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Sample records for adjuvant system as02a

  1. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1 administered in adjuvant system AS01B or AS02A.

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    Michele D Spring

    Full Text Available BACKGROUND: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1 representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems. METHODOLOGY/PRINCIPAL FINDINGS: After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.5 mL of AMA-1/AS01B (n = 15 or AMA-1/AS02A (n = 15, followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs with 95% Confidence Intervals (CIs were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL, full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA, against homologous but not against heterologous (FVO parasites as well as demonstrable interferon-gamma (IFN-gamma responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR. However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements. SIGNIFICANCE: All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite

  2. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-l) administered in adjuvant system AS01B or AS02A

    NARCIS (Netherlands)

    M.D. Spring (Michele Donna); J.F. Cummings (James); C.F. Ockenhouse (Christian); S. Dutta (Shantanu); R. Reidler (Randall); E. Angov (Evelina); E. Bergmann-Leitner (Elke); V.A. Stewart (Ann); S. Bittner (Stacey); L. Juompan (Laure); M.G. Kortepeter (Mark); R. Nielsen (Robin); U. Krzych (Urszula); E. Tierney (Ev); L.A. Ware (Lisa); M. Dowler (Megan); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake); O. Ofori-Anyinam (Opokua); D.E. Lanar (David); J.L. Williams (Jack); K.E. Kester (Kent); K. Tucker (Kathryn); M. Shi (Meng); E. Malkin (Elissa); C. Long (Carole); C.L. Diggs (Carter); L. Soisson (Lorraine Amory); M.C. Dubois; W.R. Ballou (Ripley); J. Cohen (Joe); D.G. Heppner (Gray)

    2009-01-01

    textabstractBackground: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuv

  3. Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

    Science.gov (United States)

    2009-04-01

    International Conference on Harmonisation (ICH) guidelines and confirmed the vaccine antigen was stable and potent from date of manufacture through...Maryland, United States of America, 8 Malaria Vaccine Development Program, United States Agency for International Development, Washington D. C., United...into a multi-stage, multi-component vaccine [22]. First, an AMA-1 vaccine must confer significant clinical benefit in either a Phase 2a malaria

  4. (Neo)adjuvant systemic therapy for melanoma.

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    van Zeijl, M C T; van den Eertwegh, A J; Haanen, J B; Wouters, M W J M

    2017-03-01

    Surgery still is the cornerstone of treatment for patients with stage II and III melanoma, but despite great efforts to gain or preserve locoregional control with excision of the primary tumour, satellites, intransits, sentinel node biopsy and lymphadenectomy, surgery alone does not seem to improve survival any further. Prognosis for patients with high risk melanoma remains poor with 5-year survival rates of 40 to 80%. Only interferon-2b has been approved as adjuvant therapy since 1995, but clinical integration is low considering the high risk-benefit ratio. In recent years systemic targeted- and immunotherapy have proven to be beneficial in advanced melanoma and could be a promising strategy for (neo)adjuvant treatment of patients with resectable high risk melanomas as well. Randomised, placebo- controlled phase III trials on adjuvant systemic targeted- and immunotherapy are currently being performed using new agents like ipilimumab, pembrolizumab, nivolumab, vemurafenib and dabrafenib plus trametinib. In this article we review the literature on currently known adjuvant therapies and currently ongoing trials of (neo)adjuvant therapies in high risk melanomas.

  5. Adjuvants and vector systems for allergy vaccines.

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    Moingeon, Philippe; Lombardi, Vincent; Saint-Lu, Nathalie; Tourdot, Sophie; Bodo, Véronique; Mascarell, Laurent

    2011-05-01

    Allergen-specific immunotherapy represents a curative treatment of type I allergies. Subcutaneous immunotherapy is conducted with allergens adsorbed on aluminum hydroxide or calcium phosphate particles, whereas sublingual immunotherapy relies on high doses of soluble allergen without any immunopotentiator. There is a potential benefit of adjuvants enhancing regulatory and Th1 CD4+T cell responses during specific immunotherapy. Molecules affecting dendritic cells favor the induction of T regulatory cell and Th1 responses and represent valid candidate adjuvants for allergy vaccines. Furthermore, the interest in viruslike particles and mucoadhesive particulate vector systems, which may better address the allergen(s) to tolerogenic antigen-presenting cells, is documented.

  6. Defined tuberculosis vaccine, Mtb72F/AS02A, evidence of protection in cynomolgus monkeys.

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    Reed, Steven G; Coler, Rhea N; Dalemans, Wilfried; Dalemans, Wilifred; Tan, Esterlina V; DeLa Cruz, Eduardo C; Basaraba, Randall J; Orme, Ian M; Skeiky, Yasir A W; Alderson, Mark R; Cowgill, Karen D; Prieels, Jean-Paul; Abalos, Rodolfo M; Dubois, Marie-Claude; Cohen, Joe; Mettens, Pascal; Lobet, Yves

    2009-02-17

    The development of a vaccine for tuberculosis requires a combination of antigens and adjuvants capable of inducing appropriate and long-lasting T cell immunity. We evaluated Mtb72F formulated in AS02A in the cynomolgus monkey model. The vaccine was immunogenic and caused no adverse reactions. When monkeys were immunized with bacillus Calmette-Guérin (BCG) and then boosted with Mtb72F in AS02A, protection superior to that afforded by using BCG alone was achieved, as measured by clinical parameters, pathology, and survival. We observed long-term survival and evidence of reversal of disease progression in monkeys immunized with the prime-boost regimen. Antigen-specific responses from protected monkeys receiving BCG and Mtb72F/AS02A had a distinctive cytokine profile characterized by an increased ratio between 3 Th1 cytokines, IFN-gamma, TNF, and IL-2 and an innate cytokine, IL-6. To our knowledge, this is an initial report of a vaccine capable of inducing long-term protection against tuberculosis in a nonhuman primate model, as determined by protection against severe disease and death, and by other clinical and histopathological parameters.

  7. From discovery to licensure, the Adjuvant System story

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    Garçon, Nathalie; Di Pasquale, Alberta

    2017-01-01

    ABSTRACT Adjuvants are substances added to vaccines to improve their immunogenicity. Used for more than 80 years, aluminum, the first adjuvant in human vaccines, proved insufficient to develop vaccines that could protect against new challenging pathogens such as HIV and malaria. New adjuvants and new combinations of adjuvants (Adjuvant Systems) have opened the door to the delivery of improved and new vaccines against re-emerging and difficult pathogens. Adjuvant Systems concept started through serendipity. The access to new developments in technology, microbiology and immunology have been instrumental for the dicephering of what they do and how they do it. This knowledge opens the door to more rational vaccine design with implications for developing new and better vaccines. PMID:27636098

  8. Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy

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    Juliana De Souza Rebouças

    2012-01-01

    Full Text Available In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines.

  9. Nanoparticulate adjuvants and delivery systems for allergen immunotherapy.

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    De Souza Rebouças, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, María Luisa; Irache, Juan Manuel; Gamazo, Carlos

    2012-01-01

    In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines.

  10. Regulatory considerations on new adjuvants and delivery systems.

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    Sesardic, D

    2006-04-12

    New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.

  11. Mucosal and systemic adjuvant activity of alphavirus replicon particles

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    Thompson, Joseph M.; Whitmore, Alan C.; Konopka, Jennifer L.; Collier, Martha L.; Richmond, Erin M. B.; Davis, Nancy L.; Staats, Herman F.; Johnston, Robert E.

    2006-03-01

    Vaccination represents the most effective control measure in the fight against infectious diseases. Local mucosal immune responses are critical for protection from, and resolution of, infection by numerous mucosal pathogens. Antigen processing across mucosal surfaces is the natural route by which mucosal immunity is generated, as peripheral antigen delivery typically fails to induce mucosal immune responses. However, we demonstrate in this article that mucosal immune responses are evident at multiple mucosal surfaces after parenteral delivery of Venezuelan equine encephalitis virus replicon particles (VRP). Moreover, coinoculation of null VRP (not expressing any transgene) with inactivated influenza virions, or ovalbumin, resulted in a significant increase in antigen-specific systemic IgG and fecal IgA antibodies, compared with antigen alone. Pretreatment of VRP with UV light largely abrogated this adjuvant effect. These results demonstrate that alphavirus replicon particles possess intrinsic systemic and mucosal adjuvant activity and suggest that VRP RNA replication is the trigger for this activity. We feel that these observations and the continued experimentation they stimulate will ultimately define the specific components of an alternative pathway for the induction of mucosal immunity, and if the activity is evident in humans, will enable new possibilities for safe and inexpensive subunit and inactivated vaccines. vaccine vector | Venezuelan equine encephalitis virus | viral immunology | RNA virus

  12. Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant.

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    Coler, Rhea N; Bertholet, Sylvie; Moutaftsi, Magdalini; Guderian, Jeff A; Windish, Hillarie Plessner; Baldwin, Susan L; Laughlin, Elsa M; Duthie, Malcolm S; Fox, Christopher B; Carter, Darrick; Friede, Martin; Vedvick, Thomas S; Reed, Steven G

    2011-01-26

    Innate immune responses to vaccine adjuvants based on lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls, are driven by Toll-like receptor (TLR) 4 and adaptor proteins including MyD88 and TRIF, leading to the production of inflammatory cytokines, type I interferons, and chemokines. We report here on the characterization of a synthetic hexaacylated lipid A derivative, denoted as glucopyranosyl lipid adjuvant (GLA). We assessed the effects of GLA on murine and human dendritic cells (DC) by combining microarray, mRNA and protein multiplex assays and flow cytometry analyses. We demonstrate that GLA has multifunctional immunomodulatory activity similar to naturally-derived monophosphory lipid A (MPL) on murine DC, including the production of inflammatory cytokines, chemokines, DC maturation and antigen-presenting functions. In contrast, hexaacylated GLA was overall more potent on a molar basis than heterogeneous MPL when tested on human DC and peripheral blood mononuclear cells (PBMC). When administered in vivo, GLA enhanced the immunogenicity of co-administered recombinant antigens, producing strong cell-mediated immunity and a qualitative T(H)1 response. We conclude that the GLA adjuvant stimulates and directs innate and adaptive immune responses by inducing DC maturation and the concomitant release of pro-inflammatory cytokines and chemokines associated with immune cell trafficking, activities which have important implications for the development of future vaccine adjuvants.

  13. Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant.

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    Rhea N Coler

    Full Text Available Innate immune responses to vaccine adjuvants based on lipopolysaccharide (LPS, a component of gram-negative bacterial cell walls, are driven by Toll-like receptor (TLR 4 and adaptor proteins including MyD88 and TRIF, leading to the production of inflammatory cytokines, type I interferons, and chemokines. We report here on the characterization of a synthetic hexaacylated lipid A derivative, denoted as glucopyranosyl lipid adjuvant (GLA. We assessed the effects of GLA on murine and human dendritic cells (DC by combining microarray, mRNA and protein multiplex assays and flow cytometry analyses. We demonstrate that GLA has multifunctional immunomodulatory activity similar to naturally-derived monophosphory lipid A (MPL on murine DC, including the production of inflammatory cytokines, chemokines, DC maturation and antigen-presenting functions. In contrast, hexaacylated GLA was overall more potent on a molar basis than heterogeneous MPL when tested on human DC and peripheral blood mononuclear cells (PBMC. When administered in vivo, GLA enhanced the immunogenicity of co-administered recombinant antigens, producing strong cell-mediated immunity and a qualitative T(H1 response. We conclude that the GLA adjuvant stimulates and directs innate and adaptive immune responses by inducing DC maturation and the concomitant release of pro-inflammatory cytokines and chemokines associated with immune cell trafficking, activities which have important implications for the development of future vaccine adjuvants.

  14. Adjuvant systemic therapy in older women with breast cancer

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    Leone, Julieta; Leone, Bernardo Amadeo; Leone, José Pablo

    2016-01-01

    Breast cancer in the elderly is an increasing clinical problem. In addition, ~60% of deaths from breast cancer occur in women aged 65 years and older. Despite this, older women with breast cancer have been underrepresented in clinical trials, and this has led to less than optimal evidence to guide their therapy. The management of elderly women with early breast cancer is a complex process that requires careful evaluation of life expectancy, comorbidities, patient values, and risks and benefits of available treatment options. This review will focus on current adjuvant systemic therapy options for older women with breast cancer, discuss the principles in the decision-making process, and define the role of endocrine therapy, chemotherapy, and targeted agents. PMID:27524919

  15. Unraveling molecular signatures of immunostimulatory adjuvants in the female genital tract through systems biology.

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    Madelene Lindqvist

    Full Text Available Sexually transmitted infections (STIs unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha-galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome data determined which signature pathways, processes and networks are shared by or otherwise exclusive to these 2 classes of experimental vaginal adjuvants in the mouse vagina. To our knowledge, this is the first integrated genome-wide transcriptome analysis of the effects of immunomodulatory adjuvants on the female genital tract of a mammal. These results could inform rational development of effective mucosal adjuvants for vaccination against STIs.

  16. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants.

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    Olafsdottir, Thorunn A; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H E; Reed, Steven G; Harandi, Ali M

    2016-12-13

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

  17. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants

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    Olafsdottir, Thorunn A.; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H. E.; Reed, Steven G.; Harandi, Ali M.

    2016-12-01

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

  18. Postoperative Adjuvant Systemic Therapy in Completely Resected Non-Small-Cell Lung Cancer: A Systematic Review.

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    Bradbury, Penelope; Sivajohanathan, Duvaraga; Chan, Adrien; Kulkarni, Swati; Ung, Yee; Ellis, Peter M

    2017-05-01

    The purpose of the present review was to determine whether the use of postoperative adjuvant systemic therapy in patients with completely resected non-small-cell lung cancer (NSCLC) improves survival. Cancer Care Ontario's Program in Evidence-Based Care reviewed the evidence to update previously published recommendations for patients with completely resected NSCLC. Relevant studies were identified from a systematic MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews search of studies published from 2010 to 2016. All phase III randomized controlled trials (RCTs) and relevant systematic reviews were included. Data on overall survival (OS), disease-free survival, adverse events, and quality of life were extracted from each of the studies. Two relevant systematic reviews, 13 RCTs, and a series of pooled analyses by Lung Adjuvant Cisplatin Evaluation-Biomarker were included in the present review. Adjuvant chemotherapy statistically significantly improved OS for resected stage II-IIIA NSCLC and is recommended. For patients with stage IB NSCLC, no significant improvement was seen in OS; however, the results from subgroup analyses indicate that it would be reasonable to consider adjuvant chemotherapy for patients with larger tumors (≥ 4 cm). The present data do not support the use of adjuvant novel therapies (ie, epidermal growth factor receptor tyrosine kinase inhibitor, bevacizumab, and immunotherapy) either as an addition to, or instead of, cytotoxic chemotherapy. No predictive biomarkers are available to select patients more likely to benefit from adjuvant chemotherapy. Cytotoxic chemotherapy remains the standard of care as adjuvant therapy for patients with resected stage II-IIIA NSCLC. Additional clinical trials are needed to evaluate targeted agents in molecularly defined subgroups before these agents can be recommended in the adjuvant setting. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Polyacrylate-based delivery system for self-adjuvanting anticancer peptide vaccine.

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    Liu, Tzu-Yu; Hussein, Waleed M; Giddam, Ashwini Kumar; Jia, Zhongfan; Reiman, Jennifer M; Zaman, Mehfuz; McMillan, Nigel A J; Good, Michael F; Monteiro, Michael J; Toth, Istvan; Skwarczynski, Mariusz

    2015-01-22

    Vaccination can provide a safe alternative to chemotherapy by using the body's natural defense mechanisms to create a potent immune response against tumor cells. Peptide-based therapeutic vaccines against human papillomavirus (HPV)-related cancers are usually designed to elicit cytotoxic T cell responses by targeting the HPV-16 E7 oncoprotein. However, peptides alone lack immunogenicity, and an additional adjuvant or external delivery system is required. In this study, we developed new polymer-peptide conjugates to create an efficient self-adjuvanting system for peptide-based therapeutic vaccines. These conjugates reduced tumor growth and eradicated E7-positive TC-1 tumors in mice after a "single shot" immunization, without the help from an external adjuvant. The new conjugates had a significantly higher anticancer efficacy than the antigen formulated with a commercial adjuvant. Furthermore, the polymer-peptide conjugates were promptly taken up by antigen presenting cells, including dendritic cells and macrophages, and efficiently activated CD4(+) T-helper cells and CD8(+) cytotoxic T lymphocyte cells.

  20. Tubular carcinoma of the breast: prognosis and response to adjuvant systemic therapy.

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    Kitchen, P R; Smith, T H; Henderson, M A; Goldhirsch, A; Castiglione-Gertsch, M; Coates, A S; Gusterson, B; Brown, R W; Gelber, R D; Collins, J P

    2001-01-01

    Tubular carcinoma of the breast is an uncommon and usually small tumour, and is thought to have a favourable prognosis. The present study examined the long-term prognosis of patients with tubular breast carcinoma and the roles of axillary dissection and adjuvant therapy. Eighty-six tubular cases were identified from a large worldwide database of 9520 breast carcinoma patients entered into randomized adjuvant therapy trials run by the International Breast Cancer Study Group from 1978 to 1999. These patients were followed for a median of 12 years. Forty-two (49%) cases were node-positive, of which 33 (79%) had 1-3 nodes involved. Ten (32%) of the 31 smaller tumours (survival (P = 0.006) and survival (P survival was similar for node-positive and node-negative tubular carcinoma. Overall, 71 patients (83%) received some form of adjuvant systemic therapy. Of the 86 cases, 43 (50%) received more than one course of chemotherapy. There was an 85% decrease in the risk of death for patients who received more than one course of chemotherapy compared to those who did not (hazard ratio 0.15, 95% confidence interval (CI): 0.03-0.82; P = 0.03). Compared to other histological types of breast cancer, tubular carcinoma has a better long-term prognosis. Adjuvant chemotherapy may further improve prognosis and involvement of axillary nodes may not be an indicator for early death due to breast carcinoma.

  1. Nanoparticulate Tubular Immunostimulating Complexes: Novel Formulation of Effective Adjuvants and Antigen Delivery Systems

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    Nina Sanina

    2017-01-01

    Full Text Available New generation vaccines, based on isolated antigens, are safer than traditional ones, comprising the whole pathogen. However, major part of purified antigens has weak immunogenicity. Therefore, elaboration of new adjuvants, more effective and safe, is an urgent problem of vaccinology. Tubular immunostimulating complexes (TI-complexes are a new type of nanoparticulate antigen delivery systems with adjuvant activity. TI-complexes consist of cholesterol and compounds isolated from marine hydrobionts: cucumarioside A2-2 (CDA from Cucumaria japonica and monogalactosyldiacylglycerol (MGDG from marine algae or seagrass. These components were selected due to immunomodulatory and other biological activities. Glycolipid MGDG from marine macrophytes comprises a high level of polyunsaturated fatty acids (PUFAs, which demonstrate immunomodulatory properties. CDA is a well-characterized individual compound capable of forming stable complex with cholesterol. Such complexes do not possess hemolytic activity. Ultralow doses of cucumariosides stimulate cell as well as humoral immunity. Therefore, TI-complexes comprising biologically active components turned out to be more effective than the strongest adjuvants: immunostimulating complexes (ISCOMs and complete Freund’s adjuvant. In the present review, we discuss results published in series of our articles on elaboration, qualitative and quantitative composition, ultrastructure, and immunostimulating activity of TI-complexes. The review allows immersion in the history of creating TI-complexes.

  2. Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area.

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    Mark E Polhemus

    Full Text Available BACKGROUND: This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine. METHODOLOGY: A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1ratio1ratio1 to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (Rabipur; Chiron Behring GmbH at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3 solicited or unsolicited general (i.e. systemic adverse events (AEs during 7 days follow up after each vaccination. PRINCIPAL FINDINGS: Both candidate vaccines had a good safety profile and were well tolerated. One grade 3 systemic AE occurred within 7 days of vaccination (RTS,S/AS01B group. No unsolicited AEs or SAEs were related to vaccine. A marked increase in anti-CS antibody GMTs was observed post Dose 2 of both RTS,S/AS01B (31.6 EU/mL [95% CI: 23.9 to 41.6] and RTS,S/AS02A (16.7 EU/mL [95% CI: 12.9 to 21.7]. A further increase was observed post Dose 3 in both the RTS,S/AS01B (41.4 EU/mL [95% CI: 31.7 to 54.2] and RTS,S/AS02A (21.4 EU/mL [95% CI: 16.0 to 28.7] groups. Anti-CS antibody GMTs were significantly greater with RTS,S/AS01B compared to RTS,S/AS02A at all time points post Dose 2 and Dose 3. Both candidate vaccines produced strong anti-HBs responses. Vaccine efficacy in the RTS,S/AS01B group was 29.5% (95% CI: -15.4 to 56.9, p = 0.164 and in the RTS,S/AS02A group 31.7% (95% CI: -11.6 to 58.2, p = 0.128. CONCLUSIONS: Both candidate malaria vaccines were well tolerated over a 12 month surveillance period. A more favorable immunogenicity profile was observed with RTS,S/AS01B than with RTS,S/AS02A. TRIAL REGISTRATION

  3. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity.

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    Shaw, C A; Tomljenovic, L

    2013-07-01

    We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.

  4. Healthcare System Distrust, Physician Trust, and Patient Discordance with Adjuvant Breast Cancer Treatment Recommendations.

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    Dean, Lorraine T; Moss, Shadiya L; McCarthy, Anne Marie; Armstrong, Katrina

    2017-09-29

    Adjuvant therapy after breast cancer surgery decreases recurrence and increases survival, yet not all women receive and complete it. Previous research has suggested that distrust in medical institutions plays a role in who initiates adjuvant treatment, but has not assessed treatment completion treatment, nor the potential mediating role of physician distrust. Women listed in Pennsylvania and Florida cancer registries, who were under the age of 65 when diagnosed with localized invasive breast cancer between 2005 and 2007, were surveyed by mail in 2007-2009. Survey participants self-reported: demographics; cancer stage and treatments; treatment discordance, as defined by not following their surgeon or oncologist treatment recommendation; healthcare system distrust, and physician trust. Age and cancer stage were verified against cancer registry records. Logistic regression assessed the relationship between highest and lowest tertiles of healthcare system distrust and the dichotomous outcome of treatment discordance, controlling for demographics and clinical treatment factors, and testing for mediation by physician trust. Of the 2,754 participants, 30.2% (n=832) reported not pursing at least one recommended treatment. The mean age was 52. Patients in the highest tertile of healthcare system distrust were 22% more likely to report treatment discordance than the lowest tertile; physician trust did not mediate the association between healthcare system distrust and treatment discordance. Healthcare system distrust is positively associated with treatment discordance, defined as failure to initiate or complete physician recommended adjuvant treatment after breast cancer. Interventions should test whether or not resolving institutional distrust reduces treatment discordance. Copyright ©2017, American Association for Cancer Research.

  5. Adjuvant Systemic Therapy in Older Breast Cancer Women: Can We Optimize the Level of Care?

    Directory of Open Access Journals (Sweden)

    Anna Rachelle Mislang

    2015-07-01

    Full Text Available Defining optimal adjuvant treatment for older women with breast cancer is challenged by the lack of level-1 clinical evidence and the heterogeneity of the older population. Nevertheless, recommendations based on reviews of available evidence mainly from retrospective subgroup analyses and extrapolation of study results from younger patients, and expert opinions, may be useful to guide treatment decisions in fit patients. But how can we properly define a “fit” older patient? In clinical practice, age by itself and clinical impression generally drive treatment decision, although the appropriateness of this judgment is under-documented. Such an approach risks overtreatment or, more frequently, undertreatment. A geriatric assessment can be valuable in oncology practice to address this issue. In this review article, we will focus only on systemic treatment and will discuss “standard” adjuvant systemic treatment strategies for fit older breast cancer patients and the role of “personalized” systemic therapy in unfit patients. The concepts conveyed in this review cannot be extrapolated to locoregional therapy.

  6. Systems Pharmacology-based strategy to screen new adjuvant for hepatitis B vaccine from Traditional Chinese Medicine Ophiocordyceps sinensis

    Science.gov (United States)

    Wang, Jingbo; Liu, Rui; Liu, Baoxiu; Yang, Yan; Xie, Jun; Zhu, Naishuo

    2017-01-01

    Adjuvants are common component for many vaccines but there are still few licensed for human use due to low efficiency or side effects. The present work adopted Systems Pharmacology analysis as a new strategy to screen adjuvants from traditional Chinese medicine. Ophiocordyceps sinensis has been used for many years in China and other Asian countries with many biological properties, but the pharmacological mechanism has not been fully elucidated. First in this study, 190 putative targets for 17 active compounds in Ophiocordyceps sinensis were retrieved and a systems pharmacology-based approach was applied to provide new insights into the pharmacological actions of the drug. Pathway enrichment analysis found that the targets participated in several immunological processes. Based on this, we selected cordycepin as a target compound to serve as an adjuvant of the hepatitis B vaccine because the existing vaccine often fails to induce an effective immune response in many subjects. Animal and cellular experiments finally validated that the new vaccine simultaneously improves the humoral and cellular immunity of BALB/c mice without side effects. All this results demonstrate that cordycepin could work as adjuvant to hepatitis b vaccine and systems-pharmacology analysis could be used as a new method to select adjuvants. PMID:28317886

  7. Adjuvants and delivery systems in veterinary vaccinology: current state and future developments

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Dedieu, Laurence; Johnson, Nicholas;

    2011-01-01

    low immunogenicity themselves. The development of such adjuvants may take advantage of the increased knowledge of the molecular mechanisms and factors controlling these responses. However, knowledge of such molecular details of immune mechanisms is relatively scarce for species other than humans......Modern adjuvants should induce strong and balanced immune responses, and it is often desirable to induce specific types of immunity. As an example, efficient Th1-immunity-inducing adjuvants are highly in demand. Such adjuvants promote good cell-mediated immunity against subunit vaccines that have...

  8. Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases

    NARCIS (Netherlands)

    Boer, M. de; Adang, E.M.M.; Dycke, K.C.G. van; Dijck, J.A.A.M. van; Borm, G.F.; Seferina, S.C.; Deurzen, C.H. van; Diest, P.J. van; Bult, P.; Donders, A.R.T.; Tjan-Heijnen, V.C.

    2012-01-01

    BACKGROUND: The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown. PATIENTS AND METHODS: A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event

  9. Stimulation of immune systems by conjugated polymers and their potential as an alternative vaccine adjuvant

    Science.gov (United States)

    Gong, Hua; Xiang, Jian; Xu, Ligeng; Song, Xuejiao; Dong, Ziliang; Peng, Rui; Liu, Zhuang

    2015-11-01

    Recently, conjugated polymers have been widely explored in the field of nanomedicine. Careful evaluations of their biological effects are thus urgently needed. Hereby, we systematically evaluated the biological effects of different types of conjugated polymers on macrophages and dendritic cells (DCs), which play critical roles in the innate and adaptive immune systems, respectively. While naked poly-(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) exhibits a high level of cytotoxicity, polyethylene glycol (PEG) modified PEDOT:PSS (PEDOT:PSS-PEG) shows greatly reduced toxicity to various types of cells. To our surprise, PEGylation of PEDOT:PSS could obviously enhance the cellular uptake of these nanoparticles, leading to subsequent immune stimulations of both macrophages and DCs. In contrast, another type of conjugated polymer, polypyrrole (PPy), is found to be an inert material with neither significant cytotoxicity nor noticeable immune-stimulation activity. Interestingly, utilizing ovalbumin (OVA) as a model antigen, it is further uncovered in our ex vivo experiment that PEDOT:PSS-PEG may serve as an adjuvant to greatly enhance the immunogenicity of OVA upon simple mixing. Our study on the one hand suggests the promise of developing novel nano-adjuvants based on conjugated polymers, and on the other hand highlights the importance of careful evaluations of the impacts of any new nanomaterials developed for nanomedicine on the immune systems.Recently, conjugated polymers have been widely explored in the field of nanomedicine. Careful evaluations of their biological effects are thus urgently needed. Hereby, we systematically evaluated the biological effects of different types of conjugated polymers on macrophages and dendritic cells (DCs), which play critical roles in the innate and adaptive immune systems, respectively. While naked poly-(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) exhibits a high level of cytotoxicity

  10. Elucidating the mechanisms of protein antigen adsorption to the CAF/NAF liposomal vaccine adjuvant systems

    DEFF Research Database (Denmark)

    Hamborg, Mette; Rose, Fabrice; Jorgensen, Lene

    2014-01-01

    adjuvant CAF01 composed of cationic dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB) or ii) the neutral adjuvant formulation NAF01, where DDA was replaced with zwitterionic distearoylphosphatidylcholine (DSPC). The effect of liposome charge, bilayer rigidity, isoelectric point...... interaction with the zwitterionic liposomes. In contrast, the net cationic lysozyme showed very little interaction with either types of liposome. Adsorption of α-lactalbumin altered its tertiary structure, affected lipid membrane packing below and above the phase transition temperature, and neutralized...

  11. PIKA Provides an Adjuvant Effect to Induce Strong Mucosal and Systemic Humoral Immunity Against SARS-CoV

    Institute of Scientific and Technical Information of China (English)

    Wei-wei Gai; Yan Zhang; Di-han Zhou; Yao-qing Chen; Jing-yi Yang; Hui-min Yan

    2011-01-01

    Severe Acute Respiratory Syndrome(SARS)is a deadly infectious disease caused by SARS Coronavirus(SARS-CoV).Inactivated SARS-CoV has been explored as a vaccine against SARS-CoV.However,safe and potent adjuvants,especially with more efficient and economical needle-free vaccination are always needed more urgently in a pandemic.The development of a safe and effective mucosal adjuvant and vaccine for prevention of emergent infectious diseases such as SARS will be an important advancement.PIKA,a stabilized derivative of Poly(I:C),was previously reported to be safe and potent as adjuvant in mouse models.In the present study,we demonstrated that the intraperitoneal and intranasal co-administration of inactivated SARS-CoV vaccine together with this improved Poly(I:C)derivative induced strong anti-SARS-CoV mucosal and systemic humoral immune responses with neutralizing activity against pseudotyped virus.Although intraperitoneal immunization of inactivated SARS-CoV vaccine alone could induce a certain level of neutralizing activity in serum as well as in mucosal sites,co-administration of inactivated SARS-CoV vaccine with PIKA as adjuvant could induce a much higher neutralizing activity.When intranasal immunization was used,PIKA was obligatorily for inducing neutralizing activity in serum as well as in mucosal sites and was correlated with both mucosal IgA and mucosal IgG response.Overall,PIKA could be a good mucosal adjuvant candidate for inactivated SARS-CoV vaccine for use in possible future pandemic.

  12. Systemic Administration of CpG Oligodeoxynucleotide and Levamisole as Adjuvants for Gene-Gun-Delivered Antitumor DNA Vaccines

    Science.gov (United States)

    Šmahel, Michal; Poláková, Ingrid; Sobotková, Eva; Vajdová, Eva

    2011-01-01

    DNA vaccines showed great promise in preclinical models of infectious and malignant diseases, but their potency was insufficient in clinical trials and is needed to be improved. In this study, we tested systemic administration of two conventional adjuvants, synthetic oligodeoxynucleotide carrying immunostimulatory CpG motifs (CpG-ODN) and levamisole (LMS), and evaluated their effect on immune reactions induced by DNA vaccines delivered by a gene gun. DNA vaccination was directed either against the E7 oncoprotein of human papillomavirus type 16 or against the BCR-ABL1 oncoprotein characteristic for chronic myeloid leukemia. High doses of both adjuvants reduced activation of mouse splenic CD8+ T lymphocytes, but the overall antitumor effect was enhanced in both tumor models. High-dose CpG-ODN exhibited a superior adjuvant effect in comparison with any combination of CpG-ODN with LMS. In summary, our results demonstrate the benefit of combined therapy with gene-gun-delivered antitumor DNA vaccines and systemic administration of CpG-ODN or LMS. PMID:22028727

  13. Systemic Administration of CpG Oligodeoxynucleotide and Levamisole as Adjuvants for Gene-Gun-Delivered Antitumor DNA Vaccines

    Directory of Open Access Journals (Sweden)

    Michal Šmahel

    2011-01-01

    Full Text Available DNA vaccines showed great promise in preclinical models of infectious and malignant diseases, but their potency was insufficient in clinical trials and is needed to be improved. In this study, we tested systemic administration of two conventional adjuvants, synthetic oligodeoxynucleotide carrying immunostimulatory CpG motifs (CpG-ODN and levamisole (LMS, and evaluated their effect on immune reactions induced by DNA vaccines delivered by a gene gun. DNA vaccination was directed either against the E7 oncoprotein of human papillomavirus type 16 or against the BCR-ABL1 oncoprotein characteristic for chronic myeloid leukemia. High doses of both adjuvants reduced activation of mouse splenic CD8+ T lymphocytes, but the overall antitumor effect was enhanced in both tumor models. High-dose CpG-ODN exhibited a superior adjuvant effect in comparison with any combination of CpG-ODN with LMS. In summary, our results demonstrate the benefit of combined therapy with gene-gun-delivered antitumor DNA vaccines and systemic administration of CpG-ODN or LMS.

  14. Fluorescence imaging for investigating the efficiency of formulations, adjuvants and application systems

    NARCIS (Netherlands)

    Ruiter, de H.; Schoor, van der R.; Jalink, H.

    2005-01-01

    Several herbicides reduce, directly or indirectly, the efficiency of photosynthesis of plants. As a consequence, the fluorescence of the chlorophyll increases. The relative increase of fluorescence [(Fm-F0)/Fm] can be used to compare the influence of formulations and adjuvants on the activity of her

  15. Adjuvants and delivery systems in veterinary vaccinology: current state and future developments

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Dedieu, Laurence; Johnson, Nicholas

    2011-01-01

    and laboratory rodents, and in addition, there are special considerations pertaining to the use of adjuvants in veterinary animals, such as production and companion animals. With a focus on veterinary animals, this review highlights a number of approaches being pursued, including cytokines, CpG oligonucleotides...

  16. Vaccines, adjuvants and autoimmunity.

    Science.gov (United States)

    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Carbohydrate-based immune adjuvants

    Science.gov (United States)

    Petrovsky, Nikolai; Cooper, Peter D

    2011-01-01

    The role for adjuvants in human vaccines has been a matter of vigorous scientific debate, with the field hindered by the fact that for over 80 years, aluminum salts were the only adjuvants approved for human use. To this day, alum-based adjuvants, alone or combined with additional immune activators, remain the only adjuvants approved for use in the USA. This situation has not been helped by the fact that the mechanism of action of most adjuvants has been poorly understood. A relative lack of resources and funding for adjuvant development has only helped to maintain alum’s relative monopoly. To seriously challenge alum’s supremacy a new adjuvant has many major hurdles to overcome, not least being alum’s simplicity, tolerability, safety record and minimal cost. Carbohydrate structures play critical roles in immune system function and carbohydrates also have the virtue of a strong safety and tolerability record. A number of carbohydrate compounds from plant, bacterial, yeast and synthetic sources have emerged as promising vaccine adjuvant candidates. Carbohydrates are readily biodegradable and therefore unlikely to cause problems of long-term tissue deposits seen with alum adjuvants. Above all, the Holy Grail of human adjuvant development is to identify a compound that combines potent vaccine enhancement with maximum tolerability and safety. This has proved to be a tough challenge for many adjuvant contenders. Nevertheless, carbohydrate-based compounds have many favorable properties that could place them in a unique position to challenge alum’s monopoly over human vaccine usage. PMID:21506649

  18. Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine.

