving saline vehicle and those receiving (90)Yttrium-labeled and native forms of the ubiquitous antibody, MOPC21. Short-term treatments (4 doses over 6 days) not only with (90)Yttrium-MAG-1 but also native MAG-1 produced large reductions in size of rapidly growing tumors of both types, while both (90)Yttrium- MOPC21 and native MOPC21 had no effect. Native and (90)Yttrium-MAG-1 effects were similar, and arrested tumors recommenced growing soon after treatments stopped. Increasing native MAG-1 treatment to single dosing for 16 consecutive days shrank tumors of both types with no regrowth apparent over a 20-day post-treatment period of observation. Pathological examination of such tumors revealed they had undergone very extensive (>66%) necrosis.

  3. Transplantation Immunity. Contemporary Views.

    PubMed

    Zaretskaya, Yuliya M.

    1999-12-01

    "Transplantation immunity in Cyclosporin era" is a special chapter in science under name transplantation immunity. Nowadays, practically all the organs can be grafted: kidney, heart, lung, liver, pancreas both as organ, and as islet cells, bone marrow from relative and unrelative donors. The broad spectrum of grafted organs gave one more surprising peculiarity of transplantation immunity: it operates with different strength after transplantation of various organs. If the decreasing gradient of transplantation immunity could be composed, then it appeared to be approximately in the following order: bone marrow - skin - kidney - heart - lung. The most complicated operating activity of transplantation immunity is occurring after bone marrow transplantation, especially from unrelative donor, because in bone marrow transplantation immunological process develops in both directions. Therefore now, bone marrow is the only organ (tissue), when the complete compatibility between donor and recipient is required after its transplantation; especially in cases with unrelative donors.

  4. Nutrition in kidney transplantation.

    PubMed

    Veroux, Massimiliano; Corona, Daniela; Sinagra, Nunziata; Tallarita, Tiziano; Ekser, Burcin; Giaquinta, Alessia; Zerbo, Domenico; Veroux, Pierfrancesco

    2013-10-01

    Organ transplantation has progressively established itself as the preferred therapy for many end-stage organ failures. However, many of these chronic diseases and their treatments can negatively affect nutritional status, leading to malnutrition and mineral deficiencies.Nutritional status is an important determinant of the clinical outcome of kidney transplant recipients.Malnutrition and obesity may represent a contraindication to transplantation in many cases and may increase the risk of postoperative complications after the transplantation. Nutritional support in kidney transplant recipients is challenging, since it must take into account the pre-transplant nutritional status, the side effects of immunosuppression, the function of the transplanted graft, the presence of infection, and the general status of the patient at the time of the transplantation.With these considerations in mind, we reviewed current literature on the impact of nutritional status on the outcome of kidney transplantation.

  5. Why is a landscape perspective important in studies of primates?

    PubMed

    Arroyo-Rodríguez, Víctor; Fahrig, Lenore

    2014-10-01

    With accelerated deforestation and fragmentation through the tropics, assessing the impact that landscape spatial changes may have on biodiversity is paramount, as this information is required to design and implement effective management and conservation plans. Primates are expected to be particularly dependent on the landscape context; yet, our understanding on this topic is limited as the majority of primate studies are at the local scale, meaning that landscape-scale inferences are not possible. To encourage primatologists to assess the impact of landscape changes on primates, and help future studies on the topic, we describe the meaning of a "landscape perspective" and evaluate important assumptions of using such a methodological approach. We also summarize a number of important, but unanswered, questions that can be addressed using a landscape-scale study design. For example, it is still unclear if habitat loss has larger consistent negative effects on primates than habitat fragmentation per se. Furthermore, interaction effects between habitat area and other landscape effects (e.g., fragmentation) are unknown for primates. We also do not know if primates are affected by synergistic interactions among factors at the landscape scale (e.g., habitat loss and diseases, habitat loss and climate change, hunting, and land-use change), or whether landscape complexity (or landscape heterogeneity) is important for primate conservation. Testing for patterns in the responses of primates to landscape change will facilitate the development of new guidelines and principles for improving primate conservation. © 2014 Wiley Periodicals, Inc.

  6. Sexual selection and the evolution of brain size in primates.

    PubMed

    Schillaci, Michael A

    2006-12-20

    Reproductive competition among males has long been considered a powerful force in the evolution of primates. The evolution of brain size and complexity in the Order Primates has been widely regarded as the hallmark of primate evolutionary history. Despite their importance to our understanding of primate evolution, the relationship between sexual selection and the evolutionary development of brain size is not well studied. The present research examines the evolutionary relationship between brain size and two components of primate sexual selection, sperm competition and male competition for mates. Results indicate that there is not a significant relationship between relative brain size and sperm competition as measured by relative testis size in primates, suggesting sperm competition has not played an important role in the evolution of brain size in the primate order. There is, however, a significant negative evolutionary relationship between relative brain size and the level of male competition for mates. The present study shows that the largest relative brain sizes among primate species are associated with monogamous mating systems, suggesting primate monogamy may require greater social acuity and abilities of deception.

  7. The adaptive value of primate color vision for predator detection.

    PubMed

    Pessoa, Daniel Marques Almeida; Maia, Rafael; de Albuquerque Ajuz, Rafael Cavalcanti; De Moraes, Pedro Zurvaino Palmeira Melo Rosa; Spyrides, Maria Helena Constantino; Pessoa, Valdir Filgueiras

    2014-08-01

    The complex evolution of primate color vision has puzzled biologists for decades. Primates are the only eutherian mammals that evolved an enhanced capacity for discriminating colors in the green-red part of the spectrum (trichromatism). However, while Old World primates present three types of cone pigments and are routinely trichromatic, most New World primates exhibit a color vision polymorphism, characterized by the occurrence of trichromatic and dichromatic females and obligatory dichromatic males. Even though this has stimulated a prolific line of inquiry, the selective forces and relative benefits influencing color vision evolution in primates are still under debate, with current explanations focusing almost exclusively at the advantages in finding food and detecting socio-sexual signals. Here, we evaluate a previously untested possibility, the adaptive value of primate color vision for predator detection. By combining color vision modeling data on New World and Old World primates, as well as behavioral information from human subjects, we demonstrate that primates exhibiting better color discrimination (trichromats) excel those displaying poorer color visions (dichromats) at detecting carnivoran predators against the green foliage background. The distribution of color vision found in extant anthropoid primates agrees with our results, and may be explained by the advantages of trichromats and dichromats in detecting predators and insects, respectively. © 2014 Wiley Periodicals, Inc.

  8. Evolutionary Glycomics: Characterization of Milk Oligosaccharides in Primates

    PubMed Central

    Tao, Nannan; Wu, Shuai; Kim, Jaehan; An, Hyun Joo; Hinde, Katie; Power, Michael L.; Gagneux, Pascal; German, J. Bruce; Lebrilla, Carlito B.

    2011-01-01

    Free oligosaccharides are abundant components of mammalian milk and have primary roles as prebiotic compounds, in immune defense, and in brain development. Mass spectrometry-based technique is applied to profile milk oligosaccharides from apes (chimpanzee, gorilla, and siamang), new world monkeys (golden lion tamarin and common marmoset), and an old world monkey (rhesus). The purpose of this study was to evaluate the patterns of primate milk oligosaccharide composition from a phylogenetic perspective in order to assess the extent to which the compositions of hMOs derives from ancestral, primate patterns as opposed to more recent evolutionary events. Milk oligosaccharides were quantitated by nanoflow liquid chromatography on chip-based devices. The relative abundances of fucosylated and sialylated milk oligosaccharides in primates were also determined. For a systematic and comprehensive study of evolutionary patterns of milk oligosaccharides, cluster analysis of primate milk was performed using the chromatographic profile. In general, the oligosaccharides in primate milk, including humans, are more complex and exhibit greater diversity compared to the ones in non-primate milk. A detailed comparison of the oligosaccharides across evolution revealed non-sequential developmental pattern, i.e. that primate milk oligosaccharides do not necessarily cluster according to the primate phylogeny. This report represents the first comprehensive and quantitative effort to profile and elucidate the structures of free milk oligosaccharides so that they can be related to glycan function in different primates. PMID:21214271

  9. Comparative primate genomics: emerging patterns of genome content and dynamics.

    PubMed

    Rogers, Jeffrey; Gibbs, Richard A

    2014-05-01

    Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for various primate species, and analyses of several others are underway. Whole-genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other non-human primates offer valuable insights into genetic similarities and differences among species that are used as models for disease-related research. This Review summarizes current knowledge regarding primate genome content and dynamics, and proposes a series of goals for the near future.

  10. Comparative primate genomics: emerging patterns of genome content and dynamics

    PubMed Central

    Rogers, Jeffrey; Gibbs, Richard A.

    2014-01-01

    Preface Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for several primates, with analyses of several others underway. Whole genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other nonhuman primates provide valuable insight into genetic similarities and differences among species used as models for disease-related research. This review summarizes current knowledge regarding primate genome content and dynamics and offers a series of goals for the near future. PMID:24709753

  11. Organ transplantation in Tunisia.

    PubMed

    El Matri, Aziz; Ben Abdallah, Taieb

    2015-04-01

    Kidney transplants were first performed in Tunisia in 1986, and transplants soon extended to other organs including the heart, liver, and pancreas. Live-related donor and deceased-donor kidney transplants were both began in the summer of 1986. An organ procurement and transplant law was passed in March 1991, and the National Centre for Advancement of Organ Transplantation was created in 1995. The number of transplantation units has increased to 7 throughout the country, and the yearly transplant number has progressively increased to 139 in 2010, including 20% from deceased kidney donors. Despite these gains, the need continues to grow. Heart transplants began in January 1993, and Tunisia and Jordan are currently the only Arab countries where it is practiced. However, only 16 patients have received a heart transplant as of 2004, and the number of recipients has decreased in the past 10 years. Liver transplants are rare in other Arab countries, but began in Tunisia in January 1998. Over 10 years, 38 patients benefited from this procedure. After a few years of stagnation, the number of liver transplants is increasing. While all types of transplantation are needed, kidney transplantation is a priority in Tunisia. The target is to perform 400 transplants annually, which would require a long-term strategy to provide full financial coverage using the National Health Insurance Funds in both the public and private sectors.

  12. Comparative analysis of the primate X-inactivation center region and reconstruction of the ancestral primate XIST locus

    PubMed Central

    Horvath, Julie E.; Sheedy, Christina B.; Merrett, Stephanie L.; Diallo, Abdoulaye Banire; Swofford, David L.; NISC Comparative Sequencing Program; Green, Eric D.; Willard, Huntington F.

    2011-01-01

    Here we provide a detailed comparative analysis across the candidate X-Inactivation Center (XIC) region and the XIST locus in the genomes of six primates and three mammalian outgroup species. Since lemurs and other strepsirrhine primates represent the sister lineage to all other primates, this analysis focuses on lemurs to reconstruct the ancestral primate sequences and to gain insight into the evolution of this region and the genes within it. This comparative evolutionary genomics approach reveals significant expansion in genomic size across the XIC region in higher primates, with minimal size alterations across the XIST locus itself. Reconstructed primate ancestral XIC sequences show that the most dramatic changes during the past 80 million years occurred between the ancestral primate and the lineage leading to Old World monkeys. In contrast, the XIST locus compared between human and the primate ancestor does not indicate any dramatic changes to exons or XIST-specific repeats; rather, evolution of this locus reflects small incremental changes in overall sequence identity and short repeat insertions. While this comparative analysis reinforces that the region around XIST has been subject to significant genomic change, even among primates, our data suggest that evolution of the XIST sequences themselves represents only small lineage-specific changes across the past 80 million years. PMID:21518738

  13. Chondrocytic differentiation of peripheral neuroectodermal tumor cell line in nude mouse xenograft.

    PubMed

    Goji, J; Sano, K; Nakamura, H; Ito, H

    1992-08-01

    We have established a cell line (KU-SN) from a peripheral neuroectodermal tumor originating in the left scapula of a 4-year-old girl. The original tumor was immunoreactive with antibodies for neurofilament proteins, neuron-specific enolase, vimentin, S100 protein, and beta 2-microglobulin. Dense core granules, 50-150 nm in diameter, were identified by electron microscopy. The cell line was established from tumor cells in metastatic lung fluid. KU-SN cells were immunoreactive with the antibodies for neurofilament proteins, vimentin, neuron-specific enolase, S100 protein, glial fibrillary acidic protein, cytokeratin, and carcinoembryonic antigen. Besides these neuronal features, KU-SN cells express type 2 collagen and insulin-like growth factor 1 receptor. The addition of insulin-like growth factor 1 (100 ng/ml) increased the growth rate of KU-SN cells 2.1-fold over control. Some cells were positive for Alcian blue and alkaline phosphatase staining. Cytogenetic analysis of KU-SN cells disclosed a reciprocal chromosomal translocation [t(11,22)]. Northern blot analysis of KU-SN cells demonstrated amplified expression of the c-myc gene but not the N-myc gene. When tumor cells were transplanted into nude mice, cartilage was formed. The cartilage was immunoreactive with the antibody for HLA-ABC, indicating that it was derived from the tumor cells, not from mouse tissue. Chondrocytic differentiation was not observed in xenografts of Ewing's sarcoma cell lines SK-ES or RD-ES or the peripheral neuroectodermal tumor cell line SK-N-MC. These results indicate that KU-SN cells represent primitive neural crest cells having the potential for chondrocytic differentiation.

  14. Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis.

    PubMed

    Eyre, Rachel; Alférez, Denis G; Spence, Kath; Kamal, Mohamed; Shaw, Frances L; Simões, Bruno M; Santiago-Gómez, Angélica; Sarmiento-Castro, Aida; Bramley, Maria; Absar, Mohammed; Saad, Zahida; Chatterjee, Sumohan; Kirwan, Cliona; Gandhi, Ashu; Armstrong, Anne C; Wardley, Andrew M; O'Brien, Ciara S; Farnie, Gillian; Howell, Sacha J; Clarke, Robert B

    2016-12-01

    Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease.

  15. Assessment of Hypoxia in Human Cervical Carcinoma Xenografts by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

    SciTech Connect

    Ellingsen, Christine; Egeland, Tormod A.M.; Gulliksrud, Kristine M.Sc.; Gaustad, Jon-Vidar; Mathiesen, Berit; Rofstad, Einar K.

    2009-03-01

    Purpose: Patients with advanced cervical cancer and highly hypoxic primary tumors show increased frequency of locoregional treatment failure and poor disease-free and overall survival rates. The potential usefulness of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing tumor hypoxia noninvasively was investigated in the present preclinical study. Methods and Materials: CK-160 and TS-415 human cervical carcinoma xenografts transplanted intramuscularly (i.m.) or subcutaneously (s.c.) in BALB/c nu/nu mice were subjected to DCE-MRI and measurement of fraction of radiobiologically hypoxic cells. Tumor images of K{sup trans} (the volume transfer constant of Gd-DTPA) and v{sub e} (the extracellular volume fraction of the imaged tissue) were produced by pharmacokinetic analysis of the DCE-MRI data. Fraction of radiobiologically hypoxic cells was measured by using the paired survival curve method. Results: Fraction of radiobiologically hypoxic cells differed significantly among the four tumor groups. The mean values {+-} SE were determined to be 44% {+-} 7% (i.m. CK-160), 77% {+-} 10% (s.c. CK-160), 23% {+-} 5% (i.m. TS-415), and 52% {+-} 6% (s.c. TS-415). The four tumor groups differed significantly also in K{sup trans}, and there was an unambiguous inverse relationship between K{sup trans} and fraction of radiobiologically hypoxic cells. On the other hand, significant differences among the groups in v{sub e} could not be detected. Conclusions: The study supports the clinical development of DCE-MRI as a method for assessing the extent of hypoxia in carcinoma of the cervix.

  16. Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

    PubMed Central

    Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P.; Taylor, Renea A.; Watt, Matthew J.

    2016-01-01

    There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis. PMID:27351281

  17. Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts.

    PubMed

    Lo, Jennifer C Y; Clark, Ashlee K; Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P; Taylor, Renea A; Watt, Matthew J

    2016-07-26

    There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis.

  18. Biohybrid artificial pancreas. Long-term function of discordant islet xenografts in streptozotocin diabetic rats.

    PubMed

    Lanza, R P; Beyer, A M; Staruk, J E; Chick, W L

    1993-11-01

    Long-term function of canine, bovine, and porcine islet xenografts implanted in streptozotocin-induced diabetic rats has been achieved by islet encapsulation within permselective acrylic membrane chambers. Intraperitoneal implants of 1 x 10(4) (n = 11) or 2 x 10(4) (n = 2) encapsulated canine islets reversed the diabetic state of the recipients within 24 hr, with plasma glucose levels dropping from a preimplantation level of 480 +/- 26 (mean +/- SEM) to 97 +/- 4 mg/dl during the first month. Chambers from 2 of the animals were removed, bisected, and reimplanted at 1 week and 2 months; both animals reverted to hyperglycemia (glucose, > 200 mg/dl) in < 2 weeks. The remaining implants maintained function for a mean time of 138 +/- 16 days, whereas the 2 animals that received the higher islet dose maintained function for > 260 days. Membranes containing 2 x 10(4) bovine (n = 6) or porcine (n = 10) islets also normalized glucose concentrations, with plasma glucose levels dropping from 468 +/- 61 to 91 +/- 10 (bovine) and 97 +/- 11 (porcine) mg/dl during the first month (vs. 94 +/- 3 mg/dl for nondiabetic control rats). Three of the latter implants were removed at 1 month. All 3 animals promptly reverted to diabetes. The 3-, 6-, 9-, and 12-month graft survival rates for the remaining animals were 100%, 100%, 60%, and 40%, and 100%, 75%, 50%, and 25%, respectively. The transplant recipients showed an approximately 38-54% gain in body weight during the first 100 days after implantation, compared with < 1% (P < 0.001) and 86% (P < 0.001) for the untreated diabetic (n = 5) and normal control (n = 6) groups. Immunohistochemical staining of long-term grafts (1-20 months) revealed varying degrees of alpha-, beta-, and delta-cell granulation; the external membrane surfaces were generally free of fibrotic overgrowth and exhibited only occasional host cell adherence. Despite a problem of membrane breakage in long-term implants, these results suggest that prolonged survival of

  19. Diurnality, nocturnality, and the evolution of primate visual systems.

    PubMed

    Ankel-Simons, F; Rasmussen, D T

    2008-01-01

    Much of the recent research on the evolution of primate visual systems has assumed that a minimum number of shifts have occurred in circadian activity patterns over the course of primate evolution. The evolutionary origins of key higher taxonomic groups have been interpreted by some researchers as a consequence of a rare shift from nocturnality to diurnality (e.g., Anthropoidea) or from diurnality to nocturnality (e.g., Tarsiidae). Interpreting the evolution of primate visual systems with an ecological approach without parsimony constraints suggests that the evolutionary transitions in activity pattern are more common than what would be allowed by parsimony models, and that such transitions are probably less important in the origin of higher level taxa. The analysis of 17 communities of primates distributed widely around the world and through geological time shows that primate communities consistently contain both nocturnal and diurnal forms, regardless of the taxonomic sources of the communities. This suggests that primates in a community will adapt their circadian pattern to fill empty diurnal or nocturnal niches. Several evolutionary transitions from one pattern to the other within narrow taxonomic groups are solidly documented, and these cases probably represent a small fraction of such transitions throughout the Cenozoic. One or more switches have been documented among platyrrhine monkeys, Malagasy prosimians, Eocene omomyids, Eocene adapoids, and early African anthropoids, with inconclusive but suggestive data within tarsiids. The interpretation of living and extinct primates as fitting into one of two diarhythmic categories is itself problematic, because many extant primates show significant behavioral activity both nocturnally and diurnally. Parsimony models routinely interpret ancestral primates to have been nocturnal, but analyses of morphological and genetic data indicate that they may have been diurnal, or that early primate radiations were likely to

  20. Pancreas transplantation: review

    PubMed Central

    Meirelles, Roberto Ferreira; Salvalaggio, Paolo; Pacheco-Silva, Alvaro

    2015-01-01

    ABSTRACT Vascularized pancreas transplantation is the only treatment that establishes normal glucose levels and normalizes glycosylated hemoglobin levels in type 1 diabetic patients. The first vascularized pancreas transplant was performed by William Kelly and Richard Lillehei, to treat a type 1 diabetes patient, in December 1966. In Brazil, Edison Teixeira performed the first isolated segmental pancreas transplant in 1968. Until the 1980s, pancreas transplants were restricted to a few centers of the United States and Europe. The introduction of tacrolimus and mycophenolate mofetil in 1994, led to a significant outcome improvement and consequently, an increase in pancreas transplants in several countries. According to the International Pancreas Transplant Registry, until December 31st, 2010, more than 35 thousand pancreas transplants had been performed. The one-year survival of patients and pancreatic grafts exceeds 95 and 83%, respectively. The better survival of pancreatic (86%) and renal (93%) grafts in the first year after transplantation is in the simultaneous pancreas-kidney transplant group of patients. Immunological loss in the first year after transplant for simultaneous pancreas-kidney, pancreas after kidney, and pancreas alone are 1.8, 3.7, and 6%, respectively. Pancreas transplant has 10 to 20% surgical complications requiring laparotomy. Besides enhancing quality of life, pancreatic transplant increases survival of uremic diabetic patient as compared to uremic diabetic patients on dialysis or with kidney transplantation alone. PMID:26154551

  1. Primate malarias: Diversity, distribution and insights for zoonotic Plasmodium.

    PubMed

    Faust, Christina; Dobson, Andrew P

    2015-12-01

    Protozoans within the genus Plasmodium are well-known as the causative agents of malaria in humans. Numerous Plasmodium species parasites also infect a wide range of non-human primate hosts in tropical and sub-tropical regions worldwide. Studying this diversity can provide critical insight into our understanding of human malarias, as several human malaria species are a result of host switches from non-human primates. Current spillover of a monkey malaria, Plasmodium knowlesi, in Southeast Asia highlights the permeability of species barriers in Plasmodium. Also recently, surveys of apes in Africa uncovered a previously undescribed diversity of Plasmodium in chimpanzees and gorillas. Therefore, we carried out a meta-analysis to quantify the global distribution, host range, and diversity of known non-human primate malaria species. We used published records of Plasmodium parasites found in non-human primates to estimate the total diversity of non-human primate malarias globally. We estimate that at least three undescribed primate malaria species exist in sampled primates, and many more likely exist in unstudied species. The diversity of malaria parasites is especially uncertain in regions of low sampling such as Madagascar, and taxonomic groups such as African Old World Monkeys and gibbons. Presence-absence data of malaria across primates enables us to highlight the close association of forested regions and non-human primate malarias. This distribution potentially reflects a long coevolution of primates, forest-adapted mosquitoes, and malaria parasites. The diversity and distribution of primate malaria are an essential prerequisite to understanding the mechanisms and circumstances that allow Plasmodium to jump species barriers, both in the evolution of malaria parasites and current cases of spillover into humans.

  2. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates

    NASA Astrophysics Data System (ADS)

    Veiseh, Omid; Doloff, Joshua C.; Ma, Minglin; Vegas, Arturo J.; Tam, Hok Hei; Bader, Andrew R.; Li, Jie; Langan, Erin; Wyckoff, Jeffrey; Loo, Whitney S.; Jhunjhunwala, Siddharth; Chiu, Alan; Siebert, Sean; Tang, Katherine; Hollister-Lock, Jennifer; Aresta-Dasilva, Stephanie; Bochenek, Matthew; Mendoza-Elias, Joshua; Wang, Yong; Qi, Merigeng; Lavin, Danya M.; Chen, Michael; Dholakia, Nimit; Thakrar, Raj; Lacík, Igor; Weir, Gordon C.; Oberholzer, Jose; Greiner, Dale L.; Langer, Robert; Anderson, Daniel G.

    2015-06-01

    The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions.

  3. Imaging Axl expression in pancreatic and prostate cancer xenografts

    SciTech Connect

    Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala; Hu, Chaoxin; Maitra, Anirban; Pomper, Martin G

    2014-01-10

    Highlights: •Axl is overexpressed in a variety of cancers. •Axl overexpression confers invasive phenotype. •Axl imaging would be useful for therapeutic guidance and monitoring. •Axl expression imaging is demonstrated in pancreatic and prostate cancer xenografts. •Graded levels of Axl expression imaging is feasible. -- Abstract: The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl–Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with {sup 125}I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axl{sup high}) and Panc1 (Axl{sup low}) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [{sup 125}I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axl{sup low}) or DU145 (Axl{sup high}) prostate tumors by ex vivo biodistribution and imaging studies at 72 h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [{sup 125}I]Axl mAb in Axl{sup high} (CFPAC and DU145) expression tumors compared to the Axl{sup low} (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [{sup 125}I]IgG1 antibody in the Axl{sup high} and Axl{sup low} expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic

  4. Why Primates? The Importance of Nonhuman Primates for Understanding Human Infancy

    ERIC Educational Resources Information Center

    Weiss, Daniel J.; Santos, Laurie R.

    2006-01-01

    We introduce the thematic collection by noting some striking similarities in the cognitive abilities of human infants and nonhuman primates. What are the implications of these similarities for our comprehension of human infant cognition? After providing a brief historical and conceptual background on comparative behavioral research, we discuss how…

  5. Therapeutic efficacy evaluation of 111in-VNB-liposome on human colorectal adenocarcinoma HT-29/ luc mouse xenografts

    NASA Astrophysics Data System (ADS)

    Lee, Wan-Chi; Hwang, Jeng-Jong; Tseng, Yun-Long; Wang, Hsin-Ell; Chang, Ya-Fang; Lu, Yi-Ching; Ting, Gann; Whang-Peng, Jaqueline; Wang, Shyh-Jen

    2006-12-01

    The purpose of this study is to evaluate the therapeutic efficacy of the liposome encaged with vinorelbine (VNB) and 111In-oxine on human colorectal adenocarcinoma (HT-29) using HT-29/ luc mouse xenografts. HT-29 cells stably transfected with plasmid vectors containing luciferase gene ( luc) were transplanted subcutaneously into the male NOD/SCID mice. Biodistribution of the drug was performed when tumor size reached 500-600 mm 3. The uptakes of 111In-VNB-liposome in tumor and normal tissues/organs at various time points postinjection were assayed. Multimodalities, including gamma scintigraphy, bioluminescence imaging (BLI) and whole-body autoradiography (WBAR), were applied for evaluating the therapeutic efficacy when tumor size was about 100 mm 3. The tumor/blood ratios of 111In-VNB-liposome were 0.044, 0.058, 2.690, 20.628 and 24.327, respectively, at 1, 4, 24, 48 and 72 h postinjection. Gamma scinitigraphy showed that the tumor/muscle ratios were 2.04, 2.25 and 4.39, respectively, at 0, 5 and 10 mg/kg VNB. BLI showed that significant tumor control was achieved in the group of 10 mg/kg VNB ( 111In-VNB-liposome). WBAR also confirmed this result. In this study, we have demonstrated a non-invasive imaging technique with a luciferase reporter gene and BLI for evaluation of tumor treatment efficacy in vivo. The SCID mice bearing HT-29/ luc xenografts treated with 111In-VNB-liposome were shown with tumor reduction by this technique.

  6. Pancreatic islet xenograft survival in mice is extended by a combination of alpha-1-antitrypsin and single-dose anti-CD4/CD8 therapy.

    PubMed

    Ashkenazi, Efrat; Baranovski, Boris M; Shahaf, Galit; Lewis, Eli C

    2013-01-01

    Clinical pancreatic islet transplantation is under evaluation for the treatment of autoimmune diabetes, yet several limitations preclude widespread use. For example, there is a critical shortage of human pancreas donors. Xenotransplantation may solve this problem, yet it evokes a rigorous immune response which can lead to graft rejection. Alpha-1-antitrypsin (AAT), a clinically available and safe circulating anti-inflammatory and tissue protective glycoprotein, facilitates islet alloimmune-tolerance and protects from inflammation in several models. Here, we examine whether human AAT (hAAT), alone or in combination with clinically relevant approaches, achieves long-term islet xenograft survival. Rat-to-mouse islet transplantation was examined in the following groups: untreated (n = 6), hAAT (n = 6, 60-240 mg/kg every 3 days from day -10), low-dose co-stimulation blockade (anti-CD154/LFA-1) and single-dose anti-CD4/CD8 (n = 5-7), either as mono- or combination therapies. Islet grafting was accompanied by blood glucose follow-up. In addition, skin xenografting was performed in order to depict responses that occur in draining lymph nodes. According to our results hAAT monotherapy and hAAT/anti-CD154/LFA-1 combined therapy, did not delay rejection day (11-24 days untreated vs. 10-22 day treated). However, host and donor intragraft inflammatory gene expression was diminished by hAAT therapy in both setups. Single dose T-cell depletion using anti-CD4/CD8 depleting antibodies, which provided 14-15 days of reduced circulating T-cells, significantly delayed rejection day (28-52 days) but did not achieve graft acceptance. In contrast, in combination with hAAT, the group displayed significantly extended rejection days and a high rate of graft acceptance (59, 61, >90, >90, >90). In examination of graft explants, marginal mononuclear-cell infiltration containing regulatory T-cells predominated surviving xenografts. We suggest that temporal T-cell depletion, as in the

  7. Hibernation in a primate: does sleep occur?

    PubMed Central

    Dausmann, Kathrin H.; Faherty, Sheena L.; Klopfer, Peter; Krystal, Andrew D.; Schopler, Robert; Yoder, Anne D.

    2016-01-01

    During hibernation, critical physiological processes are downregulated and thermogenically induced arousals are presumably needed periodically to fulfil those physiological demands. Among the processes incompatible with a hypome tabolic state is sleep. However, one hibernating primate, the dwarf lemur Cheirogaleus medius, experiences rapid eye movement (REM)-like states during hibernation, whenever passively reaching temperatures above 30°C, as occurs when it hibernates in poorly insulated tree hollows under tropical conditions. Here, we report electroencephalographic (EEG) recordings, temperature data and metabolic rates from two related species (C. crossleyi and C. sibreei), inhabiting high-altitude rainforests and hibernating underground, conditions that mirror, to some extent, those experienced by temperate hibernators. We compared the physiology of hibernation and spontaneous arousals in these animals to C. medius, as well as the much more distantly related non-primate hibernators, such as Arctic, golden-mantled and European ground squirrels. We observed a number of commonalities with non-primate temperate hibernators including: (i) monotonous ultra-low voltage EEG during torpor bouts in these relatively cold-weather hibernators, (ii) the absence of sleep during torpor bouts, (iii) the occurrence of spontaneous arousals out of torpor, during which sleep regularly occurred, (iv) relatively high early EEG non-REM during the arousal, and (v) a gradual transition to the torpid EEG state from non-REM sleep. Unlike C. medius, our study species did not display sleep-like states during torpor bouts, but instead exclusively exhibited them during arousals. During these short euthermic periods, non-REM as well as REM sleep-like stages were observed. Differences observed between these two species and their close relative, C. medius, for which data have been published, presumably reflect differences in hibernaculum temperature. PMID:27853604

  8. After the Transplant: Medications

    MedlinePlus

    ... are many financial resources for transplants. Living donation increases the existing organ supply. It's important to get to know your transplant team. ... store Stories of hope Policies Public comment Support ...

  9. Corneal transplant - discharge

    MedlinePlus

    ... page: //medlineplus.gov/ency/patientinstructions/000243.htm Corneal transplant - discharge To use the sharing features on this page, please enable JavaScript. You had a corneal transplant. Most of the tissue of your cornea (the ...