    Science.gov (United States)

    Sun, HongWu; Wei, Chao; Liu, BaoShuai; Jing, HaiMing; Feng, Qiang; Tong, YaNan; Yang, Yun; Yang, LiuYang; Zuo, QianFei; Zhang, Yi; Zou, QuanMing; Zeng, Hao

    2015-01-01

    The Gram-positive bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA) can cause infections in the bloodstream, endocardial tissue, respiratory tract, culture-confirmed skin, or soft tissue. There are currently no effective vaccines, and none are expected to become available in the near future. An effective vaccine capable of eliciting both systemic and mucosal immune responses is also urgently needed. Here, we reported a novel oil-in-water nanoemulsion adjuvant vaccine containing an MRSA recombination protein antigen, Cremophor EL-35(®) as a surfactant, and propylene glycol as a co-surfactant. This nanoemulsion vaccine, whose average diameter was 31.34±0.49 nm, demonstrated good protein structure integrity, protein specificity, and good stability at room temperature for 1 year. The intramuscular systemic and nasal mucosal immune responses demonstrated that this nanoemulsion vaccine could improve the specific immune responses of immunoglobulin (Ig)G and related subclasses, such as IgG1, IgG2a, and IgG2b, as well as IgA, in the serum after Balb/c mice intramuscular immunization and C57 mice nasal immunization. Furthermore, this nanoemulsion vaccine also markedly enhanced the interferon-γ and interleukin-17A cytokine cell immune response, improved the survival ratio, and reduced bacterial colonization. Taken together, our results show that this novel nanoemulsion vaccine has great potential and is a robust generator of an effective intramuscular systemic and nasal mucosal immune response without the need for an additional adjuvant. Thus, the present study serves as a sound scientific foundation for future strategies in the development of this novel nanoemulsion adjuvant vaccine to enhance both the intramuscular systemic and nasal mucosal immune responses.

  19. Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

    Directory of Open Access Journals (Sweden)

    Sun HW

    2015-12-01

    Full Text Available HongWu Sun,1,* Chao Wei,1,* BaoShuai Liu,1 HaiMing Jing,1 Qiang Feng,2 YaNan Tong,1 Yun Yang,1 LiuYang Yang,1 QianFei Zuo,1 Yi Zhang,1 QuanMing Zou,1 Hao Zeng1 1National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University of Chinese PLA, 2Department of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, People’s Republic of China *These authors contributed equally to this work Abstract: The Gram-positive bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA can cause infections in the bloodstream, endocardial tissue, respiratory tract, culture-confirmed skin, or soft tissue. There are currently no effective vaccines, and none are expected to become available in the near future. An effective vaccine capable of eliciting both systemic and mucosal immune responses is also urgently needed. Here, we reported a novel oil-in-water nanoemulsion adjuvant vaccine containing an MRSA recombination protein antigen, Cremophor EL-35® as a surfactant, and propylene glycol as a co-surfactant. This nanoemulsion vaccine, whose average diameter was 31.34±0.49 nm, demonstrated good protein structure integrity, protein specificity, and good stability at room temperature for 1 year. The intramuscular systemic and nasal mucosal immune responses demonstrated that this nanoemulsion vaccine could improve the specific immune responses of immunoglobulin (IgG and related subclasses, such as IgG1, IgG2a, and IgG2b, as well as IgA, in the serum after Balb/c mice intramuscular immunization and C57 mice nasal immunization. Furthermore, this nanoemulsion vaccine also markedly enhanced the interferon-γ and interleukin-17A cytokine cell immune response, improved the survival ratio, and reduced bacterial colonization. Taken together, our results show that this novel nanoemulsion vaccine has great potential and is a

  20. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy.

    Science.gov (United States)

    Klos, Kevin J; Bower, James H; Josephs, Keith A; Matsumoto, Joseph Y; Ahlskog, J Eric

    2005-09-01

    Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

  1. Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial

    Science.gov (United States)

    Samir, Parimal; Galassie, Allison; Allos, Tara M.; Niu, Xinnan; Gordy, Laura E.; Creech, C. Buddy; Prasad, Nripesh; Jensen, Travis L.; Hill, Heather; Levy, Shawn E.; Joyce, Sebastian; Link, Andrew J.; Edwards, Kathryn M.

    2017-01-01

    Background Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. Objective and Methods We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18–49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Results Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Conclusions Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. Trial Registration ClinicalTrials.gov NCT

  2. Adjuvant effect of polysaccharide from fruits of Physalis alkekengi L. in DNA vaccine against systemic candidiasis.

    Science.gov (United States)

    Yang, Huimin; Han, Shuying; Zhao, Danyang; Wang, Guiyun

    2014-08-30

    Adjuvant effect mediated by polysaccharide (PPSB) isolated from the fruits of Physalis alkekengi L. in DNA vaccine was evaluated in mice. Recombinant plasmid containing epitope C (LKVIRK) from heat shock protein 90 (HSP90) of Candida albicans (C. albican) was used as DNA vaccine (pD-HSP90C). The results indicated that PPSB significantly enhanced specific antibody titers IgG, IgG1, IgG2b, and concentration of IL-2 and IL-4 in sera of mice immunized with pD-HSP90C (p<0.05). More importantly, it was found that the mice immunized with pD-HSP90C/PPSB not only had fewer CFU (colony forming unites) in the kidneys than mice immunized with pD-HSP90C, but also a statistically significant higher survival rate over PBS-injected group (p<0.05) when the immunized mice were challenged with living C. albican cells. However, no statistically significant difference in survival rate was observed between pD-HSP90C-immunized group and PBS-injected group. Therefore, PPSB can be considered as a promising adjuvant eliciting both Th1 and Th2 responses to enhance the efficacy of DNA vaccines.

  3. Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen Plasmodium falciparum FVO merozoite surface protein-1 (MSP142 administered intramuscularly with adjuvant system AS01

    Directory of Open Access Journals (Sweden)

    Otsyula Nekoye

    2013-01-01

    Full Text Available Abstract Background The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1 antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. Methods Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 μg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 μg dose with a rabies vaccine comparator. Results In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele previously tested at both study sites. Conclusions Given that the primary

  4. Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

    DEFF Research Database (Denmark)

    Johansen, Jørgen; Overgaard, Jens; Overgaard, Marie

    2007-01-01

    To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed......-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg per m(2)) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia....... In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p = 0.32). However...

  5. Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

    DEFF Research Database (Denmark)

    Johansen, Jørgen; Overgaard, Jens; Overgaard, Marie

    2007-01-01

    To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed......-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg per m(2)) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia....... In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p = 0.32). However...

  6. Timing of radiotherapy in breast-conserving therapy: a large prospective cohort study of node-negative breast cancer patients without adjuvant systemic therapy

    NARCIS (Netherlands)

    Jobsen, J.J.; Palen, van der J.; Baum, M.; Brinkhuis, M.; Struikmans, H.

    2013-01-01

    Background: To investigate the issue of timing of radiation therapy (RT) after lumpectomy in relation to recurrences and outcome. Methods: Analysis was done on 1107 breast-conserving therapies (BCT) with 1070 women, all without lymph node metastasis and without any adjuvant systemic therapy. Timing

  7. Evaluation of mucosal and systemic immune responses elicited by GPI-0100- adjuvanted influenza vaccine delivered by different immunization strategies.

    Directory of Open Access Journals (Sweden)

    Heng Liu

    Full Text Available Vaccines for protection against respiratory infections should optimally induce a mucosal immune response in the respiratory tract in addition to a systemic immune response. However, current parenteral immunization modalities generally fail to induce mucosal immunity, while mucosal vaccine delivery often results in poor systemic immunity. In order to find an immunization strategy which satisfies the need for induction of both mucosal and systemic immunity, we compared local and systemic immune responses elicited by two mucosal immunizations, given either by the intranasal (IN or the intrapulmonary (IPL route, with responses elicited by a mucosal prime followed by a systemic boost immunization. The study was conducted in BALB/c mice and the vaccine formulation was an influenza subunit vaccine supplemented with GPI-0100, a saponin-derived adjuvant. While optimal mucosal antibody titers were obtained after two intrapulmonary vaccinations, optimal systemic antibody responses were achieved by intranasal prime followed by intramuscular boost. The latter strategy also resulted in the best T cell response, yet, it was ineffective in inducing nose or lung IgA. Successful induction of secretory IgA, IgG and T cell responses was only achieved with prime-boost strategies involving intrapulmonary immunization and was optimal when both immunizations were given via the intrapulmonary route. Our results underline that immunization via the lungs is particularly effective for priming as well as boosting of local and systemic immune responses.

  8. Review: Adjuvant effects of saponins on animal immune responses

    Institute of Scientific and Technical Information of China (English)

    RAJPUT Zahid Iqbal; HU Song-hua; XIAO Chen-wen; ARIJO Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines,ISCOMs (immunostimulating complexes), Freund's complete adjuvant, Freund's incomplete adjuvant, alums, bacterial toxins etc.,are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed.

  9. [Biopersistence and systemic distribution of intramuscularly injected particles: what impact on long-term tolerability of alum adjuvants?].

    Science.gov (United States)

    Gherardi, Romain K; Cadusseau, Josette; Authier, François-jérôme

    2014-01-01

    Aluminium oxyhydroxide (alum), a nanocrystalline compound that forms agglomerates, has been widely used as a vaccine adjuvant since 1927, but the mechanisms by which it stimulates immune responses remain poorly understood. Although generally well tolerated, alum may occasionally cause chronic health problems in presumably susceptible individuals. Some individuals may rarely develop delayed-onset diffuse myalgia, chronic exhaustion and cognitive dysfunction, associated with long-term persistence (up to 12 years) of alum-loaded macrophages at site of i.m. immunization, defining so-called macrophagic myofasciitis (MMF). Symptoms are consistent with the chronic fatigue/myalgic encephalomyelitis (CFS/ME) syndrome, and have been used as a paradigm of the "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA). Cognitive dysfunction is reminiscent of that described in workers exposed to inhaled Al particles. Individual susceptibility may influence both alum biopersistence and difusion away from injection sites. Biopersistent particles such as fluorescent alum-coated nanohybrids, when injected into mouse muscle, are captured by monocyte-lineage cells and then carried to distant organs, draining lymph nodes and blood, probably via the thoracic duct, with delayed and accumulative translocation to the brain (microglial cells). Brain penetration occurs at extremely low levels in normal conditions, possibly explaining the good tolerance of alum despite its high neurotoxic potential. However, systemic diffusion is considerably enhanced by the potentiating effect of MCP-1, the main monocyte chemoattractant factor, the production of which is subject to marked variations linked to age and to genetic and environmental factors. Selective MCP-1 elevation is the only known circulating biomarker of MMF.

  10. Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 agonist, promotes potent systemic and mucosal responses to intranasal immunization with HIVgp140.

    Science.gov (United States)

    Arias, Mauricio A; Van Roey, Griet A; Tregoning, John S; Moutaftsi, Magdalini; Coler, Rhea N; Windish, Hillarie P; Reed, Steven G; Carter, Darrick; Shattock, Robin J

    2012-01-01

    Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellular immune responses in both the systemic and mucosal compartments. Based on the known immunological linkage between the upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for the induction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 together with micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA) and responses were compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatly enhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG and IgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with high numbers of gp140-specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cell responses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Our results show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses, both systemically and mucosally.

  11. Glucopyranosyl Lipid Adjuvant (GLA, a Synthetic TLR4 agonist, promotes potent systemic and mucosal responses to intranasal immunization with HIVgp140.

    Directory of Open Access Journals (Sweden)

    Mauricio A Arias

    Full Text Available Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellular immune responses in both the systemic and mucosal compartments. Based on the known immunological linkage between the upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for the induction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 together with micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA and responses were compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatly enhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG and IgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with high numbers of gp140-specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cell responses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Our results show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses, both systemically and mucosally.

  12. Adjuvants for allergy vaccines.

    Science.gov (United States)

    Moingeon, Philippe

    2012-10-01

    Allergen-specific immunotherapy is currently performed via either the subcutaneous or sublingual routes as a treatment for type I (IgE dependent) allergies. Aluminum hydroxide or calcium phosphate are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts in the absence of any immunopotentiator. Adjuvants to be included in the future in products for allergen specific immunotherapy should ideally enhance Th1 and CD4+ regulatory T cell responses. Imunomodulators impacting dendritic or T cell functions to induce IL10, IL12 and IFNγ production are being investigated in preclinical allergy models. Such candidate adjuvants encompass synthetic or biological immunopotentiators such as glucocorticoids, 1,25-dihydroxy vitamin D3, selected probiotic strains (e.g., Lactobacillus and Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4 (monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 (CpGs) ligands. Furthermore, the use of vector systems such as mucoadhesive particules, virus-like particles or liposomes are being considered to enhance allergen uptake by tolerogenic antigen presenting cells present in mucosal tissues.

  13. Adjuvants for Animal Vaccines.

    Science.gov (United States)

    Burakova, Yulia; Madera, Rachel; McVey, Scott; Schlup, John R; Shi, Jishu

    2017-06-15

    Vaccines are essential tools for the prevention and control of infectious diseases in animals. One of the most important steps in vaccine development is the selection of a suitable adjuvant. The focus of this review is the adjuvants used in vaccines for animals. We will discuss current commercial adjuvants and experimental formulations with attention to mineral salts, emulsions, bacterial-derived components, saponins, and several other immunoactive compounds. In addition, we will also examine the mechanisms of action for different adjuvants, examples of adjuvant combinations in one vaccine formulation, and challenges in the research and development of veterinary vaccine adjuvants.

  14. Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

    Energy Technology Data Exchange (ETDEWEB)

    Johansen, Joergen [Dept. of Oncology, Odense Univ. Hospital, Odense (Denmark); Overgaard, Jens [Dept. of Experimental Clinical Oncology, Danish Cancer Society, Aarhus (Denmark); Overgaard, Marie [Dept. of Oncology, Aarhus Univ. Hospital, Aarhus (Denmark)

    2007-05-15

    To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed. The patients were treated with lumpectomy and axillary dissection followed by external beam radiotherapy to the residual breast. High-risk patients (n 94), as well as 31 low-risk patients, received additional radiation to the regional lymph nodes. Adjuvant systemic treatment was given to all high-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg/m{sup 2}) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia, and dyspigmentation which were scored on a 4-point categorical scale after median 6.6 years. The observations were analyzed in multivariate logistic regression analysis which included potential risk factors on outcome related to systemic treatment, surgery, radiation technique, tumor, and patient characteristics. In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p 0.32). However, univariate analysis showed that tamoxifen was significantly associated with breast fibrosis (p <0.004), as was radiation to the regional lymph nodes (p <0.0001). A strong interaction between axillary irradiation and tamoxifen treatment occurred since 26 of 27 high-risk postmenopausal patients had received both tamoxifen and axillary irradiation. In multivariate regression analysis, axillary irradiation independently predicted moderate/severe breast fibrosis with a relative risk of

  15. Improving the extraction and purification of immunoglobulin G by the use of ionic liquids as adjuvants in aqueous biphasic systems.

    Science.gov (United States)

    Ferreira, Ana M; Faustino, Vânia F M; Mondal, Dibyendu; Coutinho, João A P; Freire, Mara G

    2016-10-20

    Immunoglobulins G (IgG) could become widespread biopharmaceuticals if cost-efficient processes for their extraction and purification are available. In this work, aqueous biphasic systems (ABS) composed of polyethylene glycols and a buffered salt, and with ionic liquids (ILs) as adjuvants, have been studied as alternative extraction and purification platforms of IgG from a rabbit serum source. Eleven ILs were investigated to provide insights on the chemical features which maximize the IgG partitioning. It is shown that in polymer-salt systems pure IgG preferentially partitions to the polymer-rich phase; yet, the complete extraction was never attained. Remarkably, after the addition of 5wt% of adequate ILs to polymer-salt ABS, the complete extraction of pure IgG in a single-step was accomplished. The best systems and conditions were then applied to the extraction and purification of IgG directly from rabbit serum samples. The complete extraction of IgG in a single-step was maintained while its purity in the polymer-rich phase was enhanced by ca. 37% as compared to the IL-free ABS. The antibody stability was also evaluated revealing that appropriate ILs are able to maintain the IgG stability and can be used as phase-forming components of ABS when envisaging the purification of high-cost biopharmaceuticals.

  16. Adjuvants for malaria vaccines.

    Science.gov (United States)

    Coler, R N; Carter, D; Friede, M; Reed, S G

    2009-09-01

    There is a renewed enthusiasm about subunit vaccines for malaria coincident with the formation of new alliances and partnerships raising international public awareness, attracting increased resources and the re-focusing of research programs on adjuvant development for infectious disease vaccines. It is generally accepted that subunit vaccines for malaria will require adjuvants to induce protective immune responses, and availability of suitable adjuvants has in the past been a barrier to the development of malaria vaccines. Several novel adjuvants are now in licensed products or in late stage clinical development, while several others are in the earlier development pipeline. Successful vaccine development requires knowing which adjuvants to use and knowing how to formulate adjuvants and antigens to achieve stable, safe, and immunogenic vaccines. For the majority of vaccine researchers this information is not readily available, nor is access to well-characterized adjuvants. In this minireview, we outline the current state of adjuvant research and development as it pertains to effective malaria vaccines.

  17. Trends in vaccine adjuvants

    NARCIS (Netherlands)

    Schijns, V.E.J.C.; Lavelle, E.C.

    2011-01-01

    Adjuvants are essential components of most clinically used vaccines. This is because the majority of nonliving vaccines are relatively poor inducers of adaptive immunity unless effective adjuvants are co-administered. Aluminum salts (alum) have been used as adjuvants with great success for almost a

  18. Enhanced mucosal immune responses against tetanus toxoid using novel delivery system comprised of chitosan-functionalized gold nanoparticles and botanical adjuvant: characterization, immunogenicity, and stability assessment.

    Science.gov (United States)

    Barhate, Ganesh; Gautam, Manish; Gairola, Sunil; Jadhav, Suresh; Pokharkar, Varsha

    2014-11-01

    Approaches based on combined use of delivery systems and adjuvants are being favored to maximize efficient mucosal delivery of antigens. Here, we describe a novel delivery system comprised of chitosan-functionalized gold nanoparticles (CsAuNPs) and saponin-containing botanical adjuvant; Asparagus racemosus extract (ARE) for oral delivery of tetanus toxoid (TT). A significant increase in TT-specific IgG (34.53-fold) and IgA (43.75-fold) was observed when TT-CsAuNPs were formulated with ARE (TT-ARE-CsAuNPs). The local IgA immune responses for TT also showed a significant increase (106.5-fold in intestine washes and 99.74-fold in feces) with ARE-based formulations as compared with plain TT group. No effect of ARE was observed on size, charge, and loading properties of CsAuNPs. Additionally, no effect of ARE and CsAuNPs was observed on antigenicity and secondary structure of TT as determined by fluorescence, circular dichroism, and Fourier transform infrared spectroscopy. The stability studies demonstrated excellent stability profile of formulation at recommended storage conditions. The study establishes the possible role of immunomodulatory adjuvants in particulate delivery systems for mucosal delivery of vaccines.

  19. Potent Antigen-Adjuvant Delivery System by Conjugation of Mycobacterium tuberculosis Ag85B-HspX Fusion Protein with Arabinogalactan-Poly(I:C) Conjugate.

    Science.gov (United States)

    Huang, Qingrui; Yu, Weili; Hu, Tao

    2016-04-20

    Protein-based vaccine is promising to improve or replace Mycobacterium bovis BCG vaccine for its specificity, safety, and easy production. However, protein-based vaccine calls for potent adjuvants and improved delivery systems to protect against Mycobacterium tuberculosis. Poly(I:C) is one of the most potent pathogen-associated molecular patterns that signals primarily via TLR3. Arabinogalactan (AG) is a biocompatible polysaccharide that can increase splenocyte proliferation and stimulate macrophages. The AG-poly(I:C) conjugate (AG-P) showed an adjuvant potency through a synergistic interaction of AG and poly(I:C). Ag85B and HspX are two important virulent protein antigens of Mycobacterium tuberculosis and Ag85B-HspX fusion protein (AH) was prepared. An antigen-adjuvant delivery system (AH-AG-P) was developed by conjugation of AH with AG-P to ensure that both AH and AG-P reach the APCs simultaneously. AH-AG-P elicited high AH-specific IgG titers and stimulated lymphocyte proliferation. AH-AG-P provoked the secretion of Th1-type cytokines (TNF-α, IFN-γ, and IL-2) and Th2-type cytokines (IL-4 and IL-10). Pharmacokinetics revealed that conjugation with AG-P could prolong the serum exposure of AH to the immune system. Pharmacodynamics suggested that conjugation with AG-P led to a rapid and intense production of AH-specific IgG. Accordingly, conjugation with AG-P could promote a robust cellular and humoral immune response to AH. Thus, conjugation of AH with a potent adjuvant AG-P is an effective strategy to develop an efficacious protein-based vaccine against Mycobacterium tuberculosis.

  20. Trajectories of self-reported cognitive function in postmenopausal women during adjuvant systemic therapy for breast cancer.

    Science.gov (United States)

    Merriman, John D; Sereika, Susan M; Brufsky, Adam M; McAuliffe, Priscilla F; McGuire, Kandace P; Myers, Jamie S; Phillips, Mary L; Ryan, Christopher M; Gentry, Amanda L; Jones, Lindsay D; Bender, Catherine M

    2017-01-01

    In a sample of 368 postmenopausal women, we (1) determined within-cohort and between-cohort relationships between adjuvant systemic therapy for breast cancer and self-reported cognitive function during the first 18 months of therapy and (2) evaluated the influence of co-occurring symptoms, neuropsychological function, and other covariates on relationships. We evaluated self-reported cognitive function, using the Patient Assessment of Own Functioning Inventory (PAOFI), and potential covariates (e.g., co-occurring symptom scores and neuropsychological function z-scores) in 158 women receiving aromatase inhibitor (AI) therapy alone, 104 women receiving chemotherapy followed by AI therapy, and 106 non-cancer controls. Patients were assessed before systemic therapy and then every 6 months, for a total of four assessments over 18 months. Controls were assessed at matched time points. Mixed-effects modeling was used to determine longitudinal relationships. Controlling for covariates, patients enrolled before chemotherapy reported poorer global cognitive function (p cognitive and intellectual functions from before chemotherapy to 12 months after initiation of AI therapy (p cognitive function over time. PAOFI total score was a predictor of executive function (p = 0.048) and visual working memory (p = 0.005) z-scores, controlling for covariates. Findings provide further evidence of poorer self-reported cognitive function after chemotherapy and of relationships between co-occurring symptoms and cognitive changes. AI therapy alone does not have an impact on self-reported cognitive function. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  1. [Influenza vaccine and adjuvant].

    Science.gov (United States)

    Nakayama, Tetsuo

    2011-01-01

    Adjuvant is originated from the Latin word "adjuvare" which means "help" in English to enhance the immunological responses when given together with antigens. The beginning of adjuvant was mineral oil which enhanced the immune response when it was given with inactivated Salmonella typhimurium. Aluminium salt was used to precipitate diphtheria toxoid and increased level of antibody response was demonstrated when administered with alum-precipitated antigens. Since 1930, aluminium salt has been used as DTaP (diphtheria-tetanus-acellular pertussis vaccine) adjuvant. Many candidates were tested for adjuvant activity but only aluminum salt is allowed to use for human vaccines. New adjuvant MF59, oil-in-water emulsion type, was developed for influenza vaccine for elderly (Fluad) and series of AS adjuvant are used for hepatitis B, pandemic flue, and human papiloma virus vaccines. Oil-adjuvanted influenza pandemic vaccines induced higher antibody response than alum-adjuvanted vaccine with higher incidence of adverse events, especially for local reactions. Alum-adjuvanted whole virion inactivated H5N1 vaccine was developed in Japan, and it induced relatively well immune responses in adults. When it applied for children, febrile reaction was noted in approximately 60% of the subjects, with higher antibodies. Recent investigation on innate immunity demonstrates that adjuvant activity is initiated from the stimulation on innate immunity and/or inflammasome, resulting in cytokine induction and antigen uptake by monocytes and macrophages. The probable reason for high incidence of febrile reaction should be investigated to develop a safe and effective influenza vaccine.

  2. Current and Emerging Systemic Therapy in Gastro-Esophageal Cancer "The Old and New Therapy for Metastatic Disease, The Role of Adjuvant and Neoadjuvant Therapy for Localized Disease".

    Science.gov (United States)

    Lim, Bora; Jiang, Yixing

    2015-01-01

    Cancers of esophagus and stomach are common malignant diseases worldwide, and they are associated with serious morbidity and high mortality rates. When diagnosed at an early stage, gastro-esophageal cancers are potentially curable. Neo-adjuvant or adjuvant therapies using both chemotherapy and radiation therapy have been shown to reduce the risk of local recurrence and distant metastasis. For advanced or metastatic tumors, systemic chemotherapy offers symptomatic palliation and moderate benefits in survival. With recent advances in anti-cancer therapeutics, progress has been made to improve treatment response and life expectancy in patients with advanced gastro-esophageal cancers. Furthermore, the clinical use of molecularly targeted agents in combination with cytotoxic chemotherapeutics is being evaluated in a number of ongoing clinical trials. In this article, we review currently used standard systemic therapies including recently evolving targeted therapies for metastatic gastro-esophageal cancers, as well as the proven role and the regimens that are used as neoadjuvant and adjuvant treatment in localized gastro-esophageal cancers.

  3. Adjuvants: Classification, Modus Operandi, and Licensing

    Science.gov (United States)

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations. PMID:27274998

  4. Vaccine Adjuvants: Putting Innate Immunity to Work

    Science.gov (United States)

    Coffman, Robert L.; Sher, Alan; Seder, Robert A.

    2012-01-01

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens. PMID:21029960

  5. Salivary proteomics: A new adjuvant approach to the early diagnosis of familial juvenile systemic lupus erythematosus.

    Science.gov (United States)

    Abrão, Aline Lauria P; Falcao, Denise Pinheiro; de Amorim, Rivadávio Fernandes Batista; Bezerra, Ana Cristina B; Pombeiro, Gilson Augusto N M; Guimarães, Luciano Junqueira; Fregni, Felipe; Silva, Luciano Paulino; da Mota, Licia Maria Henrique

    2016-04-01

    Systemic lupus erythematosus (SLE) is a chronic multisystemic disease characterized by autoimmune inflammatory disturbance. Pleomorphic manifestations are present and a potentially progressive and debilitating course can be detected. SLE rarely manifests before age 5, and its onset peaks is around puberty. Although clinical manifestations, immunological alterations and treatment do not differ between juvenile and adult SLE, children tend to present with a more aggressive disease course than adults. Hence, autoimmune rheumatic diseases are the most common cause of morbidity and mortality in pediatric populations. Blood serum analysis plays an especially important role in the detection and monitoring of autoantibodies in SLE. However, since blood sampling is an uncomfortable procedure, especially in children, novel less invasive techniques and approaches are of utmost importance to evaluate pediatric subjects. In this regard, saliva samples have several advantages, such as: easy access, fast collection, painless and riskless procedure. Saliva has antimicrobial, immunomodulatory and anti-inflammatory properties, as well as several other relevant features. The whole saliva is a complex mixture of major and minor salivary gland secretion, gingival crevicular fluid, transudates plasma protein, keratinocyte products and oral microbiota. This biological fluid reflects the physiological state of the body, including the emotional condition, and endocrine, nutritional and metabolic changes. Therefore, salivary proteomics is becoming increasingly used for the early diagnosis of several diseases such as breast cancer, oral cancer, Sjögren's syndrome, diffuse systemic sclerosis, rheumatoid arthritis, among others. Considering the detection of some potential markers related to SLE in serum and urine, this study aims to conduct an initial evaluation of the possible presence of such biomarkers in saliva. Furthermore, it is expected to track down new salivary proteins that could be

  6. Adjuvants for allergy vaccines

    National Research Council Canada - National Science Library

    Moingeon, Philippe

    2012-01-01

    .... Aluminum hydroxide or calcium phosphate are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts...

  7. Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

    OpenAIRE

    Samantha Sayers; Guerlain Ulysse; Zuoshuang Xiang; Yongqun He

    2012-01-01

    Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bi...

  8. Adjuvant systemic chemotherapy for stages II and III colon cancer after complete resection: a clinical practice guideline

    Science.gov (United States)

    Meyers, B.M.; Cosby, R.; Quereshy, F.; Jonker, D.

    2016-01-01

    Background Updated practice guidelines on adjuvant chemotherapy for completely resected colon cancer are lacking. In 2008, Cancer Care Ontario’s Program in Evidence-Based Care developed a guideline on adjuvant therapy for stages ii and iii colon cancer. With newer regimens being assessed in this patient population and older agents being either abandoned because of non-effectiveness or replaced by agents that are more efficacious, a full update of the original guideline was undertaken. Methods Literature searches (January 1987 to August 2015) of medline, embase, and the Cochrane Library were conducted; in addition, abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress were reviewed (the latter for January 2007 to August 2015). A practice guideline was drafted that was then scrutinized by internal and external reviewers whose comments were incorporated into the final guideline. Results Twenty-six unique reports of eighteen randomized controlled trials and thirteen unique reports of twelve meta-analyses or pooled analyses were included in the evidence base. The 5 recommendations developed included 3 for stage ii colon cancer and 2 for stage iii colon cancer. Conclusions Patients with completely resected stage iii colon cancer should be offered adjuvant 5-fluorouracil (5fu)–based chemotherapy with or without oxaliplatin (based on definitive data for improvements in survival and disease-free survival). Patients with resected stage ii colon cancer without “high-risk” features should not receive adjuvant chemotherapy. For patients with “high-risk” features, 5fu-based chemotherapy with or without oxaliplatin should be offered, although no clinical trials have been conducted to conclusively demonstrate the same benefits seen in stage iii colon cancer. PMID:28050138

  9. Cholera toxin B subunit acts as a potent systemic adjuvant for HIV-1 DNA vaccination intramuscularly in mice.

    Science.gov (United States)

    Hou, Jue; Liu, Ying; Hsi, Jenny; Wang, Hongzhi; Tao, Ran; Shao, Yiming

    2014-01-01

    Cholera toxin B subunit (CTB) was investigated as a classical mucosal adjuvant that can increase vaccine immunogenicity. In this study, we found out the in vitro efficacy of cholera toxin B subunit (CTB) in activating mice bone marrow-derived dendritic cells (BMDCs) through Toll-like receptor signaling pathways. In vitro RNA and transcriptional level profiling arrays revealed that CTB guides high levels of Th1 and Th2 type cytokines, inflammatory cytokines, and chemokines. Based on the robustness of these profiling results, we examined the induction of HIV Env-specific immunity by CTB co-inoculated with HIV Env DNA vaccine intramuscularly in vivo. CTB enhanced HIV-Env specific cellular immune responses in Env-specific IFN-γ ELISPOT, compared with DNA vaccine alone. Moreover, CTB induced high levels of Env specific humoral response and promoted antibody maturation after the third round of vaccination. This combination immunization strategy induced a Th2-type bias response which is indicative of a high ratio of IgG1/IgG2a. This study reports that CTB as a classical mucosal adjuvant could enhance HIV-1 DNA-based vaccine immunogenicity intramuscularly; therefore, these findings suggest that CTB could serve as an effective candidate adjuvant for DNA vaccination.

  10. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women.

    Science.gov (United States)

    Petäjä, Tiina; Pedersen, Court; Poder, Airi; Strauss, Gitte; Catteau, Gregory; Thomas, Florence; Lehtinen, Matti; Descamps, Dominique

    2011-11-01

    Vaccination against oncogenic human papillomavirus (HPV) types is one key intervention for cervical cancer prevention. This follow-up study assessed the persistence of the systemic and mucosal immune responses together with the safety profile of the HPV-16/18 AS04-adjuvanted vaccine administered to young women aged 10-25 years. Serum and cervicovaginal secretion (CVS) samples were collected at prespecified time-points during the 48-month follow-up period. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay (ELISA). At Month 48, all subjects remained seropositive for serum anti-HPV-16 and -18 antibodies. As previously observed, anti-HPV-16 and -18 antibodies levels (ELISA Units/mL) were higher in subjects vaccinated at the age of 10-14 years (2862.2 and 940.8) compared to subjects vaccinated at the age of 15-25 years (1186.2 and 469.8). Moreover, anti-HPV-16 and -18 antibodies in CVS were still detectable for subjects aged 15-25 years (84.1% and 69.7%, respectively). There was a strong correlation between serum and CVS anti-HPV-16 and -18 antibodies levels (correlation coefficients = 0.84 and 0.90 at Month 48, respectively) supporting the hypothesis of transudation or exudation of serum immunoglobulin G antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women induces long-term systemic and mucosal immune response and has a clinically acceptable safety profile up to 4 years after the first vaccine dose.

  11. Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

    Directory of Open Access Journals (Sweden)

    Samantha Sayers

    2012-01-01

    Full Text Available Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO in the Web Ontology Language (OWL format.

  12. The influence of socioeconomic status and ethnicity on adjuvant systemic treatment guideline adherence for early-stage breast cancer in the Netherlands.

    Science.gov (United States)

    Kuijer, A; Verloop, J; Visser, O; Sonke, G; Jager, A; van Gils, C H; van Dalen, T; Elias, S G

    2017-08-01

    We aimed to assess whether socioeconomic status (SES) and ethnicity affect adjuvant systemic therapy (AST) guideline adherence in early breast cancer patients in a health care setting with assumed equal access to care. Data from all female patients surgically treated for primary unifocal early breast cancer between January 2005 and December 2014 were retrieved from the Netherlands Cancer Registry. We assessed the association between SES, ethnicity and non-adherence to adjuvant chemotherapy (CT) or endocrine therapy (ET) guideline indications with Poisson regression models, adjusting for clinicopathological variables. A total of 104 201 patients were included in the current analysis. Of patients without an indication, 4% and 13% received adjuvant CT or ET (overtreatment), whereas 39% and 14% of patients with an indication did not receive CT or ET (undertreatment). Medium and low SES patients were 1.01 (95% CI 1.00-1.01) and 1.01 (95% CI 1.00-1.01) times more likely to be undertreated and 0.85 (95% CI 0.76-0.94) and 0.67 (95% CI 0.60-0.75) times more likely to be overtreated with CT compared with high SES patients [resulting in an overall relative risk of CT use of 0.94 (95% CI 0.92-0.96) and 0.85 (95% CI 0.83-0.87), respectively]. No association between SES and ET guideline adherence or ethnicity and CT/ET guideline adherence was observed. In the Netherlands, minimal SES disparities in CT guideline adherence were observed: low SES patients are less likely be overtreated and marginally more likely to be undertreated with CT resulting in an overall decreased risk of receiving CT. No ethnical disparities in AST guideline adherence were observed.