  10. Effect of ionizing radiation on the primate pancreas: an endocrine and morphologic study

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Zuurmond, T.; Louw, G.; Laker, L.; Els, D.; Weideman, A.; Wolfe-Coote, S.; Du Toit, L.B.

    1987-01-01

    In this study we evaluated the endocrine, biochemical, and haematological derangements as well as pancreatic and histological changes of the bonemarrow in the primate following external fractionated subtotal marrow irradiation without bonemarrow reconstitution. The irradiation was administered in preparation for pancreatic transplantation. Two groups of animals (ten in each group) received 800 rad (8 Gy) and 1000 rad (10 Gy) respectively over 4 to 5 weeks. A maximum of 200 rads (2 Gy) were administered weekly as photons from a 6 MV linear accelerator. During irradiation the animals remained normoglycaemic in the presence of transiently elevated liver enzymes and serum amylase values, which returned to normal on completion of the irradiation. Insulin release was significantly reduced in both groups during irradiation and was associated with minimally decreased K-values in the presence of mild glucose intolerance. Pancreatic light morphologic changes included structural changes of both exocrine and endocrine elements and included necrosis of the islet cells and acinar tissue. Islet histology demonstrated striking cytocavitary network changes of alpha and beta cells, including degranulation, vacuolization, mitochondrial destruction, and an increase in lysosomes. A hypoplastic bonemarrow ranging from moderate to severe was observed in all irradiated recipients. Near total fractionated body irradiation in the primate is therefore associated with elevated liver enzymes, pancytopenia, transient hyperamylasaemia, hypoinsulinaemia, a varying degree of pancreatitis, and bonemarrow hypoplasia.

  11. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.

    PubMed

    Chong, James J H; Yang, Xiulan; Don, Creighton W; Minami, Elina; Liu, Yen-Wen; Weyers, Jill J; Mahoney, William M; Van Biber, Benjamin; Cook, Savannah M; Palpant, Nathan J; Gantz, Jay A; Fugate, James A; Muskheli, Veronica; Gough, G Michael; Vogel, Keith W; Astley, Cliff A; Hotchkiss, Charlotte E; Baldessari, Audrey; Pabon, Lil; Reinecke, Hans; Gill, Edward A; Nelson, Veronica; Kiem, Hans-Peter; Laflamme, Michael A; Murry, Charles E

    2014-06-12

    Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

  12. No monkey business: why studying NK cells in non-human primates pays off.

    PubMed

    Hong, Henoch S; Rajakumar, Premeela A; Billingsley, James M; Reeves, R Keith; Johnson, R Paul

    2013-01-01

    Human NK (hNK) cells play a key role in mediating host immune responses against various infectious diseases. For practical reasons, the majority of the data on hNK cells has been generated using peripheral blood lymphocytes. In contrast, our knowledge of NK cells in human tissues is limited, and not much is known about developmental pathways of hNK cell subpopulations in vivo. Although research in mice has elucidated a number of fundamental features of NK cell biology, mouse, and hNK cells significantly differ in their subpopulations, functions, and receptor repertoires. Thus, there is a need for a model that is more closely related to humans and yet allows experimental manipulations. Non-human primate models offer numerous opportunities for the study of NK cells, including the study of the role of NK cells after solid organ and stem cell transplantation, as well as in acute viral infection. Macaque NK cells can be depleted in vivo or adoptively transferred in an autologous system. All of these studies are either difficult or unethical to carry out in humans. Here we highlight recent advances in rhesus NK cell research and their parallels in humans. Using high-throughput transcriptional profiling, we demonstrate that the human CD56(bright) and CD56(dim) NK cell subsets have phenotypically and functionally analogous counterparts in rhesus macaques. Thus, the use of non-human primate models offers the potential to substantially advance hNK cell research.

  13. Earliest known simian primate found in Algeria.

    PubMed

    Godinot, M; Mahboubi, M

    1992-05-28

    The record of early fossil Simiiformes (Anthropoidea) from the Late Eocene and Early Oligocene of Africa and the Arabian Peninsula has increased dramatically in recent years. We report here the discovery of a new, diminutive and much older (Early or Middle Eocene) simian from an Algerian locality, Glib Zegdou. This species is smaller than any other living or fossil African simiiform. Derived similarities shared with Aegyptopithecus suggest that the new genus is more closely related to propliopithecines than to oligopithecines, implying that these two subfamilies differentiated during the Early Eocene. The new discovery confirms predictions about the great antiquity of Simiiformes and emphasizes a long and endemic African history for higher primates.

  14. Biorhythms and space experiments with nonhuman primates

    NASA Technical Reports Server (NTRS)

    Winget, C. M.

    1977-01-01

    Man's response to exposure to spaceflight and weightlessness is expressed in physiological adjustments which involve his health and ability to function. The amplitude and periodicity of fluctuations in biological processes affect various functions and responses to provocative stimuli. Primates and other species are subjected to tests to determine the consequences of an altered biorhythm on work and performance, emotional stability, biomedical evaluation in space, the ability to cope with the unexpected, and susceptibility to infection, toxicity, radiation, drugs, and stress. Factors in the environment or operational setup which can change the physiological baseline must be determined and controlled.

  15. Primate immunodeficiency virus classification and nomenclature: Review.

    PubMed

    Foley, Brian T; Leitner, Thomas; Paraskevis, Dimitrios; Peeters, Martine

    2016-12-01

    The International Committee for the Taxonomy and Nomenclature of Viruses does not rule on virus classifications below the species level. The definition of species for viruses cannot be clearly defined for all types of viruses. The complex and interesting epidemiology of Human Immunodeficiency Viruses demands a detailed and informative nomenclature system, while at the same time it presents challenges such that many of the rules need to be flexibly applied or modified over time. This review outlines the nomenclature system for primate lentiviruses and provides an update on new findings since the last review was written in 2000.

  16. Biorhythms and space experiments with nonhuman primates

    NASA Technical Reports Server (NTRS)

    Winget, C. M.

    1977-01-01

    Man's response to exposure to spaceflight and weightlessness is expressed in physiological adjustments which involve his health and ability to function. The amplitude and periodicity of fluctuations in biological processes affect various functions and responses to provocative stimuli. Primates and other species are subjected to tests to determine the consequences of an altered biorhythm on work and performance, emotional stability, biomedical evaluation in space, the ability to cope with the unexpected, and susceptibility to infection, toxicity, radiation, drugs, and stress. Factors in the environment or operational setup which can change the physiological baseline must be determined and controlled.

  17. Two Influential Primate Classifications Logically Aligned

    PubMed Central

    Franz, Nico M.; Pier, Naomi M.; Reeder, Deeann M.; Chen, Mingmin; Yu, Shizhuo; Kianmajd, Parisa; Bowers, Shawn; Ludäscher, Bertram

    2016-01-01

    Classifications and phylogenies of perceived natural entities change in the light of new evidence. Taxonomic changes, translated into Code-compliant names, frequently lead to name:meaning dissociations across succeeding treatments. Classification standards such as the Mammal Species of the World (MSW) may experience significant levels of taxonomic change from one edition to the next, with potential costs to long-term, large-scale information integration. This circumstance challenges the biodiversity and phylogenetic data communities to express taxonomic congruence and incongruence in ways that both humans and machines can process, that is, to logically represent taxonomic alignments across multiple classifications. We demonstrate that such alignments are feasible for two classifications of primates corresponding to the second and third MSW editions. Our approach has three main components: (i) use of taxonomic concept labels, that is name sec. author (where sec. means according to), to assemble each concept hierarchy separately via parent/child relationships; (ii) articulation of select concepts across the two hierarchies with user-provided Region Connection Calculus (RCC-5) relationships; and (iii) the use of an Answer Set Programming toolkit to infer and visualize logically consistent alignments of these input constraints. Our use case entails the Primates sec. Groves (1993; MSW2–317 taxonomic concepts; 233 at the species level) and Primates sec. Groves (2005; MSW3–483 taxonomic concepts; 376 at the species level). Using 402 RCC-5 input articulations, the reasoning process yields a single, consistent alignment and 153,111 Maximally Informative Relations that constitute a comprehensive meaning resolution map for every concept pair in the Primates sec. MSW2/MSW3. The complete alignment, and various partitions thereof, facilitate quantitative analyses of name:meaning dissociation, revealing that nearly one in three taxonomic names are not reliable across

  18. Primate immunodeficiency virus classification and nomenclature: Review

    DOE PAGES

    Foley, Brian T.; Leitner, Thomas; Paraskevis, Dimitrios; ...

    2016-10-24

    The International Committee for the Taxonomy and Nomenclature of Viruses does not rule on virus classifications below the species level. The definition of species for viruses cannot be clearly defined for all types of viruses. The complex and interesting epidemiology of Human Immunodeficiency Viruses demands a detailed and informative nomenclature system, while at the same time it presents challenges such that many of the rules need to be flexibly applied or modified over time. As a result, this review outlines the nomenclature system for primate lentiviruses and provides an update on new findings since the last review was written inmore » 2000.« less

  19. Primate immunodeficiency virus classification and nomenclature: Review

    SciTech Connect

    Foley, Brian T.; Leitner, Thomas; Paraskevis, Dimitrios; Peeters, Martine

    2016-10-24

    The International Committee for the Taxonomy and Nomenclature of Viruses does not rule on virus classifications below the species level. The definition of species for viruses cannot be clearly defined for all types of viruses. The complex and interesting epidemiology of Human Immunodeficiency Viruses demands a detailed and informative nomenclature system, while at the same time it presents challenges such that many of the rules need to be flexibly applied or modified over time. As a result, this review outlines the nomenclature system for primate lentiviruses and provides an update on new findings since the last review was written in 2000.

  20. Non-Human Primate Models of Tuberculosis.

    PubMed

    Peña, Juliet C; Ho, Wen-Zhe

    2016-08-01

    Among the animal models of tuberculosis (TB), the non-human primates, particularly rhesus macaques (Macaca fascicularis) and cynomolgus macaques (Macaca mulatta), share the greatest anatomical and physiological similarities with humans. Macaques are highly susceptible to Mycobacterium tuberculosis infection and manifest the complete spectrum of clinical and pathological manifestations of TB as seen in humans. Therefore, the macaque models have been used extensively for investigating the pathogenesis of M. tuberculosis infection and for preclinical testing of drugs and vaccines against TB. This review focuses on published major studies that exemplify how the rhesus and cynomolgus macaques have enhanced and may continue to advance global efforts in TB research.

  1. Primates, Provisioning and Plants: Impacts of Human Cultural Behaviours on Primate Ecological Functions

    PubMed Central

    Sengupta, Asmita; McConkey, Kim R.; Radhakrishna, Sindhu

    2015-01-01

    Human provisioning of wildlife with food is a widespread global practice that occurs in multiple socio-cultural circumstances. Provisioning may indirectly alter ecosystem functioning through changes in the eco-ethology of animals, but few studies have quantified this aspect. Provisioning of primates by humans is known to impact their activity budgets, diets and ranging patterns. Primates are also keystone species in tropical forests through their role as seed dispersers; yet there is no information on how provisioning might affect primate ecological functions. The rhesus macaque is a major human-commensal species but is also an important seed disperser in the wild. In this study, we investigated the potential impacts of provisioning on the role of rhesus macaques as seed dispersers in the Buxa Tiger Reserve, India. We studied a troop of macaques which were provisioned for a part of the year and were dependent on natural resources for the rest. We observed feeding behaviour, seed handling techniques and ranging patterns of the macaques and monitored availability of wild fruits. Irrespective of fruit availability, frugivory and seed dispersal activities decreased when the macaques were provisioned. Provisioned macaques also had shortened daily ranges implying shorter dispersal distances. Finally, during provisioning periods, seeds were deposited on tarmac roads that were unconducive for germination. Provisioning promotes human-primate conflict, as commensal primates are often involved in aggressive encounters with humans over resources, leading to negative consequences for both parties involved. Preventing or curbing provisioning is not an easy task as feeding wild animals is a socio-cultural tradition across much of South and South-East Asia, including India. We recommend the initiation of literacy programmes that educate lay citizens about the ill-effects of provisioning and strongly caution them against the practice. PMID:26536365

  2. 13C Tracer Studies of Metabolism in Mouse Tumor Xenografts

    PubMed Central

    Lane, Andrew N.; Yan, Jun; Fan, Teresa W-M.

    2015-01-01

    Mice are widely used for human tumor xenograft studies of cancer development and drug efficacy and toxicity. Stable isotope tracing coupled with metabolomic analysis is an emerging approach for assaying metabolic network activity. In mouse models there are several routes of tracer introduction, which have particular advantages and disadvantages that depend on the model and the questions addressed. This protocol describes the bolus i.v. route via repeated tail vein injections of solutions of stable isotope enriched tracers including 13C6-glucose and 13C5,15N2-glutamine. Repeated injections give higher enrichments and over longer labeling periods than a single bolus. Multiple injections of glutamine are necessary to achieve adequate enrichment in engrafted tumors. PMID:26693168

  3. Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates

    NASA Astrophysics Data System (ADS)

    Trail, P. A.; Willner, D.; Lasch, S. J.; Henderson, A. J.; Hofstead, S.; Casazza, A. M.; Firestone, R. A.; Hellstrom, I.; Hellstrom, K. E.

    1993-07-01

    Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.

  4. Demand for nonhuman primate resources in the age of biodefense.

    PubMed

    Patterson, Jean L; Carrion, Richardo

    2005-01-01

    The demand for nonhuman primates will undoubtedly increase to meet biomedical needs in this current age of biodefense. The availability of funding has increased the research on select agents and has created a requirement to validate results in relevant primate models. This review provides a description of current and potential biological threats that are likely to require nonhuman primates for the development of vaccines and therapeutics. Primates have been an invaluable resource in the dissection of viral disease pathogenesis as well as in testing vaccine efficacy. DNA vaccine approaches have been studied successfully for Ebola, Lassa, and anthrax in nonhuman primate models. Nonhuman primate research with monkeypox has provided insight into the role of cytokines in limiting disease severity. Biodefense research that has focused on select agents of bacterial origin has also benefited from nonhuman primate studies. Rhesus macaques have traditionally been the model of choice for anthrax research and have yielded successful findings in vaccine development. In plague research, African green monkeys have contributed to vaccine development. However, the disadvantages of current vaccines will undoubtedly require the generation of new vaccines, thus increasing the need for nonhuman primate research. Unfortunately, the current biosafety level (BSL)-3 and BSL-4 facilities equipped to perform this research are limited, which may ultimately impede progress in this era of biodefense.

  5. 76 FR 13120 - Requirements for Importers of Nonhuman Primates

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-10

    ... (42 CFR 71.53) for the importation of live nonhuman primates (NHPs). Written comments were to be... the imporation of live nonhuman primates (NHPs) by extending existing requirements for the importation of Macaca fascicularis (cyanmologus), Chlororcebus aethlops (African green) and Macaca...

  6. Developmental processes and canine dimorphism in primate evolution.

    PubMed

    Schwartz, Gary T; Miller, Ellen R; Gunnell, Gregg F

    2005-01-01

    Understanding the evolutionary history of canine sexual dimorphism is important for interpreting the developmental biology, socioecology and phylogenetic position of primates. All current evidence for extant primates indicates that canine dimorphism is achieved through bimaturism rather than via differences in rates of crown formation time. Using incremental growth lines, we charted the ontogeny of canine formation within species of Eocene Cantius, the earliest known canine-dimorphic primate, to test whether canine dimorphism via bimaturism was developmentally canalized early in primate evolution. Our results show that canine dimorphism in Cantius is achieved primarily through different rates of crown formation in males and females, not bimaturism. This is the first demonstration of rate differences resulting in canine dimorphism in any primate and therefore suggests that canine dimorphism is not developmentally homologous across Primates. The most likely interpretation is that canine dimorphism has been selected for at least twice during the course of primate evolution. The power of this approach is its ability to identify underlying developmental processes behind patterns of morphological similarity, even in long-extinct primate species.

  7. A comprehensive characterization of cell cultures and xenografts derived from a human verrucous penile carcinoma.

    PubMed

    Muñoz, Juan J; Drigo, Sandra A; Kuasne, Hellen; Villacis, Rolando A R; Marchi, Fabio A; Domingues, Maria A C; Lopes, Ademar; Santos, Tiago G; Rogatto, Silvia R

    2016-08-01

    This study aimed to establish and characterize primary cell cultures and xenografts derived from penile carcinoma (PeCa) in order to provide experimental models for cellular processes and efficacy of new treatments. A verrucous squamous cell carcinoma (VSCC) was macrodissected, dissociated, and cultivated in KSFM/DF12 medium. Cell cultures were evaluated at passage 5 (P5) using migration and invasion assays and were serially propagated, in vivo, in BALB/c nude mice until passage 3 (X1-X3). Immunophenotypic characterization of cultures and xenografts was performed. Genomic (CytoScan HD, Affymetrix) and transcriptomic profiles (HTA 2.0 platform, Affymetrix) for VSCC, cell cultures, and xenografts were assessed. P5 cells were able to migrate, invade the Matrigel, and produce tumors in immunodeficient mice, demonstrating their malignant potential. The xenografts unexpectedly presented a sarcomatoid-like carcinoma phenotype. Genomic analysis revealed a high similarity between the VSCC and tumor-derived xenograft, confirming its xenograft origin. Interestingly, a subpopulation of P5 cells presented stem cell-related markers (CD44(+)CD24(-) and ALDH1(high)) and sphere-forming capacity, suggesting their potential xenograft origin. Cell cultures and xenografts retained the genomic alterations present in the parental tumor. Compared to VSCC, differentially expressed transcripts detected in all experimental conditions were associated with cellular morphology, movement, and metabolism and organization pathways. Malignant cell cultures and xenografts derived from a verrucous penile carcinoma were established and fully characterized. Nevertheless, xenograft PeCa models must be used with caution, taking into consideration the selection of specific cell populations and anatomical sites for cell/tumor implantation.

  8. Retrospective growth kinetics and radiosensitivity analysis of various human xenograft models

    PubMed Central

    Lee, Ji Young; Kim, Eun Ho; Chung, Namhyun

    2016-01-01

    The purpose of this study was to delineate the various factors that affect the growth characteristics of human cancer xenografts in nude mice and to reveal the relationship between the growth characteristics and radiosensitivity. We retrospectively analyzed 390 xenografts comprising nine different human cancer lines grown in nude mice used in our institute between 2009 and 2015. Tumor growth rate (TGR) was calculated using exponential growth equations. The relationship between the TGR of xenografts and the proliferation of the cells in vitro was examined. Additionally, we examined the correlations between the surviving fractions of cells after 2 Gy irradiation in vitro and the response of the xenograft to radiation. The TGR of xenografts was positively related to the proliferation of the cells in vitro (rP=0.9714, p<0.0001), whereas it was independent of the histological type of the xenografts. Radiation-induced suppression of the growth rate (T/C%) of xenografts was positively related to the radiosensitivity of the cells in vitro (SF2; rP=0.8684, p=0.0284) and TGR (rP=0.7623, p=0.0780). The proliferation of human cancer cells in vitro and the growth rate of xenografts were positively related. The radiosensitivity of cancer cells, as judged from the SF2 values in vitro, and the radiation-induced suppression of xenograft growth were positively related. In conclusion, the growth rate of human xenografts was independent of histological type and origin of the cancer cells, and was positively related to the proliferation of the cancer cells in vitro. PMID:28053611

  9. Macroporous Three Dimensional PDMS Scaffolds for Extrahepatic Islet Transplantation

    PubMed Central

    Pedraza, Eileen; Brady, Ann-Christina; Fraker, Christopher A.; Molano, R. Damaris; Sukert, Steven; Berman, Dora M.; Kenyon, Norma S.; Pileggi, Antonello; Ricordi, Camillo; Stabler, Cherie L.

    2015-01-01

    Clinical islet transplantation has demonstrated success in treating type 1 diabetes. A current limitation is the intrahepatic portal vein transplant site, which is prone to mechanical stress and inflammation. Transplantation of pancreatic islets into alternative sites is preferable, but challenging, as it may require a three-dimensional vehicle to confer mechanical protection and to confine islets to a well-defined, retrievable space where islet neovascularization can occur. We have fabricated biostable, macroporous scaffolds from poly(dimethylsiloxane) (PDMS) and investigated islet retention and distribution, metabolic function, and glucose-dependent insulin secretion within these materials. Islets from multiple sources, including rodents, non-human primates, and humans, were tested in vitro. We observed high islet retention and distribution within PDMS scaffolds, with retention of small islets (< 100 µm) improved through the post-loading addition of fibrin gel. Islets loaded within PDMS scaffolds exhibited viability and function comparable to standard culture conditions when incubated under normal oxygen tensions, but displayed improved viability compared to standard two-dimensional culture controls under low oxygen tensions. In vivo efficacy of scaffolds to support islet grafts was evaluated after transplantation in the omental pouch of chemically-induced diabetic syngeneic rats, which promptly achieved normoglycemia. Collectively, these results are promising in that they indicate the potential for transplanting islets into a clinically relevant, extrahepatic site that provides spatial distribution of islets, as well as intra-device vascularization. PMID:23031502

  10. Organ Transplants in Kazakhstan.

    PubMed

    Baigenzhin, Abay; Doskaliyev, Zhaksylyk; Tuganbekova, Saltanat; Zharikov, Serik; Altynova, Sholpan; Gaipov, Abduzhappar

    2015-11-01

    The Republic of Kazakhstan is one of the fastest developing countries in the world and has a health care system that is unique in Central Asia. Its organ transplant services are also developing rapidly. We aimed to analyze and briefly report on the current status of organ transplant in the Republic of Kazakhstan. We analyzed organ transplant activities in that country for the period 2012 to 2014. All data were collected from the official database of the National Transplant Coordinating Center of the Republic of Kazakhstan. At the end of 2014, the number of transplant centers had increased to 10, three of which could perform multiorgan transplants; during the same period, the number of deceased-donor organ-donating hospitals increased up to 37. By 2013, the transplant activity rate for all centers had reached 9.22 per million population. During the previous 3 years (2012-2014), there was a 3-fold increase in the number of living donors and an 18-fold increase in the number of kidney transplants. Between 2012 and 2014, the number of living-donor liver transplants increased from 17 to 25, and the number of deceased-donor transplants increased from 3 to 7. During the last 3 years (2012-2014), the number of heart transplants increased to 7 cases. During the last 3 years (2012-2014), Kazakhstan achieved a significant improvement in the organization of its transplant services, and a noticeable upward trend in the system continues.

  11. The outer subventricular zone and primate-specific cortical complexification.

    PubMed

    Dehay, Colette; Kennedy, Henry; Kosik, Kenneth S

    2015-02-18

    Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to the emergence of the outer subventricular zone (OSVZ), a uniquely structured germinal zone that generates the expanded primate supragranular layers. The primate OSVZ departs from rodent germinal zones in that it includes a higher diversity of precursor types, inter-related in bidirectional non-hierarchical lineages. In addition, primate-specific regulatory mechanisms are operating in primate cortical precursors via the occurrence of novel miRNAs. Here, we propose that the origin and evolutionary importance of the OSVZ is related to genetic changes in multiple regulatory loops and that cell-cycle regulation is a favored target for evolutionary adaptation of the cortex.

  12. What Cognitive Representations Support Primate Theory of Mind?

    PubMed

    Martin, Alia; Santos, Laurie R

    2016-05-01

    Much recent work has examined the evolutionary origins of human mental state representations. This work has yielded strikingly consistent results: primates show a sophisticated ability to track the current and past perceptions of others, but they fail to represent the beliefs of others. We offer a new account of the nuanced performance of primates in theory of mind (ToM) tasks. We argue that primates form awareness relations tracking the aspects of reality that other agents are aware of. We contend that these awareness relations allow primates to make accurate predictions in social situations, but that this capacity falls short of our human-like representational ToM. We end by explaining how this new account makes important new empirical predictions about primate ToM. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Hematopoietic Cell Transplantation after Solid Organ Transplantation.

    PubMed

    Doney, Kristine C; Mielcarek, Marco; Stewart, F Marc; Appelbaum, Frederick R

    2015-12-01

    Solid organ transplantation (SOT) followed by hematopoietic cell transplantation (HCT) has been used to treat a single disease with multiorgan involvement or 2 separate diseases, the first requiring SOT and the second often a possible complication of SOT. Results of such serial transplants have been reported sporadically in the literature, usually as single case studies. Thirteen autologous and 27 allogeneic HCTs after SOT published previously are summarized. A more detailed review is provided for an additional 16 patients transplanted at a single institution, 8 of whom had autologous and 8 of whom had allogeneic HCT after SOT. Five of 8 autologous transplant recipients are alive a median of 4.6 years after HCT. Four of 8 allogeneic HCT recipients are alive a median of 8.7 years after HCT. In carefully selected patients, HCT after SOT is feasible and associated with a low incidence of either solid organ or hematopoietic cell rejection.

  14. Primate vaginal microbiomes exhibit species specificity without universal Lactobacillus dominance.

    PubMed

    Yildirim, Suleyman; Yeoman, Carl J; Janga, Sarath Chandra; Thomas, Susan M; Ho, Mengfei; Leigh, Steven R; White, Bryan A; Wilson, Brenda A; Stumpf, Rebecca M

    2014-12-01

    Bacterial communities colonizing the reproductive tracts of primates (including humans) impact the health, survival and fitness of the host, and thereby the evolution of the host species. Despite their importance, we currently have a poor understanding of primate microbiomes. The composition and structure of microbial communities vary considerably depending on the host and environmental factors. We conducted comparative analyses of the primate vaginal microbiome using pyrosequencing of the 16S rRNA genes of a phylogenetically broad range of primates to test for factors affecting the diversity of primate vaginal ecosystems. The nine primate species included: humans (Homo sapiens), yellow baboons (Papio cynocephalus), olive baboons (Papio anubis), lemurs (Propithecus diadema), howler monkeys (Alouatta pigra), red colobus (Piliocolobus rufomitratus), vervets (Chlorocebus aethiops), mangabeys (Cercocebus atys) and chimpanzees (Pan troglodytes). Our results indicated that all primates exhibited host-specific vaginal microbiota and that humans were distinct from other primates in both microbiome composition and diversity. In contrast to the gut microbiome, the vaginal microbiome showed limited congruence with host phylogeny, and neither captivity nor diet elicited substantial effects on the vaginal microbiomes of primates. Permutational multivariate analysis of variance and Wilcoxon tests revealed correlations among vaginal microbiota and host species-specific socioecological factors, particularly related to sexuality, including: female promiscuity, baculum length, gestation time, mating group size and neonatal birth weight. The proportion of unclassified taxa observed in nonhuman primate samples increased with phylogenetic distance from humans, indicative of the existence of previously unrecognized microbial taxa. These findings contribute to our understanding of host-microbe variation and coevolution, microbial biogeography, and disease risk, and have important

  15. Primate vaginal microbiomes exhibit species specificity without universal Lactobacillus dominance

    PubMed Central

    Yildirim, Suleyman; Yeoman, Carl J; Janga, Sarath Chandra; Thomas, Susan M; Ho, Mengfei; Leigh, Steven R; Consortium, Primate Microbiome; White, Bryan A; Wilson, Brenda A; Stumpf, Rebecca M

    2014-01-01

    Bacterial communities colonizing the reproductive tracts of primates (including humans) impact the health, survival and fitness of the host, and thereby the evolution of the host species. Despite their importance, we currently have a poor understanding of primate microbiomes. The composition and structure of microbial communities vary considerably depending on the host and environmental factors. We conducted comparative analyses of the primate vaginal microbiome using pyrosequencing of the 16S rRNA genes of a phylogenetically broad range of primates to test for factors affecting the diversity of primate vaginal ecosystems. The nine primate species included: humans (Homo sapiens), yellow baboons (Papio cynocephalus), olive baboons (Papio anubis), lemurs (Propithecus diadema), howler monkeys (Alouatta pigra), red colobus (Piliocolobus rufomitratus), vervets (Chlorocebus aethiops), mangabeys (Cercocebus atys) and chimpanzees (Pan troglodytes). Our results indicated that all primates exhibited host-specific vaginal microbiota and that humans were distinct from other primates in both microbiome composition and diversity. In contrast to the gut microbiome, the vaginal microbiome showed limited congruence with host phylogeny, and neither captivity nor diet elicited substantial effects on the vaginal microbiomes of primates. Permutational multivariate analysis of variance and Wilcoxon tests revealed correlations among vaginal microbiota and host species-specific socioecological factors, particularly related to sexuality, including: female promiscuity, baculum length, gestation time, mating group size and neonatal birth weight. The proportion of unclassified taxa observed in nonhuman primate samples increased with phylogenetic distance from humans, indicative of the existence of previously unrecognized microbial taxa. These findings contribute to our understanding of host–microbe variation and coevolution, microbial biogeography, and disease risk, and have important

  16. Chemical carcinogenesis studies in nonhuman primates

    PubMed Central

    Takayama, Shozo; Thorgeirsson, Unnur P.; Adamson, Richard H.

    2008-01-01

    This review covers chemical carcinogenesis studies in nonhuman primates performed by the National Cancer Institute, USA, to provide hitherto unavailable information on their susceptibility to compounds producing carcinogenic effects in rodents. From autopsy records of 401 breeders and untreated controls, incidences of spontaneous malignant tumors were found to be relatively low in cynomolgus (1.9%) and rhesus monkeys (3.8%), but higher in African green monkeys (8%). Various chemical compounds, and in particular 6 antineoplastic agents, 13 food-related compounds including additives and contaminants, 1 pesticide, 5 N-nitroso compounds, 3 heterocyclic amines, and 7 “classical” rodent carcinogens, were tested during the 34 years period, generally at doses 10∼40 times the estimated human exposure. Results were inconclusive in many cases but unequivocal carcinogenicity was demonstrated for IQ, procarbazine, methylnitrosourea and diethylnitrosamine. Furthermore, negative findings for saccharine and cyclamate were in line with results in other species. Thus susceptibility to carcinogens is at least partly shared by nonhuman primates and rodents. PMID:18941297

  17. Fish cognition: a primate's eye view.

    PubMed

    Bshary, Redouan; Wickler, Wolfgang; Fricke, Hans

    2002-03-01

    We provide selected examples from the fish literature of phenomena found in fish that are currently being examined in discussions of cognitive abilities and evolution of neocortex size in primates. In the context of social intelligence, we looked at living in individualized groups and corresponding social strategies, social learning and tradition, and co-operative hunting. Regarding environmental intelligence, we searched for examples concerning special foraging skills, tool use, cognitive maps, memory, anti-predator behaviour, and the manipulation of the environment. Most phenomena of interest for primatologists are found in fish as well. We therefore conclude that more detailed studies on decision rules and mechanisms are necessary to test for differences between the cognitive abilities of primates and other taxa. Cognitive research can benefit from future fish studies in three ways: first, as fish are highly variable in their ecology, they can be used to determine the specific ecological factors that select for the evolution of specific cognitive abilities. Second, for the same reason they can be used to investigate the link between cognitive abilities and the enlargement of specific brain areas. Third, decision rules used by fish could be used as 'null-hypotheses' for primatologists looking at how monkeys might make their decisions. Finally, we propose a variety of fish species that we think are most promising as study objects.

  18. Postradiation regional cerebral blood flow in primates

    SciTech Connect

    Cockerham, L.G.; Cerveny, T.J.; Hampton, J.D.