  13. Using procedure of emulsification-lyophilization to form lipid A-incorporating cochleates as an effective oral mucosal vaccine adjuvant-delivery system (VADS).

    Science.gov (United States)

    Wang, Ning; Wang, Ting; Zhang, Meiling; Chen, Ruonan; Deng, Yihui

    2014-07-01

    Using a procedure of emulsification-lyophilization (PEL), adjuvant lipid A-cochleates (LACs) were prepared as a carrier for model antigen bovine serum albumin (BSA). With phosphatidylserine and lipid A as emulsifiers dissolved in oil phase (O), sucrose and CaCl2 in the inner water phase (W1), and BSA, sucrose and PEG2000 in the outer water phase (W2), the W1/O/W2 emulsions were prepared and subsequently lyophilized to form a dry product which was stable enough to be stored at room temperature. Upon rehydration of the dry products, cochleates formed with a size of 800 nm and antigen association rates of 38%. After vaccination of mice through oral mucosal (o.m.) administration, LACs showed no side effects but induced potent immune responses as evidenced by high levels of IgG in the sera and IgA in the salivary, intestinal and vaginal secretions of mice. In addition, high levels of IgG2a and IFN-γ in the sera or culture supernatants of splenocytes of the immunized mice were also detected. These results revealed that LACs induced a mixed Th1/Th2 response against the loaded antigens. Thus, the LACs prepared by PEL were able to induce both systemic and mucosal immune responses and may act as a potent cold-chain-free oral mucosal vaccine adjuvant delivery system (VADS).

  14. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

    Science.gov (United States)

    Harris, Lyndsay N.; McShane, Lisa M.; Andre, Fabrice; Collyar, Deborah E.; Gonzalez-Angulo, Ana M.; Hammond, Elizabeth H.; Kuderer, Nicole M.; Liu, Minetta C.; Mennel, Robert G.; Van Poznak, Catherine; Bast, Robert C.; Hayes, Daniel F.

    2016-01-01

    Purpose To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. Methods A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. Recommendations In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences. PMID:26858339

  15. A novel adjuvant-free H fusion system for the production of recombinant immunogens in Escherichia coli

    Science.gov (United States)

    Costa, Sofia J; Silva, Pedro; Almeida, André; Conceição, Antónia; Domingues, Lucília; Castro, António

    2013-01-01

    The production of recombinant antigens in Escherichia coli and specific polyclonal antibodies for diagnosis and therapy is still a challenge for world-wide researchers. Several different strategies have been explored to improve both antigen and antibody production, all of them depending on a successful expression and immunogenicity of the antigen. Gene fusion technology attempted to address these challenges: fusion partners have been applied to optimize recombinant antigen production in E. coli, and to increase protein immunogenicity. Taking a 12-kDa surface adhesion antigen from Cryptosporidium parvum (CP12) by example, the novel H fusion partner was presented in this work as an attractive option for the development of recombinant immunogens and its adjuvant-free immunization. The H tag (of only 1 kDa) efficiently triggered a CP12-specific immune response, and it also improved the immunization procedure without requiring co-administration of adjuvants. Moreover, polyclonal antibodies raised against the HCP12 fusion antigen detected native antigen structures displayed on the surface of C. parvum oocysts. The H tag proved to be an advanced strategy and promising technology for the diagnosis and therapy of C. parvum infections in animals and humans, allowing a rapid and simple recombinant production of the CP12 antigen. PMID:23941978

  16. Semecarpus anacardium Linn. nut milk extract, an indigenous drug preparation, modulates reactive oxygen/nitrogen species levels and antioxidative system in adjuvant arthritic rats.

    Science.gov (United States)

    Ramprasath, Vanu Ramkumar; Shanthi, Palanivelu; Sachdanandam, Panchanatham

    2005-08-01

    Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive transient chemical species, which play an important role in the etiology of tissue injury in rheumatoid arthritis (RA). The effects of milk extract of Semecarpus anacardium Linn. nut (SA) was studied on adjuvant arthritis in rats. Arthritis was induced by injecting 0.1 ml of heat killed mycobacterium tuberculosis (10 mg/ml of paraffin oil) intradermally into the left hind paw. A significant increase in the levels of lipid peroxides (LPO), ROS (superoxide radical, hydroxyl radical, H(2)O(2) and myeloperoxidase) and RNS (nitrate+nitrite) observed in adjuvant arthritic animals were found to be significantly decreased on administration of the drug at 150 mg/kg body weight/day. The antioxidant defense system studied in arthritic animals were altered significantly as evidenced by the decrease in antioxidants. Treatment with SA recouped the altered antioxidant defense components to near normal levels. These evidences suggest that the free radical mediated damage during arthritis could have been controlled by SA by its free radical quenching and antioxidative potential. (Mol Cell Biochem 276: 97-104, 2005).

  17. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway.

    Science.gov (United States)

    Fukasaka, Masahiro; Asari, Daisuke; Kiyotoh, Eiji; Okazaki, Arimichi; Gomi, Yasuyuki; Tanimoto, Takeshi; Takeuchi, Osamu; Akira, Shizuo; Hori, Mitsuhiko

    2015-01-01

    A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens.

  18. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway.

    Directory of Open Access Journals (Sweden)

    Masahiro Fukasaka

    Full Text Available A lipopolysaccharide from Pantoea agglomerans (LPSpa has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine with LPSpa induced both HA-specific IgG (systemic and IgA (mucosal antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens.

  19. Locoregional Failure in Early-Stage Breast Cancer Patients Treated With Radical Mastectomy and Adjuvant Systemic Therapy: Which Patients Benefit From Postmastectomy Irradiation?

    Energy Technology Data Exchange (ETDEWEB)

    Trovo, Marco, E-mail: marcotrovo33@hotmail.com [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Durofil, Elena [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Polesel, Jerry [Department of Epidemiology and Biostatistics, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Roncadin, Mario [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Perin, Tiziana [Department of Pathology, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Mileto, Mario; Piccoli, Erica [Department of Surgery, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Quitadamo, Daniela [Scientific Direction, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Massarut, Samuele [Department of Surgery, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Carbone, Antonino [Department of Pathology, Centro di Riferimento Oncologico of Aviano, Aviano (Italy); Trovo, Mauro G. [Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano (Italy)

    2012-06-01

    Purpose: To assess the locoregional failure in patients with Stage I-II breast cancer treated with radical mastectomy and to evaluate whether a subset of these patients might be at sufficiently high risk of locoregional recurrence (LRR) to benefit from postmastectomy irradiation (PMRT). Methods and Materials: Stage I-II breast cancer patients (n = 150) treated with radical mastectomy without adjuvant irradiation between 1999 and 2005 were analyzed. The pattern of LRR was reported. Kaplan-Meier analysis was used to calculate rates of LRR, and Cox proportional hazards methods were used to evaluate potential risk factors. Results: Median follow-up was 75 months. Mean patient age was 56 years. One-hundred forty-three (95%) patients received adjuvant systemic therapy: 85 (57%) hormonal therapy alone, 14 (9%) chemotherapy alone, and 44 (29%) both chemotherapy and hormonal therapy. Statistically significant factors associated with increased risk of LRR were premenopausal status (p = 0.004), estrogen receptor negative cancer (p = 0.02), pathologic grade 3 (p = 0.02), and lymphovascular invasion (p = 0.001). T and N stage were not associated with increased risk of regional recurrence. The 5-year LRR rate for patients with zero or one, two, three, and four risk factors was 1%, 10.3%, 24.2%, and 75%, respectively. Conclusions: A subset of patients with early-stage breast cancer is at high risk of LRR, and therefore PMRT might be beneficial.

  20. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway

    Science.gov (United States)

    Kiyotoh, Eiji; Okazaki, Arimichi; Gomi, Yasuyuki; Tanimoto, Takeshi; Takeuchi, Osamu; Akira, Shizuo; Hori, Mitsuhiko

    2015-01-01

    A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens. PMID:25978818

  1. Influence of race, insurance, socioeconomic status, and hospital type on receipt of guideline-concordant adjuvant systemic therapy for locoregional breast cancers.

    Science.gov (United States)

    Wu, Xiao-Cheng; Lund, Mary Jo; Kimmick, Gretchen G; Richardson, Lisa C; Sabatino, Susan A; Chen, Vivien W; Fleming, Steven T; Morris, Cyllene R; Huang, Bin; Trentham-Dietz, Amy; Lipscomb, Joseph

    2012-01-10

    For breast cancer, guidelines direct the delivery of adjuvant systemic therapy on the basis of lymph node status, histology, tumor size, grade, and hormonal receptor status. We explored how race/ethnicity, insurance, census tract-level poverty and education, and hospital Commission on Cancer (CoC) status were associated with the receipt of guideline-concordant adjuvant systemic therapy. Locoregional breast cancers diagnosed in 2004 (n = 6,734) were from the National Program of Cancer Registries-funded seven-state Patterns of Care study of the Centers for Disease Control and Prevention. Predictors of guideline-concordant (receiving/not receiving) adjuvant systemic therapy, according to National Comprehensive Cancer Network Guidelines, were explored by logistic regression. Overall, 35% of women received nonguideline chemotherapy, 12% received nonguideline regimens, and 20% received nonguideline hormonal therapy. Significant predictors of nonguideline chemotherapy included Medicaid insurance (odds ratio [OR], 0.66; 95% CI, 0.50 to 0.86), high-poverty areas (OR, 0.77; 95% CI, 0.62 to 0.96), and treatment at non-CoC hospitals (OR, 0.69; 95% CI, 0.56 to 0.85), with adjustment for age, registry, and clinical variables. Predictors of nonguideline regimens among chemotherapy recipients included lack of insurance (OR, 0.47; 95% CI, 0.25 to 0.92), high-poverty areas (OR, 0.71; 95% CI, 0.51 to 0.97), and low-education areas (OR, 0.65; 95% CI, 0.48 to 0.89) after adjustment. Living in high-poverty areas (OR, 0.78; 95% CI, 0.64 to 0.96) and treatment at non-CoC hospitals (OR, 0.68; 95% CI, 0.55 to 0.83) predicted nonguideline hormonal therapy after adjustment. ORs for poverty, education, and insurance were attenuated in the full models. Sociodemographic and hospital factors are associated with guideline-concordant use of systemic therapy for breast cancer. The identification of modifiable factors that lead to nonguideline treatment may reduce disparities in breast cancer

  2. Mycophenolate mofetil as adjuvant in pemphigus vulgaris

    Directory of Open Access Journals (Sweden)

    Sarma Nilendu

    2007-01-01

    Full Text Available Pemphigus vulgaris (PV is a life threatening autoimmune blistering disease of skin and mucous membranes. Advent of systemic steroids has greatly reduced the mortality rate. However, steroids and adjuvant immunosuppressive therapy are nowadays frequent contributory agents of morbidity and mortality of PV. Mycophenolate mofetil (MMF has been reported to be an effective adjuvant to systemic steroids. It helps in increasing the immunosuppressive effect and minimizing the toxicities by steroid sparing effect. However, its efficacy in refractory cases of PV is not well documented. The lowest possible dose with satisfactory therapeutic efficacy and least side effects is known. We used MMF 1 g/day and systemic steroids in 3 Indian patients with pemphigus vulgaris who were resistant to systemic steroid monotherapy or combination treatment with azathioprine. In our experience, MMF offers an effective adjuvant with minimal side-effects in the treatment of resistant PV.

  3. Mixed adjuvant formulations reveal a new combination that elicit antibody response comparable to Freund's adjuvants.

    Directory of Open Access Journals (Sweden)

    Rachel P J Lai

    Full Text Available Adjuvant formulations capable of inducing high titer and high affinity antibody responses would provide a major advance in the development of vaccines to viral infections such as HIV-1. Although oil-in-water emulsions, such as Freund's adjuvant (FCA/FIA, are known to be potent, their toxicity and reactogenicity make them unacceptable for human use. Here, we explored different adjuvants and compared their ability to elicit antibody responses to FCA/FIA. Recombinant soluble trimeric HIV-1 gp140 antigen was formulated in different adjuvants, including FCA/FIA, Carbopol-971P, Carbopol-974P and the licensed adjuvant MF59, or combinations of MF59 and Carbopol. The antigen-adjuvant formulation was administered in a prime-boost regimen into rabbits, and elicitation of antigen binding and neutralizing antibodies (nAbs was evaluated. When used individually, only FCA/FIA elicited significantly higher titer of nAbs than the control group (gp140 in PBS (p<0.05. Sequential prime-boost immunizations with different adjuvants did not offer improvements over the use of FCA/FIA or MF59. Remarkably however, the concurrent use of the combination of Carbopol-971P and MF59 induced potent adjuvant activity with significantly higher titer nAbs than FCA/FIA (p<0.05. This combination was not associated with any obvious local or systemic adverse effects. Antibody competition indicated that the majority of the neutralizing activities were directed to the CD4 binding site (CD4bs. Increased antibody titers to the gp41 membrane proximal external region (MPER and gp120 V3 were detected when the more potent adjuvants were used. These data reveal that the combination of Carbopol-971P and MF59 is unusually potent for eliciting nAbs to a variety of HIV-1 nAb epitopes.

  4. Immunogenicity and immunization costs of adjuvanted versus non-adjuvanted hepatitis B vaccine in chronic kidney disease patients.

    Science.gov (United States)

    Vilajeliu, Alba; Sequera, Víctor-Guillermo; García-Basteiro, Alberto L; Sicuri, Elisa; Aldea, Marta; Velasco, César; Bayas, José M

    2016-09-01

    Hepatitis B virus (HBV) vaccination is recommended for all susceptible chronic pre-hemodialysis and hemodialysis patients. This study assessed the immunogenicity of HBV vaccines (adjuvanted and non-adjuvanted) in chronic kidney disease patients vaccinated at the Hospital Clinic of Barcelona (Spain) between January 2007 and July 2012. In addition, the costs for the health system were evaluated accor-ding to the proportion of vaccine responders after receiving either vaccine. Patients receiving 3 doses of hepatitis B adjuvanted vaccine were 3 times more likely to seroconvert than patients immunized with non-adjuvanted vaccines, OR 3.56 (95% CI 1.84-6.85). This resulted in fewer patients requiring a second course of HBV vaccination and fewer outpatient visits, saving more than €9,500 per 100 patients. The higher immunogenicity of the adjuvanted HBV vaccine would counterbalance the lower costs associated with the non-adjuvanted vaccine.

  5. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women

    DEFF Research Database (Denmark)

    Petäjä, T; Pedersen, Court; Poder, A;

    2011-01-01

    of transudation or exudation of serum IgG antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women...

  6. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women

    DEFF Research Database (Denmark)

    Petäjä, T; Pedersen, C; Andersen, Anne Poder;

    2010-01-01

    of transudation or exudation of serum IgG antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women...

  7. Evaluation of antioxidant effect of Semecarpus anacardium Linn. nut extract on the components of immune system in adjuvant arthritis.

    Science.gov (United States)

    Ramprasath, Vanu Ramkumar; Shanthi, Palanivelu; Sachdanandam, Panchanatham

    2005-03-01

    The effect of Semecarpus anacardium Linn. nut extract (SA) on the level of Lipid peroxides (LPO) and activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) in the lymphocytes and lymphoid organs, namely spleen and thymus of adjuvant induced arthritic rats, were investigated. The results were compared with normal and untreated arthritic rats. The levels of reactive oxygen species (ROS), namely Hydroxy radical, Superoxide radical, and H2O2 were also measured in spleen, thymus, and lymphocytes of control and experimental animals. Biochemical markers of inflammation namely C-reactive protein (CRP) level and Erythrocyte sedimentation rate (ESR) were determined. Anti-arthritic profile was evaluated from the changes in the paw edema and arthritic scores of arthritic and drug-treated rats. A significant increase in the level of LPO, ROS and decreased levels of antioxidant enzymes in arthritic rats were observed. On treatment with the drug, the above changes were reverted back to near normal levels. The increment in CRP level and ESR observed in arthritic animals were found to be significantly restored in SA treated rats. There were no significant changes in sole drug-administered normal rats. Semecarpus anacardium Linn. nut extract significantly decreased the paw edema and arthritic score in arthritic rats on administration, whereas in untreated arthritic rats, there was a significant edema in the hind paw.

  8. Microbiota Influences Vaccine and Mucosal Adjuvant Efficacy

    Science.gov (United States)

    2017-01-01

    A symbiotic relationship between humans and the microbiota is critical for the maintenance of our health, including development of the immune system, enhancement of the epithelial barrier, and acquisition of nutrients. Recent research has shown that the microbiota impacts immune cell development and differentiation. These findings suggest that the microbiota may also influence adjuvant and vaccine efficacy. Indeed, several factors such as malnutrition and poor sanitation, which affect gut microbiota composition, impair the efficacy of vaccines. Although there is little evidence that microbiota alters vaccine efficacy, further understanding of human immune system-microbiota interactions may lead to the effective development of adjuvants and vaccines for the treatment of diseases. PMID:28261017

  9. Time-dependent estimates of recurrence and survival in colon cancer: clinical decision support system tool development for adjuvant therapy and oncological outcome assessment.

    Science.gov (United States)

    Steele, Scott R; Bilchik, Anton; Johnson, Eric K; Nissan, Aviram; Peoples, George E; Eberhardt, John S; Kalina, Philip; Petersen, Benjamin; Brücher, Björn; Protic, Mladjan; Avital, Itzhak; Stojadinovic, Alexander

    2014-05-01

    Unanswered questions remain in determining which high-risk node-negative colon cancer (CC) cohorts benefit from adjuvant therapy and how it may differ in an equal access population. Machine-learned Bayesian Belief Networks (ml-BBNs) accurately estimate outcomes in CC, providing clinicians with Clinical Decision Support System (CDSS) tools to facilitate treatment planning. We evaluated ml-BBNs ability to estimate survival and recurrence in CC. We performed a retrospective analysis of registry data of patients with CC to train-test-crossvalidate ml-BBNs using the Department of Defense Automated Central Tumor Registry (January 1993 to December 2004). Cases with events or follow-up that passed quality control were stratified into 1-, 2-, 3-, and 5-year survival cohorts. ml-BBNs were trained using machine-learning algorithms and k-fold crossvalidation and receiver operating characteristic curve analysis used for validation. BBNs were comprised of 5301 patients and areas under the curve ranged from 0.85 to 0.90. Positive predictive values for recurrence and mortality ranged from 78 to 84 per cent and negative predictive values from 74 to 90 per cent by survival cohort. In the 12-month model alone, 1,132,462,080 unique rule sets allow physicians to predict individual recurrence/mortality estimates. Patients with Stage II (N0M0) CC benefit from chemotherapy at different rates. At one year, all patients older than 73 years of age with T2-4 tumors and abnormal carcinoembryonic antigen levels benefited, whereas at five years, all had relative reduction in mortality with the largest benefit amongst elderly, highest T-stage patients. ml-BBN can readily predict which high-risk patients benefit from adjuvant therapy. CDSS tools yield individualized, clinically relevant estimates of outcomes to assist clinicians in treatment planning.

  10. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    Science.gov (United States)

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

    Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.

  11. SULT1A1 rs9282861 polymorphism-a potential modifier of efficacy of the systemic adjuvant therapy in breast cancer?

    Directory of Open Access Journals (Sweden)

    Tengström Maria

    2012-06-01

    Full Text Available Abstract Background Sulfotransferase 1A1 (SULT1A1 participates in the elimination of 4-hydroxy-tamoxifen (4-OH-TAM, which is one of the major active metabolites of tamoxifen (TAM. Homozygous SULT1A1 variant allele genotype has been associated with lower catalytic activity and thermostability of the enzyme. Previous clinical studies suggest that the SULT1A1 rs9282861 polymorphism may influence the survival of breast cancer patients treated with TAM in the adjuvant setting. We investigated the effect of rs9282861 genotypes on the survival of Finnish breast cancer patients treated with adjuvant chemotherapy or TAM. Methods The rs9282861 genotypes of 412 Finnish breast cancer patients with early breast cancer were identified by using PCR-RFLP method. Seventy six patients were treated with adjuvant cyclophosphamide based chemotherapy only, 65 patients received adjuvant TAM, and four patients were treated with both adjuvant chemotherapy and TAM. Overall long-term survival (OS, breast cancer specific survival (BCSS, and relapse-free survival (RFS by rs9282861 genotypes were evaluated by the Kaplan-Meier method and Cox regression analysis. Results The multivariate analysis of 145 patients receiving either adjuvant TAM or chemotherapy showed a statistically significantly improved OS in patients with the rs9282861 homozygous variant AA genotype (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.29-0.88, P = 0.015. In the separate analyses of patients receiving only chemotherapy or adjuvant TAM, there were no statistically significant differences in survival. Conclusions In this prospective study, we observed a previously unreported association between the SULT1A1 rs9282861 genotype and OS of breast cancer patients treated with adjuvant chemotherapy or TAM. This novel finding suggests that the rs9282861 polymorphism modifies the long-term clinical outcome of patients receiving adjuvant TAM or chemotherapy.

  12. Effect on Cellular and Humoral Immune Responses of the AS03 Adjuvant System in an A/H1N1/2009 Influenza Virus Vaccine Administered to Adults during Two Randomized Controlled Trials ▿ †

    Science.gov (United States)

    Roman, François; Clément, Frédéric; Dewé, Walthère; Walravens, Karl; Maes, Cathy; Willekens, Julie; De Boever, Fien; Hanon, Emmanuel; Leroux-Roels, Geert

    2011-01-01

    The influence of AS03A, a tocopherol oil-in-water emulsion-based adjuvant system, on humoral and cell-mediated responses to A/California/7/2009 H1N1 pandemic vaccine was investigated. In two observer-blind studies, a total of 261 healthy adults aged 18 to 60 years were randomized to receive either AS03A-adjuvanted H1N1 vaccine containing 3.75 μg hemagglutinin (HA) or nonadjuvanted H1N1 vaccine containing 15 or 3.75 μg HA on days 0 and 21. Hemagglutination inhibition (HI) antibody and T-cell responses were analyzed up to day 42. A first dose of AS03A-adjuvanted vaccine (3.75 μg HA) or nonadjuvanted vaccine (15 μg HA) induced HI responses of similar magnitudes that exceeded licensure criteria (e.g., 94 to 100% with titers of ≥40). A lower response following 3.75 μg HA without adjuvant was observed (73% with titers of ≥40). Following a second dose, geometric mean HI titers at day 42 were higher for AS03A-adjuvanted vaccine (636 and 637) relative to nonadjuvanted vaccine (341 for 15 μg HA and 150 for 3.75 μg HA). Over the 42-day period, the increase in frequency of A/H1N1/2009-specific CD4+ T cells was significantly higher in the adjuvanted group than in the nonadjuvanted group. There was no evidence of correlation between baseline CD4+ T-cell frequencies and day 21 HI antibody titers, while there was some correlation (R = 0.35) between day 21 CD4+ T-cell frequencies and day 42 HI titers. AS03A adjuvant enhanced the humoral and CD4+ T-cell-mediated responses to A/H1N1/2009 vaccine. Baseline A/H1N1/2009-specific CD4+ T-cell frequencies did not predict post-dose 1 antibody responses, but there was some correlation between post-dose 1 CD4+ T-cell frequencies and post-dose 2 antibody responses. PMID:21450978

  13. Progress in adjuvant chemotherapy for breast cancer: an overview.

    Science.gov (United States)

    Anampa, Jesus; Makower, Della; Sparano, Joseph A

    2015-01-01

    Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy.

  14. Evaluation of Mucosal and Systemic Immune Responses Elicited by GPI-0100-Adjuvanted Influenza Vaccine Delivered by Different Immunization Strategies

    NARCIS (Netherlands)

    Liu, Heng; Patil, Harshad P.; de Vries-Idema, Jacqueline; Wilschut, Jan; Huckriede, Anke

    2013-01-01

    Vaccines for protection against respiratory infections should optimally induce a mucosal immune response in the respiratory tract in addition to a systemic immune response. However, current parenteral immunization modalities generally fail to induce mucosal immunity, while mucosal vaccine delivery

  15. Adjuvant Therapy: Melanoma

    Directory of Open Access Journals (Sweden)

    Diwakar Davar

    2011-01-01

    Full Text Available With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4 monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway.

  16. Adjuvant therapies for colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The management of colon and rectal cancer has changed dramatically over the last 25 years. The use of adjuvant therapies has become standard practice in locally advanced (stage Ⅲ and selected stage Ⅱ) colorectal cancer. Improved surgical techniques, chemotherapeutics and radiotherapy are resulting in higher cure rates and the development of agents targeting proliferative and angiogenic pathways offer further promise. Here we explore risk factors for local and distant recurrence after resection of colon and rectal cancer, and the role of adjuvant treatments. Discussion will focus on the evidence base for adjuvant therapies utilised in colorectal cancer, and the treatment of sub-groups such as the elderly and stage Ⅱ disease. The role of adjuvant radiotherapy in rectal cancer in reduction of recurrence will be explored and the role and optimal methods for surveillance post-curative resection with or without adjuvant therapy will also be addressed.

  17. Adjuvant Strategies for Resectable Pancreatic Cancer: Have We Made Progress?

    Directory of Open Access Journals (Sweden)

    Suzanne Russo

    2012-03-01

    Full Text Available Substantial controversy remains regarding the optimal adjuvant treatment for patients with resectable pancreatic adenocarcinoma. Despite improvements in radiation techniques, systemic therapies, and incorporation of targeted agents, the 5-year survival rates for early stage patients remains less than 25% and the optimal adjuvant treatment approach remains unclear. Here we summarize the data presented at the 2012 American Society of Clinical Oncology (ASCO Gastrointestinal Cancers Symposium regarding controversial issues surrounding the role, timing, and selection of patients for adjuvant chemoradiation strategies following curative resection for pancreatic adenocarcinoma. (Abstracts #301, #333, and #206.

  18. Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Fumito Ito

    Full Text Available While surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre-resectional RFA in a preclinical mouse model.Therapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma.Treatment with pre-resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen. Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity.Improved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant treatment for cancer patients with

  19. Development and controversies of adjuvant therapy for pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Wan-Yee Lau; Eric C. H. Lai

    2008-01-01

    BACKGROUND:Pancreatic cancer is an aggressive malignancy with a dismal prognosis. Radical surgery provides the only chance for a cure with a 5-year survival rate of 7%-25%. An effective adjuvant therapy is urgently needed to improve the surgical outcome. This review describes the current status of adjuvant therapy for pancreatic cancer, and highlights its controversies. DATA SOURCES:A Medline database search was performed to identify relevant articles using the keywords"pancreatic neoplasm", and"adjuvant therapy". Additional papers were identiifed by a manual search of the references from the key articles. RESULTS:Eight prospective randomized controlled trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation for pancreatic cancer could be identiifed. The results for adjuvant regimens based on systemic 5-lfuorouracil with or without external radiotherapy were conlficting. The recent two RCTs on gemcitabine based regimen gave promising results. CONCLUSIONS:Based on the available data, no standard adjuvant therapy for pancreatic cancer can be established yet. The best adjuvant regimen remains to be determined in large-scale RCTs. Future trials should use a gemcitabine based regimen.

  20. Adjuvants for veterinary vaccines--types and modes of action.

    Science.gov (United States)

    Gerdts, Volker

    2015-01-01

    Adjuvants are used to improve the immune response to vaccines. Formulation with adjuvants can result in an earlier onset of immunity, an overall stronger immune response, a specific type of immunity, or a longer duration of immunity to the vaccine. Adjuvants were discovered empirically, and for decades, have been used in both humans and animals without understanding the mechanisms of action. With an improved understanding of the immune system, and in particular the interplay between innate and adaptive immunity, we are now getting better insight into the function of adjuvants. As a result, new adjuvants are being developed that are safe and highly effective for common use in humans and animals, as well as for use in high risk populations such as immunocompromised animals, neonates or very old animals. Furthermore, adjuvants can help to reduce the amount of antigen needed in the vaccine, increase the stability of the vaccine and enable alternatiye administration routes such as needle-free delivery of the vaccine. Here, I will provide an over view of the existing adjuvant technologies for veterinary vaccines and provide an outlook into some of the new technologies in preclinical and clinical development.

  1. ERM immersion vaccination and adjuvants

    DEFF Research Database (Denmark)

    Skov, J.; Chettri, J. K.; Jaafar, R. M.

    2015-01-01

    Two candidate adjuvants were tested with a commercial ERM dip vaccine (AquaVac™ Relera, MSD Animal Health) for rainbow trout in an experimental design compatible with common vaccination practices at farm level, i.e. immersion of fish in vaccine (±adjuvant) for 30 s. The adjuvants were...... the commercial product Montanide™ IMS 1312 VG PR (SEPPIC), and a soluble and ≥98% pure β-glucan from yeast (Saccharomyces cerevisiae) (Sigma-Aldrich). Hence, five experimental groups in duplicate were established and exposed to vaccine and adjuvants in the following combinations: AquaVac™ Relera (alone); Aqua......Vac™ Relera + Montanide™; AquaVac™ Relera + β-glucan; Montanide™ (alone); and β-glucan (alone). Approximately 450 degree days post-vaccination, the fish were bath-challenged with live Yersinia ruckeri to produce survival curves. Blood, skin and gills were sampled at selected time points during the course...

  2. Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Thyroid Autoimmunity

    Science.gov (United States)

    Watad, Abdulla; David, Paula; Brown, Stav; Shoenfeld, Yehuda

    2017-01-01

    The autoimmune/inflammatory syndrome induced by adjuvants (ASIA), presented by Shoenfeld and Agmon-Levin in 2011, is an entity that incorporates diverse autoimmune conditions induced by the exposure to various adjuvants. Adjuvants are agents that entail the capability to induce immune reactions. Adjuvants are found in many vaccines and used mainly to increase the response to vaccination in the general population. Silicone has also been reported to be able to induce diverse immune reactions. Clinical cases and series of heterogeneous autoimmune conditions including systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis have been reported to be induced by several adjuvants. However, only a small number of cases of autoimmune thyroid disorder have been included under the umbrella of ASIA syndrome. Indeed, clinical cases of Hashimoto’s thyroiditis and/or subacute thyroiditis were observed after the exposure to vaccines as well as silicone implantation. In our review, we aimed to summarize the current knowledge on ASIA syndrome presented as endocrinopathies, focusing on autoimmune thyroid disorders associated with the various adjuvants. PMID:28167927

  3. The Quest for an HIV-1 Vaccine Adjuvant: Bacterial Toxins as New Potential Platforms.

    Science.gov (United States)

    Nashar, Toufic O

    2014-06-01

    While tremendous efforts are undergoing towards finding an effective HIV-1 vaccine, the search for an HIV-1 vaccine adjuvant lags behind and is understudied. More recently, however, efforts have focused on testing adjuvant formulations that can boost the immune response and generate broadly neutralizing antibodies to HIV-1 ENV (gp160). Despite this, there remain a number of challenges towards achieving this goal. These include safety of adjuvant formulations; stability of the incorporated antigens; maintenance of ENV immunogenicity; optimal inoculation sites; the effective combination of adjuvants; stability of ENV neutralizing epitopes in some adjuvant formulations; mucosal immunity; and long-term maintenance of the immune response. A new class of adjuvants for HIV-1 proteins is suggested to overcome many of the limitations of some other adjuvants. Type 1 (LT-I) and type 2 (LT-II) human E. coli enterotoxins (HLTs) and their non-toxic B-subunits derivatives are strong systemic and mucosal adjuvants and effective carriers for other proteins and epitopes. Their stable molecular structure in the presence of fused proteins and epitopes, and their ability to target surface receptors on antigen presenting cells make them ideal for the delivery of HIV-1 ENV or HIV other proteins. Importantly, unlike some other adjuvants, HLTs and derivatives have well-defined modes of immune system activation. The challenges in finding optimal HIV-1 vaccine adjuvant formulation and the important properties of HLTs are discussed.

  4. A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema.

    Science.gov (United States)

    Wang, Yang; Wang, Enmin; Pan, Li; Dai, Jiazhong; Zhang, Nan; Wang, Xin; Liu, Xiaoxia; Mei, Guanghai; Sheng, Xiaofang

    2014-09-01

    Bevacizumab blocks the effects of vascular endothelial growth factor in leakage-prone capillaries and has been suggested as a new treatment for cerebral radiation edema and necrosis. CyberKnife is a new, frameless stereotactic radiosurgery system. This work investigated the safety and efficacy of CyberKnife followed by early bevacizumab treatment for brain metastasis with extensive cerebral edema. The eligibility criteria of the patients selected for radiosurgery followed by early use of adjuvant bevacizumab treatment were: (1) brain tumors from metastasis with one solitary brain lesion and symptomatic extensive cerebral edema; (2) >18 years of age; (3) the patient refused surgery due to the physical conditions and the risk of surgery; (4) no contraindications for bevacizumab. (5) bevacizumab was applied for a minimum of 2 injections and a maximum of 6 injections with a 2-week interval between treatments, beginning within 2 weeks of the CyberKnife therapy; (6) Karnofsky performance status (KPS) ≥30. Tumor size and edema were monitored by magnetic resonance imaging (MRI). Dexamethasone dosage, KPS, adverse event occurrence and associated clinical outcomes were also recorded. Eight patients were accrued for this new treatment. Radiation dose ranged from 20 to 33 Gy in one to five sessions, prescribed to the 61-71 % isodose line. Bevacizumab therapy was administered 3-10 days after completion of CyberKnife treatment for a minimum of two cycles (5 mg/kg, at 2-week intervals). MRI revealed average reductions of 55.8 % (post-gadolinium) and 63.4 % (T2/FLAIR). Seven patients showed significant clinical neurological improvements. Dexamethasone was reduced in all patients, with five successfully discontinuing dexamethasone treatment 4 weeks after bevacizumab initiation. Hypertension, a bevacizumab-related adverse event, occurred in one patient. After 3-8 months, all patients studied were alive and primary brain metastases were under control, 2 developed new brain

  5. DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5, Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4, and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant

    Directory of Open Access Journals (Sweden)

    Steven E. Applequist

    2013-09-01

    Full Text Available Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5 and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4. To test the ability of pFliC(-gly to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly and plasmid encoding a model antigen (ovalbumin by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly. Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly. We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes.