    1986-06-01

    Early transient incapacitation (ETI) is the complete cessation of performance during the first 30 min after radiation exposure and performance decrement (PD) is a reduction in performance at the same time. Supralethal doses of radiation have been shown to produce a marked decrease in regional cerebral blood flow in primates concurrent with hypotension and a dramatic release of mast cell histamine. In an attempt to elucidate mechanisms underlying the radiation-induced ETI/PD phenomenon and the postradiation decrease in cerebral blood flow, primates were exposed to 100 Gy (1 Gy = 100 rads), whole-body, gamma radiation. Pontine and cortical blood flows were measured by hydrogen clearance, before and after radiation exposure. Systemic blood pressures were determined simultaneously. Systemic arterial histamine levels were determined preradiation and postradiation. Data obtained indicated that radiated animals showed a decrease in blood flow of 63% in the motor cortex and 51% in the pons by 10 min postradiation. Regional cerebral blood flow of radiated animals showed a slight recovery 20 min postradiation, followed by a fall to the 10 min nadir by 60 min postradiation. Immediately, postradiation systemic blood pressure fell 67% and remained at that level for the remainder of the experiment. Histamine levels in the radiated animals increased a hundredfold 2 min postradiation. This study indicates that regional cerebral blood flow decreases postradiation with the development of hypotension and may be associated temporally with the postradiation release of histamine.

  19. Primate pelvic anatomy and implications for birth

    PubMed Central

    Trevathan, Wenda

    2015-01-01

    The pelvis performs two major functions for terrestrial mammals. It provides somewhat rigid support for muscles engaged in locomotion and, for females, it serves as the birth canal. The result for many species, and especially for encephalized primates, is an ‘obstetric dilemma’ whereby the neonate often has to negotiate a tight squeeze in order to be born. On top of what was probably a baseline of challenging birth, locomotor changes in the evolution of bipedalism in the human lineage resulted in an even more complex birth process. Negotiation of the bipedal pelvis requires a series of rotations, the end of which has the infant emerging from the birth canal facing the opposite direction from the mother. This pattern, strikingly different from what is typically seen in monkeys and apes, places a premium on having assistance at delivery. Recently reported observations of births in monkeys and apes are used to compare the process in human and non-human primates, highlighting similarities and differences. These include presentation (face, occiput anterior or posterior), internal and external rotation, use of the hands by mothers and infants, reliance on assistance, and the developmental state of the neonate. PMID:25602069

  20. Primate Socioecology: New Insights from Males

    NASA Astrophysics Data System (ADS)

    Kappeler, Peter M.

    Primate males have only recently returned to the center stage of socioecological research. This review surveys new studies that examine variation in the behavior of adult males and their role in social evolution. It is shown that group size, composition, and social behavior are determined not only by resource distribution, predation risk, and other ecological factors, but that life history traits and social factors, especially those related to sexual coercion, can have equally profound consequences for social systems. This general point is illustrated by examining male behavior at three levels: the evolution of permanent associations between males and females, the causes and consequences of variation in the number of males between group-living species, and the determinants of social relationships within and between the sexes. Direct and indirect evidence reviewed in connection with all three questions indicates that the risk of infanticide has been a pervasive force in primate social evolution. Several areas are identified for future research on male life histories that should contribute to a better understanding of male reproductive strategies and corresponding female counterstrategies.

  1. Men, primates, and germs: an ongoing affair.

    PubMed

    Gonzalez, Jean Paul; Prugnolle, Frank; Leroy, Eric

    2013-01-01

    Humans and nonhuman primates are phylogenetically (i.e., genetically) related and share pathogens that can jump from one species to another. The specific strategies of three groups of pathogens for crossing the species barrier among primates will be discussed. In Africa, gorillas and chimpanzees have succumbed for years to simultaneous epizootics (i.e.. "multi-emergence") of Ebola virus in places where they are in contact with Chiropters, which could be animal reservoirs of these viruses. Human epidemics often follow these major outbreaks. Simian immunodeficiency viruses (SIVs) have an ancient history of coevolution and many interspecific exchanges with their natural hosts. Chimpanzee and gorilla SIVs have crossed the species barrier at different times and places, leading to the emergence of HIV-1 and HIV-2. Other retroviruses, such as the Simian T-Lymphotropic Viruses and Foamiviruses, have also a unique ancient or recent history of crossing the species barrier. The identification of gorilla Plasmodium parasites that are genetically close to P. falciparum suggests that gorillas were the source of the deadly human P. falciparum. Nonhuman plasmodium species that can infect humans represent an underestimated risk.

  2. Dynamic actin gene family evolution in primates.

    PubMed

    Zhu, Liucun; Zhang, Ying; Hu, Yijun; Wen, Tieqiao; Wang, Qiang

    2013-01-01

    Actin is one of the most highly conserved proteins and plays crucial roles in many vital cellular functions. In most eukaryotes, it is encoded by a multigene family. Although the actin gene family has been studied a lot, few investigators focus on the comparison of actin gene family in relative species. Here, the purpose of our study is to systematically investigate characteristics and evolutionary pattern of actin gene family in primates. We identified 233 actin genes in human, chimpanzee, gorilla, orangutan, gibbon, rhesus monkey, and marmoset genomes. Phylogenetic analysis showed that actin genes in the seven species could be divided into two major types of clades: orthologous group versus complex group. Codon usages and gene expression patterns of actin gene copies were highly consistent among the groups because of basic functions needed by the organisms, but much diverged within species due to functional diversification. Besides, many great potential pseudogenes were found with incomplete open reading frames due to frameshifts or early stop codons. These results implied that actin gene family in primates went through "birth and death" model of evolution process. Under this model, actin genes experienced strong negative selection and increased the functional complexity by reproducing themselves.

  3. Hormones and Human and Nonhuman Primate Growth.

    PubMed

    Bernstein, Robin Miriam

    2017-01-01

    The aim of this paper was to review information pertaining to the hormonal regulation of nonhuman primate growth, with specific focus on the growth hormone (GH)-insulin-like growth factor (IGF) axis and adrenal androgens. Hormones of the GH-IGF axis are consistently associated with measures of growth - linear, weight, or both - during the growth period; in adulthood, concentrations of IGF-I, IGF-binding protein-3, and GH-binding protein are not associated with any measures of size. Comparing patterns of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may be especially relevant for understanding whether the childhood stage of growth and development is unique to humans and perhaps other apes. Genetic, hormonal, and morphological data on adrenarche in other nonhuman primate species suggest that this endocrine transition is delayed in humans, chimpanzees, and possibly gorillas, while present very early in postnatal life in macaques. This suggests that although perhaps permitted by an extension of the pre-adolescent growth period, childhood builds upon existing developmental substrates rather than having been inserted de novo into an ancestral growth trajectory. Hormones can provide insight regarding the evolution of the human growth trajectory. © 2017 S. Karger AG, Basel.

  4. Hunting, law enforcement, and African primate conservation.

    PubMed

    N'Goran, Paul K; Boesch, Christophe; Mundry, Roger; N'Goran, Eliezer K; Herbinger, Ilka; Yapi, Fabrice A; Kühl, Hjalmar S

    2012-06-01

    Primates are regularly hunted for bushmeat in tropical forests, and systematic ecological monitoring can help determine the effect hunting has on these and other hunted species. Monitoring can also be used to inform law enforcement and managers of where hunting is concentrated. We evaluated the effects of law enforcement informed by monitoring data on density and spatial distribution of 8 monkey species in Taï National Park, Côte d'Ivoire. We conducted intensive surveys of monkeys and looked for signs of human activity throughout the park. We also gathered information on the activities of law-enforcement personnel related to hunting and evaluated the relative effects of hunting, forest cover and proximity to rivers, and conservation effort on primate distribution and density. The effects of hunting on monkeys varied among species. Red colobus monkeys (Procolobus badius) were most affected and Campbell's monkeys (Cercopithecus campbelli) were least affected by hunting. Density of monkeys irrespective of species was up to 100 times higher near a research station and tourism site in the southwestern section of the park, where there is little hunting, than in the southeastern part of the park. The results of our monitoring guided law-enforcement patrols toward zones with the most hunting activity. Such systematic coordination of ecological monitoring and law enforcement may be applicable at other sites. ©2012 Society for Conservation Biology.

  5. Safety Signals in the Primate Amygdala

    PubMed Central

    Genud-Gabai, Rotem; Klavir, Oded

    2013-01-01

    The ability to distinguish danger from safety is crucial for survival. On the other hand, anxiety disorders can result from failures to dissociate safe cues from those that predict dangerous outcomes. The amygdala plays a major role in learning and signaling danger, and recently, evidence accumulates that it also acquires information to signal safety. Traditionally, safety is explored by paradigms that change the value of a previously dangerous cue, such as extinction or reversal; or by paradigms showing that a safe cue can inhibit responses to another danger-predicting cue, as in conditioned-inhibition. In real-life scenarios, many cues are never paired or tested with danger and remain neutral all along. A detailed study of neural responses to unpaired conditioned-stimulus (CS−) can therefore indicate whether information on safety-by-comparison is also acquired in the amygdala. We designed a multiple-CS study, with CS− from both visual and auditory modalities. Using discriminative aversive-conditioning, we find that responses in the primate amygdala develop for CS− of the same modality and of a different modality from that of the aversive CS+. Moreover, we find that responses are comparable in proportion, sign (increase/decrease), onset, and magnitude. These results indicate that the primate amygdala actively acquires signals about safety, and strengthen the hypothesis that failure in amygdala processing can result in failure to distinguish dangerous cues from safe ones and lead to maladaptive behaviors. PMID:24227710

  6. Short hyperdynamic profiles influence primate temperature regulation

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.; Williams, B. A.

    1982-01-01

    Primates have been shown to be sensitive to hyperdynamic fields. That is, when exposed to + 2Gz, body temperature falls. The purpose of this study was to examine the relative sensitivity of these animals to short centrifugation profiles which mimic the gravitational envelope seen on the Space Shuttle during launch (8 minutes, 2.9 Gz max) and re-entry (19 min, 1.7 Gz max). Four loosely restrained squirrel monkeys, isolated from additional external stimuli, were exposed to these profiles. During launch simulation, the temperatures never fell markedly below control levels. However, subsequent to return to 1G, the recovery phase showed decreases in body temperature in all four animals averaging 0.4 C over the next 10 to 15 minutes. The two animals exposed to the reentry profile showed decreases in body temperature within five minutes of the onset of centrifugation. Maximum fall in body temperature was reached by the end of the centrifugation phase and averaged 0.7 C. Thus, the temperature regulation system of this primate is sensitive to short hyperdynamic field exposures.

  7. Social signals in primate orbitofrontal cortex

    PubMed Central

    Watson, Karli K.; Platt, Michael L.

    2012-01-01

    Summary Primate evolution produced an increased capacity to respond flexibly to varying social contexts as well as expansion of the prefrontal cortex [1, 2]. Despite this association, how prefrontal neurons respond to social information remains virtually unknown. People with damage to orbitofrontal cortex (OFC) struggle to recognize facial expressions [3, 4], make poor social judgments [5] [6], and frequently make social faux pas [7, 8]. Here we test explicitly whether neurons in primate OFC signal social information and, if so, how such signals compare with responses to primary fluid rewards. We find OFC neurons distinguish images that belong to socially-defined categories, such as female perinea and faces, as well as the social dominance of those faces. These modulations signaled both how much monkeys valued these pictures and their interest in continuing to view them. Far more neurons signaled social category than signaled fluid value, despite the stronger impact of fluid rewards on monkeys’ choices. These findings indicate that OFC represents both the motivational value and attentional priority of other individuals, thus contributing to both the acquisition of information about others and subsequent social decisions. Our results betray a fundamental disconnect between preferences expressed through overt choice, which were primarily driven by the desire for more fluid, and preferential neuronal processing, which favored social computations. PMID:23122847

  8. Canine tooth size variability in primates.

    PubMed

    Beauchamp, G

    1989-01-01

    I present an analysis of canine tooth size variability in male and female primates. The coefficient of variation (CV = SD X 100/mean) as an index of canine size variability proved to be dependent on mean canine size in males and, to a lower extent, in females. Therefore, variability tends to increase with increasing values of mean canine size. Using residuals from the regression of log SD on log mean canine size in male and female primates, I analysed the contribution of diet, habitat and mating system to canine size variability. Habitat and mating system are known to influence to a certain extent the degree of sexual dimorphism in canine size. Given the well-known relationship between sexual dimorphism and phenotypic variability, it was suggested that these factors might influence variability in canine size. Everything else being equal, males of polygynous species are characterized by more variable canine sizes than males of monogamous species. Habitat and diet did not contribute to the level of variability observed in either males or females. It is proposed that a high level of variability in canine size may be related to the likelihood that enlarged canines evolved as a result of male-male competition for mates in polygynous species.

  9. An audiometric comparison of primate audiograms

    NASA Astrophysics Data System (ADS)

    Coleman, Mark N.

    2001-05-01

    Audiogram data for 18 species of primates were collected from the literature and analyzed by measuring 13 audiometric variables: frequency and threshold of the primary peak, frequency and threshold of the secondary peak, frequency and threshold of the notch between peaks, low-frequency cutoff, high-frequency cutoff, total area of the audible field, low area, middle area, high area, and total audible range in octaves. All areal measurements were made using IGOR PRO 4.04 wave measurement software. Platyrrhines were found to have significantly better low-frequency sensitivity than like-sized lorisoids with an average of 15-dB difference between the means for the two groups. This difference remains significant even when interindividual variation is considered. Callithrix jacchus and Erythrocebus patas have unusual hearing patterns for primates of their size with marmosets showing a reduction in high-frequency sensitivity, while patas monkeys show a reduction in low-frequency sensitivity. It was also noted that chimps have a notch in sensitivity that falls within the range of greatest sensitivity for humans. These findings are discussed in relation to the morphological adaptations that appear to influence these hearing patterns and the evolutionary significance of such patterns for group communication and predator-prey interactions.

  10. The evolution of face processing in primates

    PubMed Central

    Parr, Lisa A.

    2011-01-01

    The ability to recognize faces is an important socio-cognitive skill that is associated with a number of cognitive specializations in humans. While numerous studies have examined the presence of these specializations in non-human primates, species where face recognition would confer distinct advantages in social situations, results have been mixed. The majority of studies in chimpanzees support homologous face-processing mechanisms with humans, but results from monkey studies appear largely dependent on the type of testing methods used. Studies that employ passive viewing paradigms, like the visual paired comparison task, report evidence of similarities between monkeys and humans, but tasks that use more stringent, operant response tasks, like the matching-to-sample task, often report species differences. Moreover, the data suggest that monkeys may be less sensitive than chimpanzees and humans to the precise spacing of facial features, in addition to the surface-based cues reflected in those features, information that is critical for the representation of individual identity. The aim of this paper is to provide a comprehensive review of the available data from face-processing tasks in non-human primates with the goal of understanding the evolution of this complex cognitive skill. PMID:21536559

  11. Primate pelvic anatomy and implications for birth.

    PubMed

    Trevathan, Wenda

    2015-03-05

    The pelvis performs two major functions for terrestrial mammals. It provides somewhat rigid support for muscles engaged in locomotion and, for females, it serves as the birth canal. The result for many species, and especially for encephalized primates, is an 'obstetric dilemma' whereby the neonate often has to negotiate a tight squeeze in order to be born. On top of what was probably a baseline of challenging birth, locomotor changes in the evolution of bipedalism in the human lineage resulted in an even more complex birth process. Negotiation of the bipedal pelvis requires a series of rotations, the end of which has the infant emerging from the birth canal facing the opposite direction from the mother. This pattern, strikingly different from what is typically seen in monkeys and apes, places a premium on having assistance at delivery. Recently reported observations of births in monkeys and apes are used to compare the process in human and non-human primates, highlighting similarities and differences. These include presentation (face, occiput anterior or posterior), internal and external rotation, use of the hands by mothers and infants, reliance on assistance, and the developmental state of the neonate. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  12. The evolution of face processing in primates.

    PubMed

    Parr, Lisa A

    2011-06-12

    The ability to recognize faces is an important socio-cognitive skill that is associated with a number of cognitive specializations in humans. While numerous studies have examined the presence of these specializations in non-human primates, species where face recognition would confer distinct advantages in social situations, results have been mixed. The majority of studies in chimpanzees support homologous face-processing mechanisms with humans, but results from monkey studies appear largely dependent on the type of testing methods used. Studies that employ passive viewing paradigms, like the visual paired comparison task, report evidence of similarities between monkeys and humans, but tasks that use more stringent, operant response tasks, like the matching-to-sample task, often report species differences. Moreover, the data suggest that monkeys may be less sensitive than chimpanzees and humans to the precise spacing of facial features, in addition to the surface-based cues reflected in those features, information that is critical for the representation of individual identity. The aim of this paper is to provide a comprehensive review of the available data from face-processing tasks in non-human primates with the goal of understanding the evolution of this complex cognitive skill.

  13. Stem cell transplantation for ischemic stroke.

    PubMed

    Boncoraglio, Giorgio Battista; Bersano, Anna; Candelise, Livia; Reynolds, Brent A; Parati, Eugenio A

    2010-09-08

    Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in ischemic stroke patients is lacking. To assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the field and stem cell manufacturers (last contacted December 2008). We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections and neoplastic transformation). Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information. We identified three very small RCTs. Two are still awaiting classification because only subgroups of patients could be included in this meta

  14. Pediatric Liver Transplantation.

    PubMed

    Rawal, Nidhi; Yazigi, Nada

    2017-06-01

    Excellent outcomes over the last 3 decades have made liver transplantation the treatment of choice for many advanced liver disorders. This success also opened liver transplantation to new indications such as liver tumors and metabolic disorders. The emergence of such new indications for liver transplantation is bringing a new stream of patients along with disease-specific challenges. The cumulative number of liver transplant recipients is peaking, requiring novel systems of health care delivery that meet the needs of this special patient population. This article reviews updates and new development in pediatric liver transplantation. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Anesthesia for Heart Transplantation.

    PubMed

    Ramsingh, Davinder; Harvey, Reed; Runyon, Alec; Benggon, Michael

    2017-09-01

    This article seeks to evaluate current practices in heart transplantation. The goals of this article were to review current practices for heart transplantation and its anesthesia management. The article reviews current demographics and discusses the current criteria for candidacy for heart transplantation. The process for donor and receipt selection is reviewed. This is followed by a review of mechanical circulatory support devices as they pertain to heart transplantation. The preanesthesia and intraoperative considerations are also discussed. Finally, management after transplantation is also reviewed. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Effects of Hypericum perforatum on the healing of xenografts: a histomorphometric study in rabbits.

    PubMed

    Damlar, I; Arpağ, O F; Tatli, U; Altan, A

    2016-12-19

    The aim of this study was to investigate effects of the Hypericum perforatum (St John's Wort) on bone healing in rabbit calvarium. Ten male New Zealand rabbits each had three bicortical defects made in the calvarial bones, which were filled with xenograft, xenograft+H perforatum oil extract, and autogenous graft. Four weeks postoperatively all rabbits were killed and the bony defects examined histomorphometrically. Tissue compartments including new bone (p<0.001), marrow space (p<0.001), and residual bone grafts (p=0.014) differed significantly among groups (p=0.00?). The volume of residual graft was significantly decreased in the xenograft/H perforatum group compared with those with xenografts alone (p=0.0147). The differences in microarchitectural variables of de novo bone formation were also significant (trabecular thickness (p<0.001), trabecular width (p<0.001), trabecular separation (p=0.001). There were no significant differences in node:terminus ratio between the xenograft/H perforatum group and the other two groups. However, the difference in node:terminus ratio between the autogenous graft and xenograft group was significant (p=0.001) Oil extracts of H perforatum improved bony healing in defects filled with bovine-derived xenografts.

  17. Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts

    PubMed Central

    Zhang, Yu-An; Maitra, Anirban; Hsieh, Jer-Tsong; Rudin, Charles M; Peacock, Craig D; Karikari, Collins; Brekken, Rolf A; Stastny, Victor; Gao, Boning; Girard, Luc; Wistuba, Ignacio; Frenkel, Eugene; Minna, John D

    2011-01-01

    Purpose To investigate the frequency of xenotropic murine leukemia virus (MLV) presence in human cell lines established from mouse xenografts and to search for the evidence of horizontal viral spread to other cell lines. Results Six of 23 (26%) mouse DNA free xenograft cultures were strongly positive for MLV and their sequences had greater than 99% homology to known MLV strains. Four of five available supernatant fluids from these viral positive cultures were strongly positive for RT activity. Three of these supernatant fluids were studied to confirm the infectivity of the released virions for other human culture cells. Of the 78 non-xenograft derived cell lines maintained in the xenograft culture-containing facilities, 13 (17%) were positive for MLV, including XMRV, a virus strain first identified in human tissues. By contrast, all 50 cultures maintained in a xenograft culture-free facility were negative for viral sequences. Methodology We examined xenograft tumor cell lines from seven independent laboratories and 128 non-xenografted tumor cell lines. Cell line DNA was examined for mouse DNA contamination, and by 3 Taqman qPCR assays targeting the gag, env or pol regions of MLV. Sequencing was used for viral strain identification. Supernatant fluids were tested for reverse transcriptase (RT) activity. Conclusions Human cultures derived after mouse xenografting frequently contain and release highly infectious xenotropic MLV viruses. Laboratories working with xenograft-derived human cultures should be aware of the risk of contamination with potentially biohazardous human-tropic mouse viruses and their horizontal spread to other cultures. PMID:21750403

  18. Histological advantages of the tumor graft: a murine model involving transplantation of human pancreatic cancer tissue fragments.

    PubMed

    Akashi, Yoshimasa; Oda, Tatsuya; Ohara, Yusuke; Miyamoto, Ryoichi; Hashimoto, Shinji; Enomoto, Tsuyoshi; Yamada, Keiichi; Kobayashi, Akihiko; Fukunaga, Kiyoshi; Ohkochi, Nobuhiro

    2013-11-01

    Experimental data based on cell line-derived xenograft models (cell xenograft) seldom reproduce the clinical situation, and therefore we demonstrated here the superiority of a murine model involving transplantation of human pancreatic cancer tissue fragments (tumor graft), focusing on the histological features and drug delivery characteristics. Tumor pieces from 10 pancreatic cancer patients were transplanted into SCID (severe combined immunodeficient) mice. Histological characteristics of tumor grafts, including morphology, desmoplastic reaction, and vascularization, were compared with those of cell xenografts. Drug delivery was evaluated by quantifying the concentrations of injected drug, and the results were compared with its histological features. Eight of the 10 transplanted tumors successfully engrafted. Histological comparisons between tumor grafts and cell xenografts revealed the following: the amount of stroma was more (22.9% ± 11.8% vs 10.8% ± 5.4%; P < 0.05), vessel-cancer cell distance was longer (35.3 ± 39.0 vs 3.9 ± 3.1 μm; P < 0.001), and microvessel density was lower (6.8 ± 1.9 vs 10.8 ± 2.1 vessels/0.4 mm(2); P < 0.05) in tumor grafts. Drug concentrations in tumor grafts were lower than those in cell xenografts (3.3 ± 1.2 vs 6.0±0.2 μg/mL; P = 0.003), and the differences were correlated with the histological differences. Pancreatic tumor grafts better reproduce the histological nature of clinical cancer and thus provide a more realistic model that is applicable for pharmacokinetic studies.

  19. The evolution of the primate foot from the earliest primates to the Miocene hominoids.

    PubMed

    Conroy, G C; Rose, M D

    1983-01-01

    The fossil evidence relating to the evolution of the primate foot is reviewed and evaluated. Many of the characteristic features of the primate foot had evolved by the early Tertiary over 40 million years ago. Probably the most significant of these developments was the progressive migration of the talus to a position over the calcaneum. These morphological features are followed through the Miocene hominoid genera from East Africa, Europe, and South Asia. While some features of Miocene hominoids, especially those relating to climbing abilities, are still evident in the predominantly bipedal earliest hominids of the Plio-Pleistocene, there is no evidence yet from the Miocene of the first stages in the evolution of that bipedalism.

  20. Characterization of Circulating Natural Killer Cells in Neotropical Primates

    PubMed Central

    Carville, Angela; Evans, Tristan I.; Reeves, R. Keith

    2013-01-01

    Despite extensive use of nonhuman primates as models for infectious diseases and reproductive biology, imprecise phenotypic and functional definitions exist for natural killer (NK) cells. This deficit is particularly significant in the burgeoning use of small, less expensive New World primate species. Using polychromatic flow cytometry, we identified peripheral blood NK cells as CD3-negative and expressing a cluster of cell surface molecules characteristic of NK cells (i.e., NKG2A, NKp46, NKp30) in three New World primate species – common marmosets, cotton-top tamarins, and squirrel monkeys. We then assessed subset distribution using the classical NK markers, CD56 and CD16. In all species, similar to Old World primates, only a minor subset of NK cells was CD56+, and the dominant subset was CD56–CD16+. Interestingly, CD56+ NK cells were primarily cytokine-secreting cells, whereas CD56–CD16+ NK cells expressed significantly greater levels of intracellular perforin, suggesting these cells might have greater potential for cytotoxicity. New World primate species, like Old World primates, also had a minor CD56–CD16– NK cell subset that has no obvious counterpart in humans. Herein we present phenotypic profiles of New World primate NK cell subpopulations that are generally analogous to those found in humans. This conservation among species should support the further use of these species for biomedical research. PMID:24244365

  1. Postcopulatory sexual selection influences baculum evolution in primates and carnivores

    PubMed Central

    Brindle, Matilda

    2016-01-01

    The extreme morphological variability of the baculum across mammals is thought to be the result of sexual selection (particularly, high levels of postcopulatory selection). However, the evolutionary trajectory of the mammalian baculum is little studied and evidence for the adaptive function of the baculum has so far been elusive. Here, we use Markov chain Monte Carlo methods implemented in a Bayesian phylogenetic framework to reconstruct baculum evolution across the mammalian class and investigate the rate of baculum length evolution within the primate order. We then test the effects of testes mass (postcopulatory sexual selection), polygamy, seasonal breeding and intromission duration on the baculum in primates and carnivores. The ancestral mammal did not have a baculum, but both ancestral primates and carnivores did. No relationship was found between testes mass and baculum length in either primates or carnivores. Intromission duration correlated with baculum presence over the course of primate evolution, and prolonged intromission predicts significantly longer bacula in extant primates and carnivores. Both polygamous and seasonal breeding systems predict significantly longer bacula in primates. These results suggest the baculum plays an important role in facilitating reproductive strategies in populations with high levels of postcopulatory sexual selection. PMID:27974519

  2. Contributions of Nonhuman Primates to Research on Aging

    PubMed Central

    Didier, E. S.; MacLean, A. G.; Mohan, M.; Didier, P. J.; Lackner, A. A.; Kuroda, M. J.

    2016-01-01

    Aging is the biological process of declining physiologic function associated with increasing mortality rate during advancing age. Humans and higher nonhuman primates exhibit unusually longer average life spans as compared with mammals of similar body mass. Furthermore, the population of humans worldwide is growing older as a result of improvements in public health, social services, and health care systems. Comparative studies among a wide range of organisms that include nonhuman primates contribute greatly to our understanding about the basic mechanisms of aging. Based on their genetic and physiologic relatedness to humans, nonhuman primates are especially important for better understanding processes of aging unique to primates, as well as for testing intervention strategies to improve healthy aging and to treat diseases and disabilities in older people. Rhesus and cynomolgus macaques are the predominant monkeys used in studies on aging, but research with lower nonhuman primate species is increasing. One of the priority topics of research about aging in nonhuman primates involves neurologic changes associated with cognitive decline and neurodegenerative diseases. Additional areas of research include osteoporosis, reproductive decline, caloric restriction, and their mimetics, as well as immune senescence and chronic inflammation that affect vaccine efficacy and resistance to infections and cancer. The purpose of this review is to highlight the findings from nonhuman primate research that contribute to our understanding about aging and health span in humans. PMID:26869153

  3. Historical contingency in the evolution of primate color vision.

    PubMed

    Dominy, Nathaniel J; Svenning, Jens Christian; Li, Wen Hsiung

    2003-01-01

    Primates are unique among eutherian mammals for possessing three types of retinal cone. Curiously, catarrhines, platyrrhines, and strepsirhines share this anatomy to different extents, and no hypothesis has hitherto accounted for this variability. Here we propose that the historical biogeography of figs and arborescent palms accounts for the global variation in primate color vision. Specifically, we suggest that primates invaded Paleogene forests characterized by figs and palms, the fruits of which played a keystone function. Primates not only relied on such resources, but also provided high-quality seed dispersal. In turn, figs and palms lost or simply did not evolve conspicuous coloration, as this conferred little advantage for attracting mammals. We suggest that the abundance and coloration of figs and palms offered a selective advantage to foraging groups with mixed capabilities for chromatic distinction. Climatic cooling at the end of the Eocene and into the Neogene resulted in widespread regional extinction or decimation of palms and (probably) figs. In regions where figs and palms became scarce, we suggest primates evolved routine trichromatic vision in order to exploit proteinaceous young leaves as a replacement resource. A survey of the hue and biogeography of extant figs and palms provides some empirical support. Where these resources are infrequent, primates are routinely trichromatic and consume young leaves during seasonal periods of fruit dearth. These results imply a link between the differential evolution of primate color vision and climatic changes during the Eocene-Oligocene transition.

  4. Fruits, foliage and the evolution of primate colour vision.

    PubMed

    Regan, B C; Julliot, C; Simmen, B; Viénot, F; Charles-Dominique, P; Mollon, J D

    2001-03-29

    Primates are apparently unique amongst the mammals in possessing trichromatic colour vision. However, not all primates are trichromatic. Amongst the haplorhine (higher) primates, the catarrhines possess uniformly trichromatic colour vision, whereas most of the platyrrhine species exhibit polymorphic colour vision, with a variety of dichromatic and trichromatic phenotypes within the population. It has been suggested that trichromacy in primates and the reflectance functions of certain tropical fruits are aspects of a coevolved seed-dispersal system: primate colour vision has been shaped by the need to find coloured fruits amongst foliage, and the fruits themselves have evolved to be salient to primates and so secure dissemination of their seeds. We review the evidence for and against this hypothesis and we report an empirical test: we show that the spectral positioning of the cone pigments found in trichromatic South American primates is well matched to the task of detecting fruits against a background of leaves. We further report that particular trichromatic platyrrhine phenotypes may be better suited than others to foraging for particular fruits under particular conditions of illumination; and we discuss possible explanations for the maintenance of polymorphic colour vision amongst the platyrrhines.

  5. A comparative neurological approach to emotional expressions in primate vocalizations.

    PubMed

    Gruber, Thibaud; Grandjean, Didier

    2017-02-01

    Different approaches from different research domains have crystallized debate over primate emotional processing and vocalizations in recent decades. On one side, researchers disagree about whether emotional states or processes in animals truly compare to those in humans. On the other, a long-held assumption is that primate vocalizations are innate communicative signals over which nonhuman primates have limited control and a mirror of the emotional state of the individuals producing them, despite growing evidence of intentional production for some vocalizations. Our goal is to connect both sides of the discussion in deciphering how the emotional content of primate calls compares with emotional vocal signals in humans. We focus particularly on neural bases of primate emotions and vocalizations to identify cerebral structures underlying emotion, vocal production, and comprehension in primates, and discuss whether particular structures or neuronal networks solely evolved for specific functions in the human brain. Finally, we propose a model to classify emotional vocalizations in primates according to four dimensions (learning, control, emotional, meaning) to allow comparing calls across species.