  6. How to define green adjuvants.

    Science.gov (United States)

    Beck, Bert; Steurbaut, Walter; Spanoghe, Pieter

    2012-08-01

    The concept 'green adjuvants' is difficult to define. This paper formulates an answer based on two approaches. Starting from the Organisation for Economic Cooperation and Development (OECD) definition for green chemistry, production-based and environmental-impact-based definitions for green adjuvants are proposed. According to the production-based approach, adjuvants are defined as green if they are manufactured using renewable raw materials as much as possible while making efficient use of energy, preferably renewable energy. According to the environmental impact approach, adjuvants are defined as green (1) if they have a low human and environmental impact, (2) if they do not increase active ingredient environmental mobility and/or toxicity to humans and non-target organisms, (3) if they do not increase the exposure to these active substances and (4) if they lower the impact of formulated pesticides by enhancing the performance of active ingredients, thus potentially lowering the required dosage of active ingredients. Based on both approaches, a tentative definition for 'green adjuvants' is given, and future research and legislation directions are set out.

  7. Inactivated Eyedrop Influenza Vaccine Adjuvanted with Poly(I:C) Is Safe and Effective for Inducing Protective Systemic and Mucosal Immunity.

    Science.gov (United States)

    Kim, Eun-Do; Han, Soo Jung; Byun, Young-Ho; Yoon, Sang Chul; Choi, Kyoung Sub; Seong, Baik Lin; Seo, Kyoung Yul

    2015-01-01

    The eye route has been evaluated as an efficient vaccine delivery routes. However, in order to induce sufficient antibody production with inactivated vaccine, testing of the safety and efficacy of the use of inactivated antigen plus adjuvant is needed. Here, we assessed various types of adjuvants in eyedrop as an anti-influenza serum and mucosal Ab production-enhancer in BALB/c mice. Among the adjuvants, poly (I:C) showed as much enhancement in antigen-specific serum IgG and mucosal IgA antibody production as cholera toxin (CT) after vaccinations with trivalent hemagglutinin-subunits or split H1N1 vaccine antigen in mice. Vaccination with split H1N1 eyedrop vaccine antigen plus poly(I:C) showed a similar or slightly lower efficacy in inducing antibody production than intranasal vaccination; the eyedrop vaccine-induced immunity was enough to protect mice from lethal homologous influenza A/California/04/09 (H1N1) virus challenge. Additionally, ocular inoculation with poly(I:C) plus vaccine antigen generated no signs of inflammation within 24 hours: no increases in the mRNA expression levels of inflammatory cytokines nor in the infiltration of mononuclear cells to administration sites. In contrast, CT administration induced increased expression of IL-6 cytokine mRNA and mononuclear cell infiltration in the conjunctiva within 24 hours of vaccination. Moreover, inoculated visualizing materials by eyedrop did not contaminate the surface of the olfactory bulb in mice; meanwhile, intranasally administered materials defiled the surface of the brain. On the basis of these findings, we propose that the use of eyedrop inactivated influenza vaccine plus poly(I:C) is a safe and effective mucosal vaccine strategy for inducing protective anti-influenza immunity.

  8. Inactivated Eyedrop Influenza Vaccine Adjuvanted with Poly(I:C Is Safe and Effective for Inducing Protective Systemic and Mucosal Immunity.

    Directory of Open Access Journals (Sweden)

    Eun-Do Kim

    Full Text Available The eye route has been evaluated as an efficient vaccine delivery routes. However, in order to induce sufficient antibody production with inactivated vaccine, testing of the safety and efficacy of the use of inactivated antigen plus adjuvant is needed. Here, we assessed various types of adjuvants in eyedrop as an anti-influenza serum and mucosal Ab production-enhancer in BALB/c mice. Among the adjuvants, poly (I:C showed as much enhancement in antigen-specific serum IgG and mucosal IgA antibody production as cholera toxin (CT after vaccinations with trivalent hemagglutinin-subunits or split H1N1 vaccine antigen in mice. Vaccination with split H1N1 eyedrop vaccine antigen plus poly(I:C showed a similar or slightly lower efficacy in inducing antibody production than intranasal vaccination; the eyedrop vaccine-induced immunity was enough to protect mice from lethal homologous influenza A/California/04/09 (H1N1 virus challenge. Additionally, ocular inoculation with poly(I:C plus vaccine antigen generated no signs of inflammation within 24 hours: no increases in the mRNA expression levels of inflammatory cytokines nor in the infiltration of mononuclear cells to administration sites. In contrast, CT administration induced increased expression of IL-6 cytokine mRNA and mononuclear cell infiltration in the conjunctiva within 24 hours of vaccination. Moreover, inoculated visualizing materials by eyedrop did not contaminate the surface of the olfactory bulb in mice; meanwhile, intranasally administered materials defiled the surface of the brain. On the basis of these findings, we propose that the use of eyedrop inactivated influenza vaccine plus poly(I:C is a safe and effective mucosal vaccine strategy for inducing protective anti-influenza immunity.

  9. Induction of systemic and mucosal immunity and maintenance of its memory against influenza A virus by nasal vaccination using a new mucosal adjuvant SF-10 derived from pulmonary surfactant in young cynomolgus monkeys.

    Science.gov (United States)

    Mizuno, Dai; Kimoto, Takashi; Sakai, Satoko; Takahashi, Etsuhisa; Kim, Hyejin; Kido, Hiroshi

    2016-04-07

    Induction of systemic and mucosal immunity and maintenance of its memory was investigated in 12 young male cynomolgus monkeys after intranasal instillation of flu vaccine using a new mucosal adjuvant SF-10 derived from pulmonary surfactant constituents. Split-product of influenza virus A/California/7/2009(H1N1)pdm hemagglutinin vaccine (HAv) at 15 μg with or without SF-10 and the adjuvant alone were instilled intranasally three times every 2 weeks. SF-10-adjuvanted HAv (SF-10-HAv) elicited significantly higher HAv-specific IgG and hemagglutinin inhibition (HI) titers in serum and HAv-specific secretory IgA and its neutralizing activities in nasal washes compared with HAv antigen and SF-10 alone. Significant cross-neutralizing activities of nasal washes after the third vaccination to several other H1N1 and H3N2 strains were observed. HI titers in serum and neutralizing activities in nasal washes reached peak levels at 6 weeks after initial vaccination, then gradually decreased after 10 weeks and returned to the baseline levels at 36 weeks. A single intranasal revaccination of SF-10-HAv at 36 weeks rapidly and significantly increased both immunity in serum and nasal washes compared with naïve monkeys. Revaccination by one or two doses achieved almost maximal immunity at 2 or 4 weeks after instillation. Statistically significant adverse effects (e.g., body weight loss, elevated body temperature, nasal discharge, change in peripheral blood leukocyte and platelet counts) were not observed for 2 weeks after vaccination of SF-10-HAv, HAv or SF-10 and also during the experimental period. These results in young monkey model suggest the potential of clinical use SF-10 for intranasal flu vaccine.

  10. Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial.

    Science.gov (United States)

    Panahi, Yunes; Saadat, Alireza; Beiraghdar, Fatemeh; Sahebkar, Amirhossein

    2014-10-01

    Curcuminoids are bioactive polyphenolics with potent antiinflammatory properties. Although several lines of in vitro and preclinical evidence suggest potent anticancer effects of curcuminoids, clinical findings have not been conclusive. The present randomized double-blind placebo-controlled trial aimed to evaluate the efficacy of curcuminoids as adjuvant therapy in cancer patients. Eighty subjects with solid tumors who were under standard chemotherapy regimens were randomly assigned to a bioavailability-boosted curcuminoids preparation (180 mg/day; n = 40) or matched placebo (n = 40) for a period of 8 weeks. Efficacy measures were changes in the health-related quality of life (QoL) score (evaluated using the University of Washington index) and serum levels of a panel of mediators implicated in systemic inflammation including interleukins 6 (IL-6) and 8 (IL-8), TNF-α, transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene-related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). Curcuminoid supplementation was associated with a significantly greater improvement in QoL compared with placebo (p life variations were associated with changes in serum TGFβ levels in both correlation and regression analyses. Adjuvant therapy with a bioavailable curcuminoid preparation can significantly improve QoL and suppress systemic inflammation in patients with solid tumors who are under treatment with standard chemotherapy protocols.

  11. Chemokines as Cancer Vaccine Adjuvants

    Directory of Open Access Journals (Sweden)

    Agne Petrosiute

    2013-10-01

    Full Text Available We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants.

  12. Mucosal delivery switches the response to an adjuvanted tuberculosis vaccine from systemic TH1 to tissue-resident TH17 responses without impacting the protective efficacy.

    Science.gov (United States)

    Orr, Mark T; Beebe, Elyse A; Hudson, Thomas E; Argilla, David; Huang, Po-Wei D; Reese, Valerie A; Fox, Christopher B; Reed, Steven G; Coler, Rhea N

    2015-11-27

    Pulmonary tuberculosis (TB) remains one of the leading causes of infectious disease death despite widespread usage of the BCG vaccine. A number of new TB vaccines have moved into clinical evaluation to replace or boost the BCG vaccine including ID93+GLA-SE, an adjuvanted subunit vaccine. The vast majority of new TB vaccines in trials are delivered parenterally even though intranasal delivery can augment lung-resident immunity and protective efficacy in small animal models. Parenteral immunization with the adjuvanted subunit vaccine ID93+GLA-SE elicits robust TH1 immunity and protection against aerosolized Mycobacterium tuberculosis in mice and guinea pigs. Here we describe the immunogenicity and efficacy of this vaccine when delivered intranasally. Intranasal delivery switches the CD4 T cell response from a TH1 to a TH17 dominated tissue-resident response with increased frequencies of ID93-specific cells in both the lung tissue and at the lung surface. Surprisingly these changes do not affect the protective efficacy of ID93+GLA-SE. Unlike intramuscular immunization, ID93+GLA does not require the squalene-based oil-in-water emulsion SE to elicit protective CD4 T cells when delivered intranasally. Finally we demonstrate that TNF and the IL-17 receptor are dispensable for the efficacy of the intranasal vaccine suggesting an alternative mechanism of protection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Mucosal delivery switches the response to an adjuvanted tuberculosis vaccine from systemic TH1 to tissue-resident TH17 responses without impacting the protective efficacy§

    Science.gov (United States)

    Orr, Mark T.; Beebe, Elyse A.; Hudson, Thomas; Argilla, David; Huang, Po-Wei D.; Reese, Valerie A.; Fox, Christopher B.; Reed, Steven G.; Coler, Rhea N.

    2015-01-01

    Pulmonary tuberculosis (TB) remains one of the leading causes of infectious disease death despite widespread usage of the BCG vaccine. A number of new TB vaccines have moved into clinical evaluation to replace or boost the BCG vaccine including ID93+GLA-SE, an adjuvanted subunit vaccine. The vast majority of new TB vaccines in trials are delivered parenterally even though intranasal delivery can augment lung-resident immunity and protective efficacy in small animal models. Parenteral immunization with the adjuvanted subunit vaccine ID93+GLA-SE elicits robust TH1 immunity and protection against aerosolized Mycobacterium tuberculosis in mice and guinea pigs. Here we describe the immunogenicity and efficacy of this vaccine when delivered intranasally. Intranasal delivery switches the CD4 T cell response from a TH1 to a TH17 dominated tissue-resident response with increased frequencies of ID93-specific cells in both the lung tissue and at the lung surface. Surprisingly these changes do not affect the protective efficacy of ID93+GLA-SE. Unlike intramuscular immunization, ID93+GLA does not require the squalene-based oil-in-water emulsion SE to elicit protective CD4 T cells when delivered intranasally. Finally we demonstrate that TNF and the IL-17 receptor are dispensable for the efficacy of the intranasal vaccine suggesting an alternative mechanism of protection. PMID:26541135

  14. New horizons in adjuvants for vaccine development.

    Science.gov (United States)

    Reed, Steven G; Bertholet, Sylvie; Coler, Rhea N; Friede, Martin

    2009-01-01

    Over the last decade, there has been a flurry of research on adjuvants for vaccines, and several novel adjuvants are now in licensed products or in late stage clinical development. The success of adjuvants in enhancing the immune response to recombinant antigens has led many researchers to re-focus their vaccine development programs. Successful vaccine development requires knowing which adjuvants to use and knowing how to formulate adjuvants and antigens to achieve stable, safe and immunogenic vaccines. For the majority of vaccine researchers this information is not readily available, nor is access to well-characterized adjuvants. In this review, we outline the current state of adjuvant research and development and how formulation parameters can influence the effectiveness of adjuvants.

  15. A Review and Prospect on Herbicide Adjuvants

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The history, present status and future prospects of adjuvants application in herbicides were briefly reviewed. Adjuvants can be separated into two groups, activator adjuvants and utility adjuvants. The former directly enhances the efficacy of a herbicide through increasement of herbicide absorption, spreading, cuticular penetration, rainfastness and retention enhancement, and photodegradation of the herbicide can also be decreased. And the latter is utilized for improving application characteristics, behaviors and physical properties of herbicides and reducing or minimizing unwanted side effects on application.

  16. Adjuvant therapy in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Paula Ghaneh; John Slavin; Robert Sutton; Mark Hartley; John P Neoptolemos

    2001-01-01

    The outlook for patients with pancreatic cancer has been grim. There have been major advances in the surgical treatment of pancreatic csncer, leading to a drsmatic reduction in post-operative mortality from the development of high volume specialized centres. This stimulated the study of adjuvant and neoadjuvant treatments in pancreatic cancer including chemoradiotherapy and chemotherapy. Initial protocols have been based on the original but rather small GITSG study first reported in 1985. There have been two large European trials totalling over 600 patients (EORTC and ESPAC-1) that do not support the use of chemoradiation as adjuvant therapy. A second major finding from the ESPAC-1 trial (541 patients randomized) was some but not conclusive evidence for a survival benefit associated with chemotherapy. A third major finding from the ESPAC-1 trial was that the quality of life was not affected by the use of adjuvant treatments compared to surgery alone.The ESPAC-3 trial aims to assess the definitive use of adjuvant chemotherapy in a randomized controlled trial of 990 patients.

  17. Adjuvants and immunostimulants in fish vaccines: current knowledge and future perspectives.

    Science.gov (United States)

    Tafalla, Carolina; Bøgwald, Jarl; Dalmo, Roy A

    2013-12-01

    Vaccination is the most adequate method to control infectious diseases that threaten the aquaculture industry worldwide. Unfortunately, vaccines are usually not able to confer protection on their own; especially those vaccines based on recombinant antigens or inactivated pathogens. Therefore, the use of adjuvants or immunostimulants is often necessary to increase the vaccine efficacy. Traditional adjuvants such as mineral oils are routinely used in different commercial bacterial vaccines available for fish; however, important side effects may occur with this type of adjuvants. A search for alternative molecules or certain combinations of them as adjuvants is desirable in order to increase animal welfare without reducing protection levels. Especially, combinations that may target specific cell responses and thus a specific pathogen, with no or minor side effects, should be explored. Despite this, the oil adjuvants currently used are quite friendlier with respect to side effects compared with the oil adjuvants previously used. The great lack of fish antiviral vaccines also evidences the importance of identifying optimal combinations of a vaccination strategy with the use of a targeting adjuvant, especially for the promising fish antiviral DNA vaccines. In this review, we summarise previous studies performed with both traditional adjuvants as well as the most promising new generation adjuvants such as ligands for Toll receptors or different cytokines, focussing mostly on their protective efficacies, and also on what is known concerning their effects on the fish immune system when delivered in vivo.

  18. Novel adjuvants & delivery vehicles for vaccines development: a road ahead.

    Science.gov (United States)

    Mohan, Teena; Verma, Priyanka; Rao, D Nageswara

    2013-11-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines.

  19. Adjuvants for Clostridium tetani and Clostridium diphtheriae vaccines updating.

    Science.gov (United States)

    Alshanqiti, Fatimah M; Al-Masaudi, Saad B; Al-Hejin, Ahmed M; Redwan, Elrashdy M

    2017-01-01

    It's known that diphtheria and tetanus are a contagious lethal diseases over the years, they caused by pathogenic microbes corynebacterium diphtheria and Clostridium tetani, respectively. The diseases result from the production of bacterial toxin. Vaccination with bacterial toxoid vaccines adsorbed on particulates adjuvants still are the best way to prevent this epidemic diseases from spread. The particulate vaccines have been shown to be more efficient than soluble one for the induction of the immune responses. Nanoparticles can be engineered to enhance the immune responses. As well known the immune response to inactivate killed and subunit vaccine enhances by alum adjuvants. The adjuvants examined and tested after reducing its size to particle size, thus mimic size of viruses which is considered smallest units can derive the immune system. The major issue is minimizing the adjuvant particles, to gain insight of resulting immunity types and impact on immune response. The adjuvant effect of micro/nanoparticles appears to largely be a consequence of their uptake into antigen presenting cells.

  20. Who Benefits From Adjuvant Radiation Therapy for Gastric Cancer? A Meta-Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Ohri, Nitin, E-mail: ohri.nitin@gmail.com [Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York (United States); Garg, Madhur K. [Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York (United States); Aparo, Santiago; Kaubisch, Andreas [Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York (United States); Tome, Wolfgang [Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kennedy, Timothy J. [Department of Surgical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kalnicki, Shalom; Guha, Chandan [Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York (United States)

    2013-06-01

    Purpose: Large randomized trials have demonstrated significant survival benefits with the use of adjuvant chemotherapy or chemoradiation therapy for gastric cancer. The importance of adjuvant radiation therapy (RT) remains unclear. We performed an up-to-date meta-analysis of randomized trials testing the use of RT for resectable gastric cancer. Methods and Materials: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant (including neoadjuvant) RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine whether the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, or lymph node status. Results: Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR = 0.78, 95% CI: 0.70-0.86, P<.001) and DFS (HR = 0.71, 95% CI: 0.63-0.80, P<.001). In the 5 studies that tested adjuvant chemoradiation therapy against adjuvant chemotherapy, similar effects were seen for OS (HR = 0.83, 95% CI: 0.67-1.03, P=.087) and DFS (HR = 0.77, 95% CI: 0.91-0.65, P=.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusion: In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regard to patient selection and integration with systemic therapy.

  1. Markers of inflammation and oxidative stress studied in adjuvant-induced arthritis in the rat on systemic and local level affected by pinosylvin and methotrexate and their combination.

    Science.gov (United States)

    Bauerova, Katarina; Acquaviva, Alessandra; Ponist, Silvester; Gardi, Concetta; Vecchio, Daniela; Drafi, Frantisek; Arezzini, Beatrice; Bezakova, Lydia; Kuncirova, Viera; Mihalova, Danica; Nosal, Radomir

    2015-02-01

    Oxidative stress (OS) is important in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and its experimental model--adjuvant arthritis (AA). Antioxidants are scarcely studied in autoimmunity, and future analyses are needed to assess its effects in ameliorating these diseases. Although there are studies about antioxidants effects on the course of RA, their role in combination therapy has not yet been studied in detail, especially on extra-articular manifestations of AA. During the 28-d administration of pinosylvin (PIN) in monotherapy and in combination with methotrexate (MTX) to AA rats, we evaluated the impact of the treatment on selected parameters. The experiment included: healthy controls, untreated AA, AA administered 50 mg/kg b.w. of PIN daily p.o., AA administered 0.4 mg/kg b.w. of MTX twice weekly p.o. and AA treated with a combination of PIN+MTX. AA was monitored using: hind paw volume, C-reactive protein, monocyte chemotactic protein-1 (MCP-1), thiobarbituric acid reactive substances (TBARS) and F2-isoprostanes in plasma, γ-glutamyltransferase activity in spleen, activity of lipoxygenase (LOX) in lung, heme oxygenase-1 (HO-1) and nuclear factor kappa B (NF-κB) in liver and lung. PIN monotherapy significantly improved the activation of NF-κB in liver and lung, HO-1 expression and activity of LOX in the lung, MCP-1 levels in plasma (on 14th d) and plasmatic levels of F2-isoprostanes. An important contribution of PIN to MTX effect was the reduction of OS (an increase of HO-1 expression in lung and reduction of plasmatic TBARS) and decrease of LOX activity in the lung.

  2. Adjuvant

    Directory of Open Access Journals (Sweden)

    Ramadan M. Nafae

    2013-07-01

    Conclusion: Adjunctive 7 day course of low dose hydrocortisone IV in patients with CAP hastens clinical recovery and prevents the development of sepsis-related complications with a significant reduction in the duration of mechanical ventilation, duration of IV antibiotics and length of hospital stay with the improvement in hospital outcome and weaning success from mechanical ventilation.

  3. Novel Adjuvants and Immunomodulators for Veterinary Vaccines

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Fang, Yongxiang; Jungersen, Gregers

    2016-01-01

    Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the va...

  4. House dust extracts contain potent immunological adjuvants

    NARCIS (Netherlands)

    Beukelman, C.J.; Dijk, H. van; Aerts, P.C.; Rademaker, P.M.; Berrens, L.; Willers, J.M.N.

    1987-01-01

    A crude aqueous extract of house dust and two house dust subfractions were tested for adjuvant activity in a sensitivity assay performed in mice. Evidence is presented that house dust contains at least two potent immunological adjuvants. One of these, present in both subfractions, was probably endot

  5. Modulation of primary immune response by different vaccine adjuvants

    Directory of Open Access Journals (Sweden)

    Annalisa Ciabattini

    2016-10-01

    Full Text Available Adjuvants contribute to enhancing and shaping the vaccine immune response through different modes of action. Since the primary immune response can influence the overall quality of the response generated, here we investigate early biomarkers of adjuvanticity after primary immunization with four different adjuvants combined with the chimeric tuberculosis vaccine antigen H56. C57BL/6 mice were immunized by the subcutaneous route with different vaccine formulations, and the modulation of primary CD4+ T cell and B cell responses was assessed within draining lymph nodes, blood and spleen, 7 and 12 days after priming. Vaccine formulations containing the liposome system CAF01 or a squalene-based oil-in-water emulsion (o/w Squalene, but not aluminum hydroxide (Alum or CpG ODN 1826, elicited a significant primary antigen-specific CD4+ T cell response compared to antigen alone, 7 days after immunization. The effector function of activated CD4+ T cells was skewed towards a Th1/Th17 response by CAF01, while a Th1/Th2 response was elicited by o/w Squalene. Differentiation of B cells in short-lived plasma cells, and subsequent early H56-specific IgG secretion, was observed in mice immunized with o/w Squalene or CpG adjuvants. Tested adjuvants promoted the germinal centre reaction with different magnitude. These results show that the immunological activity of different adjuvants can be characterized by profiling early immunization biomarkers after primary immunization. These data and this approach could give an important contribution to the rational development of heterologous prime-boost vaccine immunization protocols.

  6. Adjuvants are Key Factors for the Development of Future Vaccines: Lessons from the Finlay Adjuvant Platform

    Science.gov (United States)

    Pérez, Oliver; Romeu, Belkis; Cabrera, Osmir; González, Elizabeth; Batista-Duharte, Alexander; Labrada, Alexis; Pérez, Rocmira; Reyes, Laura M.; Ramírez, Wendy; Sifontes, Sergio; Fernández, Nelson; Lastre, Miriam

    2013-01-01

    The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs), AFPL (proteoliposome), and AFCo (cochleate), were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed. PMID:24348475

  7. Evaluation of mucoadhesive carrier adjuvant: toward an oral anthrax vaccine.

    Science.gov (United States)

    Mangal, Sharad; Pawar, Dilip; Agrawal, Udita; Jain, Arvind K; Vyas, Suresh P

    2014-02-01

    The aim of present study was to evaluate the potential of mucoadhesive alginate-coated chitosan microparticles (A-CHMp) for oral vaccine against anthrax. The zeta potential of A-CHMp was -29.7 mV, and alginate coating could prevent the burst release of antigen in simulated gastric fluid. The results indicated that A-CHMp was mucoadhesive in nature and transported it to the peyer's patch upon oral delivery. The immunization studies indicated that A-CHMp resulted in the induction of potent systemic and mucosal immune responses, whereas alum-adjuvanted rPA could induce only systemic immune response. Thus, A-CHMp represents a promising acid carrier adjuvant for oral immunization against anthrax.

  8. Antifungal adjuvants: Preserving and extending the antifungal arsenal.

    Science.gov (United States)

    Butts, Arielle; Palmer, Glen E; Rogers, P David

    2017-02-17

    As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance.

  9. Freund's vaccine adjuvant promotes Her2/Neu breast cancer

    Directory of Open Access Journals (Sweden)

    Woditschka Stephan

    2009-01-01

    Full Text Available Abstract Background Inflammation has been linked to the etiology of many organ-specific cancers. Indirect evidence suggests a possible role for inflammation in breast cancer. We investigated whether the systemic inflammation induced by Freund's adjuvant (FA promotes mammary carcinogenesis in a rat model in which cancer is induced by the neu oncogene. Methods The effects of FA on hyperplastic mammary lesions and mammary carcinomas were determined in a neu-induced rat model. The inflammatory response to FA treatment was gauged by measuring acute phase serum haptoglobin. In addition, changes in cell proliferation and apoptosis following FA treatment were assessed. Results Rats receiving FA developed twice the number of mammary carcinomas as controls. Systemic inflammation following FA treatment is chronic, as shown by a doubling of the levels of the serum biomarker, haptoglobin, 15 days following initial treatment. We also show that this systemic inflammation is associated with the increased growth of hyperplastic mammary lesions. This increased growth results from a higher rate of cellular proliferation in the absence of changes in apoptosis. Conclusion Our data suggests that systemic inflammation induced by Freund's adjuvant (FA promotes mammary carcinogenesis. It will be important to determine whether adjuvants currently used in human vaccines also promote breast cancer.

  10. Safety of vaccine adjuvants: focus on autoimmunity.

    Science.gov (United States)

    van der Laan, Jan Willem; Gould, Sarah; Tanir, Jennifer Y

    2015-03-24

    Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in relation to autoimmunity or autoimmune disease(s)/disorder(s) (AID). The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. The types of adjuvants considered included oil-in-water emulsions and toll-like receptor (TLR) agonists. The state of science around the use of animal models and biomarkers for the evaluation and prediction of AID were also discussed. Following extensive literature reviews by the HESI committee, and presentations by experts at the workshop, several key points were identified, including the value of animal models used to study autoimmunity and AID toward studying novel vaccine adjuvants; whether there is scientific evidence indicating an intrinsic risk of autoimmunity and AID with adjuvants, or a higher risk resulting from the mechanism of action; and if there is compelling clinical data linking adjuvants and AID. The tripartite group of experts concluded that there is no compelling evidence supporting the association of vaccine adjuvants with autoimmunity signals. Additionally, it is recommended that future research on the potential effects of vaccine adjuvants on AID should consider carefully the experimental design in animal models particularly if they are to be used in any risk assessment, as an improper design and model could result in misleading information. Finally, studies on the mechanistic aspects and potential biomarkers related to adjuvants and autoimmunity phenomena could be developed.

  11. Glucocorticosteroids: as Adjuvant Therapy for Bacterial Infections

    Directory of Open Access Journals (Sweden)

    WONDIM MELKAM

    2015-01-01

    Full Text Available Glucocorticoids (GCs, synthetic analogues of the natural steroid hormones, are well known for their antiinflammatory and immunosuppressive properties in the periphery. They are widely and successfully used in the treatment of autoimmune diseases, chronic inflammation, and transplant rejection. Nowadays, GCs are claimed to have a beneficial role being as adjunct therapy in various infections. Different studies have been conducted to investigate their use as adjuvant therapy for different bacterial infection. This review, therefore, summarizes various bacterial infections for which glucocorticoids are reported to be used as adjuvant therapy, strategies for administration of glucocorticoids, and challenges of using glucocorticoids as adjuvant therapy.

  12. Adjuvants to local anesthetics: Current understanding and future trends

    Science.gov (United States)

    Swain, Amlan; Nag, Deb Sanjay; Sahu, Seelora; Samaddar, Devi Prasad

    2017-01-01

    Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal

  13. [Adjuvant dermato-cosmetic acne therapy].

    Science.gov (United States)

    Bayerl, Christiane; Degitz, Klaus; Meigel, Eva; Kerscher, Martina

    2010-03-01

    Adjuvant dermato-cosmetic therapy in acne is an essential part of the concept of treating acne after initiation and during maintenance therapy. Those are mechanical peeling, chemical peeling and its combination. It needs supervision by an experienced dermatologist.

  14. Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: Facts and controversies.

    Science.gov (United States)

    Schiavo, Ada Lo; Puca, Rosa Valentina; Ruocco, Vincenzo; Ruocco, Eleonora

    2010-01-01

    During the last decades, the conventional therapy for autoimmune blistering diseases has been high-dose, long-term systemic corticosteroid and immunosuppressive agents or adjuvant drugs. Long-term, high-dose steroid therapy can result in serious adverse effects. The rationale for using adjuvant drugs is that concerns reducing the need for corticosteroids, and hence, their side effects, or it may result in better control of the disease, or both. Immunosuppressive agents are not free of adverse effects, however. Prolonged immune suppression may account for high rates of morbidity, disability, and possible death. There is no consensus about the first-choice adjuvant drug for the management of blistering autoimmune diseases. This contribution evaluates six adjuvant drugs-cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, intravenous immunoglobulin, and rituximab-and discusses the choice of a "winning drug" that is effective and safe.

  15. THE EFFECT OF SYNTHETIC ADJUVANT ON THE FORMATION OF THE IMMUNE RESPONSE

    Directory of Open Access Journals (Sweden)

    Savina, S.V.

    2016-08-01

    Full Text Available The paper contains experimental materials on the effects of synthetic adjuvants on the formation of the immune responses. Currently, the search continues for new effective vaccines based on polymeric compounds having immunostimulating properties (Petrov R. V. et al. 1986, V. Schijns,2000 An important condition in the development of certain carriers (adjuvants is the creation of a drug capable of long-term is in the body, with its active immune system and no local and General negative reactions in the body (Volpin O. M.,1992, etc.. We carried out experiments to study the synthetic adjuvant (BP, the raw material which is polydiallyldimethyl chloride - PES. Conducted preclinical trials to study acute and chronic toxicity in laboratory animals showed no abnormalities in physiological and Toxicological parameters, i.e. its harmlessness. The results show positive effects of synthetic adjuvants on the formation of General immune responses in animals that allow it to be used as a filler in vaccines.

  16. Adjuvants for spraying of fungicides in wheat

    OpenAIRE

    2014-01-01

    The foliar diseases and spike can markedly reduce the yield of wheat. Despite prevailing chemical control in the management of disease, studies with adjuvants to improve the performance of fungicides are still incipient. The aim of this study was to evaluate the effect of adding adjuvants to chemical fungicides to control leaf diseases and spike, as well as on the yield of wheat crop. The experimental design was a randomized block design with 05 treatments: control (no fungicide application i...

  17. Applications of nanomaterials as vaccine adjuvants.

    Science.gov (United States)

    Zhu, Motao; Wang, Rongfu; Nie, Guangjun

    2014-01-01

    Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials' physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants.

  18. Molecular Dynamic Analysis of Hyaluronic Acid and Phospholipid Interaction in Tribological Surgical Adjuvant Design for Osteoarthritis.

    Science.gov (United States)

    Siódmiak, Jacek; Bełdowski, Piotr; Augé, Wayne K; Ledziński, Damian; Śmigiel, Sandra; Gadomski, Adam

    2017-09-04

    Tribological surgical adjuvants constitute a therapeutic discipline made possible by surgical advances in the treatment of damaged articular cartilage beyond palliative care. The purpose of this study is to analyze interactions between hyaluronic acid and phospholipid molecules, and the formation of geometric forms, that play a role in the facilitated lubrication of synovial joint organ systems. The analysis includes an evaluation of the pathologic state to detail conditions that may be encountered by adjuvants during surgical convalescence. The synovial fluid changes in pH, hyaluronic acid polydispersity, and phospholipid concentration associated with osteoarthritis are presented as features that influence the lubricating properties of adjuvant candidates. Molecular dynamic simulation studies are presented, and the Rouse model is deployed, to rationalize low molecular weight hyaluronic acid behavior in an osteoarthritic environment of increased pH and phospholipid concentration. The results indicate that the hyaluronic acid radius of gyration time evolution is both pH- and phospholipid concentration-dependent. Specifically, dipalmitoylphosphatidylcholine induces hydrophobic interactions in the system, causing low molecular weight hyaluronic acid to shrink and at high concentration be absorbed into phospholipid vesicles. Low molecular weight hyaluronic acid appears to be insufficient for use as a tribological surgical adjuvant because an increased pH and phospholipid concentration induces decreased crosslinking that prevents the formation of supramolecular lubricating forms. Dipalmitoylphosphatidylcholine remains an adjuvant candidate for certain clinical situations. The need to reconcile osteoarthritic phenotypes is a prerequisite that should serve as a framework for future adjuvant design and subsequent tribological testing.

  19. Micro/nanoparticle adjuvants for antileishmanial vaccines: present and future trends.

    Science.gov (United States)

    Badiee, Ali; Heravi Shargh, Vahid; Khamesipour, Ali; Jaafari, Mahmoud Reza

    2013-01-21

    Leishmania infection continues to have a major impact on public health inducing significant morbidity and mortality mostly in the poorest populations. Drug resistance, toxicity and side effects associated with expensive chemotherapeutic treatments and difficult reservoir control emphasize the need for a safe and effective vaccine which is not available yet. Although, Leishmanization (LZ) was shown to be effective against cutaneous leishmaniasis, standardization and safety are the main problems of LZ. First generation killed parasites demonstrated limited efficacy in phase 3 trials and moreover well defined molecules have not reached to phase 3 yet. Limited efficacy in vaccines against leishmaniasis is partly due to lack of an appropriate adjuvant. Hence, the use of particulate delivery systems as carriers for antigen and/or immunostimulatory adjuvants for effective delivery to the antigen-presenting cells (APCs) is a valuable strategy to enhance vaccine efficacies. Particle-based delivery systems such as emulsions, liposomes, virosomes, and polymeric microspheres have the potential for successfully delivering antigens, which can then be further improved via incorporation of additional antigenic or immustimulatory adjuvant components in or onto the particle carrier system. In this review, we have attempted to provide a list of particulate vaccine delivery systems involved in the production of candidate leishmaniasis vaccines and introduced some potentially useful vaccine delivery systems for leishmaniasis in future experiments. In conclusion, combination vaccines (adjuvant systems) composed of candidate antigens and more importantly well-developed particulate delivery systems, such as lipid-based particles containing immunostimulatory adjuvants, have a chance to succeed as antileishmanial vaccines.

  20. Liposome as vaccine adjuvant and delivery system%脂质体作为疫苗佐剂和给药系统的应用

    Institute of Scientific and Technical Information of China (English)

    郭秀侠; 杨倩; 于洪涛

    2006-01-01

    Liposomes are artificial, spherical, closed vesicles consisting of one or more lipid bilayer (s). Liposomes made from ester phospholipids have been studied extensively over the last 3 decades as artificial membrane models. Considerable interest has been generated for applications of liposomes in medicine, including their use as diagnostic reagents, as carrier vehicles in vaccine formulations, or as delivery systems for drugs, genes, or cancer imaging agents[1]. There are now liposomal formulations of conventional drugs that have received clinical approval and many others in clinical trials that bring benefits of reduced toxicity and enhanced efficacy for the treatment of cancer and other life-threatening diseases[2].

  1. Mesoporous silica nanoparticles as antigen carriers and adjuvants for vaccine delivery

    Science.gov (United States)

    Mody, Karishma T.; Popat, Amirali; Mahony, Donna; Cavallaro, Antonino S.; Yu, Chengzhong; Mitter, Neena

    2013-05-01

    Vaccines have been at the forefront of improving human health for over two centuries. The challenges faced in developing effective vaccines flow from complexities associated with the immune system and requirement of an efficient and safe adjuvant to induce a strong adaptive immune response. Development of an efficient vaccine formulation requires careful selection of a potent antigen, efficient adjuvant and route of delivery. Adjuvants are immunological agents that activate the antigen presenting cells (APCs) and elicit a strong immune response. In the past decade, the use of mesoporous silica nanoparticles (MSNs) has gained significant attention as potential delivery vehicles for various biomolecules. In this review, we aim to highlight the potential of MSNs as vaccine delivery vehicles and their ability to act as adjuvants. We have provided an overview on the latest progress on synthesis, adsorption and release kinetics and biocompatibility of MSNs as next generation antigen carriers and adjuvants. A comprehensive summary on the ability of MSNs to deliver antigens and elicit both humoral and cellular immune responses is provided. Finally, we give insight on fundamental challenges and some future prospects of these nanoparticles as adjuvants.

  2. Inducible nitric oxide synthase and guinea-pig ileitis induced by adjuvant

    Directory of Open Access Journals (Sweden)

    N. D. Seago

    1995-01-01

    Full Text Available We sought to establish a model of inflammatory bowel disease by augmenting the activity of the local immune system with Freund's complete adjuvant, and to determine if inducible nitric oxide synthase (iNOS expression and peroxynitrite formation accompanied the inflammatory condition. In anaesthetized guinea-pigs, a loop of distal ileum received intraluminal 50% ethanol followed by Freund's complete adjuvant. Control animals were sham operated. When the animals were killed 7 or 14 days later, loop lavage fluid was examined for nitrite and PGE2 levels; mucosal levels of granulocyte and macrophages were estimated by myeloperoxidase (MPO and N-acetyl-D-glucosaminidase (NAG activity, respectively. Cellular localization if iNOS and peroxynitrite formation were determined by immunohistochemistry with polyclonal antibodies directed against peptide epitopes of mouse iNOS and nitrotyrosine, respectfully. Adjuvant administration resulted in a persistent ileitis, featuring gut thickening, crypt hyperplasia, villus tip swelling and disruption, and cellular infiltration. Lavage levels of PGE2 and nitrite were markedly elevated by adjuvant treatment. Immunoreactive iNOS and nitrotyrosine bordered on detectability in normal animals but were markedly evident with adjuvant treatment at day 7 and particularly day 14. Immunohistochemistry suggested that enteric neurons and epithelia were major sites of iNOS activity and peroxynitrite formation. We conclude that local administration of adjuvant establishes a chronic ileitis. Inducible nitric oxide synthase may contribute to the inflammatory process.

  3. Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

    Directory of Open Access Journals (Sweden)

    Karen A.O. Martins

    2016-01-01

    Full Text Available Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol, MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development.

  4. Squalene and squalane emulsions as adjuvants.

    Science.gov (United States)

    Allison, A C

    1999-09-01

    Microfluidized squalene or squalane emulsions are efficient adjuvants, eliciting both humoral and cellular immune responses. Microfluidization stabilizes the emulsions and allows sterilization by terminal filtration. The emulsions are stable for years at ambient temperature and can be frozen. Antigens are added after emulsification so that conformational epitopes are not lost by denaturation and to facilitate manufacture. A Pluronic block copolymer can be added to the squalane or squalene emulsion. Soluble antigens administered in such emulsions generate cytotoxic T lymphocytes able to lyse target cells expressing the antigen in a genetically restricted fashion. Optionally a relatively nontoxic analog of muramyl dipeptide (MDP) or another immunomodulator can be added; however, the dose of MDP must be restricted to avoid systemic side effects in humans. Squalene or squalane emulsions without copolymers or MDP have very little toxicity and elicit potent antibody responses to several antigens in nonhuman primates. They could be used to improve a wide range of vaccines. Squalene or squalane emulsions have been administered in human cancer vaccines, with mild side effects and evidence of efficacy, in terms of both immune responses and antitumor activity.

  5. Suppression of complete Freund's adjuvant-induced adjuvant arthritis by cobratoxin

    Institute of Scientific and Technical Information of China (English)

    Yan-li LIU; Hai-ming LIN; Rong ZOU; Jun-chao WU; Rong HAN; Laurence N RAYMOND; Paul F REID; Zheng-hong QIN

    2009-01-01

    Aim:Cobratoxin (CTX),the long-chain α-neurotoxin from Thailand cobra venom,has been demonstrated to have analgesic action in rodent pain models.The present study evaluated the anti-inflammatory and anti-nociceptive effects of CTX on adju-vant arthritis (AA) in rats.Methods: Arthritis was induced by injection of complete Freund's adjuvant (CFA) in rats.Paw swelling and hyperalgesia of AA rats were measured at various times after CFA administration.Tumor necrosis factor-a (TNF-α),interleukin-1 (IL-1),interleukin-2 (IL-2) and interleukin-10 (IL-10) levels in serum were determined with ELISA.Histopathological changes in synoviocytes were examined under a microscope.Involvement of the cholinergic system in the effects of CTX was examinedby pretreatment of animals with the α7 nicotinic receptor (α7-nAChR) antagonist methyllycaconitine (MLA).Results: CFA induced marked paw swelling and reduced thresholds of mechanical and cold-induced paw withdrawal.The lev-els of TNF-α,IL-1 and IL-2 in the serum of AA rats were increased,whereas the level of IL-10 was decreased.Histopathologi-cal examination of synoviocytes showed pronounced inflammation and accumulation of collagen.The administration of CTX (17.0 μg/kg,ip) significantly reduced paw swelling and mechanical and thermal hyperalgesia.CTX also reduced the produc-tion ofTNF-α,IL-1,and IL-2 but increased the production of IL-10 and altered pathohistological changes.The analgesic and anti-inflammatory efficacy of CTX was significantly reduced by MLA (3 mg/kg,sc).Conclusion: These results indicate that CTX has a beneficial effect on CFA-induced arthritis by modulating the production of inflammatory cytokines,α7-nAChR appears to mediate the anti-nociceptive and anti-inflammatory actions of CTX.

  6. Adjuvant chemotherapy in early breast cancer

    DEFF Research Database (Denmark)

    Ejlertsen, Bent

    2016-01-01

    % of patients aged 40 or younger in 77B had regular menses throughout chemotherapy, the corresponding percentage was 37 in 82B and 47 in 89B. The DBCG in collaboration with a Swedish and a Dutch centre participating in the DBCG trial 89B compared CMF with ovarian ablation in premenopausal high-risk breast...... are not clinically useful by themselves as other chemotherapy regimens have been more efficacious, and knowledge is still lacking regarding the benefits from adding ovarian suppression to chemotherapy plus tamoxifen. The results from the DBCG 77B and 82C are in accordance with other large adjuvant trials...... adjuvant trials demonstrated that patients with either TOP2A or centromere 17 aberrations, but not with HER2 amplification, benefit from anthracycline-containing adjuvant chemotherapy. Anthracyclins have additional distinct biological mechanisms; and results from the DBCG 89D suggested that tumours...

  7. [Adjuvant chemotherapy for patients with rectal cancer].

    Science.gov (United States)

    Qvortrup, Camilla; Mortensen, John Pløen; Pfeiffer, Per

    2013-09-09

    A new Cochrane meta-analysis evaluated adjuvant chemotherapy (5-fluorouracil (5FU)-based, not modern combination chemotherapy) in almost 10,000 patients with rectal cancer and showed a 17% reduction in mortality corresponding well to the efficacy observed in recent studies, which reported a reduction in mortality just about 20%. The authors recommend adjuvant chemotherapy which is in accordance with the Danish national guidelines where 5-FU-based chemotherapy is recommended for stage III and high-risk stage II rectal cancer.

  8. The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma:a systematic review

    Institute of Scientific and Technical Information of China (English)

    Wan-Yee Lau; Eric C. H. Lai; Stephanie H. Y. Lau

    2009-01-01

    BACKGROUND: Following curative treatment for hepato-cellular carcinoma (HCC), 50%-90% of postoperative death is due to recurrent disease. Intra-hepatic recurrence is frequently the only site of recurrence. Thus, any neoadjuvant or adjuvant therapy, which can decrease or delay the incidence of intra-hepatic recurrence, or any cancer chemoprevention which can prevent a new HCC from developing in the liver remnant, will improve the results of liver resection. This article systematically reviewed the current evidence of neoadjuvant, adjuvant, and chemoprevention in partial hepatectomy of HCC. DATA SOURCES: Studies were identiifed by searching MEDLINE and PubMed databases for articles from January 1990 to November 2008 using the keywords"hepatocellular carcinoma", "hepatectomy", "adjuvant therapy", "neoadjuvant therapy", and "regional therapy". Additional papers and book chapters were identiifed by a manual search of the references from the key articles. RESULTS: Neoadjuvant transarterial chemoembolization or adjuvant regional transarterial chemotherapy± embolization+systemic chemotherapy did not add beneift. Both adjuvant transarterial radioembolization with 131I-lipiodol and adjuvant systemic interferon showed promising results. However, there were only a limited number of such studies.CONCLUSIONS: Further randomized controlled studies need to be carried out. Currently, there is no consensus on a standard neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for HCC.

  9. Gaps in knowledge and prospects for research of adjuvanted vaccines.

    Science.gov (United States)

    Seder, Robert; Reed, Steven G; O'Hagan, Derek; Malyala, Padma; D'Oro, Ugo; Laera, Donatello; Abrignani, Sergio; Cerundolo, Vincenzo; Steinman, Lawrence; Bertholet, Sylvie

    2015-06-08

    A panel of researchers working in different areas of adjuvanted vaccines deliberated over the topic, "Gaps in knowledge and prospects for research of adjuvanted vaccines" at, "Enhancing Vaccine Immunity and Value" conference held in July 2014. Several vaccine challenges and applications for new adjuvant technologies were discussed.

  10. Soluble proteins modified with acetaldehyde and malondialdehyde are immunogenic in the absence of adjuvant.

    Science.gov (United States)

    Thiele, G M; Tuma, D J; Willis, M S; Miller, J A; McDonald, T L; Sorrell, M F; Klassen, L W

    1998-11-01

    Recent studies have shown that the alcohol metabolites malondialdehyde and acetaldehyde can combine to form a stable adduct (MAA) on proteins. This adduct has been detected in the livers of rats chronically consuming ethanol, and serum antibodies to MAA have been observed at significantly higher concentrations in ethanol-fed when compared with pair-fed or chow-fed control rats. More recently, preliminary studies have strongly suggested that the MAA adduct is capable of stimulating antibody responses to soluble proteins in the absence of adjuvants. The antibodies produced recognize either the MAA epitope or the carrier protein itself. Therefore, it was the purpose of this study to examine the potential immunogenicity of MAA-modified exogenous proteins in the absence of adjuvants. Balb/c mice were immunized in the presence or absence of adjuvant with different concentrations of unmodified or MAA-modified proteins. The antibody response to both the MAA epitope and unmodified protein epitopes were determined by ELISA. In the absence of adjuvant, significant antibody responses were induced to both the MAA epitope and nonmodified protein epitopes. Smaller immunizing doses of MAA-protein conjugate favored the production of antibodies to nonmodified proteins, whereas larger doses induced a strong anti-MAA response. In studies to begin determining a mechanism for the specificity of the response in the absence of adjuvants, peritoneal macrophages were found to bind and degrade MAA-adducted proteins through the use of a scavenger receptor. This indicated that MAA-adducted proteins may be specifically taken up and epitopes presented to the humoral immune system in the absence of adjuvants. Importantly, these are the first data showing that an alcohol-related metabolite can induce an antibody response in the absence of adjuvant and suggesting a mechanism by which antibody to the MAA adduct or its carrier (exogenous or endogenous) proteins may be generated in vivo.

  11. Computational prediction of multidisciplinary team decision-making for adjuvant breast cancer drug therapies: a machine learning approach.

    Science.gov (United States)

    Lin, Frank P Y; Pokorny, Adrian; Teng, Christina; Dear, Rachel; Epstein, Richard J

    2016-12-01

    Multidisciplinary team (MDT) meetings are used to optimise expert decision-making about treatment options, but such expertise is not digitally transferable between centres. To help standardise medical decision-making, we developed a machine learning model designed to predict MDT decisions about adjuvant breast cancer treatments. We analysed MDT decisions regarding adjuvant systemic therapy for 1065 breast cancer cases over eight years. Machine learning classifiers with and without bootstrap aggregation were correlated with MDT decisions (recommended, not recommended, or discussable) regarding adjuvant cytotoxic, endocrine and biologic/targeted therapies, then tested for predictability using stratified ten-fold cross-validations. The predictions so derived were duly compared with those based on published (ESMO and NCCN) cancer guidelines. Machine learning more accurately predicted adjuvant chemotherapy MDT decisions than did simple application of guidelines. No differences were found between MDT- vs. ESMO/NCCN- based decisions to prescribe either adjuvant endocrine (97%, p = 0.44/0.74) or biologic/targeted therapies (98%, p = 0.82/0.59). In contrast, significant discrepancies were evident between MDT- and guideline-based decisions to prescribe chemotherapy (87%, p machine learning models. A machine learning approach based on clinicopathologic characteristics can predict MDT decisions about adjuvant breast cancer drug therapies. The discrepancy between MDT- and guideline-based decisions regarding adjuvant chemotherapy implies that certain non-clincopathologic criteria, such as patient preference and resource availability, are factored into clinical decision-making by local experts but not captured by guidelines.

  12. in vivo evaluation of chitosan as an adjuvant in subcutaneous vaccine formulations

    DEFF Research Database (Denmark)

    Scherließ, Regina; Buske, Simon; Young, Katherine

    2013-01-01

    Vaccines utilising pure antigens instead of whole pathogens and alternative administration routes require the use of potent adjuvants and effective antigen delivery systems. Chitosan has been reported to act as both an adjuvant as well as a matrix for delivery systems. Chitosan is a natural product...... produced predominantly from crab shell and commercially available preparations vary in molecular weight, degree of deacetylation and purity. In this study, the impact of chitosan characteristics (molecular weight, degree of deacetylation, particle size, viscosity and impurities) on adjuvant activity were...... examined. It could be shown that the degree of immune response differed if different chitosan qualities were used and this could be attributed to different characteristics of the chitosan qualities: the immunoadjuvant effect of chitosan probably is a result of an interplay between chemical properties...

  13. Comparative assessment of humoral immune responses of aluminum hydroxide and oil-emulsion adjuvants in Influenza (H9N2) and Newcastle inactive vaccines to chickens.

    Science.gov (United States)

    Jafari, Mahdie; Moghaddam Pour, Masoud; Taghizadeh, Morteza; Masoudi, Shahin; Bayat, Zahra

    2017-02-01

    Context Adjuvants are compounds used in the preparation of inactive vaccines to enhance the immune response. Aluminum hydroxide (alum) is one of the first compounds approved by the Food and Drug Administration, which is used as adjuvants in vaccine products for humans. Montanide ISA 70 is an oil-emulsion adjuvant and is used in poultry inactive vaccines. Objective In this study, the effects of alum adjuvant on the efficiency and induction of immune response in inactive vaccines of Influenza and Newcastle are compared with those of ISA 70. Materials and methods Six groups of 7-d-old specific-pathogen-free chickens were inoculated with 0.3 ml of the prepared vaccines via the subcutaneous route in the neck. Immune response in each group after 7, 14, 21, 31, 41, and 45 d was evaluated using the technique of hemagglutination inhibition. Results The results were compared using SPSS software. Results showed that vaccines containing adjuvant ISA 70 depicted a higher increase in the immune response and adjuvant of 20% alum is similar to adjuvant of ISA 70 in boosting the immune system. There was no statistically significant difference between 10% and 20% alum, but these adjuvants are visibly different from ISA 70. Conclusion In conclusion, alum can be used as an easily accessible, harmless, and effective adjuvant; however, to increase the immune period using the inactive vaccines for poultry, more research would be necessary.

  14. Vitamins as influenza vaccine adjuvant components.

    Science.gov (United States)

    Quintilio, Wagner; de Freitas, Fábio Alessandro; Rodriguez, Dunia; Kubrusly, Flavia Saldanha; Yourtov, Dimitri; Miyaki, Cosue; de Cerqueira Leite, Luciana Cezar; Raw, Isaias

    2016-10-01

    A number of adjuvant formulations were assayed in mice immunized with 3.75 µg of A/California/7/2009 (H1N1) pdm09 influenza vaccine with vitamins A, D and/or E in emulsions or B2 and/or B9 combined with Bordetella pertussis MPLA and/or alum as adjuvants. Squalene was used as positive control, as well as MPLA with alum. The immune response was evaluated by a panel of tests, including a hemagglutination inhibition (HAI) test, ELISA for IgG, IgG1, and IgG2a and IFN-γ, IL-2, IL-6 and IL-10 quantification in splenocyte culture supernatant after stimulus with influenza antigen. Immunological memory was evaluated using a 1/10 dose booster 60 days after the first immunization followed by assessment of the response by HAI, IgG ELISA, and determination of the antibody affinity index. The highest increases in HAI, IgG1 and IgG2a titers were obtained with the adjuvant combinations containing vitamin E, or the hydrophilic combinations containing MPLA and alum or B2 and alum. The IgG1/IgG2a ratio indicates that the response to the combination of B2 with alum would have more Th2 character than the combination of MPLA with alum. In an assay to investigate the memory response, a significant increase in HAI titer was observed with a booster vaccine dose at 60 days after immunization with vaccines containing MPLA with alum or B2 with alum. Overall, of the 27 adjuvant combinations, MPLA with alum and B2 with alum were the most promising adjuvants to be evaluated in humans.

  15. Review article: surgical, neo-adjuvant and adjuvant management strategies in biliary tract cancer.

    Science.gov (United States)

    Skipworth, J R A; Olde Damink, S W M; Imber, C; Bridgewater, J; Pereira, S P; Malagó, M

    2011-11-01

    The majority of patients with cholangiocarcinoma present with advanced, irresectable tumours associated with poor prognosis. The incidence and mortality rates associated with cholangiocarcinoma continue to rise, mandating the development of novel strategies for early detection, improved resection and treatment of residual lesions. To review the current evidence base for surgical, adjuvant and neo-adjuvant techniques in the management of cholangiocarcinoma. A search strategy incorporating PubMed/Medline search engines and utilising the key words biliary tract carcinoma; cholangiocarcinoma; management; surgery; chemotherapy; radiotherapy; photodynamic therapy; and radiofrequency ablation, in various combinations, was employed. Data on neo-adjuvant and adjuvant techniques remain limited, and much of the literature concerns palliation of inoperable disease. The only opportunity for long-term survival remains surgical resection with negative pathological margins or liver transplantation, both of which remain possible in only a minority of selected patients. Neo-adjuvant and adjuvant techniques currently provide only limited success in improving survival. The development of novel strategies and treatment techniques is crucial. However, the shortage of randomised controlled trials is compounded by the low feasibility of conducting adequately powered trials in liver surgery, due to the large sample sizes that are required. © 2011 Blackwell Publishing Ltd.

  16. Meta-Analysis on Randomized Controlled Trials of Vaccines with QS-21 or ISCOMATRIX Adjuvant: Safety and Tolerability.

    Directory of Open Access Journals (Sweden)

    Emilia Bigaeva

    Full Text Available QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™ from vaccine trials.A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs and their 95% confidence intervals (CIs were calculated using a random-effects model. Jadad scale was used to assess the study quality.Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines (RR 2.55, 95% CI 1.04-6.24. No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain (RR 4.11, 95% CI 1.10-15.35 and RR 2.55, 95% CI 1.41-4.59, respectively. ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling (RR 3.43, 95% CI 1.08-10.97.Our findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the

  17. Side effects in melanoma patients receiving adjuvant interferon alfa-2b therapy: a nurse's perspective.

    Science.gov (United States)

    Rubin, Krista M; Vona, Karen; Madden, Kathleen; McGettigan, Suzanne; Braun, Ilana M

    2012-08-01

    The aim of this review was to examine the toxicity profile of adjuvant interferon (IFN) alfa-2b in melanoma patients from a nursing perspective and to summarize practical information to guide the effective management of common IFN toxicities to improve patient comfort. This is a narrative summary of both research and review articles identified by searching PubMed, National Cancer Institute, and American Cancer Society websites. It also assesses recognized guidelines on the management of adjuvant IFN toxicity relevant to nurses who are caring for patients receiving adjuvant IFN therapy. Adjuvant high-dose IFN alfa-2b (HDI) as compared with observation significantly prolongs relapse-free survival in patients with melanoma at high risk for recurrence after surgical resection; however, treatment compliance and patient quality of life can be compromised by its toxicity profile. HDI toxicities affect a number of organ systems and the majority of patients will experience some side effects. Common toxicities such as flu-like symptoms, fatigue, anorexia, neuropsychiatric symptoms, and laboratory abnormalities are discussed, along with both pharmacological and nonpharmacological management strategies. The considerable side effects of HDI can be managed using established strategies. Oncology nurses play a significant role in the management of patients with melanoma receiving adjuvant HDI, and their prompt recognition of side effects, together with an understanding of effective pharmacological and nonpharmacological interventions, will improve patient comfort; this has the potential to positively influence treatment adherence and completion of the recommended treatment course.

  18. Effects of adjuvants on IgG subclasses elicited by virus-like Particles

    Directory of Open Access Journals (Sweden)

    Visciano Maria Luisa

    2012-01-01

    Full Text Available Abstract Background Virus-Like Particles (VLPs represent an efficient strategy to present and deliver conformational antigens to the immune system, inducing both arms of the adaptive immune response. Moreover, their particulate structure surrounded by cell membrane provides an adjuvanted effect to VLP-based immunizations. In the present study, the elicitation of different patterns of IgG subclasses by VLPs, administered in CpG ODN1826 or poly(I:C adjuvants, has been evaluated in an animal model. Results Adjuvanted VLPs elicited a higher titer of total specific IgG compared to VLPs alone. Furthermore, while VLPs alone induced a balanced TH2 pattern, VLPs formulated with either adjuvant elicited a TH1-biased IgG subclasses (IgG2a and IgG3, with poly(I:C more potent than CpG ODN1826. Conclusions The results confirmed that adjuvants efficiently improve antigen immunogenicity and represent a suitable strategy to skew the adaptive immune response toward the differentiation of the desired T helper subset, also using VLPs as antigen.

  19. Infected dendritic cells are sufficient to mediate the adjuvant activity generated by Venezuelan equine encephalitis virus replicon particles

    OpenAIRE

    Tonkin, Daniel R.; Whitmore, Alan; Robert E Johnston; Barro, Mario

    2012-01-01

    Replicon particles derived from Venezuelan equine encephalitis virus (VEE) are infectious non-propagating particles which act as a safe and potent systemic, mucosal, and cellular adjuvant when delivered with antigen. VEE and VEE replicon particles (VRP) can target multiple cell types including dendritic cells (DCs). The role of these cell types in VRP adjuvant activity has not been previously evaluated, and for these studies we focused on the contribution of DCs to the response to VRP. By ana...

  20. Infected dendritic cells are sufficient to mediate the adjuvant activity generated by Venezuelan equine encephalitis virus replicon particles

    OpenAIRE

    Tonkin, Daniel R.; Whitmore, Alan; Johnston, Robert E.; Barro,Mario

    2012-01-01

    Replicon particles derived from Venezuelan equine encephalitis virus (VEE) are infectious non-propagating particles which act as a safe and potent systemic, mucosal, and cellular adjuvant when delivered with antigen. VEE and VEE replicon particles (VRP) can target multiple cell types including dendritic cells (DCs). The role of these cell types in VRP adjuvant activity has not been previously evaluated, and for these studies we focused on the contribution of DCs to the response to VRP. By ana...

  1. New generation adjuvants--from empiricism to rational design.

    Science.gov (United States)

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-08

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. [Gastrointestinal surgeons should master the adjuvant therapy of colorectal cancer].

    Science.gov (United States)

    Gu, Jin; Chen, Pengju

    2015-10-01

    The diagnosis and treatment of colorectal cancer is one of the main diseases of gastrointestinal surgeons. It is very important to master the adjuvant chemotherapy of colorectal cancer for gastrointestinal surgeons. In recent years, with the development of a number of clinical trials and the appearance of new drugs, fluorouracil combined with oxaliplatin had been established as the standard regimen of adjuvant chemotherapy for colorectal cancer. In the current guidelines, stage III( colon cancer is the indication for adjuvant chemotherapy, while stage II( colon cancer should receive adjuvant chemotherapy is uncertain. Unlike colon cancer, adjuvant therapy of rectal cancer is not evidence-based. Especially, the indication and duration of adjuvant chemotherapy for rectal cancer after neoadjuvant chemoradiotherapy remain controversial. Adjuvant therapy of colorectal cancer still needs further investigation.

  3. Treg inducing adjuvants for therapeutic vaccination against chronic inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Chantal eKeijzer

    2013-08-01

    Full Text Available Many existing therapies in autoimmune diseases are based on systemic suppression of inflammation, the observed side effects illustrate the need for more specific interventions. Regulatory T cells (Treg are pivotal controllers of (autoaggressive immune responses, and decreased Treg numbers and/or functioning have been associated with autoimmune disease. Especially antigen-specific targeting of Treg would enable tailor made interventions, while obviating negative side effects of general immuno-suppression. Self-antigens that participate in inflammation, irrespective of the etiology of the different autoimmune diseases, are held to be candidate antigens for such interventions. Rather than tolerance induction to disease inciting self-antigens, which are frequently unknown, general self-antigens expressed at sites of inflammation would allow targeting of disease independent, but inflammatory-site specific, regulatory mechanisms. Preferably, such self-antigens should be abundantly expressed and up-regulated at the inflammatory site. Heat shock proteins show several of these characteristics.The development of antigen-specific Treg inducing vaccines is a major novel goal in the field of immunotherapy in autoimmune diseases. Progress is hampered by the lack of effective antigens and by the fact that other factors such as dose, route and the presence or absence of an adjuvant, turned out to be critical unknowns, with respect to effective induction of Treg. The use of a Treg inducing adjuvant might be required to achieve effective regulatory responses, in the case of ongoing inflammation. Future goals will be the optimization of natural Treg expansion (or the induction of adaptive Treg without loss of their suppressive function or the concomitant induction of non-regulatory T cells. Here, we discuss the potential use of protein/peptide-based vaccines combined with Treg inducing adjuvants for the development of therapeutic vaccines against chronic

  4. Lipopolysaccharide contamination in intradermal DNA vaccination: toxic impurity or adjuvant?

    Science.gov (United States)

    van den Berg, Joost H; Quaak, Susanne G L; Beijnen, Jos H; Hennink, Wim E; Storm, Gert; Schumacher, Ton N; Haanen, John B A G; Nuijen, Bastiaan

    2010-05-05

    Lipopolysaccharides (LPS) are known both as potential adjuvants for vaccines and as toxic impurity in pharmaceutical preparations. The aim of this study was to assess the role of LPS in intradermal DNA vaccination administered by DNA tattooing. Mice were vaccinated with a model DNA vaccine (Luc-NP) with an increasing content of residual LPS. The effect of LPS on systemic toxicity, antigen expression and cellular immunity was studied. The presence of LPS in the DNA vaccine neither induced systemic toxicity (as reflected by IL-6 concentration in serum), nor influenced antigen expression (measured by intravital imaging). Higher LPS contents however, appeared to be associated with an elevated cytotoxic T-lymphocyte (CTL) response but without reaching statistical significance. Interestingly, the DNA tattoo procedure by itself was shown to induce a serum cytokine response that was at least as potent as that induced by parenteral LPS administration. LPS does not show toxicity in mice vaccinated by DNA tattooing at dose levels well above those encountered in GMP-grade DNA preparations. Thus, residual LPS levels in the pharmaceutical range are not expected to adversely affect clinical outcome of vaccination trials and may in fact have some beneficial adjuvant effect. The observed pro-inflammatory effects of DNA tattoo may help explain the high immunogenicity of this procedure. Copyright 2009 Elsevier B.V. All rights reserved.

  5. The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes

    DEFF Research Database (Denmark)

    Korsholm, Karen Smith; Agger, Else Marie; Foged, Camilla

    2007-01-01

    Cationic liposomes are being used increasingly as efficient adjuvants for subunit vaccines but their precise mechanism of action is still unknown. Here, we investigated the adjuvant mechanism of cationic liposomes based on the synthetic amphiphile dimethyldioctadecylammonium (DDA). The liposomes...... concentrations. This efficient adsorption onto the liposomes led to an enhanced uptake of OVA by BM-DCs as assessed by flow cytometry and confocal fluorescence laser-scanning microscopy. This was an active process, which was arrested at 4 degrees and by an inhibitor of actin-dependent endocytosis, cytochalasin D....... In vivo studies confirmed the observed effect because adsorption of OVA onto DDA liposomes enhanced the uptake of the antigen by peritoneal exudate cells after intraperitoneal injection. The liposomes targeted antigen preferentially to antigen-presenting cells because we only observed a minimal uptake...

  6. Glucocorticosteroids: as Adjuvant Therapy for Bacterial Infections

    OpenAIRE

    2015-01-01

    Glucocorticoids (GCs), synthetic analogues of the natural steroid hormones, are well known for their antiinflammatory and immunosuppressive properties in the periphery. They are widely and successfully used in the treatment of autoimmune diseases, chronic inflammation, and transplant rejection. Nowadays, GCs are claimed to have a beneficial role being as adjunct therapy in various infections. Different studies have been conducted to investigate their use as adjuvant therapy for different bact...

  7. Inflammatory responses following intramuscular and subcutaneous immunization with aluminum-adjuvanted or non-adjuvanted vaccines.

    Science.gov (United States)

    Kashiwagi, Yasuyo; Maeda, Mika; Kawashima, Hisashi; Nakayama, Tetsuo

    2014-06-05

    Aluminum-adjuvanted vaccines are administered through an intramuscular injection (IM) in the US and EU, however, a subcutaneous injection (SC) has been recommended in Japan because of serious muscle contracture previously reported following multiple IMs of antibiotics. Newly introduced adjuvanted vaccines, such as the human papillomavirus (HPV) vaccines, have been recommended through IM. In the present study, currently available vaccines were evaluated through IM in mice. Aluminum-adjuvanted vaccines induced inflammatory nodules at the injection site, which expanded into the intra-muscular space without any muscle degeneration or necrosis, whereas non-adjuvanted vaccines did not. These nodules consisted of polymorph nuclear neutrophils with some eosinophils within the initial 48h, then monocytes/macrophages 1 month later. Inflammatory nodules were observed 6 months after IM, had decreased in size, and were absorbed 12 months after IM, which was earlier than that after SC. Cytokine production was examined in the injected muscular tissues and AS04 adjuvanted HPV induced higher IL-1β, IL-6, KC, MIP-1, and G-CSF levels in muscle tissues than any other vaccine, but similar serum cytokine profiles were observed to those induced by the other vaccines. Currently available vaccines did not induce muscular degeneration or fibrotic scar as observed with muscle contracture caused by multiple IMs of antibiotics in the past.

  8. Adjuvant and neoadjuvant treatment in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic adenocarcinoma is one of the most aggressive human malignancies,ranking 4th among causes for cancer-related death in the Western world including the United States.Surgical resection offers the only chance of cure,but only 15 to 20 percent of cases are potentially resectable at presentation.Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy.Currently there is no consensus around the world on what constitutes "standard"adjuvant therapy for pancreatic cancer.This controversy derives from several studies,each fraught with its own limitations.Standards of care also vary somewhat with regard to geography and economy,for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe.Regardless of the efforts in adjuvant and neoadjuvant improved therapy,the major goal to combat pancreatic cancer is to find diagnostic markers,identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients.In this review,authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.

  9. Adjuvant chemotherapy for advanced endometrial cancer.

    Science.gov (United States)

    Galaal, Khadra; Al Moundhri, Mansour; Bryant, Andrew; Lopes, Alberto D; Lawrie, Theresa A

    2014-05-15

    Approximately 13% of women diagnosed with endometrial cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV). The standard treatment of advanced endometrial cancer consists of cytoreductive surgery followed by radiation therapy, or chemotherapy, or both. There is currently little agreement about which adjuvant treatment is the safest and most effective. To evaluate the effectiveness and safety of adjuvant chemotherapy compared with radiotherapy or chemoradiation, and to determine which chemotherapy agents are most effective in women presenting with advanced endometrial cancer (FIGO stage III/IV). We searched the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 2013), MEDLINE and EMBASE up to November 2013. Also we searched electronic clinical trial registries for ongoing trials. Randomised controlled trials (RCTs) of adjuvant chemotherapy compared with radiotherapy or chemoradiation in women with FIGO stage III and IV endometrial cancer. Two review authors selected trials, extracted data, and assessed trials for risk of bias. Where necessary, we contacted trial investigators for relevant, unpublished data. We pooled data using the random-effects model in Review Manager (RevMan) software. We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data

  10. Evaluation of TLR agonists as potential mucosal adjuvants for HIV gp140 and tetanus toxoid in mice.

    Directory of Open Access Journals (Sweden)

    Viviana Buffa

    Full Text Available In the present study we investigate the impact of a range of TLR ligands and chitosan as potential adjuvants for different routes of mucosal immunisation (sublingual (SL, intranasal (IN, intravaginal (IVag and a parenteral route (subcutaneous (SC in the murine model. We assess their ability to enhance antibody responses to HIV-1 CN54gp140 (gp140 and Tetanus toxoid (TT in systemic and vaginal compartments. A number of trends were observed by route of administration. For non-adjuvanted antigen, SC>SL>IN immunisation with respect to systemic IgG responses, where endpoint titres were greater for TT than for gp140. In general, co-administration with adjuvants increased specific IgG responses where IN = SC>SL, while in the vaginal compartment IN>SL>SC for specific IgA. In contrast, for systemic and mucosal IgA responses to antigen alone SL>IN = SC. A number of adjuvants increased specific systemic IgA responses where in general IN>SL>SC immunisation, while for mucosal responses IN = SL>SC. In contrast, direct intravaginal immunisation failed to induce any detectable systemic or mucosal responses to gp140 even in the presence of adjuvant. However, significant systemic IgG responses to TT were induced by intravaginal immunisation with or without adjuvant, and detectable mucosal responses IgG and IgA were observed when TT was administered with FSL-1 or Poly I∶C. Interestingly some TLRs displayed differential activity dependent upon the route of administration. MPLA (TLR4 suppressed systemic responses to SL immunisation while enhancing responses to IN or SC immunisation. CpG B enhanced SL and IN responses, while having little or no impact on SC immunisation. These data demonstrate important route, antigen and adjuvant effects that need to be considered in the design of mucosal vaccine strategies.