  6. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    SciTech Connect

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C.; Ballestas, Mary E.; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  7. Evaluation of 89Zr-pertuzumab in Breast Cancer Xenografts

    PubMed Central

    2015-01-01

    Pertuzumab is a monoclonal antibody that binds to HER2 and is used in combination with another HER2–specific monoclonal antibody, trastuzumab, for the treatment of HER2+ metastatic breast cancer. Pertuzumab binds to an HER2 binding site distinct from that of trastuzumab, and its affinity is enhanced when trastuzumab is present. We aim to exploit this enhanced affinity of pertuzumab for its HER2 binding epitope and adapt this antibody as a PET imaging agent by radiolabeling with 89Zr to increase the sensitivity of HER2 detection in vivo. Here, we investigate the biodistribution of 89Zr-pertuzumab in HER2–expressing BT-474 and HER2–nonexpressing MDA-MB-231 xenografts to quantitatively assess HER2 expression in vivo. In vitro cell binding studies were performed resulting in retained immunoreactivity and specificity for HER2–expressing cells. In vivo evaluation of 89Zr-pertuzumab was conducted in severely combined immunodeficient mice, subcutaneously inoculated with BT-474 and MDA-MB-231 cells. 89Zr-pertuzumab was systemically administered and imaged at 7 days postinjection (p.i.) followed by terminal biodistribution studies. Higher tumor uptake was observed in BT-474 compared to MDA-MB-231 xenografts with 47.5 ± 32.9 and 9.5 ± 1.7% ID/g, respectively at 7 days p.i (P = 0.0009) and blocking studies with excess unlabeled pertuzumab showed a 5-fold decrease in BT-474 tumor uptake (P = 0.0006), confirming the in vivo specificity of this radiotracer. Importantly, we observed that the tumor accumulation of 89Zr-pertuzumab was increased in the presence of unlabeled trastuzumab, at 173 ± 74.5% ID/g (P = 0.01). Biodistribution studies correlate with PET imaging quantification using max SUV (r = 0.98, P = 0.01). Collectively, these results illustrate that 89Zr-pertuzumab as a PET imaging agent may be beneficial for the quantitative and noninvasive assessment of HER2 expression in vivo especially for patients undergoing trastuzumab therapy. PMID:25058168

  8. Retrovirus Studies in Nonhuman Primates at Four Regional Primate Research Centers.

    DTIC Science & Technology

    1990-09-30

    rhesus macaques (Miller, et. al. 1990). Significance. The initial objective of this project was to determine if a nonhuman primate model for the sexual...rhesus monkeys infected with simian immunodeficiency virus. Am J Pathol. (Submitted) SPECIFIC AIM 2.2: Maternal - Fetal Transmission Studies Female rhesus...Perinatal Transmission of SIVsmm Studies to evaluate the perinatal transmission of SIVsmm were initiated by infecting 15 timed pregnant rhesus monkeys with

  9. Biomechanical research of joints: IV. the biohinge of primates

    NASA Astrophysics Data System (ADS)

    Zhang, Renxiang; Yu, Jie; Lan, Zu-yun; Qu, Wen-ji; Zhang, Hong-zi; Zhang, Kui; Zhang, Liang

    1991-04-01

    In this paper moire topography is applied to study the femoral articular facies of the knee of Primates. For compari son with each other of different families of Primates we suggest the comparative targets a y and the grade G of the moire contour fringes on two condyles of knee of Primates and comparative study of the articulation of knee between the Macaca assamensis M cellaud Presbytis phayrei Rhinopithecus roxellanae Hylobates concolor leucogenys Nycticebus concany Gorilla gorilla Anthropopithecus troglodytes Sirnia satyrus and human being are given. The results may be useful reference in the study of Biomechanics Zoology and Anthropology.

  10. The Evolution of Primate Communication and Metacommunication

    PubMed Central

    2016-01-01

    Abstract Against the prior view that primate communication is based only on signal decoding, comparative evidence suggests that primates are able, no less than humans, to intentionally perform or understand impulsive or habitual communicational actions with a structured evaluative nonconceptual content. These signals convey an affordance‐sensing that immediately motivates conspecifics to act. Although humans have access to a strategic form of propositional communication adapted to teaching and persuasion, they share with nonhuman primates the capacity to communicate in impulsive or habitual ways. They are also similarly able to monitor fluency, informativeness and relevance of messages or signals through nonconceptual cues. PMID:27134332

  11. The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma.

    PubMed

    Zhang, Caiqin; Zhao, Yong; Zhang, He; Chen, Xue; Zhao, Ningning; Tan, Dengxu; Zhang, Hai; Shi, Changhong

    2017-06-21

    Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC.

  12. XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer

    PubMed Central

    Morton, J. Jason; Bird, Gregory; Keysar, Stephen B.; Astling, David P.; Lyons, Traci R; Anderson, Ryan T.; Glogowska, Magdalena J.; Estes, Patricia; Eagles, Justin R.; Le, Phuong N.; Gan, Gregory; McGettigan, Brett; Fernandez, Pamela; Padilla-Just, Nuria; Varella-Garcia, Marileila; Song, John I.; Bowles, Daniel W.; Schedin, Pepper; Tan, Aik-Choon; Roop, Dennis R.; Wang, Xiao-Jing; Refaeli, Yosef; Jimeno, Antonio

    2015-01-01

    The limitations of cancer cell lines have led to the development of direct patient derived xenograft (PDX) models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg−/− (NSG) mouse on which a patient’s tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal, and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice – an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice, and provide a more accurate tumor model to guide patient treatment. PMID:25893296

  13. Character displacement of Cercopithecini primate visual signals

    PubMed Central

    Allen, William L.; Stevens, Martin; Higham, James P.

    2014-01-01

    Animal visual signals have the potential to act as an isolating barrier to prevent interbreeding of populations through a role in species recognition. Within communities of competing species, species recognition signals are predicted to undergo character displacement, becoming more visually distinctive from each other, however this pattern has rarely been identified. Using computational face recognition algorithms to model primate face processing, we demonstrate that the face patterns of guenons (tribe: Cercopithecini) have evolved under selection to become more visually distinctive from those of other guenon species with whom they are sympatric. The relationship between the appearances of sympatric species suggests that distinguishing conspecifics from other guenon species has been a major driver of diversification in guenon face appearance. Visual signals that have undergone character displacement may have had an important role in the tribe’s radiation, keeping populations that became geographically separated reproductively isolated on secondary contact. PMID:24967517

  14. Primate training at Disney's Animal Kingdom.

    PubMed

    Colahan, Hollie; Breder, Chris

    2003-01-01

    A training program has been in place at Disney's Animal Kingdom since the nonhuman animals first arrived at the park. The Primate Team and the Behavioral Husbandry Team have worked together closely to establish a philosophy and framework for this program. This framework emphasizes setting goals, planning, implementing, documenting, and evaluating. The philosophy focuses on safety, staff training, and an integrated approach to training as an animal management tool. Behaviors to be trained include husbandry and veterinary as well as behaviors identified for specific species, individuals, or situations. Input from all the teams was used to prioritize these behaviors. Despite the challenges to maintaining such a program, the benefits to animal care and welfare have been enormous.

  15. Laser-induced primate glaucoma. II. Histopathology.

    PubMed

    Radius, R L; Pederson, J E

    1984-11-01

    A sustained, moderate pressure elevation was produced in 15 nonhuman primate eyes by application of laser energy to the trabecular meshwork. By light and electron microscopy, the trabecular beams were blunted, and scattered synechiae were present. Backward bowing of the lamina cribrosa, partial loss of the myelin sheath surrounding axonal segments just posterior to the lamina, and diffuse axonal loss involving the entire nerve cross section were noted. A quantitative analysis of this axonal loss revealed that eyes with moderate nerve head damage (cup-disc ratio, 0.6 to 0.8) had only 38% to 69% of the expected normal axonal count. The eyes with nearly total cupping (cup-disc ratio, 0.9 to 1.0) maintained between 10% and 36% of the normal axonal count. The disc changes in these experimental eyes are similar to those previously described in human eyes with glaucoma.

  16. Environmental enrichment for primates in laboratories

    NASA Astrophysics Data System (ADS)

    Buchanan-Smith, H. M.

    2010-06-01

    Environmental enrichment is a critical component of Refinement, one of the 3Rs underlying humane experimentation on animals. In this paper I discuss why primates housed in laboratories, which often have constraints of space and study protocols, are a special case for enrichment. I outline a framework for categorising the different types of enrichment, using the marmoset as a case study, and summarise the methods used to determine what animals want/prefer. I briefly review the arguments that enrichment does not negatively affect experimental outcomes. Finally I focus on complexity and novelty, choice and control, the underlying features of enrichment that makes it successful, and how combined with a thorough understanding of natural history we can put effective enrichment into practice in laboratories. Throughout the paper I emphasise the need to evaluate enrichment to ensure it is having the desired effect.

  17. Primate communication in the pure ultrasound

    PubMed Central

    Ramsier, Marissa A.; Cunningham, Andrew J.; Moritz, Gillian L.; Finneran, James J.; Williams, Cathy V.; Ong, Perry S.; Gursky-Doyen, Sharon L.; Dominy, Nathaniel J.

    2012-01-01

    Few mammals—cetaceans, domestic cats and select bats and rodents—can send and receive vocal signals contained within the ultrasonic domain, or pure ultrasound (greater than 20 kHz). Here, we use the auditory brainstem response (ABR) method to demonstrate that a species of nocturnal primate, the Philippine tarsier (Tarsius syrichta), has a high-frequency limit of auditory sensitivity of ca 91 kHz. We also recorded a vocalization with a dominant frequency of 70 kHz. Such values are among the highest recorded for any terrestrial mammal, and a relatively extreme example of ultrasonic communication. For Philippine tarsiers, ultrasonic vocalizations might represent a private channel of communication that subverts detection by predators, prey and competitors, enhances energetic efficiency, or improves detection against low-frequency background noise. PMID:22319094

  18. Conserved Sequence Processing in Primate Frontal Cortex.

    PubMed

    Wilson, Benjamin; Marslen-Wilson, William D; Petkov, Christopher I

    2017-02-01

    An important aspect of animal perception and cognition is learning to recognize relationships between environmental events that predict others in time, a form of relational knowledge that can be assessed using sequence-learning paradigms. Humans are exquisitely sensitive to sequencing relationships, and their combinatorial capacities, most saliently in the domain of language, are unparalleled. Recent comparative research in human and nonhuman primates has obtained behavioral and neuroimaging evidence for evolutionarily conserved substrates involved in sequence processing. The findings carry implications for the origins of domain-general capacities underlying core language functions in humans. Here, we synthesize this research into a 'ventrodorsal gradient' model, where frontal cortex engagement along this axis depends on sequencing complexity, mapping onto the sequencing capacities of different species. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Identification of bacterial infection in neotropical primates.

    PubMed

    Menezes-Costa, Andre; Machado-Ferreira, Erik; Voloch, Carolina M; Bonvicino, Cibele R; Seuánez, Hector N; Leoncini, Orilio; Soares, Carlos A G

    2013-08-01

    Emerging infectious diseases usually arise from wild animal populations. In the present work, we performed a screening for bacterial infection in natural populations of New World primates. The blood cell bulk DNAs from 181 individuals of four Platyrrhini genera were PCR screened for eubacterial 16S rRNA genes. Bacteria were detected and identified in 13 distinct individuals of Alouatta belzebul, Alouatta caraya, and Cebus apella monkeys from geographically distant regions in the states of Mato Grosso and Pará, Brazil. Sequence analyses showed that these Platyrrhini bacteria are closely related not only to human pathogens Pseudomonas spp. but also to Pseudomonas simiae and sheep-Acari infecting Pseudomonas spp. The identified Pseudomonas possibly represents a group of bacteria circulating in natural monkey populations.

  20. Comprehensive transcriptional map of primate brain development

    PubMed Central

    Bakken, Trygve E.; Miller, Jeremy A.; Ding, Song-Lin; Sunkin, Susan M.; Smith, Kimberly A.; Ng, Lydia; Szafer, Aaron; Dalley, Rachel A.; Royall, Joshua J.; Lemon, Tracy; Shapouri, Sheila; Aiona, Kaylynn; Arnold, James; Bennett, Jeffrey L.; Bertagnolli, Darren; Bickley, Kristopher; Boe, Andrew; Brouner, Krissy; Butler, Stephanie; Byrnes, Emi; Caldejon, Shiella; Carey, Anita; Cate, Shelby; Chapin, Mike; Chen, Jefferey; Dee, Nick; Desta, Tsega; Dolbeare, Tim A.; Dotson, Nadia; Ebbert, Amanda; Fulfs, Erich; Gee, Garrett; Gilbert, Terri L.; Goldy, Jeff; Gourley, Lindsey; Gregor, Ben; Gu, Guangyu; Hall, Jon; Haradon, Zeb; Haynor, David R.; Hejazinia, Nika; Hoerder-Suabedissen, Anna; Howard, Robert; Jochim, Jay; Kinnunen, Marty; Kriedberg, Ali; Kuan, Chihchau L.; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Luong, Lon; Mastan, Naveed; May, Ryan; Melchor, Jose; Mosqueda, Nerick; Mott, Erika; Ngo, Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D.; Parry, Sheana; Pendergraft, Julie; Potekhina, Lydia; Reding, Melissa; Riley, Zackery L.; Roberts, Tyson; Rogers, Brandon; Roll, Kate; Rosen, David; Sandman, David; Sarreal, Melaine; Shapovalova, Nadiya; Shi, Shu; Sjoquist, Nathan; Sodt, Andy J.; Townsend, Robbie; Velasquez, Lissette; Wagley, Udi; Wakeman, Wayne B.; White, Cassandra; Bennett, Crissa; Wu, Jennifer; Young, Rob; Youngstrom, Brian L.; Wohnoutka, Paul; Gibbs, Richard A.; Rogers, Jeffrey; Hohmann, John G.; Hawrylycz, Michael J.; Hevner, Robert F.; Molnár, Zoltán; Phillips, John W.; Dang, Chinh; Jones, Allan R.; Amaral, David G.; Bernard, Amy; Lein, Ed S.

    2017-01-01

    The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny. PMID:27409810

  1. A nonhuman primate model of chikungunya disease

    PubMed Central

    Higgs, Stephen; Ziegler, Sarah A.

    2010-01-01

    Chikungunya disease is a severely debilitating, mosquito-borne, viral illness that has reached epidemic proportions in Africa, Asia, and the islands of the Indian Ocean. A mutation enhancing the ability of the chikungunya virus (CHIKV) to infect and be transmitted by Aedes albopictus has increased the geographical range at risk for infection due to the continuing global spread of this mosquito. Research into disease pathogenesis, vaccine development, and therapeutic design has been hindered by the lack of appropriate animal models of this disease. The meticulous study reported in this issue of the JCI by Labadie et al. is one of the first reports describing CHIKV infection of adult immunocompetent nonhuman primates. Using traditional and modern molecular and immunological approaches, the authors demonstrate that macaques infected with CHIKV are a good model of human CHIKV infection and also show that persistent arthralgia in humans may be caused by persistent CHIKV infection of macrophages. PMID:20179348

  2. [Renal blood flow investigations with 133xenon and the Anger scintillation camera in the hyperacute xenograft rejection of the rabbit kidney (author's transl)].

    PubMed

    Heidenreich, P; Erhardt, W; Oberdorfer, M; Krüger, P; Pielsticker, K; Hör, G

    1976-08-25

    The aim of this study was to demonstrate the advantage and validity of 133Xe-washout externally monitored by the scintillation camera. Until now there were no reports on quantitative blood flow studies in Hyperacute rejection of transplanted kidneys using a scintillation camera. Within 35 minutes after e-vivo hemoperfusion of rabbit kidneys by cats we found a simultaneous progressive decrease of renal blood flow, renal cortical blood flow as well as of the intrarenal distribution of renal cortical blood flow in all cases. The hyperacute rejection of xenografts could be verified in every case histologically. Using the scintillation camera we were able to detect regional perfusion defects caused by artifical air embolism as well as by preexisting cortical infarction.