  11. Activation of the NLRP3 inflammasome is not a feature of all particulate vaccine adjuvants

    DEFF Research Database (Denmark)

    Neumann, Silke; Burkert, Kristina; Kemp, Roslyn

    2014-01-01

    was common to many delivery systems. We prepared polymer-based chitosan nanoparticles (CNPs), lipid-based cubosomes, a water in oil emulsion of incomplete Freund's adjuvant (IFA) and alum formulations and examined inflammasome activation in vitro using murine bone-marrow-derived dendritic cells and human...

  12. Does Dexmedetomidine Have a Perineural Mechanism of Action When Used as an Adjuvant to Ropivacaine?

    DEFF Research Database (Denmark)

    Andersen, Jakob H; Grevstad, Ulrik; Siegel, Hanna

    2017-01-01

    BACKGROUND: Dexmedetomidine used as an adjuvant to local anesthetics may prolong the duration of peripheral nerve blocks. Whether this is mediated by a perineural or systemic mechanism remains unknown. The authors hypothesized that dexmedetomidine has a peripheral mechanism of action. METHODS: Th...

  13. Adjuvant chemotherapy for early-stage cervical cancer.

    Science.gov (United States)

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-04-01

    The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery (RS) has not yet been established, and radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life (QOL) or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival (OS) with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin (TP) regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group (GOG), had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial (RCT) of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable

  14. Adjuvant radiotherapy following radical hysterectomy for patients with stage IB and IIA cervical cancer

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    Soisson, A.P.; Soper, J.T.; Clarke-Pearson, D.L.; Berchuck, A.; Montana, G.; Creasman, W.T. (Duke Univ. Medical Center, Durham, NC (USA))

    1990-06-01

    From 1971 through 1984, 320 women underwent radical hysterectomy as primary therapy of stage IB and IIA cervical cancer. Two hundred forty-eight patients (78%) were treated with surgery alone and 72 patients (22%) received adjuvant postoperative external-beam radiotherapy. Presence of lymph node metastasis, large lesion (greater than 4 cm in diameter), histologic grade, race (noncaucasian), and age (greater than 40 years) were significant poor prognostic factors for the entire group of patients. Patients treated with surgery alone had a better disease-free survival than those who received combination therapy (P less than 0.001). However, patients receiving adjuvant radiation therapy had a higher incidence of lymphatic metastases, tumor involvement of the surgical margin, and large cervical lesions. Adjuvant pelvic radiation therapy did not improve the survival of patients with unilateral nodal metastases or those who had a large cervical lesion with free surgical margins and the absence of nodal involvement. Radiation therapy appears to reduce the incidence of pelvic recurrences. Unfortunately, 84% of patients who developed recurrent tumor after combination therapy had a component of distant failure. The incidence of severe gastrointestinal or genitourinary tract complications was not different in the two treatment groups. However, the incidence of lymphedema was increased in patients who received adjuvant radiation therapy. Although adjuvant radiation therapy appears to be tolerated without a significant increase in serious complications, the extent to which it may improve local control rates and survival in high-risk patients appears to be limited. In view of the high incidence of distant metastases in high-risk patients, consideration should be given to adjuvant systemic chemotherapy in addition to radiation therapy.

  15. Synthetic Toll like receptor-4 (TLR-4 agonist peptides as a novel class of adjuvants.

    Directory of Open Access Journals (Sweden)

    Arulkumaran Shanmugam

    Full Text Available BACKGROUND: Adjuvants serve as catalysts of the innate immune response by initiating a localized site of inflammation that is mitigated by the interactions between antigens and toll like receptor (TLR proteins. Currently, the majority of vaccines are formulated with aluminum based adjuvants, which are associated with various side effects. In an effort to develop a new class of adjuvants, agonists of TLR proteins, such as bacterial products, would be natural candidates. Lipopolysaccharide (LPS, a major structural component of gram negative bacteria cell walls, induces the systemic inflammation observed in septic shock by interacting with TLR-4. The use of synthetic peptides of LPS or TLR-4 agonists, which mimic the interaction between TLR-4 and LPS, can potentially regulate cellular signal transduction pathways such that a localized inflammatory response is achieved similar to that generated by adjuvants. METHODOLOGY/PRINCIPAL FINDINGS: We report the identification and activity of several peptides isolated using phage display combinatorial peptide technology, which functionally mimicked LPS. The activity of the LPS-TLR-4 interaction was assessed by NF-κB nuclear translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4, and the murine macrophage cell line, RAW264.7. Furthermore, the LPS peptide mimics were capable of inducing inflammatory cytokine secretion from RAW264.7 cells. Lastly, ELISA analysis of serum from vaccinated BALB/c mice revealed that the LPS peptide mimics act as a functional adjuvant. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the identification of synthetic peptides that mimic LPS by interacting with TLR-4. This LPS mimotope-TLR-4 interaction will allow for the development and use of these peptides as a new class of adjuvants, namely TLR-4 agonists.

  16. [Assessment of the MF59-adjuvanted pandemic influenza A/H1N1 vaccine. Systematic review of literature].

    Science.gov (United States)

    Ruiz-Aragón, J; Grande Tejada, A M; Márquez-Peláez, S; Molina Linde, J M; Yang, R

    2013-10-01

    To assess the efficacy and safety of MF59-adjuvanted pandemic influenza A/H1N1 vaccine in children. A systematic review of the literature was performed after searching the MedLine and Embase electronic databases, and manual search in specialties journals, with MeSH terms and and free terms. Inclusion criteria were clinical trials with children vaccinated with MF59-adjuvanted influenza A/H1N1 vaccine, compared with other vaccines doses with/without MF59-adjuvanted. The immunogenicity and safety of the vaccine was recorded. The quality of the studies included was assessed by CASPe checklist. Four clinical trials with moderate quality were selected. The local and systemic adverse effects were rare and mild, with no differences between groups. Seroconversion and seroprotection levels were higher with MF59-adjuvanted vaccines. Antibody titres were also higher with the adjuvant vaccines. The adjuvant vaccine has a good efficacy and safety profile. The adverse effects that may occur are common and appear similarly in both vaccination groups. Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  17. Incidence of radiation toxicity in cervical cancer and endometrial cancer patients treated with radiotherapy alone versus adjuvant radiotherapy

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    Roszak, Andrzej; Wareńczak-Florczak, Żaneta; Bratos, Krystyna; Milecki, Piotr

    2012-01-01

    Aim The study was made to evaluate early and late toxicity in a diversified group of patients receiving definitive or adjuvant radiotherapy in terms of clinical diagnosis and treatment methods. Background Radiotherapy is a standard way of treatment in cervical and endometrial cancer patients, both as definitive and adjuvant therapy. But every radiation treatment may be involved with toxicity. Materials and methods A detailed analysis was performed of 263 patients with gynaecological cancer treated with definitive (90 patients with cervical cancer received radiochemotherapy or radiotherapy exclusively) and adjuvant radiotherapy (38 with cervical and 135 with endometrial cancer). Results Acute reactions were found in 51.3% and late reactions were found in 14.8% of patients. It was stated that early (p radiotherapy. The analysis of the whole group revealed higher rate of toxicity, both early and late, in the gastrointestinal tract than in the urinary system (p radiotherapy group than in the adjuvant one. The occurrence of side effects was associated with the prolongation of total irradiation time due to necessary interruptions of radiotherapy. The comparison of the subgroups showed that interruptions occurred more frequently in patients receiving definitive rather than adjuvant radiotherapy (17.7–2.9%). Conclusions Definitive radiotherapy compared with adjuvant treatment may by associated with higher percentage of side effects caused by dose of therapy and correlation with chemotherapy. PMID:24377035

  18. Liposome-Based Adjuvants for Subunit Vaccines: Formulation Strategies for Subunit Antigens and Immunostimulators

    Directory of Open Access Journals (Sweden)

    Signe Tandrup Schmidt

    2016-03-01

    Full Text Available The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens for which no effective vaccines exist. The subunit vaccine technology exploits pathogen subunits as antigens, e.g., recombinant proteins or synthetic peptides, allowing for highly specific immune responses against the pathogens. However, such antigens are usually not sufficiently immunogenic to induce protective immunity, and they are often combined with adjuvants to ensure robust immune responses. Adjuvants are capable of enhancing and/or modulating immune responses by exposing antigens to antigen-presenting cells (APCs concomitantly with conferring immune activation signals. Few adjuvant systems have been licensed for use in human vaccines, and they mainly stimulate humoral immunity. Thus, there is an unmet demand for the development of safe and efficient adjuvant systems that can also stimulate cell-mediated immunity (CMI. Adjuvants constitute a heterogeneous group of compounds, which can broadly be classified into delivery systems or immunostimulators. Liposomes are versatile delivery systems for antigens, and they can carefully be customized towards desired immune profiles by combining them with immunostimulators and optimizing their composition, physicochemical properties and antigen-loading mode. Immunostimulators represent highly diverse classes of molecules, e.g., lipids, nucleic acids, proteins and peptides, and they are ligands for pattern-recognition receptors (PRRs, which are differentially expressed on APC subsets. Different formulation strategies might thus be required for incorporation of immunostimulators and antigens, respectively, into liposomes, and the choice of immunostimulator should ideally be based on knowledge regarding the

  19. Towards an understanding of the adjuvant action of aluminium

    Science.gov (United States)

    Marrack, Philippa; McKee, Amy S.; Munks, Michael W.

    2011-01-01

    The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work. PMID:19247370

  20. In vivo evaluation of chitosan as an adjuvant in subcutaneous vaccine formulations.

    Science.gov (United States)

    Scherließ, Regina; Buske, Simon; Young, Katherine; Weber, Benjamin; Rades, Thomas; Hook, Sarah

    2013-10-01

    Vaccines utilising pure antigens instead of whole pathogens and alternative administration routes require the use of potent adjuvants and effective antigen delivery systems. Chitosan has been reported to act as both an adjuvant as well as a matrix for delivery systems. Chitosan is a natural product produced predominantly from crab shell and commercially available preparations vary in molecular weight, degree of deacetylation and purity. In this study, the impact of chitosan characteristics (molecular weight, degree of deacetylation, particle size, viscosity and impurities) on adjuvant activity were examined. It could be shown that the degree of immune response differed if different chitosan qualities were used and this could be attributed to different characteristics of the chitosan qualities: the immunoadjuvant effect of chitosan probably is a result of an interplay between chemical properties such as molecular weight and degree of deacetylation and physical properties such as particle size and preparation technique, which impacts characteristics such as solubility and viscosity. Hence, the chitosan quality to be used as adjuvant in vaccine preparations needs to be selected carefully.

  1. Postoperative adjuvant chemoradiotherapy in rectal cancer

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    Chang, Sei Kyung; Kim, Jong Woo; Oh, Do Yeun; Chong, So Young; Shin, Hyun Soo [Bundang CHA General Hospital, Pochon CHA University, Seongnam (Korea, Republic of)

    2006-09-15

    To evaluate the role of postoperative adjuvant chemoradiotherapy in rectal cancer, we retrospectively analyzed the treatment outcome of patients with rectal cancer taken curative surgical resection and postoperative adjuvant chemoradiotherapy. A total 46 patients with AJCC stage II and III carcinoma of rectum were treated with curative surgical resection and postoperative adjuvant chemoradiotherapy. T3 and T4 stage were 38 and 8 patients, respectively. N0, N1, and N2 stage were 12, 16, 18 patients, respectively. Forty patients received bolus infusions of 5-fluorouracil (500 mg/m{sup 2}/day) with leucovorin (20 mg/m{sup 2}/day), every 4 weeks interval for 6 cycles. Oral Uracil/Tegafur on a daily basis for 6 {approx} 12 months was given in 6 patients. Radiotherapy with 45 Gy was delivered to the surgical bed and regional pelvic lymph node area, followed by 5.4 {approx} 9 Gy boost to the surgical bed. The follow up period ranged from 8 to 75 months with a median 35 months. Treatment failure occurred in 17 patients (37%). Locoregional failure occurred in 4 patients (8.7%) and distant failure in 16 patients (34.8%). There was no local failure only. Five year actuarial overall survival (OS) was 51.5% and relapse free survival (RFS) was 58.7%. The OS and RFS were 100%, 100% in stage N0 patients, 53.7%, 47.6% in N1 patients, and 0%, 41.2% in N2 patients ({rho} = 0.012, {rho} = 0.009). The RFS was 55%, 78.5%, and 31.2% in upper, middle, and lower rectal cancer patients, respectively ({rho} = 0.006). Multivariate analysis showed that N stage ({rho} = 0.012) was significant prognostic factor for OS and that N stage ({rho} = 0.001) and location of tumor ({rho} = 0.006) were for RFS. Bowel complications requiring surgery occurred in 3 patients. Postoperative adjuvant chemoradiotherapy was an effective modality for locoregional control of rectal cancer. But further investigations for reducing the distant failure rate are necessary because distant failure rate is still high.

  2. 21 CFR 178.3010 - Adjuvant substances used in the manufacture of foamed plastics.

    Science.gov (United States)

    2010-04-01

    ...: ADJUVANTS, PRODUCTION AIDS, AND SANITIZERS Certain Adjuvants and Production Aids § 178.3010 Adjuvant... weight of finished foamed polyethylene. 1,1-Difluoroethane (CAS Reg. No. 75-37-6) For use as a blowing...

  3. [Endotoxin adsortion as adjuvant therapy in gram negative severe sepsis].

    Science.gov (United States)

    Candel, F J; Martínez-Sagasti, F; Borges, M; Maseda, E; Herrera-Gutiérrez, M; Garnacho-Montero, J; Maynar, F J; Zaragoza, R; Mensa, J; Azanza, J R

    2010-09-01

    The mortality rate of severe sepsis and septic shock remains still high. Within the last years a better knowledge of its physiopathology and the implementation of a group of measures addressed to a fast identification and early treatment of the septic patients have proved to reduce mortality rate. Likewise, it continues being investigated in modulating the inflammatory response and limiting the harmful action of the bacterial products on the immune system. As a result of this research some endotoxin adsorber devices have been designed to control one of the most important targets that start the inflammatory cascade when gram negative microorganisms are involved.The usefulness that these endotoxin removal devices might have as adjuvant treatment in the Septic Syndrome and its applicability are reviewed in this paper. Likewise a profile of patient that might be to the benefit of this therapy is suggested according to the current knowledge.

  4. Suppression of Cocaine-Evoked Hyperactivity by Self-Adjuvanting and Multivalent Peptide Nanofiber Vaccines.

    Science.gov (United States)

    Rudra, Jai S; Ding, Ye; Neelakantan, Harshini; Ding, Chunyong; Appavu, Rajagopal; Stutz, Sonja; Snook, Joshua D; Chen, Haiying; Cunningham, Kathryn A; Zhou, Jia

    2016-05-18

    The development of anti-cocaine vaccines that counteract the rewarding effects of the drug are currently being investigated as adjunct therapies for prevention of relapse in abstinent users. However, cocaine is weakly immunogenic and requires conjugation to carrier proteins and coadministration with strong adjuvants, which carry the risk of local reactogenicity and systemic toxicity. Here we report synthetic and multivalent self-assembling peptide nanofibers as adjuvant-free carriers for cocaine vaccines. A novel cocaine hapten modified at the P3 site was conjugated to the N-terminus of an amphipathic self-assembling domain KFE8. In aqueous buffers the cocaine-KFE8 conjugate assembled into β-sheet rich nanofibers, which raised anti-cocaine antibodies without the need for added adjuvants in mice. Vaccinated mice were treated with cocaine and a significant negative correlation was observed between antibody levels and cocaine-evoked hyperactivity. These totally synthetic and multivalent nanofibers with well-defined chemical composition represent the first generation of adjuvant-free cocaine vaccines.

  5. PMA Induces Vaccine Adjuvant Activity by the Modulation of TLR Signaling Pathway

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    Dool-Ri Oh

    2014-01-01

    Full Text Available Toll-like receptor (TLR ligands are being developed for use as vaccine adjuvants and as immunomodulators because of their ability to stimulate innate and adaptive immune responses. Flagellin, a TLR5 ligand, was reported to show potent mucosal vaccine adjuvant activity. To identify ligands that potentiate the adjuvant activity of flagellin, we screened a plant library using HEK293T cells transiently cotransfected with phTLR5 and pNF-κB-SEAP plasmids. The 90% EtOH extract from Croton tiglium showed significant NF-κB transactivation in a TLR5-independent manner along with the increase of a flagellin activity. We have studied to characterize an active component from Croton tiglium and to elucidate the action mechanisms. Phorbol 12-myristate 13-acetate (PMA was isolated as an active component of Croton tiglium by activity-guided fractionation, column chromatography, HPLC, NMR, and MS. PMA at a range of nM induced PKC-dependent NF-κB activation and IL-8 production in both TLR5− and TLR5+ assay systems. In in vivo mouse vaccination model, PMA induced antigen-specific IgG and IgA antibody responses and increased IL-12 production corresponding to T cell responses in spleen lymphocytes. These results suggest that PMA would serve as an efficacious mucosal vaccine adjuvant.

  6. Eluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital - Mayo Clinic collaborative study

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    Zhou Jessica

    2011-09-01

    Full Text Available Abstract Background The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. Methods Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n = 290; 1992-2007 and at the Mayo Clinic (n = 130; 1977-2005 were reviewed. Patients with Results Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR = 1.86, p = 0.002, node positive status (RR = 3.18, p Conclusions Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment.

  7. The mode of action of immunological adjuvants.

    Science.gov (United States)

    Allison, A C

    1998-01-01

    Adjuvants augment immune responses to antigens and influence the balance between cell-mediated and humoral responses, as well as the isotypes of antibodies formed. New adjuvant formulations include antigen-carrying vehicles and small molecules with immunomodulating activity. Widely used two-phase vehicles comprise liposomes and microfluidized squalene or squalane emulsions. These are believed to target antigens to antigen-presenting cells, including dendritic cells (DC), follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby stimulating the proliferation of the latter and the generation of B-memory. Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating agents induce the production of cytokine cascades. In a primary cascade at injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell-mediated immune responses and the formation of antibodies of protective isotypes, such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes activate complement and collaborate with antibody-dependent effector cells in protective immune responses.

  8. Neo-adjuvant chemotherapy followed by radiotherapy adapted to the tumour response in the primary seminoma of the central nervous system: experience of the Pitie-Salpetriere Hospital and review of literature; Chimiotherapie neoadjuvante suivie d'une radiotherapie adaptee a la reponse tumorale dans les tumeurs germinales seminomateuses du systeme nerveux central: experience de l'hopital de la Pitie-Salpetriere et revue de la litterature

    Energy Technology Data Exchange (ETDEWEB)

    Calugaru, V.; Taillibert, S.; Lang, P.; Simon, J.M.; Mazeron, J.J. [Groupe Hospitalier de la Pitie-Salpetriere, APHP, Service de Radiotherapie Oncologique, 75 - Paris (France); Taillibert, S.; Delattre, J.Y. [Groupe Hospitalier de la Pitie-Salpetriere, APHP, Service de Neuro-Oncologie, 75 - Paris (France)

    2007-05-15

    Purpose. Retrospective analysis of ten cases of germinoma of the central nervous system treated in Pitie Salpetriere Hospital, Paris. Patients and methods- - Ten male patients were treated from 1997 to 2005 for histologically verified primary seminoma of the central nervous system. The median age was 27 years (range 18 0 years). Our option for the treatment was the association of 3 cycles of neo-adjuvant chemotherapy (cisplatin and etoposide) to radiotherapy. Five patients received a craniospinal radiotherapy of 30 Gy (for one patient 36 Gy) followed by a tumoral boost from 20 to 24 Gy. For five patients, irradiated volume was limited to the tumour, total dose from 24 to 54 Gy (for three patients the total dose was from 24 to 30 Gy). Surgery was used for five patients, but only in one case was macroscopic complete. Results. Six patients were in situation of complete remission after neo-adjuvant chemotherapy. All the patients were in situation of complete remission after the irradiation. All the patients were alive free of disease with a median follow-up 46 months (range 13 0 months). Conclusion. In spite of the fact that the intracranial germinal tumours are not the subject of a consensual treatment strategy, this retrospective analysis pleads in favour of chemotherapy followed by limited dose and volume irradiation. (authors)

  9. Underuse of Breast Cancer Adjuvant Treatment: Patient Knowledge, Beliefs, and Medical Mistrust

    Science.gov (United States)

    Bickell, Nina A.; Weidmann, Jessica; Fei, Kezhen; Lin, Jenny J.; Leventhal, Howard

    2009-01-01

    Purpose Little is known about why women with breast cancer who have surgery do not receive proven effective postsurgical adjuvant treatments. Methods We surveyed 258 women who recently underwent surgical treatment at six New York City hospitals for early-stage breast cancer about their care, knowledge, and beliefs about breast cancer and its treatment. As per national guidelines, all women should have received adjuvant treatment. Adjuvant treatment data were obtained from inpatient and outpatient charts. Factor analysis was used to create scales scored to 100 of treatment beliefs and knowledge, medical mistrust, and physician communication about treatment. Bivariate and multivariate analyses assessed differences between treated and untreated women. Results Compared with treated women, untreated women were less likely to know that adjuvant therapies increase survival (on a 100-point scale; 66 v 75; P < .0001), had greater mistrust (64 v 53; P = .001), and had less self-efficacy (92 v 97; P < .05); physician communication about treatment did not affect patient knowledge of treatment benefits (r = 0.8; P = .21). Multivariate analysis found that untreated women were more likely to be 70 years or older (adjusted relative risk [aRR], 1.11; 95% CI, 1.00 to 1.13), to have comorbidities (aRR, 1.10; 95% CI, 1.04 to 1.12), and to express mistrust in the medical delivery system (aRR, 1.003; 95% CI, 1.00 to 1.007), even though they were more likely to believe adjuvant treatments were beneficial (aRR, 0.99; 95% CI, 0.98 to 0.99; model c, 0.84; P ≤ .0001). Conclusion Patient knowledge and beliefs about treatment and medical mistrust are mutable factors associated with underuse of effective adjuvant therapies. Physicians may improve cancer care by ensuring that discussions about adjuvant therapy include a clear presentation of the benefits, not just the risks of treatment, and by addressing patient trust in and concerns about the medical system. PMID:19770368

  10. Adjuvant chemotherapy for endometrial cancer after hysterectomy

    Science.gov (United States)

    Johnson, Nick; Bryant, Andrew; Miles, Tracie; Hogberg, Thomas; Cornes, Paul

    2014-01-01

    Background Endometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer. Objectives To assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Selection criteria Randomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment. Data collection and analysis We used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse. Main results Five RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly

  11. Construction and preclinical evaluation of mmCT, a novel mutant cholera toxin adjuvant that can be efficiently produced in genetically manipulated Vibrio cholerae.

    Science.gov (United States)

    Lebens, Michael; Terrinoni, Manuela; Karlsson, Stefan L; Larena, Maximilian; Gustafsson-Hedberg, Tobias; Källgård, Susanne; Nygren, Erik; Holmgren, Jan

    2016-04-19

    There is an urgent need for new adjuvants that are effective with mucosally administered vaccines. Cholera toxin (CT) is the most powerful known mucosal adjuvant but is much too toxic for human use. In an effort to develop a useful mucosal adjuvant we have generated a novel non-toxic mutant CT molecule that retains much of the adjuvant activity of native CT. This was achieved by making the enzymatically active A subunit (CTA) recalcitrant to the site-specific proteolytic cleavage ("nicking") required for toxicity, which was found to require mutations not only in the two residues rendering the molecule resistant to trypsin but also in neighboring sites protecting against cleavage by Vibrio cholerae proteases. This multiple-mutated CT (mmCT) adjuvant protein could be efficiently produced in and purified from the extracellular medium of CT-deleted V. cholerae. The mmCT completely lacked detectable enterotoxicity in an infant mouse model and had >1000-fold reduced cAMP inducing activity compared to native CT in a sensitive mammalian target cell system. It nonetheless proved to have potent adjuvant activity on mucosal and systemic antibody as well as cellular immune responses to mucosally co-administered antigens including oral cholera and intranasal influenza vaccines. We conclude that mmCT is an attractive novel non-toxic mucosal adjuvant for enhancing immune responses to co-administered mucosal vaccines. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Protein antigen adsorption to the DDA/TDB liposomal adjuvant

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    Hamborg, Mette; Jorgensen, Lene; Bojsen, Anders Riber;

    2013-01-01

    Understanding the nature of adjuvant-antigen interactions is important for the future design of efficient and safe subunit vaccines, but remains an analytical challenge. We studied the interactions between three model protein antigens and the clinically tested cationic liposomal adjuvant composed...

  13. Adjuvant arthritis 50 years on: The impact of the 1956 article by C. M. Pearson, 'Development of arthritis, periarthritis and periostitis in rats given adjuvants'.

    Science.gov (United States)

    Whitehouse, M W

    2007-04-01

    The Science Citation Index (Web of Science) has now accumulated over 700 citations to this report published in Proc Soc exp Biol Med 1956; 91: 95-101, including several in 2006. This memoire is a tribute to its author for revealing the opportunities for so much subsequent research in experimental pharmacology and toxicology. For half a century, the adjuvant disease in rats has enormously aided research on drugs to control arthritis and other chronic inflammatory disorders. The adjuvant also triggers many systemic responses beyond the articular tissues. So we are given simultaneously a window to explore the converse phenomenon: namely, how a chronic disease can affect drug efficacy and toxicity. This phenomenon has been variously described as patho-pharmacodynamics, conditional pharmacology/toxicology and 'a right nuisance' ! Nevertheless it has enormous heuristic value for clinical therapeutics.

  14. Immune adjuvant activity of the olive, soybean and corn oils

    Directory of Open Access Journals (Sweden)

    Ana Claudia Marinho da Silva

    2016-08-01

    Full Text Available In the last half of the century, a large amount of substances has been used as immune adjuvant. The immune adjuvant effect of olive, soybean and corn oils in Swiss mice immunized with ovalbumin (OVA plus aluminum hydroxide or emulsified in Marcol, soybean, olive or corn oils was evaluated through the OVA-specific antibodies determined by ELISA and Passive Cutaneous Anaphylaxis. In this work the comparison of the intensity of the immune response was established by the Bayesian analysis. The adjuvant effect of the vegetable oils was shown to be more effective than aluminium hydroxide. Regarding to OVA-specific IgE synthesis, olive oil had the slowest adjuvant effect of the three vegetable oils. Accordingly, olive oil was the most convenient among the vegetable oils to be used as immune adjuvant, since it stimulated a higher production of OVA-specific Ig and lower levels of anti-OVA IgE.

  15. Proinflammatory responses in the murine brain after intranasal delivery of cholera toxin: implications for the use of AB toxins as adjuvants in intranasal vaccines.

    Science.gov (United States)

    Armstrong, Michelle E; Lavelle, Ed C; Loscher, Christine E; Lynch, Marina A; Mills, Kingston H G

    2005-11-01

    Intranasal delivery of vaccines provides an attractive alternative to parenteral delivery, but it requires appropriate mucosal adjuvants. Cholera toxin (CT) is a powerful mucosal adjuvant, but it can undergo retrograde transport to the brain via the olfactory system after intranasal delivery. We demonstrate that intranasal delivery of CT increases the expression of interleukin-1 beta , cyclooxygenase-2, and chemokine messenger RNA in the murine hypothalamus, whereas parenterally delivered CT has little effect. Our findings suggest that CT can induce proinflammatory mediators in the brain when it is administered intranasally but not parenterally, and they raise concerns about the use of AB toxins as adjuvants in intranasal vaccines.

  16. Influence of adjuvant irradiation on the development of late arm lymphedema and impaired shoulder mobility after mastectomy for carcinoma of the breast

    DEFF Research Database (Denmark)

    Ryttov, N; Holm, N V; Qvist, N

    1988-01-01

    The influence of postoperative radiation therapy on development of late arm lymphedema and shoulder joint disability following mastectomy was evaluated from a series of 57 women with operable carcinoma of the breast. The patients were divided into three groups. Common for all three groups......%/38% in the group of patients receiving adjuvant irradiation and 6%/12% in the group of patients receiving adjuvant systemic therapy. It is concluded that adjuvant irradiation to the axilla in patients with metastatic lymph nodes highly increases the risk of late physical sequelae following modified radical...

  17. Advax-adjuvanted recombinant protective antigen provides protection against inhalational anthrax that is further enhanced by addition of murabutide adjuvant.

    Science.gov (United States)

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita; Merkel, Tod J

    2014-04-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.

  18. Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant

    Science.gov (United States)

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita

    2014-01-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy. PMID:24554695

  19. Endocine™, N3OA and N3OASq; three mucosal adjuvants that enhance the immune response to nasal influenza vaccination.

    Directory of Open Access Journals (Sweden)

    Tina Falkeborn

    Full Text Available Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination.

  20. Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant

    Directory of Open Access Journals (Sweden)

    Shailbala Singh

    2014-10-01

    Full Text Available Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer, a synthetic glycolipid agonist of natural killer T (NKT cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.

  1. Survival of women with clear cell and papillary serous endometrial cancer after adjuvant radiotherapy.

    Science.gov (United States)

    Foerster, Robert; Kluck, Robert; Rief, Harald; Rieken, Stefan; Debus, Juergen; Lindel, Katja

    2014-06-18

    Type II (papillary serous and clear cell) endometrial carcinoma (EC) is a rare subgroup and is considered to have an unfavorable prognosis. The purpose of this retrospective analysis was to elucidate the meaning of adjuvant radiotherapy (RT) for clinical outcome and to define prognostic factors in these patients (pts). From 2004-2012 forty-two pts with type II EC underwent surgery followed by adjuvant RT at our department. Median age was 72 years. The majority were early stage carcinomas (FIGO I n = 27 [64.3%], FIGO II n = 4 [9.5%], FIGO III n = 11 [26.2%]. Seven pts (16.7%) received adjuvant chemotherapy (ChT). Pts were treated with external beam radiotherapy (EBRT) and brachytherapy (IVB) boost. Five-year local recurrence free survival (LRFS), distant metastases free survival (DMFS) and overall survival (OS) were 85.4%, 78%, and 64.5% respectively. LRFS was better with lower pT stage, without lymphangiosis (L0), without haemangiosis (V0) and negative resection margins (R0). DMFS was prolonged in lymph node negatives (N0), L0, V0 and R0. OS was improved in younger pts, N0, L0, V0 and after lymphadenectomy (LNE). Multivariate analysis revealed haemangiosis (V1) as the only independent prognostic factor for OS (p = .014) and DMFS (p = .008). For LRFS pT stage remained as an independent prognostic factor (p = .028). Adjuvant RT with EBRT/IVB ensures adequate local control in type II EC, but control rates remain lower than in type I EC. A benefit of additional adjuvant ChT could not be demonstrated and a general omission of EBRT cannot be recommended at this point. Lymphovascular infiltration and pT stage might be the best predictive factors for a benefit from combined local and systemic treatment.

  2. Clinical outcomes of adjuvant radiation therapy and prognostic factors in early stage uterine cervical cancer.

    Science.gov (United States)

    Kim, Hyun Ju; Rhee, Woo Joong; Choi, Seo Hee; Nam, Eun Ji; Kim, Sang Wun; Kim, Sunghoon; Kim, Young Tae; Kim, Gwi Eon; Kim, Yong Bae

    2015-06-01

    To evaluate the outcomes of adjuvant radiotherapy (RT) and to analyze prognostic factors of survival in the International Federation of Gynecology and Obstetrics (FIGO) IB-IIA uterine cervical cancer. We retrospectively reviewed the medical records of 148 patients with FIGO IB-IIA uterine cervical cancer who underwent surgery followed by adjuvant RT at the Yonsei Cancer Center between June 1997 and December 2011. Adjuvant radiotherapy was delivered to the whole pelvis or an extended field with or without brachytherapy. Among all patients, 57 (38.5%) received adjuvant chemotherapy either concurrently or sequentially. To analyze prognostic factors, we assessed clinicopathologic variables and metabolic parameters measured on preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). To evaluate the predictive performance of metabolic parameters, receiver operating characteristic curve analysis was used. Overall survival (OS) and disease-free survival (DFS) were analyzed by the Kaplan-Meier method. The median follow-up period was 63.2 months (range, 2.7 to 206.8 months). Locoregional recurrence alone occurred in 6 patients, while distant metastasis was present in 16 patients, including 2 patients with simultaneous regional failure. The 5-year and 10-year OSs were 87.0% and 85.4%, respectively. The 5-year and 10-year DFSs were 83.8% and 82.5%, respectively. In multivariate analysis, pathologic type and tumor size were shown to be significant prognostic factors associated with both DFS and OS. In subset analysis of 40 patients who underwent preoperative PET/CT, total lesion glycolysis was shown to be the most significant prognostic factor among the clinicopathologic variables and metabolic parameters for DFS. Our results demonstrated that adjuvant RT following hysterectomy effectively improves local control. From the subset analysis of preoperative PET/CT, we can consider that metabolic parameters may hold prognostic significance

  3. Retroperitoneal liposarcoma; The role of adjuvant radiation therapy and the prognostic factors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hong Seok; Yu, Jeong Il; Lim, Do Hoon; Kim, Sung Joo [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2016-09-15

    To evaluate the benefit of adjuvant radiation therapy (RT) for retroperitoneal liposarcoma (RPLS) following gross tumor removal. We reviewed 77 patients with primary RPLS surgically treated between January 2000 and December 2013. Cases with gross residual disease were excluded. Tumor grade was evaluated according to the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system. Adjuvant RT was delivered to 32 patients (42%) using external beam RT alone. Median follow-up time was 36 months (range, 5 to 169). Among 77 patients, 33 (43%) presented with well-differentiated, 31 (40%) with de-differentiated, 8 (10%) with myxoid/round and 4 (5%) with pleomorphic morphology. The RT group included less well-differentiated subtype than surgery group (28% vs. 53%). During follow up, 34 patients (44%) showed local recurrence. Local recurrence rate was lower in the RT group (38%) compared to the surgery group (49%). The 3-year local control rate (LC) was 55.6%, and the 3-year overall survival (OS) was 82.1%. Tumor histology and FNCLCC grade were significantly associated with local recurrence. There was no statistical significance of adding adjuvant RT in LC (p = 0.312). However, patients with tumor histology other than well-differentiated subtype showed marginally decreased local recurrence rate after adjuvant RT (3-year LC, RT 43.9% vs. no RT 35.3%; p = 0.087). RPLS patients receiving RT experienced less local recurrence. We suggest that the addition of adjuvant RT may be related to improvement of LCs, especially in patients with non-favorable histologic subtypes.

  4. The role of adjuvants in therapeutic protection against paracoccidioidomycosis after immunization with the P10 peptide

    Directory of Open Access Journals (Sweden)

    Oriana eMayorga

    2012-05-01

    Full Text Available Paracoccidioidomycosis (PCM, a common chronic mycosis in Latin America, is a granulomatous systemic disease caused by the thermo-dimorphic fungus Paracoccidioides brasiliensis. The glycoprotein gp43 is the main antigen target of P. brasiliensis and a 15-mer internal peptide (QTLIAIHTLAIRYAN, known as P10, defines a major CD4+-specific T cell epitope. Previous results have indicated that, besides having a preventive role in conventional immunizations prior to challenge with the fungus, protective anti-fungal effects can be induced in P. brasiliensis-infected mice treated with P10 administered with complete Freund’s adjuvant (CFA. The peptide elicits an IFN--dependent Th1 immune response and is the main candidate for effective immunotherapy of patients with PCM, as an adjunctive approach to conventional chemotherapy. In the present study we tested the therapeutic effects of P10 combined with different adjuvants (aluminum hydroxide, CFA, flagellin and the cationic lipid dioctadecyl-dimethylammonium bromide (DODAB in BALB/c mice previously infected with the P. brasiliensis Pb18 strain. Significant reductions in the number of colony forming units (CFUs of the fungus were detected in lungs of mice immunized with P10 associated with the different adjuvants 52 days after infection. Mice treated with DODAB and P10, followed by mice treated with P10 and flagellin, showed the most prominent effects as demonstrated by the lowest numbers of viable yeast cells as well as reductions in granuloma formation and fibrosis. Concomitantly, secretion of IFN- and TNF-, in contrast to IL-4 and IL-10, was enhanced in the lungs of mice immunized with P10 in combination with the tested adjuvants, with the best results observed in mice treated with P10 and DODAB. In conclusion, the present results demonstrate that the co-administration of the synthetic P10 peptide with several adjuvants, particularly DODAB, have significant therapeutic effects in experimental

  5. Recent development in vaccine adjuvant research%疫苗佐剂最新研究进展

    Institute of Scientific and Technical Information of China (English)

    周洋; 耿兴超; 汪巨峰; 李波

    2013-01-01

    疫苗佐剂能够提高机体对抗原的适应性免疫应答,在疫苗的研发中具有重要的作用.随着药物研发的不断进步,近年来国内外出现了许多新型佐剂.本文分类阐述了近年来疫苗佐剂的最新研究进展及应用概况,总结了佐剂对免疫系统的影响和作用机制、临床有效性和不良反应,以及新型佐剂研发最新关注热点.在寻找并设计理想佐剂的同时我们不能忽略安全问题,应深入研究佐剂的作用机制及评价模型,全面评估其安全性.%Vaccine adjuvant can enhance adaptive immune responses to antigens, which is very important in research and development of novel vaccines. In recent years, more and more novel vaccine adjuvant has been developed. In this article, we summarized the current practice and future perspectives for different adjuvant, including the potential applications, action of mechanism, the effects on immune system, the clinical efficiency and adverse events, and the highlights on adjuvant research and development. In addition to ideal adjuvant, we also pay attention to the safety issue of vaccine adjuvant. Further understanding about the adjuvant mode of action and establishing reliable model help in assessing vaccine safety thoroughly and alleviating public health concern.

  6. Modern Vaccines/Adjuvants Formulation Session 6: Vaccine &Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland.

    Science.gov (United States)

    Fox, Christopher B

    2013-09-01

    The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characterization of adjuvant-antigen interactions, the rational formulation design of a CD8+ T cell-inducing adjuvant based on immunological principles, and the development and production of a rabies vaccine by a developing country manufacturer. Throughout the session, the practical importance of sound formulation and manufacturing design accompanied by analytical characterization was highlighted.

  7. Amphiphilic γ-PGA nanoparticles administered on rat middle ear mucosa produce adjuvant-like immunostimulation in vivo

    DEFF Research Database (Denmark)

    Nilsson, Johan; Broos, Sissela; Akagi, Takami;

    2014-01-01

    CONCLUSION: Amphiphilic biodegradable nanoparticles (NPs) composed of poly(γ-glutamic acid) conjugated with L-phenylalanine ethylester (γ-PGA-Phe NPs) applied on the rat middle ear mucosa produce an inflammatory type 1 response. The observation is of relevance for the use of γ-PGA-Phe NPs...... as a concomitant antigen delivery system and adjuvant measure in the context of vaccinations. OBJECTIVES: To examine effects of topical mucosal administration of γ-PGA-Phe NPs as a potentially combined antigen delivery system and adjuvant. METHODS: γ-PGA-Phe NPs were administered on rat middle ear mucosa in a sham...

  8. Designing CAF-adjuvanted dry powder vaccines: Spray drying preserves the adjuvant activity of CAF01

    DEFF Research Database (Denmark)

    Ingvarsson, Pall Thor; Schmidt, Signe Tandrup; Christensen, Dennis

    2013-01-01

    spray drying. The optimal excipient to stabilize CAF01 during spray drying and for the design of nanocomposite microparticles was identified among mannitol, lactose and trehalose. Trehalose and lactose were promising stabilizers with respect to preserving liposome size, as compared to mannitol......Dry powder vaccine formulations are highly attractive due to improved storage stability and the possibility for particle engineering, as compared to liquid formulations. However, a prerequisite for formulating vaccines into dry formulations is that their physicochemical and adjuvant properties...... remain unchanged upon rehydration. Thus, we have identified and optimized the parameters of importance for the design of a spray dried powder formulation of the cationic liposomal adjuvant formulation 01 (CAF01) composed of dimethyldioctadecylammonium (DDA) bromide and trehalose 6,6′-dibehenate (TDB) via...

  9. Ranitidine as adjuvant treatment in colorectal cancer

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Christensen, Ib Jarle; Moesgaard, F;

    2002-01-01

    by oral ranitidine 150 mg or placebo twice daily for 5 years. Adjuvant cytotoxic or radiation therapy was not given. An observer-blinded interim analysis performed after 40 months showed that there was no effect of ranitidine on overall survival, and the study was discontinued in accordance......BACKGROUND: Results from short-term studies of histamine type 2 (H2) receptor antagonists on survival of patients with solid tumours are debatable. In this study the efficacy of the H2-receptor antagonist ranitidine on long-term survival of patients with colorectal cancer was evaluated. METHODS...... curative resection of colorectal cancer and who do not receive perioperative blood transfusion and do not develop postoperative infectious complications....

  10. The role of adjuvant in mediating antigen structure and stability.

    Science.gov (United States)

    Braun, Latoya Jones; Eldridge, Aimee M; Cummiskey, Jessica; Arthur, Kelly K; Wuttke, Deborah S

    2012-04-01

    The purpose of this study was to probe the fate of a model antigen, a cysteine-free mutant of bacteriophage T4 lysozyme, to the level of fine structural detail, as a consequence of its interaction with an aluminum (Al)-containing adjuvant. Fluorescence spectroscopy and differential scanning calorimetry were used to compare the thermal stability of the protein in solution versus adsorbed onto an Al-containing adjuvant. Differences in accessible hydrophobic surface areas were investigated using an extrinsic fluorescence probe, 8-Anilino-1-naphthalenesulfonic acid (ANS). As has been observed with other model antigens, the apparent thermal stability of the protein decreased following adsorption onto the adjuvant. ANS spectra suggested that adsorption onto the adjuvant caused an increase in exposure of hydrophobic regions of the protein. Electrostatic interactions drove the adsorption, and disruption of these interactions with high ionic strength buffers facilitated the collection of two-dimensional (15) N heteronuclear single quantum coherence nuclear magnetic resonance data of protein released from the adjuvant. Although the altered stability of the adsorbed protein suggested changes to the protein's structure, the fine structure of the desorbed protein was nearly identical to the protein's structure in the adjuvant-free formulation. Thus, the adjuvant-induced changes to the protein that were responsible for the reduced thermal stability were not observed upon desorption.

  11. Characterization of the in situ immunological responses to vaccine adjuvants.

    Science.gov (United States)

    Horohov, D W; Dunham, J; Liu, C; Betancourt, A; Stewart, J C; Page, A E; Chambers, T M

    2015-03-15

    Adjuvants are included with many inactivated and some modified live vaccines to enhance immune responses to specific antigens. While early vaccines relied exclusively upon aluminum salts, still the major adjuvant used in human vaccines, other adjuvant products are used in veterinary medicine. In addition to enhancing antigen presentation, adjuvants can also enhance the development of specific immune responses. Thus, alum adjuvants often preferentially stimulate humoral immune responses. By contrast, lipid-based adjuvants are often more effective at stimulating cell-mediated immune responses. Metastim(®) is a lipid-based adjuvant reported to elicit both humoral and cellular immune responses, though the mechanism responsible for this activity remains unclear. In this study, we compared the ability of equine influenza virus vaccines containing either saline or Metastim(®) or an aluminum phosphate adjuvant to stimulate antigen presenting cell function in vivo. Six ponies were intradermally inoculated with inactivated equine influenza (KY97) mixed with either adjuvant or saline. Multiple sites were injected so that biopsies could be collected at different times post injection. The 4mm punch biopsies were formalin-fixed, paraffin-embedded, and stained with hematoxylin and eosin (H&E). Total RNA was isolated from 2mm punch biopsies for the determination of gene expression by real-time PCR. H&E staining revealed a variety of cells recruited to the injection sites, including lymphocytes, neutrophils, eosinophils and macrophages. Real-time PCR analysis of the injection site confirmed this cellular infiltration and identified increased expression of activation markers. Both vaccines also stimulated gene expressions of pro-inflammatory cytokines. The vaccine containing Metastim(®) elicited significantly higher gene expression of interferon-γ, IL-12, CD4 and CD83 compared to alum (psalt, there was also evidence of Th2 cytokine induction. Copyright © 2015 Elsevier B.V. All

  12. Adjuvants for vaccines to drugs of abuse and addiction.

    Science.gov (United States)

    Alving, Carl R; Matyas, Gary R; Torres, Oscar; Jalah, Rashmi; Beck, Zoltan

    2014-09-22

    Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA.

  13. Safety and Efficacy of Stereotactic Radiosurgery and Adjuvant Bevacizumab in Patients With Recurrent Malignant Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Cuneo, Kyle C. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Vredenburgh, James J.; Sampson, John H.; Reardon, David A.; Desjardins, Annick; Peters, Katherine B.; Friedman, Henry S. [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC (United States); Willett, Christopher G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Kirkpatrick, John P., E-mail: john.kirkpatrick@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC (United States)

    2012-04-01

    Purpose: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. Methods and Materials: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. Results: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17-0.82) and 0.45 (CI 0.21-0.97). KPS >70 and age <50 years were significantly associated with improved survival. Conclusions: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant

  14. Enhanced pulmonary immunization with aerosolized inactivated influenza vaccine containing delta inulin adjuvant.

    Science.gov (United States)

    Murugappan, Senthil; Frijlink, Henderik W; Petrovsky, Nikolai; Hinrichs, Wouter L J

    2015-01-23

    Vaccination is the primary intervention to contain influenza virus spread during seasonal and pandemic outbreaks. Pulmonary vaccination is gaining increasing attention for its ability to induce both local mucosal and systemic immune responses without the need for invasive injections. However, pulmonary administration of whole inactivated influenza virus (WIV) vaccine induces a Th2 dominant systemic immune response while a more balanced Th1/Th2 vaccine response may be preferred and only induces modest nasal immunity. This study evaluated immunity elicited by pulmonary versus intramuscular (i.m.) delivery of WIV, and tested whether the immune response could be improved by co-administration of delta (δ)-inulin, a novel carbohydrate-based particulate adjuvant. After pulmonary administration both unadjuvanted and δ-inulin adjuvanted WIV induced a potent systemic immune response, inducing higher serum anti-influenza IgG titers and nasal IgA titers than i.m. administration. Moreover, the addition of δ-inulin induced a more balanced Th1/Th2 response and induced higher nasal IgA titers versus pulmonary WIV alone. Pulmonary WIV alone or with δ-inulin induced hemagglutination inhibition (HI) titers>40, titers which are considered protective against influenza virus. In conclusion, in this study we have shown that δ-inulin adjuvanted WIV induces a better immune response after pulmonary administration than vaccine alone.

  15. Analysis of aluminium in rat following administration of allergen immunotherapy using either aluminium or microcrystalline-tyrosine-based adjuvants.

    Science.gov (United States)

    McDougall, Stuart A; Heath, Matthew D; Kramer, Matthias F; Skinner, Murray A

    2016-03-01

    Investigation into the absorption, distribution and elimination of aluminium in rat after subcutaneous aluminium adjuvant formulation administration using ICP-MS is described. Assays were verified under the principles of a tiered approach. There was no evidence of systemic exposure of aluminium, in brain or in kidney. Extensive and persistent retention of aluminium at the dose site was observed for at least 180 days after administration. This is the first published work that has quantified aluminium adjuvant retention based on the quantity of aluminium delivered in a typical allergy immunotherapy course. The results indicate that the repeated administration of aluminium-containing adjuvants will likely contribute directly and significantly to an individual's body burden of aluminium.

  16. An adjuvant-free mouse model to evaluate the allergenicity of milk whey protein.

    Science.gov (United States)

    Gonipeta, B; Parvataneni, S; Tempelman, R J; Gangur, V

    2009-10-01

    Milk allergy is the most common type of food allergy in humans with the potential for fatality. An adjuvant-free mouse model would be highly desirable as a preclinical research tool to develop novel hypoallergenic or nonallergenic milk products. Here we describe an adjuvant-free mouse model of milk allergy that uses transdermal sensitization followed by oral challenge with milk protein. Groups of BALB/c mice were exposed to milk whey protein via a transdermal route, without adjuvant. Systemic IgG1 and IgE antibody responses to transdermal exposure as well as systemic anaphylaxis and hypothermia response to oral protein challenge were studied. Transdermal exposure resulted in a time- and dose-dependent induction of significant IgE and IgG1 antibody responses. Furthermore, oral challenge of sensitized mice resulted in significant clinical symptoms of systemic anaphylaxis within 1 h and significant hypothermia at 30 min postchallenge. To study the underlying mechanism, we examined allergen-driven spleen cell T-helper 2 cytokine (IL-4) responses. There was a robust dose- and time-dependent activation of memory IL-4 responses in allergic mice but not in healthy control mice. These data demonstrate for the first time a novel transdermal sensitization followed by oral challenge mouse model of milk allergy that does not use adjuvant. It is expected that this model may be used not only to study mechanisms of milk allergy, but also to evaluate novel milk products for allergenic potential and aid in the production of hypo- or nonallergenic milk products.

  17. The Vaccine Formulation Laboratory: a platform for access to adjuvants.

    Science.gov (United States)

    Collin, Nicolas; Dubois, Patrice M

    2011-07-01

    Adjuvants are increasingly used by the vaccine research and development community, particularly for their ability to enhance immune responses and for their dose-sparing properties. However, they are not readily available to the majority of public sector vaccine research groups, and even those with access to suitable adjuvants may still fail in the development of their vaccines because of lack of knowledge on how to correctly formulate the adjuvants. This shortcoming led the World Health Organization to advocate for the establishment of the Vaccine Formulation Laboratory at the University of Lausanne, Switzerland. The primary mission of the laboratory is to transfer adjuvants and formulation technology free of intellectual property rights to academic institutions, small biotechnology companies and developing countries vaccine manufacturers. In this context, the transfer of an oil-in-water emulsion to Bio Farma, an Indonesian vaccine manufacturer, was initiated to increase domestic pandemic influenza vaccine production capacity as part of the national pandemic influenza preparedness plan.

  18. Activity of glycated chitosan and other adjuvants to PDT vaccines

    Science.gov (United States)

    Korbelik, Mladen; Banáth, Judit; Čiplys, Evaldas; Szulc, Zdzislaw; Bielawska, Alicja; Chen, Wei R.

    2015-03-01

    Glycated chitosan (GC), a water soluble galactose-conjugated natural polysaccharide, has proven to be an effective immunoadjuvant for treatment of tumors based on laser thermal therapy. It was also shown to act as adjuvant for tumor therapy with high-intensity ultrasound and in situ photodynamic therapy (PDT). In the present study, GC was examined as potential adjuvant to PDT-generated cancer vaccine. Two other agents, pure calreticulin protein and acid ceramidase inhibitor LCL521, were also tested as prospective adjuvants for use in conjunction with PDT vaccines. Single treatment with GC, included with PDT vaccine cells suspension, improved the therapeutic efficacy when compared to vaccine alone. This attractive prospect of GC application remains to be carefully optimized and mechanistically elucidated. Both calreticulin and LCL521 proved also effective adjuvants when combined with PDT vaccine tumor treatment.

  19. A randomised controlled trial comparing the effect of adjuvant ...

    African Journals Online (AJOL)

    between adjuvant intrathecal 2 mg midazolam as compared to intrathecal 20 micrograms fentanyl for patients undergoing ... in mental processes, respiratory depression, and other .... nificance level and power of 90%, the required sample.

  20. Editorial: Short-course adjuvant trastuzumab will increase cure rates ...

    African Journals Online (AJOL)

    Editorial: Short-course adjuvant trastuzumab will increase cure rates in patients with human epidermal growth factor receptor 2-positive breast cancer. ... Journal Home > Vol 107, No 8 (2017) >. Log in or Register to get ... from 32 Countries:.

  1. Endometrial adenocarcinoma, adjuvant radiotherapy tailored to prognostic factors.

    Science.gov (United States)

    Meerwaldt, J H; Hoekstra, C J; van Putten, W L; Tjokrowardojo, A J; Koper, P C

    1990-02-01

    The optimal adjuvant radiotherapy for surgically treated endometrial cancer has not yet been defined. We report on 389 patients treated between 1970 and 1985 with adjuvant radiotherapy. The treatment was tailored to the known prognostic factors: myometrial invasion and grade of differentiation of the tumor. Ten-year overall survival was 67%, 10-year relapse-free survival 77%; 23% relapse, of which 21% distant and 6% locoregional relapse. In a multivariate analysis, stage (pT), grade, and myometrial invasion were prognostic factors. The number of locoregional failures was very small (n = 23). This small number, the fact that radiation treatment was tailored to prognostic factors, and the absence of a nontreated control group precluded an analysis of the effect of the adjuvant irradiation. Large randomized studies with a control (no treatment) arm should be performed to determine the value of adjuvant radiotherapy.

  2. Triple negative breast cancer: adjuvant chemotherapy effect on survival

    National Research Council Canada - National Science Library

    Steponaviciene, L; Lachej-Mikeroviene, N; Smailyte, G; Aleknavicius, E; Meskauskas, R; Didziapetriene, J

    2011-01-01

    Purpose: The purpose of this study was to evaluate the overall survival of patients with triple negative breast cancer and the impact of different adjuvant chemotherapy regimens on survival.Material/Methods...

  3. Mx bio adjuvant for enhancing immune responses against influenza virus

    Directory of Open Access Journals (Sweden)

    Sina Soleimani

    2015-06-01

    Conclusion: These data revealed that Mx1 as biological adjuvant was able to increase antibody titer and induction memory immune responses against influenza immunization without causing any side effects.

  4. Over-expression of gene encoding heat shock protein 70 from Mycobacterium tuberculosis and its evaluation as vaccine adjuvant

    Directory of Open Access Journals (Sweden)

    J Dhakal

    2013-01-01

    Full Text Available Background: Heat shock proteins (Hsps are evolutionary ancient and highly conserved molecular chaperons found in prokaryotes as well as eukaryotes. Hsp70 is a predominant member of Hsp family. Microbial Hsp70s (mHsp70s have acquired special significance in immunity since they have been shown to be potent activators of the innate immune system and generate specific immune responses against tumours and infectious agents. Objectives: The present study was aimed to clone express and purify recombinant Hsp70 from the Mycobacterium tuberculosis and characterise it immunologically. The study also aimed at determining the potential of recombinant M. tuberculosis heat shock protein (rMTB-Hsp70 as adjuvant or antigen carrier. Materials and Methods: Cloning of M. tuberculosis heat shock protein (MTB-Hsp70 amplicon was carried out using the pGEMT-Easy vector although for expression, pProExHTb prokaryotic expression vector was used. Purification of recombinant Hsp70 was carried out by nickel-nitrilotriacetic acid (Ni-NTA affinity chromatography. For immunological characterization and determining the adjuvant effect of MTB-Hsp70, BALB/c mice were used. The data obtained was statistically analysed. Results: Hsp70 gene was cloned, sequenced and the sequence data were submitted to National Center for Biotechnology Information (NCBI. Recombinant MTB-Hsp70 was successfully over-expressed using the prokaryotic expression system and purified to homogeneity. The protein was found to be immunodominant. Significant adjuvant effect was produced by the rMTB-Hsp70 when inoculated with recombinant outer membrane protein 31; however, effect was less than the conventionally used the Freund′s adjuvant. Conclusion: Protocol standardised can be followed for bulk production of rHsp70 in a cost-effective manner. Significant adjuvant effect was produced by rMTB-Hsp70; however, the effect was than Freund′s adjuvant. Further, studies need to be carried out to explore its

  5. Predictive value of Ki67 for adjuvant chemotherapy in node-negative, hormone receptor-positive breast cancer.

    Science.gov (United States)

    Sutepvarnon, Apisada; Warnnissorn, Malee; Srimuninnimit, Vichien

    2013-02-01

    Ki67 labeling index (Ki67 LI) is a measure of tumor proliferation. In breast cancer, evidence supporting its prognostic value is clear and its predictive value for response to treatment finds some benefits. However studies of Ki67 LI as a predictive marker in early breast cancer are still limited worldwide and there is no data in Thailand. To assess the predictive value of Ki67 expression for adjuvant chemotherapy in patients with node-negative, hormone receptor-positive breast cancer The authors retrospectively evaluated 127 diagnosed early breast cancer with node-negative, hormone receptor-positive patients and receiving adjuvant systemic treatment at Siriraj hospital. Disease free survival (DFS) was compared with the log-rank test according to Ki67 LI and adjuvant systemic treatment (chemoendocrine therapy and endocrine therapy alone). At a median follow-up of 3.3 years. The 5-year DFS rate was 79% for patients with low Ki67 expression and 75% for patients with high Ki67 expression. Of the 127 patients, 56 (44.1%) received chemoendocrine therapy and 71 (55.9%) were treated with endocrine therapy alone. There was no different effect of DFS among those receiving adjuvant endocrine therapy alone and those receiving adjuvant chemoendocrine therapy depending on Ki67 expression. Among patients with node-negative, hormone receptor-positive breast cancer, a high Ki67 LI had worse DFS trend than a low Ki67 LI but the Ki67 LI did not predict the efficacy of adjuvant chemotherapy.

  6. CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization.

    Science.gov (United States)

    Sundling, Christopher; Schön, Karin; Mörner, Andreas; Forsell, Mattias N E; Wyatt, Richard T; Thorstensson, Rigmor; Karlsson Hedestam, Gunilla B; Lycke, Nils Y

    2008-12-01

    Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.

  7. Engineering of an Inhalable DDA/TDB Liposomal Adjuvant

    DEFF Research Database (Denmark)

    Ingvarsson, Pall Thor; Yang, Mingshi; Mulvad, Helle

    2013-01-01

    The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB).......The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB)....

  8. Learning impairment in honey bees caused by agricultural spray adjuvants.

    Directory of Open Access Journals (Sweden)

    Timothy J Ciarlo

    Full Text Available BACKGROUND: Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s. The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. METHODOLOGY/PRINCIPAL FINDINGS: An improved, automated version of the proboscis extension reflex (PER assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. CONCLUSIONS/SIGNIFICANCE: A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many

  9. Effect of Freund's adjuvant on standard dark and pastel mink.

    Science.gov (United States)

    Tabel, H; Ingram, D G

    1971-04-01

    Following a long series of injections of homologous immunoglobulin in complete and incomplete Freund's adjuvant into mink, a moderate elevation in the level of gammaglobulin in the serum was observed in a few animals. Relatively mild pathological changes also were seen in liver, spleen, lymph nodes, lungs and kidney. It is concluded that the injection of Freund's adjuvant, under the experimental conditions described, produced lesions which were readily distinguishable from the lesions characteristic of aleutian disease of mink.

  10. Liposome-Based Adjuvants for Subunit Vaccines: Formulation Strategies for Subunit Antigens and Immunostimulators

    DEFF Research Database (Denmark)

    Schmidt, Signe Tandrup; Foged, Camilla; Korsholm, Karen Smith;

    2016-01-01

    for which no effective vaccines exist. The subunit vaccine technology exploits pathogen subunits as antigens, e.g., recombinant proteins or synthetic peptides, allowing for highly specific immune responses against the pathogens. However, such antigens are usually not sufficiently immunogenic to induce......The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens...... been licensed for use in human vaccines, and they mainly stimulate humoral immunity. Thus, there is an unmet demand for the development of safe and efficient adjuvant systems that can also stimulate cell-mediated immunity (CMI). Adjuvants constitute a heterogeneous group of compounds, which can broadly...

  11. Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research

    Directory of Open Access Journals (Sweden)

    Elena Mata

    2013-01-01

    Full Text Available There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants as well as the immunostimulatory effect of the formulation components (immunostimulants modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages.

  12. Solitary fibrous tumor of the sellar region treated with adjuvant radiation therapy

    Science.gov (United States)

    Sahai, Puja; Singh, Geetika; Mondal, Dodul; Suri, Vaishali; Julka, Pramod Kumar

    2016-01-01

    The solitary fibrous tumor of central nervous system is rare. Herein, a case of solitary fibrous tumor arising from sellar region is described. A 60-year-old man underwent subtotal excision of the tumor because of extensive infiltration of optical and vascular structures. In view of the presence of residual tumor, he was treated with adjuvant radiation therapy. After a follow-up period of 1 year, there was no progression of the lesion evident on magnetic resonance imaging of the brain. Solitary fibrous tumor should be considered as one of the differential diagnosis of a mass lesion arising in sellar region. Immunohistochemistry with CD34 is valuable for discerning the diagnosis. Complete surgery should be the goal of treatment and adjuvant radiation therapy may be considered for residual or recurrent disease. PMID:27695561

  13. Antigen-Independent Restriction of Pneumococcal Density by Mucosal Adjuvant Cholera Toxin Subunit B.

    Science.gov (United States)

    Kuipers, Kirsten; Diavatopoulos, Dimitri A; van Opzeeland, Fred; Simonetti, Elles; van den Kieboom, Corné H; Kerstholt, Mariska; Borczyk, Malgorzata; van IngenSchenau, D; Brandsma, Eelke T; Netea, Mihai G; de Jonge, Marien I

    2016-11-15

    For many bacterial respiratory infections, development of (severe) disease is preceded by asymptomatic colonization of the upper airways. For Streptococcus pneumoniae, the transition to severe lower respiratory tract infection is associated with an increase in nasopharyngeal colonization density. Insight into how the mucosal immune system restricts colonization may provide new strategies to prevent clinical symptoms. Several studies have provided indirect evidence that the mucosal adjuvant cholera toxin subunit B (CTB) may confer nonspecific protection against respiratory infections. Here, we show that CTB reduces the pneumococcal load in the nasopharynx, which required activation of the caspase-1/11 inflammasome, mucosal T cells, and macrophages. Our findings suggest that CTB-dependent activation of the local innate response synergizes with noncognate T cells to restrict bacterial load. Our study not only provides insight into the immunological components required for containment and clearance of pneumococcal carriage, but also highlights an important yet often understudied aspect of adjuvants.

  14. Designing CAF-adjuvanted dry powder vaccines: spray drying preserves the adjuvant activity of CAF01.

    Science.gov (United States)

    Ingvarsson, Pall Thor; Schmidt, Signe Tandrup; Christensen, Dennis; Larsen, Niels Bent; Hinrichs, Wouter Leonardus Joseph; Andersen, Peter; Rantanen, Jukka; Nielsen, Hanne Mørck; Yang, Mingshi; Foged, Camilla

    2013-05-10

    Dry powder vaccine formulations are highly attractive due to improved storage stability and the possibility for particle engineering, as compared to liquid formulations. However, a prerequisite for formulating vaccines into dry formulations is that their physicochemical and adjuvant properties remain unchanged upon rehydration. Thus, we have identified and optimized the parameters of importance for the design of a spray dried powder formulation of the cationic liposomal adjuvant formulation 01 (CAF01) composed of dimethyldioctadecylammonium (DDA) bromide and trehalose 6,6'-dibehenate (TDB) via spray drying. The optimal excipient to stabilize CAF01 during spray drying and for the design of nanocomposite microparticles was identified among mannitol, lactose and trehalose. Trehalose and lactose were promising stabilizers with respect to preserving liposome size, as compared to mannitol. Trehalose and lactose were in the glassy state upon co-spray drying with the liposomes, whereas mannitol appeared crystalline, suggesting that the ability of the stabilizer to form a glassy matrix around the liposomes is one of the prerequisites for stabilization. Systematic studies on the effect of process parameters suggested that a fast drying rate is essential to avoid phase separation and lipid accumulation at the surface of the microparticles during spray drying. Finally, immunization studies in mice with CAF01 in combination with the tuberculosis antigen Ag85B-ESAT6-Rv2660c (H56) demonstrated that spray drying of CAF01 with trehalose under optimal processing conditions resulted in the preservation of the adjuvant activity in vivo. These data demonstrate the importance of liposome stabilization via optimization of formulation and processing conditions in the engineering of dry powder liposome formulations.

  15. Adjuvant endocrine therapy alone in patients with node-positive, luminal A type breast cancer.

    Science.gov (United States)

    Park, Sungmin; Lee, Se Kyung; Paik, Hyun-June; Ryu, Jai Min; Kim, Isaac; Bae, Soo Youn; Yu, Jonghan; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin

    2017-06-01

    Luminal A breast cancer has a much better prognosis than other subtypes, with a low risk of local or regional recurrence. However, there is controversy around under- versus overtreatment with regard to adjuvant treatment of node-positive, luminal A breast cancer. The purpose of this study was to identify whether adjuvant systemic chemotherapy has any benefit in node-positive, luminal A breast cancer and to evaluate feasibility of endocrine therapy without chemotherapy in this group.This was a retrospective study of 11,025 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between January 2004 and December 2013. Luminal A subtype was defined as ER+, HER2-, and Ki-67 < 14%. We compared AC based (AC: doxorubicin or epirubicin, plus cyclophosphamide) adjuvant chemotherapy versus endocrine therapy without chemotherapy in patients with node-positive, luminal A breast cancer.We performed 1: n matching, with a maximum n of 8 on endocrine therapy group (n = 50) to chemotherapy group (n = 642). The median age of the patients in each group at the time of surgery was 58.3 ± 9.5 years in the chemotherapy group and 58.7 ± 11.7 in the endocrine therapy only group. The median follow-up time was 51.9 months (range, 1-125 months). In multivariable analysis, omission of adjuvant chemotherapy in luminal A cancer had no influence on OS and DFS. Axillary lymph node metastasis and progesterone receptor (PR) status were significantly different between the endocrine therapy alone group and the chemotherapy group in terms of OS. Nuclear grade, PR status, and adjuvant radiotherapy were significantly different between the endocrine therapy alone group and the chemotherapy group with regard to DFS. In survival analysis, there were no differences in OS (P = .137) and DFS (P = .225) between the 2 groups.Adjuvant chemotherapy could provide little benefit to postmenopausal patients with luminal A, node-positive breast cancer, and

  16. Spa adjuvant therapy improves diabetic lower extremity arterial disease.

    Science.gov (United States)

    Qiu, Yongbin; Zhu, Yi; Jia, Wei; Chen, Songhua; Meng, Qingzhou

    2014-08-01

    To investigate the effect of spa adjuvant therapy on diabetic lower extremity arterial disease (LEAD). 128 patients with type II diabetes were separated into three groups according to the degree of lower extremity vascular stenosis. Patients within each group were then randomly divided to receive no treatment (control) or spa adjuvant therapy (treatment). Clinical symptoms, blood pressure and hemodynamic analyses were compared between control and treatment groups by Chi square or t-test. After adjuvant therapy with spa, patients' pain, numbness, and cold sensation were significantly improved compared with control groups (PSpa adjuvant therapy also significantly increased the dorsalis pedis pulse and systolic peak velocity ratio of patients with mild lower extremity vascular stenosis compared with control groups (P0.05). Both in the spa and control groups, there were no significant differences before and after medication for fasting, 2-h postprandial blood glucose and glycosylated hemoglobin (HbA1C) analyses (P>0.05). Spa adjuvant therapy can significantly alleviate lower extremity pain, numbness, and cold sensory symptoms in diabetic LEAD patients with stenosis. Moreover, in LEAD patients with mild stenosis, spa adjuvant therapy also improves the dorsalis pedis pulse and systolic peak velocity ratio, suggesting a potential role for spa therapy as an early intervention strategy to treat the initial stages of disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Communicating the role and value of vaccine adjuvants.

    Science.gov (United States)

    Gellin, Bruce G; Salisbury, David M

    2015-06-08

    Despite the inclusion of adjuvants in many routinely used vaccines to improve the immune response, their presence and role are neither clear in product details such as the packaging or in the Summaries of Product Characteristics, nor understood by health professionals or the public. For many vaccines the adjuvant may simply be described as 'Adsorbed' without clarification that the adsorbing onto a material such as aluminium hydroxide adjuvants the antigens. As many future vaccines are likely to be adjuvanted, the presence of adjuvants, either those used in existing vaccines or novel formulations, may raise public and professional concerns unless communication materials are prepared in advance to allay anxieties such as those that have arisen over some present vaccine ingredients such as thiomersal. This raises a dilemma about how active such communications should be: over-promotion of the presence of a new adjuvant may cause unneeded anxieties; under-promotion may raise concerns over concealment of information. Research is needed and appropriate communication materials should be prepared. Copyright © 2015. Published by Elsevier Ltd.

  18. Prognostic nomogram for patients with hepatocellular carcinoma underwent adjuvant transarterial chemoembolization following curative resection

    Science.gov (United States)

    Jing, Chu-Yu; Fu, Yi-Peng; Zheng, Su-Su; Yi, Yong; Shen, Hu-Jia; Huang, Jin-Long; Xu, Xin; Lin, Jia-Jia; Zhou, Jian; Fan, Jia; Ren, Zheng-Gang; Qiu, Shuang-Jian; Zhang, Bo-Heng

    2017-01-01

    Abstract Adjuvant transarterial chemoembolization (TACE) is a major option for postoperative hepatocellular carcinoma (HCC) patients with recurrence risk factors. However, individualized predictive models for subgroup of these patients are limited. This study aimed to develop a prognostic nomogram for patients with HCC underwent adjuvant TACE following curative resection. A cohort comprising 144 HCC patients who received adjuvant TACE following curative resection in the Zhongshan Hospital were analyzed. The nomogram was formulated based on independent prognostic indicators for overall survival (OS). The performance of the nomogram was evaluated by the concordance index (C-index), calibration curve, and decision curve analysis (DCA) and compared with the conventional staging systems. The results were validated in an independent cohort of 86 patients with the same inclusion criteria. Serum alpha-fetoprotein (AFP), hyper-sensitive C-reactive protein (hs-CRP), incomplete tumor encapsulation, and double positive staining of Cytokeratin 7 and Cytokeratin 19 on tumor cells were identified as independent predictors for OS. The C-indices of the nomogram for OS prediction in the training cohort and validation cohort were 0.787 (95%CI 0.775–0.799) and 0.714 (95%CI 0.695–0.733), respectively. In both the training and validation cohorts, the calibration plot showed good consistency between the nomogram-predicted and the observed survival. Furthermore, the established nomogram was superior to the conventional staging systems in terms of C-index and clinical net benefit on DCA. The proposed nomogram provided an accurate prediction on risk stratification for HCC patients underwent adjuvant TACE following curative resection. PMID:28296727

  19. Safety evaluation of monophosphoryl lipid A (MPL): an immunostimulatory adjuvant.

    Science.gov (United States)

    Baldrick, Paul; Richardson, Derek; Elliott, Gary; Wheeler, Alan W

    2002-06-01

    Animal models have shown the potential use of monophosphoryl lipid A (MPL), a detoxified bacterial lipopolysaccharide, as a vaccine adjuvant. Immunostimulatory activity with diverse effects on the cellular elements of the immune system has been demonstrated and a range of vaccines incorporating MPL, including allergy vaccines, are currently under clinical evaluation. A series of preclinical safety investigations was performed to support clinical use of MPL as used in allergy vaccines and comprised cardiovascular/respiratory assessment in dog (up to 100 microg/kg/day); repeat-dose toxicity in rat, rabbit, and dog (up to 2500 and 1200 microg/kg/day in the rat and dog, respectively); reproduction toxicity in rat and rabbit (up to 100 microg/kg/day); and genotoxicity studies. Overall, repeat-dose toxicity studies in the rat and dog showed expected immunostimulatory effects and/or signs of toxicity associated with overstimulation of the immune system (notably increased spleen weight and white blood cell values). Studies in the rabbit with weekly doses of MPL produced no effects. MPL was shown to have no adverse effects on cardiovascular/respiratory function, reproduction, and genotoxicity.