  3. Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Non-Human Primates

    PubMed Central

    Freitas, AM; Samy, KP; Farris, AB; Leopardi, FV; Song, M; Stempora, L; Strobert, EA; Jenkins, JA; Kirk, AD; Cendales, LC

    2016-01-01

    Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the non-lifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a non-human-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2hi memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model. PMID:26139552

  4. Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

    PubMed Central

    Hecht, Gil; Eventov-Friedman, Smadar; Rosen, Chava; Shezen, Elias; Tchorsh, Dalit; Aronovich, Anna; Freud, Enrique; Golan, Hana; El-Hasid, Ronit; Katchman, Helena; Hering, Bernhard J.; Zung, Amnon; Kra-Oz, Zipi; Shaked-Mishan, Pninit; Yusim, Alex; Shtabsky, Alex; Idelevitch, Pavel; Tobar, Ana; Harmelin, Alon; Bachar-Lustig, Esther; Reisner, Yair

    2009-01-01

    Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a β cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes. PMID:19433788

  5. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model.

    PubMed

    Takagi, Yasushi; Takahashi, Jun; Saiki, Hidemoto; Morizane, Asuka; Hayashi, Takuya; Kishi, Yo; Fukuda, Hitoshi; Okamoto, Yo; Koyanagi, Masaomi; Ideguchi, Makoto; Hayashi, Hideki; Imazato, Takayuki; Kawasaki, Hiroshi; Suemori, Hirofumi; Omachi, Shigeki; Iida, Hidehiko; Itoh, Nobuyuki; Nakatsuji, Norio; Sasai, Yoshiki; Hashimoto, Nobuo

    2005-01-01

    Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic (DA) neurons. ES cells are currently the most promising donor cell source for cell-replacement therapy in PD. We previously described a strong neuralizing activity present on the surface of stromal cells, named stromal cell-derived inducing activity (SDIA). In this study, we generated neurospheres composed of neural progenitors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, acts synergistically with FGF2 to increase the number of DA neurons in ES cell-derived neurospheres. We also analyzed the effect of transplantation of DA neurons generated from monkey ES cells into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP-treated) monkeys, a primate model for PD. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons and attenuated MPTP-induced neurological symptoms.

  6. Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Els, D.; Du Toit, L.B.; Weideman, A.; Davids, H.; van der Merwe, E.

    1987-09-01

    The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

  7. Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model.

    PubMed

    Hecht, Gil; Eventov-Friedman, Smadar; Rosen, Chava; Shezen, Elias; Tchorsh, Dalit; Aronovich, Anna; Freud, Enrique; Golan, Hana; El-Hasid, Ronit; Katchman, Helena; Hering, Bernhard J; Zung, Amnon; Kra-Oz, Zipi; Shaked-Mishan, Pninit; Yusim, Alex; Shtabsky, Alex; Idelevitch, Pavel; Tobar, Ana; Harmelin, Alon; Bachar-Lustig, Esther; Reisner, Yair

    2009-05-26

    Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a beta cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes.

  8. Prosocial primates: selfish and unselfish motivations.

    PubMed

    de Waal, Frans B M; Suchak, Malini

    2010-09-12

    Non-human primates are marked by well-developed prosocial and cooperative tendencies as reflected in the way they support each other in fights, hunt together, share food and console victims of aggression. The proximate motivation behind such behaviour is not to be confused with the ultimate reasons for its evolution. Even if a behaviour is ultimately self-serving, the motivation behind it may be genuinely unselfish. A sharp distinction needs to be drawn, therefore, between (i) altruistic and cooperative behaviour with knowable benefits to the actor, which may lead actors aware of these benefits to seek them by acting cooperatively or altruistically and (ii) altruistic behaviour that offers the actor no knowable rewards. The latter is the case if return benefits occur too unpredictably, too distantly in time or are of an indirect nature, such as increased inclusive fitness. The second category of behaviour can be explained only by assuming an altruistic impulse, which-as in humans-may be born from empathy with the recipient's need, pain or distress. Empathy, a proximate mechanism for prosocial behaviour that makes one individual share another's emotional state, is biased the way one would predict from evolutionary theories of cooperation (i.e. by kinship, social closeness and reciprocation). There is increasing evidence in non-human primates (and other mammals) for this proximate mechanism as well as for the unselfish, spontaneous nature of the resulting prosocial tendencies. This paper further reviews observational and experimental evidence for the reciprocity mechanisms that underlie cooperation among non-relatives, for inequity aversion as a constraint on cooperation and on the way defection is dealt with.

  9. Comparative primate energetics and hominid evolution.

    PubMed

    Leonard, W R; Robertson, M L

    1997-02-01

    There is currently great interest in developing ecological models for investigating human evolution. Yet little attention has been given to energetics, one of the cornerstones of modern ecosystem ecology. This paper examines the ecological correlates of variation in metabolic requirements among extant primate species, and uses this information to draw inferences about the changes in energy demands over the course of human evolution. Data on body size, resting metabolism, and activity budgets for selected anthropoid species and human hunter-gatherers are used to estimate total energy expenditure (TEE). Analyses indicate that relative energy expenditure levels and day ranges are positively correlated with diet quality; that is, more active species tend to consume more energy-rich diets. Human foragers fall at the positive extremes for modern primates in having high expenditure levels, large ranges, and very high quality diets. During hominid evolution, it appears that TEE increased substantially with the emergence of Homo erectus. This increase is partly attributable to larger body size as well as likely increases in day range and activity level. Assuming similar activity budgets for all early hominid species, estimated TEE for H. erectus is 40-45% greater than for the australopithecines. If, however, it is assumed that the evolution of early Homo was also associated with a shift to a more "human-like" foraging strategy, estimated expenditure levels for H. erectus are 80-85% greater than in the australopithecines. Changing patterns of resource distribution associated with the expansion of African savannas between 2.5 and 1.5 mya may been the impetus for a shift in foraging behavior among early members of the genus Homo. Such ecological changes likely would have made animal foods a more attractive resource. Moreover, greater use of animal foods and the resulting higher quality diet would have been important for supporting the larger day ranges and greater energy

  10. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey, Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of

  11. Newly arisen DNA repeats in primate phylogeny.

    PubMed

    Ryan, S C; Dugaiczyk, A

    1989-12-01

    We discovered the presence of an Alu and an Xba repetitive DNA element within introns 4 and 7, respectively, of the human alpha-fetoprotein (AFP) gene; these elements are absent from the same gene in the gorilla. The Alu element is flanked by 12-base-pair direct repeats, AGGATGTTGTGG ... (Alu) ... AGGATGTTGTGG, which presumably arose by way of duplication of the intronic target site AGGATGTTGTGG at the time of the Alu insertion. In the gorilla, only a single copy of the unoccupied target site is present, which is identical to the terminal repeat flanking the human Alu element. There are two copies of an Xba repeat in the human AFP gene, apparently the only two in the genome. Xba1 and Xba2, located within introns 8 and 7, respectively, differ from each other at 3 of 303 positions. Xba1 is referred to as the old (ancestral) repeat because it lacks direct repeats. The new (derived) Xba2 is flanked by direct repeats, TTTCTTTTT ... (Xba) ... TTTCTTCTT, and is thought to have arisen as a result of transposition of Xba1. The ancestral Xba1 and a single copy of the Xba2 target site are present at orthologous positions in the gorilla, but the new Xba2 is absent. We conclude that the Alu and Xba DNA repeats emerged in the human genome at a time postdating the human-gorilla divergence and became established as genetic novelties in the human lineage. We submit that the chronology of divergence of primate lines of evolution can be correlated with the timing of insertion of new DNA repeats into the genomes of those primates.

  12. Prosocial primates: selfish and unselfish motivations

    PubMed Central

    de Waal, Frans B. M.; Suchak, Malini

    2010-01-01

    Non-human primates are marked by well-developed prosocial and cooperative tendencies as reflected in the way they support each other in fights, hunt together, share food and console victims of aggression. The proximate motivation behind such behaviour is not to be confused with the ultimate reasons for its evolution. Even if a behaviour is ultimately self-serving, the motivation behind it may be genuinely unselfish. A sharp distinction needs to be drawn, therefore, between (i) altruistic and cooperative behaviour with knowable benefits to the actor, which may lead actors aware of these benefits to seek them by acting cooperatively or altruistically and (ii) altruistic behaviour that offers the actor no knowable rewards. The latter is the case if return benefits occur too unpredictably, too distantly in time or are of an indirect nature, such as increased inclusive fitness. The second category of behaviour can be explained only by assuming an altruistic impulse, which—as in humans—may be born from empathy with the recipient's need, pain or distress. Empathy, a proximate mechanism for prosocial behaviour that makes one individual share another's emotional state, is biased the way one would predict from evolutionary theories of cooperation (i.e. by kinship, social closeness and reciprocation). There is increasing evidence in non-human primates (and other mammals) for this proximate mechanism as well as for the unselfish, spontaneous nature of the resulting prosocial tendencies. This paper further reviews observational and experimental evidence for the reciprocity mechanisms that underlie cooperation among non-relatives, for inequity aversion as a constraint on cooperation and on the way defection is dealt with. PMID:20679114

  13. Early primate evolution in Afro-Arabia.

    PubMed

    Seiffert, Erik R

    2012-11-01

    The peculiar mammalian fauna that inhabited Afro-Arabia during the Paleogene first came to the attention of the scientific community in the early part of the twentieth century, when Andrews1 and Schlosser2 published their landmark descriptions of fossil mammals from the Fayum Depression in northern Egypt. Their studies revealed a highly endemic assemblage of land mammals that included the first known Paleogene records of hyraxes, proboscideans, and anthropoid primates, but which lacked ancestors of many iconic mammalian lineages that are found in Africa today, such as rhinos, zebras, bovids, giraffes, and cats. Over the course of the last century, the Afro-Arabian Paleogene has yielded fossil remains of several other endemic mammalian lineages,3 as well as a diversity of prosimian primates,4 but we are only just beginning to understand how the continent's faunal composition came to be, through ancient processes such as the movement of tectonic plates, changes in climate and sea level, and early phylogenetic splits among the major groups of placental mammals. These processes, in turn, made possible chance dispersal events that were critical in determining the competitive landscape--and, indeed, the survival--of our earliest anthropoid ancestors. Newly discovered fossils indicate that the persistence and later diversification of Anthropoidea was not an inevitable result of the clade's competitive isolation or adaptive superiority, as has often been assumed, but rather was as much due to the combined influences of serendipitous geographic conditions, global cooling, and competition with a group of distantly related extinct strepsirrhines with anthropoid-like adaptations known as adapiforms. Many of the important details of this story would not be known, and could never have been predicted, without the fossil evidence that has recently been unearthed by field paleontologists. Copyright © 2012 Wiley Periodicals, Inc.

  14. Microgravity Flight - Accommodating Non-Human Primates

    NASA Technical Reports Server (NTRS)

    Dalton, Bonnie P.; Searby, Nancy; Ostrach, Louis

    1994-01-01

    Spacelab Life Sciences-3 (SLS-3) was scheduled to be the first United States man-tended microgravity flight containing Rhesus monkeys. The goal of this flight as in the five untended Russian COSMOS Bion flights and an earlier American Biosatellite flight, was to understand the biomedical and biological effects of a microgravity environment using the non-human primate as human surrogate. The SLS-3/Rhesus Project and COSMOS Primate-BIOS flights all utilized the rhesus monkey, Macaca mulatta. The ultimate objective of all flights with an animal surrogate has been to evaluate and understand biological mechanisms at both the system and cellular level, thus enabling rational effective countermeasures for future long duration human activity under microgravity conditions and enabling technical application to correction of common human physiological problems within earth's gravity, e.g., muscle strength and reloading, osteoporosis, immune deficiency diseases. Hardware developed for the SLS-3/Rhesus Project was the result of a joint effort with the French Centre National d'Etudes Spatiales (CNES) and the United States National Aeronautics and Space Administration (NASA) extending over the last decade. The flight hardware design and development required implementation of sufficient automation to insure flight crew and animal bio-isolation and maintenance with minimal impact to crew activities. A variety of hardware of varying functional capabilities was developed to support the scientific objectives of the original 22 combined French and American experiments, along with 5 Russian co-investigations, including musculoskeletal, metabolic, and behavioral studies. Unique elements of the Rhesus Research Facility (RRF) included separation of waste for daily delivery of urine and fecal samples for metabolic studies and a psychomotor test system for behavioral studies along with monitored food measurement. As in untended flights, telemetry measurements would allow monitoring of

  15. Depletion of CD8 Memory T Cells for Induction of Tolerance of a Previously Transplanted Kidney Allograft

    PubMed Central

    Koyama, I.; Nadazdin, O.; Boskovic, S.; Ochiai, T.; Smith, R. N.; Sykes, M.; Sogawa, H.; Murakami, T.; Strom, T. B.; Colvin, R. B.; Sachs, D. H.; Benichou, G.; Cosimi, A. B.; Kawai, T.

    2013-01-01

    Heterologous immunologic memory has been considered a potent barrier to tolerance induction in primates. Induction of such tolerance for a previously transplanted organ may be more difficult, because specific memory cells can be induced and activated by a transplanted organ. In the current study, we attempted to induce tolerance to a previously transplanted kidney allograft in nonhuman primates. The conditioning regimen consisted of low dose total body irradiation, thymic irradiation, antithymocyte globulin, and anti- CD154 antibody followed by a brief course of a calcineurin inhibitor. This regimen had been shown to induce mixed chimerism and allograft tolerance when kidney transplantation (KTx) and donor bone marrow transplantation (DBMT) were simultaneously performed. However, the same regimen failed to induce mixed chimerism when delayed DBMT was performed after KTx. We found that significant levels of memory T cells remained after conditioning, despite effective depletion of naïve T cells. By adding humanized anti-CD8 monoclonal antibody (cM-T807), CD8 memory T cells were effectively depleted and these recipients successfully achieved mixed chimerism and tolerance. The current studies provide ‘proof of principle’ that the mixed chimerism approach can induce renal allograft tolerance, even late after organ transplantation if memory T-cell function is adequately controlled. PMID:17286617

  16. Costimulation Blockade in Kidney Transplantation: An Update

    PubMed Central

    Malvezzi, Paolo; Jouve, Thomas; Rostaing, Lionel

    2016-01-01

    Abstract In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending. PMID:27472094

  17. Role of Intrinsic (Graft) Versus Extrinsic (Host) Factors in the Growth of Transplanted Organs Following Allogeneic and Xenogeneic Transplantation.

    PubMed

    Tanabe, T; Watanabe, H; Shah, J A; Sahara, H; Shimizu, A; Nomura, S; Asfour, A; Danton, M; Boyd, L; Dardenne Meyers, A; Ekanayake-Alper, D K; Sachs, D H; Yamada, K

    2017-01-24

    In our studies of life-supporting α-1,3-galactocyltransferase knockout (GalT-KO) pig-to-baboon kidneys, we found that some recipients developed increased serum creatinine with growth of the grafts, without histological or immunological evidence of rejection. We hypothesized that the rapid growth of orthotopic pig grafts in smaller baboon recipients may have led to deterioration of organ function. To test this hypothesis for both kidneys and lungs, we assessed whether the growth of outbred (Yorkshire) organ transplants in miniature swine was regulated by intrinsic (graft) or extrinsic (host environment) factors. Yorkshire kidneys exhibited persistent growth in miniature swine, reaching 3.7 times their initial volume over 3 mo versus 1.2 times for miniature swine kidneys over the same time period. Similar rapid early growth of lung allografts was observed and, in this case, led to organ dysfunction. For xenograft kidneys, a review of our results suggests that there is a threshold for kidney graft volume of 25 cm(3) /kg of recipient body weight at which cortical ischemia is induced in transplanted GalT-KO kidneys in baboons. These results suggest that intrinsic factors are responsible, at least in part, for growth of donor