  20. Pilot scale production of the vaccine adjuvant Proteoliposome derived Cochleates (AFCo1) from Neisseria meningitidis serogroup B.

    Science.gov (United States)

    Zayas, Caridad; González, Domingo; Acevedo, Reinaldo; del Campo, Judith; Lastre, Miriam; González, Elizabeth; Romeu, Belkis; Cuello, Maribel; Balboa, Julio; Cabrera, Osmir; Guilherme, Luisa; Pérez, Oliver

    2013-01-01

    The use of new adjuvants in vaccine formulations is a subject of current research. Only few parenteral adjuvants have been licensed. We have developed a mucosal and parenteral adjuvant known as AFCo1 (Adjuvant Finlay Cochleate 1, derived from proteoliposomes of N. meningitidis B) using a dialysis procedure to produce them on lab scale. The immunogenicity of the AFCo1 produced by dialysis has been already evaluated, but it was necessary to demonstrate the feasibility of a larger-scale manufacturing process. Therefore, we used a crossflow diafiltration system (CFS) that allows easy scale up to obtain large batches in an aseptic environment. The aim of this work was to produce AFCo1 on pilot scale, while conserving the adjuvant properties. The proteoliposomes (raw material) were resuspended in a buffer containing sodium deoxycholate and were transformed into AFCo1 under the action of a calcium forming buffer. The detergent was removed from the protein solution by diafiltration to a constant volume. In this CFS, we used a hollow fiber cartridge from Amicon (polysulfona cartridge of 10 kDa porosity, 1mm channel diameter of fiber and 0.45 m² area of filtration), allowing production of a batch of up to 20 L. AFCo1 were successfully produced by tangential filtration to pilot scale. The batch passed preliminary stability tests. Nasal immunization of BALB/c mice, induced specific saliva IgA and serum IgG. The induction of Th1 responses were demonstrated by the induction of IgG2a, IFNγ and not IL-5. The adjuvant action over Neisseria (self) antigens and with co-administered (heterologous) antigens such as ovalbumin and a synthetic peptide from haemolytic Streptococcus B was also demonstrated.

  1. "Half-half" blisters in bullous pemphigoid successfully treated with adjuvant high-dose intravenous immunoglobulin.

    Science.gov (United States)

    Pacheco, David; Lopes, Leonor; Soares-Almeida, Luis; Marques, Manuel Sacramento; Filipe, Paulo

    2012-09-01

    Bullous pemphigoid is a rare, autoimmune blistering disease. Its clinical presentation is tense blisters that may arise on normal-appearing or erythematous skin. Bullous pemphigoid refractory to systemic corticosteroids in combination with immunosuppressants such as azathioprine and mycophenolate mofetil may benefit from adjuvant high-dose intravenous immunoglobulin (IVIg). We describe a particular case with an unusual clinical presentation unresponsive to systemic corticosteroids plus azathioprine, in which the addition of high-dose IVIg was successful. The combined therapy of systemic corticosteroids and azathioprine plus high-dose IVIg can be an option in refractory cases due to its efficiency and tolerability.

  2. Self-Adjuvanting Bacterial Vectors Expressing Pre-Erythrocytic Antigens Induce Sterile Protection against Malaria

    Directory of Open Access Journals (Sweden)

    Elke eBergmann-Leitner

    2013-07-01

    Full Text Available Genetically inactivated, Gram-negative bacteria that express malaria vaccine candidates represent a promising novel self-adjuvanting vaccine approach. Antigens expressed on particulate bacterial carriers not only target directly to antigen-presenting cells but also provide a strong danger signal thus circumventing the requirement for potent extraneous adjuvants. E. coli expressing malarial antigens resulted in the induction of either Th1 or Th2 biased responses that were dependent on both antigen and sub-cellular localization. Some of these constructs induced higher quality humoral responses compared to recombinant protein and most importantly they were able to induce sterile protection against sporozoite challenge in a murine model of malaria. In light of these encouraging results, two major Plasmodium falciparum pre-erythrocytic malaria vaccine targets, the Cell-Traversal protein for Ookinetes and Sporozoites (CelTOS fused to the Maltose-binding protein in the periplasmic space and the Circumsporozoite Protein (CSP fused to the Outer membrane protein A in the outer membrane were expressed in a clinically relevant, attenuated Shigella strain (Shigella flexneri 2a. This type of live attenuated vector has previously undergone clinical investigations as a vaccine against shigellosis. Using this novel delivery platform for malaria, we find that vaccination with the whole organism represents an effective vaccination alternative that induces protective efficacy against sporozoite challenge. Shigella GeMI-Vax expressing malaria targets warrant further evaluation to determine their full potential as a dual disease, multivalent, self-adjuvanting vaccine system, against both shigellosis and malaria.

  3. A genetically adjuvanted influenza B virus vector increases immunogenicity and protective efficacy in mice.

    Science.gov (United States)

    Kittel, Christian; Wressnigg, Nina; Shurygina, Anna Polina; Wolschek, Markus; Stukova, Marina; Romanovskaya-Romanko, Ekatherina; Romanova, Julia; Kiselev, Oleg; Muster, Thomas; Egorov, Andrej

    2015-10-01

    The existence of multiple antigenically distinct types and subtypes of influenza viruses allows the construction of a multivalent vector system for the mucosal delivery of foreign sequences. Influenza A viruses have been exploited successfully for the expression of extraneous antigens as well as immunostimulatory molecules. In this study, we describe the development of an influenza B virus vector whose functional part of the interferon antagonist NS1 was replaced by human interleukin 2 (IL2) as a genetic adjuvant. We demonstrate that IL2 expressed by this viral vector displays immune adjuvant activity in immunized mice. Animals vaccinated with the IL2 viral vector showed an increased hemagglutination inhibition antibody response and higher protective efficacy after challenge with a wild-type influenza B virus when compared to mice vaccinated with a control virus. Our results demonstrate that it is feasible to construct influenza B vaccine strains expressing immune-potentiating foreign sequences from the NS genomic segment. Based on these data, it is now hypothetically possible to create a trivalent (or quadrivalent) live attenuated influenza vaccine in which each component expresses a selected genetic adjuvant with tailored expression levels.

  4. Mutants of Escherichia coli heat-labile enterotoxin and cholera toxin as mucosal adjuvants

    Institute of Scientific and Technical Information of China (English)

    FENG Qiang; CAI Shaoxi; ZOU Quanming

    2003-01-01

    Mucosal vaccination has been getting more and more recognition because of its compliance and low risk of spreading infectious disease by contaminated syringes used in subcutaneous immunization. However, most vaccines are unable to induce immune responses when given mucosally, and require the use of strong adjuvant for effective delivery systems. Heat-labile enterotoxin (LT) and Cholera toxin(CT) are powerful mucosal adjuvants when co-administered with soluble antigens. But high toxicity hampers their use in humans. Thanks to the fine knowledge of the structure-function relationship of LT and CT, many nontoxic or low toxic mutants have been generated, part of them retain high adjuvanticity of mucosal immunization. Among these mutants, LTS63K, LTA72R, LTR192G and CTE29H, CTE112K have been widely investigated. LTS63K and CTE112K are fully non toxic, whereas LTA72R and CTE29H are low toxic, and LTR192G is nontoxic in vitro(it remains the same toxicity as wild type LT in vivo). These mutants are extremely active as mucosal adjuvants when co-administrated with a variety of antigens in different animal models. They will be investigated more widely and deeply in the future. Some of them will be tested soon in human bodies.

  5. Adjuvant effect enhancement of porcine interleukin-2 packaged into solid lipid nanoparticles.

    Science.gov (United States)

    Chen, Guohua; Zeng, Shuang; Jia, Huaijie; He, Xiaobing; Fang, Yongxiang; Jing, Zhizhong; Cai, Xuepeng

    2014-02-01

    In this paper, we investigated the enhancement of adjuvant effects of porcine IL-2 (pIL-2) by packaging it into a solid lipid nanoparticle (SLN) delivery system. SLN-pIL-2 was prepared using hydrogenated castor oil and Polylactide-co-glycolide by double emulsion solvent evaporation methods (w/o/w). In animal trials, BALB/c mice were immunized with inactivated foot and mouth disease virus (FMDV) antigen combined with the SLN-pIL-2 adjuvant on days 0 and 14. Antibody titer, splenocyte proliferation, and secretion of IFN-γ and IL-4 cytokines were determined. Our results showed that SLN-pIL-2 could significantly enhance FMDV-specific antibody level compared with recombinant pIL-2 alone (pSLN-pIL-2 significantly increased the proliferative responses of antigen-specific spleen cells. Furthermore, SLN-pIL-2 induced the secretion of IFN-γ at a level higher than that induced by recombinant pIL-2 alone. Our results indicate that packaging recombinant pIL-2 in SLNs can be an effective way of boosting the effectiveness of pIL-2 as an adjuvant to enhance immune responses of vaccines.

  6. Dry-powder form of chitosan nanospheres containing influenza virus and adjuvants for nasal immunization.

    Science.gov (United States)

    Dehghan, S; Tavassoti Kheiri, M; Tabatabaiean, M; Darzi, S; Tafaghodi, M

    2013-08-01

    The objective of this study was to develop and statistically optimize chitosan nanospheres. For this purpose chitosan powder was turned into nanospheres using tripolyphosphate as a crosslinker and through ionic gelation. D-optimal response surface design was applied to optimize the nanospheres. Their size and polydispersity index (PDI) were measured as the dependant variables. Then the inactivated influenza virus and/or CpG ODN or Quillaja saponin (QS) were incorporated into the chitosan nanospheres. The release profiles of the antigen and both adjuvants were obtained. The toxicity of the formulations was tested by XTT using Calu 6 cell lines. The size distribution and PDI of plain chitosan nanospheres was 581.1 ± 32.6 and 0.478 ± 0.04. After 4 h the release of antigen, QS and CpG from the chitosan matrix were 33, 36 and 62%, respectively. The inactivated virus remained intact during preparation, as revealed by the SDS-PAGE method. Differential scanning calorimetry and Fourier Transform Infrared Spectroscopy indicated no serious structural changes in the chitosan carrier in the presence of either the antigen or the immunoadjuvants. Although the antigen loaded into chitosan nanospheres showed slight cytotoxicity on lung-cancer cells, co-encapsulation of the adjuvant (especially CpG) lowered this effect. The results demonstrated that chitosan as a carrier and immunostimulator, along with CpG or QS adjuvants, creates a potential influenza vaccine delivery system which can be administered nasally.

  7. Flagellin Encoded in Gene-Based Vector Vaccines Is a Route-Dependent Immune Adjuvant.

    Directory of Open Access Journals (Sweden)

    Hamada F Rady

    Full Text Available Flagellin has been tested as a protein-based vaccine adjuvant, with the majority of studies focused on antibody responses. Here, we evaluated the adjuvant activity of flagellin for both cellular and humoral immune responses in BALB/c mice in the setting of gene-based immunization, and have made several novel observations. DNA vaccines and adenovirus (Ad vectors were engineered to encode mycobacterial protein Ag85B, with or without flagellin of Salmonella typhimurium (FliC. DNA-encoded flagellin given IM enhanced splenic CD4+ and CD8+ T cell responses to co-expressed vaccine antigen, including memory responses. Boosting either IM or intranasally with Ad vectors expressing Ag85B without flagellin led to durable enhancement of Ag85B-specific antibody and CD4+ and CD8+ T cell responses in both spleen and pulmonary tissues, correlating with significantly improved protection against challenge with pathogenic aerosolized M. tuberculosis. However, inclusion of flagellin in both DNA prime and Ad booster vaccines induced localized pulmonary inflammation and transient weight loss, with route-dependent effects on vaccine-induced T cell immunity. The latter included marked reductions in levels of mucosal CD4+ and CD8+ T cell responses following IM DNA/IN Ad mucosal prime-boosting, although antibody responses were not diminished. These findings indicate that flagellin has differential and route-dependent adjuvant activity when included as a component of systemic or mucosally-delivered gene-based prime-boost immunization. Clear adjuvant activity for both T and B cell responses was observed when flagellin was included in the DNA priming vaccine, but side effects occurred when given in an Ad boosting vector, particularly via the pulmonary route.

  8. A novel laser vaccine adjuvant increases the motility of antigen presenting cells.

    Directory of Open Access Journals (Sweden)

    Xinyuan Chen

    Full Text Available BACKGROUND: Development of a potent vaccine adjuvant without introduction of any side effects remains an unmet challenge in the field of the vaccine research. METHODOLOGY/PRINCIPAL FINDINGS: We found that laser at a specific setting increased the motility of antigen presenting cells (APCs and immune responses, with few local or systemic side effects. This laser vaccine adjuvant (LVA effect was induced by brief illumination of a small area of the skin or muscle with a nondestructive, 532 nm green laser prior to intradermal (i.d. or intramuscular (i.m. administration of vaccines at the site of laser illumination. The pre-illumination accelerated the motility of APCs as shown by intravital confocal microscopy, leading to sufficient antigen (Ag-uptake at the site of vaccine injection and transportation of the Ag-captured APCs to the draining lymph nodes. As a result, the number of Ag(+ dendritic cells (DCs in draining lymph nodes was significantly higher in both the 1° and 2° draining lymph nodes in the presence than in the absence of LVA. Laser-mediated increases in the motility and lymphatic transportation of APCs augmented significantly humoral immune responses directed against a model vaccine ovalbumin (OVA or influenza vaccine i.d. injected in both primary and booster vaccinations as compared to the vaccine itself. Strikingly, when the laser was delivered by a hair-like diffusing optical fiber into muscle, laser illumination greatly boosted not only humoral but also cell-mediated immune responses provoked by i.m. immunization with OVA relative to OVA alone. CONCLUSION/SIGNIFICANCE: The results demonstrate the ability of this safe LVA to augment both humoral and cell-mediated immune responses. In comparison with all current vaccine adjuvants that are either chemical compounds or biological agents, LVA is novel in both its form and mechanism; it is risk-free and has distinct advantages over traditional vaccine adjuvants.

  9. Flagellin Encoded in Gene-Based Vector Vaccines Is a Route-Dependent Immune Adjuvant.

    Science.gov (United States)

    Rady, Hamada F; Dai, Guixiang; Huang, Weitao; Shellito, Judd E; Ramsay, Alistair J

    2016-01-01

    Flagellin has been tested as a protein-based vaccine adjuvant, with the majority of studies focused on antibody responses. Here, we evaluated the adjuvant activity of flagellin for both cellular and humoral immune responses in BALB/c mice in the setting of gene-based immunization, and have made several novel observations. DNA vaccines and adenovirus (Ad) vectors were engineered to encode mycobacterial protein Ag85B, with or without flagellin of Salmonella typhimurium (FliC). DNA-encoded flagellin given IM enhanced splenic CD4+ and CD8+ T cell responses to co-expressed vaccine antigen, including memory responses. Boosting either IM or intranasally with Ad vectors expressing Ag85B without flagellin led to durable enhancement of Ag85B-specific antibody and CD4+ and CD8+ T cell responses in both spleen and pulmonary tissues, correlating with significantly improved protection against challenge with pathogenic aerosolized M. tuberculosis. However, inclusion of flagellin in both DNA prime and Ad booster vaccines induced localized pulmonary inflammation and transient weight loss, with route-dependent effects on vaccine-induced T cell immunity. The latter included marked reductions in levels of mucosal CD4+ and CD8+ T cell responses following IM DNA/IN Ad mucosal prime-boosting, although antibody responses were not diminished. These findings indicate that flagellin has differential and route-dependent adjuvant activity when included as a component of systemic or mucosally-delivered gene-based prime-boost immunization. Clear adjuvant activity for both T and B cell responses was observed when flagellin was included in the DNA priming vaccine, but side effects occurred when given in an Ad boosting vector, particularly via the pulmonary route.

  10. Advances in management of adjuvant chemotherapy in rectal cancer: Consequences for clinical practice.

    Science.gov (United States)

    Netter, Jeanne; Douard, Richard; Durdux, Catherine; Landi, Bruno; Berger, Anne; Taieb, Julien

    2016-11-01

    More than half the patients with rectal cancer present with locally advanced rectal disease at diagnosis with a high risk of recurrence. Preoperative chemoradiotherapy and standardized radical surgery with total mesorectal excision have been established as the 'gold standard' for treating these patients. Pathological staging using the ypTNM classification system to decide on adjuvant chemotherapy (ACT) is widely used in clinical practice, but the delivery of ACT is still controversial, as many discrepancies persist in the conclusions of different trials, due to heterogeneity of the inclusion criteria between studies, lack of statistical power, and variations in preoperative and adjuvant regimens. In 2014, a meta-analysis of four randomized phase-III trials (EORTC 22921, I-CNR-RT, PROCTOR-SCRIPT, CHRONICLE) failed to demonstrate any statistical efficacy of fluorouracil (5FU)-based ACT. Three recent randomized trials aimed to compare 5FU with 5FU plus oxaliplatin-based chemotherapy. Two of them (ADORE, CAO/ARO/AIO-04) appeared to find a disease-free survival benefit for patients treated with the combination therapy. Thus, while awaiting new data, it can be said that, as of 2015, patients with yp stage I tumors or histological complete response derived no benefit from adjuvant therapy. On the other hand, the FOLFOX chemotherapy regimen should be proposed for yp stage III patients, and may be considered for yp stage II tumors in fit patients with high-risk factors. Nevertheless, well-designed and sufficiently powered clinical trials dedicated to adjuvant treatments for rectal cancer remain justified in future to achieve a high level of proof in keeping with evidence-based medical standards.

  11. Gastric carcinoma: curative resection and adjuvant chemotherapy.

    Science.gov (United States)

    Carrillo Hernández, J F; Ernesto de Obaldía Castillo, G; Ramírez Ortega, C; Frías Mendivil, M; Pardo, M

    1994-01-01

    A retrospective study of gastric adenocarcinoma treated with surgery as curative attempt was performed at the Oncology Service, in the Hospital Regional 20 de Noviembre, ISSSTE. Morbidity and mortality of the surgical procedures were evaluated, the significance of several risk factors and the survival impact of adjuvant chemotherapy with 5-fluorouracil (5-FU) and mitomycin C (MMC). In the period from 1975 to 1991 a total of 483 new cases were seen. In only 54 patients (11.2%) was it possible to undertake a curative resection. The patients were assigned to three groups of treatment: surgery alone (14 cases), surgery + 5-FU (19 cases), and surgery + 5-FU+MMC (21 cases). Three different types of surgical techniques are regularly performed in our service for gastric cancer treatment: Billroth II distal gastrectomy, total gastrectomy with Roux-En-Y reconstruction, and esophagogastrectomy with esophagogastrostomy. Surgical morbidity and mortality was low, with 9% of duodenal stump fistulas and 27% with partial stenosis of esophagojejunostomy; the operative mortality was zero. Chemotherapy toxicity was transient and low, no related deaths were recorded. The prognostic factors associated significantly with survival were lymph node status and tumor penetration. The histologic differentiation as well as the tumor location and type of surgery had no significance. The estimated 5-year survival of the patients treated with surgery alone was 62%, while that of the patients treated with surgery plus chemotherapy was 38%. These groups were not comparable, however, because of important differences in their prognostic factors. The groups treated with 5-FU alone or in combination with MMC had no survival difference between them.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant.

    Science.gov (United States)

    Dinc, Gunes; Pennington, Jarrod M; Yolcu, Esma S; Lawrenz, Matthew B; Shirwan, Haval

    2014-09-03

    The lead candidate plague subunit vaccine is the recombinant fusion protein rF1-V adjuvanted with alum. While alum generates Th2 regulated robust humoral responses, immune protection against Yersinia pestis has been shown to also involve Th1 driven cellular responses. Therefore, the rF1-V-based subunit vaccine may benefit from an adjuvant system that generates a mixed Th1 and humoral immune response. We herein assessed the efficacy of a novel SA-4-1BBL costimulatory molecule as a Th1 adjuvant to improve cellular responses generated by the rF1-V vaccine. SA-4-1BBL as a single adjuvant had better efficacy than alum in generating CD4(+) and CD8(+) T cells producing TNFα and IFNγ, signature cytokines for Th1 responses. The combination of SA-4-1BBL with alum further increased this Th1 response as compared with the individual adjuvants. Analysis of the humoral response revealed that SA-4-1BBL as a single adjuvant did not generate a significant Ab response against rF1-V, and SA-4-1BBL in combination with alum did not improve Ab titers. However, the combined adjuvants significantly increased the ratio of Th1 regulated IgG2c in C57BL/6 mice to the Th2 regulated IgG1. Finally, a single vaccination with rF1-V adjuvanted with SA-4-1BBL+alum had better protective efficacy than vaccines containing individual adjuvants. Taken together, these results demonstrate that SA-4-1BBL improves the protective efficacy of the alum adjuvanted lead rF1-V subunit vaccine by generating a more balanced Th1 cellular and humoral immune response. As such, this adjuvant platform may prove efficacious not only for the rF1-V vaccine but also against other infections that require both cellular and humoral immune responses for protection. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Adjuvant radiotherapy for stage I endometrial cancer.

    Science.gov (United States)

    Kong, Anthony; Johnson, Nick; Kitchener, Henry C; Lawrie, Theresa A

    2012-04-18

    This is an updated version of the original Cochrane review published in Issue 2, 2007. The role of radiotherapy (both pelvic external beam radiotherapy (EBRT) and vaginal intracavity brachytherapy (VBT)) in stage I endometrial cancer following hysterectomy remains controversial. To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer. We searched The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Specialised Register to end-2005 for the original review, and extended the search to January 2012 for the update. We included randomised controlled trials (RCTs) that compared post-operative adjuvant radiotherapy (either EBRTor VBT, or both) versus no radiotherapy or VBT in women with stage I endometrial cancer. Two review authors independently assessed trials and extracted data to a specifically designed data collection form. The primary outcome was overall survival. Secondary outcomes were endometrial cancer-related deaths, locoregional recurrence and distant recurrence. Meta-analyses were performed using Cochrane Review Manager Software 5.1. We included eight trials. Seven trials (3628 women) compared EBRT with no EBRT (or VBT), and one trial (645 women) compared VBTwith no additional treatment. We considered six of the eight trials to be of a high quality. Time-to-event data were not available for all trials and all outcomes.EBRT (with or without VBT) compared with no EBRT (or VBT alone) for stage I endometrial carcinoma significantly reduced locoregional recurrence (time-to-event data: five trials, 2965 women; Hazard Ratio (HR) 0.36, 95% Confidence Interval (CI) 0.25 to 0.52; and dichotomous data: seven trials, 3628 women; Risk Ratio (RR) 0.33, 95% CI 0.23 to 0.47). This reduced risk of locoregional recurrence did not translate into improved overall survival (time-to-event data: five trials, 2,965 women; HR 0.99, 95% CI 0.82 to1.20; and dichotomous data: seven trials, 3628 women; RR 0.98, 95

  14. Adjuvant arthritis pretreatment with type II collagen and Mycobacterium butyricum.

    Science.gov (United States)

    Franch, A; Cassany, S; Castellote, C; Castell, M

    1992-11-01

    A treatment previous to adjuvant arthritis induction has been performed with type II collagen (CII) or Mycobacterium butyricum (Mb), which is the inducer of the pathology. Pretreatment was administered in two different ways: a) subcutaneously or intradermally 14 days before arthritis induction, and b) intravenously 3 days before induction. In order to relate the change in inflammation to the corresponding antigen immune response, serum antibodies and delayed type hypersensitivity (DTH) against CII or Mb were studied. Pretreatment with s.c. CII 14 days before induction produced slight protection against arthritis and significantly delayed its onset; systemic inflammation showed good positive correlation with anti-CII antibodies. The CII administered i.v. 3 days before arthritic challenge did not significantly modify the inflammatory process. The use of i.d. subarthritogenic doses of Mb 14 days before induction protected a high percentage of the animals from the posterior arthritic challenge; this protection was accompanied by high anti-Mb antibody titers and DTH reaction. When Mb was given i.v. 3 days before induction, a partial protection of inflammation was observed; arthritis was milder and its onset was delayed. These changes were accompanied by reduced humoral and cellular response to Mb.

  15. Challenges in early clinical development of adjuvanted vaccines.

    Science.gov (United States)

    Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

    2015-06-08

    A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support.

  16. Postoperative adjuvant radiotherapy and 5-fluorouracil chemotherapy for rectal carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Chao, M.W.T.; Lim-Joon, M.; Wada, M. [Peter MacCallum Cancer Institute, Melbourne, VIC (Australia). Division of Radiation Oncology; Byram, D.; Vaughan, S.; McLennan, R.; Joseph, D. [Geelong Hospital, Geelong, VIC (Australia). Department of Radiation and Medical Oncology; Bell, R.; Bond, R. [St John of God Hospital, Ballarat, VIC (Australia). Department of Medical Oncology

    1998-02-01

    Postoperative combined modality therapy with radiotherapy and 5-fluorouracil (5FU) chemotherapy is an effective adjuvant approach that reduces locoregional and distant metastatic disease in patients with high-risk rectal carcinoma. However, this approach results in a treatment regimen of at least 6 months` duration. The present prospective study investigates the integration of radiotherapy and 5FU chemotherapy in a protocol designed to minimize toxicity and reduce the overall treatment time. A total of 40 patients with TNM stage 11 or 111 disease receives postoperative radiotherapy at four fractions per week with weekly 5FU bolus injections delivered on the fifth non radiotherapy day. Patients also received systemic chemotherapy with leucovorin both before and after pelvic irradiation, with the total treatment duration extending for only 18 weeks. Patients were able to complete radiotherapy in 90% of cases, while the delivery of full-dose chemotherapy was achievable in the vast majority. The incidence of haematologic and gastrointestinal toxicities requiring the cessation of treatment was acceptable. With a median follow-up of 20.9 months among surviving patients, the estimated progression-free and overall survival at 2 years were 71% and 79%, respectively. Copyright (1998) Blackwell Science Pty Ltd 15 refs., 7 tabs., 4 figs

  17. Environmental adjuvants, apoptosis and the censorship over autoimmunity.

    Science.gov (United States)

    Rovere-Querini, Patrizia; Manfredi, Angelo A; Sabbadini, Maria Grazia

    2005-11-01

    Alterations during apoptosis lead to the activation of autoreactive T cells and the production of autoantibodies. This article discusses the pathogenic potential of cells dying in vivo, dissecting the role of signals that favor immune responses (adjuvants) and the influence of genetic backgrounds. Diverse factors determine whether apoptosis leads or not to a self-sustaining, clinically apparent autoimmune disease. The in vivo accumulation of uncleared dying cells per se is not sufficient to cause disease. However, dying cells are antigenic and their complementation with immune adjuvants causes lethal diseases in predisposed lupus-prone animals. At least some adjuvant signals directly target the function and the activation state of antigen presenting cells. Several laboratories are aggressively pursuing the molecular identification of endogenous adjuvants. Sodium monourate and the high mobility group B1 protein (HMGB1) are, among those identified so far, well known to rheumatologists. However, even the complementation of apoptotic cells with potent adjuvant signals fail to cause clinical autoimmunity in most strains: autoantibodies generated are transient, do not undergo to epitope/spreading and do not cause disease. Novel tools for drug development will derive from the molecular identification of the constraints that prevent autoimmunity in normal subjects.

  18. Optimizing Adherence to Adjuvant Imatinib in Gastrointestinal Stromal Tumor

    Science.gov (United States)

    Tetzlaff, Eric D.; Davey, Monica P.

    2013-01-01

    The increasing use of patient-administered oral anticancer drugs is paralleled by new challenges in maintaining treatment adherence. These challenges are particularly significant with adjuvant therapies for prevention of disease recurrence, where the benefits of ongoing treatment are not readily apparent to patients. Nurse practitioners and physician assistants (collectively referred to as advanced practitioners) play integral roles in providing education on disease and treatment to patients that can increase adherence to oral therapies and ideally improve outcomes. For patients with gastrointestinal stromal tumor (GIST), the oral targeted therapy imatinib has become the mainstay of treatment for advanced and recurrent disease and as adjuvant therapy following surgical resection. Recent data indicate significantly improved overall survival with 3 years vs. 1 year of adjuvant imatinib therapy. Continuous dosing with imatinib is needed for optimal efficacy and to limit additional health-care costs associated with management of disease progression in GIST. However, longer duration of therapy increases the risk of nonadherence. Imatinib adherence rates, as well as factors contributing to nonadherence to adjuvant therapy in routine clinical practice, are discussed in this review. Also explored are practical approaches for improving adherence to adjuvant imatinib therapy through greater patient education, in light of the increased duration of therapy in select patients. PMID:25032004

  19. Oral administration of bovine whey proteins to mice elicits opposing immunoregulatory responses and is adjuvant dependent

    Science.gov (United States)

    AFUWAPE, A O; TURNER, M W; STROBEL, S

    2004-01-01

    Most studies investigating the induction of oral tolerance (OT) use purified proteins such as ovalbumin (OVA), bovine serum albumin (BSA) and beta-lactoglobulin (β-LG). Little information is available regarding the induction of OT to a protein mixture, e.g. cow's milk. In this study we compared the regulatory mechanisms induced after the oral administration of a whey protein concentrate (WP) derived from cow's milk following immunization with two different adjuvants, complete Freund's adjuvant (CFA) and alum. OVA was used as a control antigen. Animals were given a single feed of these proteins at an equivalent dose of 1 mg/g body weight before they were immunized seven days later with the antigen in Freund's adjuvant or alum. Delayed type hypersensitivity (DTH) responses were suppressed by both a feed of WP and OVA after immunization with CFA. However, only OVA feeding suppressed antigen specific IgG responses. In an attempt to investigate whether WP would tolerize the more susceptible IgE responses, alum immunization replaced CFA as the adjuvant used for systemic immunizations. WP, after a single feed, significantly primed for DTH and IgE responses indicating oral sensitization to WP. In contrast, OVA suppressed DTH, IgE and IgG responses. Antigen specific proliferation of mononuclear cells was suppressed in mice fed OVA, but primed in those fed with WP. In addition cells taken from sensitized mice fed WP up-regulated levels of specific interleukin (IL) -4, -10 and -12 in vitro whereas these cytokines were suppressed in cultures from tolerant WP fed mice. Global suppression was obtained in cultures from tolerant OVA fed mice. TGF-β was not detected in draining PLN cell cultures of either tolerant or sensitized mice. These data suggest that a whey protein mixture induces divergent responses following immunization with either CFA or alum despite being fed at an identical dose. We suggest that that the choice of the adjuvant may determine the immunoregulatory

  20. The immunobiology of aluminium adjuvants: how do they really work?

    Science.gov (United States)

    Exley, Christopher; Siesjö, Peter; Eriksson, Håkan

    2010-03-01

    Aluminium adjuvants potentiate the immune response, thereby ensuring the potency and efficacy of typically sparingly available antigen. Their concomitant critical importance in mass vaccination programmes may have prompted recent intense interest in understanding how they work and their safety. Progress in these areas is stymied, however, by a lack of accessible knowledge pertaining to the bioinorganic chemistry of aluminium adjuvants, and, consequently, the inappropriate application and interpretation of experimental models of their mode of action. The objective herein is, therefore, to identify the many ways that aluminium chemistry contributes to the wide and versatile armoury of its adjuvants, such that future research might be guided towards a fuller understanding of their role in human vaccinations.

  1. Management of Pediatric Myxopapillary Ependymoma: The Role of Adjuvant Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Agbahiwe, Harold C.; Wharam, Moody [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Batra, Sachin [Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Cohen, Kenneth [Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Terezakis, Stephanie A., E-mail: sterezak@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2013-02-01

    Introduction: Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE. Methods: Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis. Results: All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT. Conclusions: Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE.

  2. Clinical outcomes of adjuvant radiation therapy and prognostic factors in early stage uterine cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyun Ju; Rhee, Woo Joong; Choi, Seo Hee; Kim, Gwi Eon; Kim, Yong Bae [Dept. of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of); Nam, EunJi; Kim, Sang Wun; Kim, Sung Hoon [Dept. of Radiation Oncology, Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2015-06-15

    To evaluate the outcomes of adjuvant radiotherapy (RT) and to analyze prognostic factors of survival in the International Federation of Gynecology and Obstetrics (FIGO) IB-IIA uterine cervical cancer. We retrospectively reviewed the medical records of 148 patients with FIGO IB-IIA uterine cervical cancer who underwent surgery followed by adjuvant RT at the Yonsei Cancer Center between June 1997 and December 2011. Adjuvant radiotherapy was delivered to the whole pelvis or an extended field with or without brachytherapy. Among all patients, 57 (38.5%) received adjuvant chemotherapy either concurrently or sequentially. To analyze prognostic factors, we assessed clinicopathologic variables and metabolic parameters measured on preoperative {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). To evaluate the predictive performance of metabolic parameters, receiver operating characteristic curve analysis was used. Overall survival (OS) and disease-free survival (DFS) were analyzed by the Kaplan-Meier method. The median follow-up period was 63.2 months (range, 2.7 to 206.8 months). Locoregional recurrence alone occurred in 6 patients, while distant metastasis was present in 16 patients, including 2 patients with simultaneous regional failure. The 5-year and 10-year OSs were 87.0% and 85.4%, respectively. The 5-year and 10-year DFSs were 83.8% and 82.5%, respectively. In multivariate analysis, pathologic type and tumor size were shown to be significant prognostic factors associated with both DFS and OS. In subset analysis of 40 patients who underwent preoperative PET/CT, total lesion glycolysis was shown to be the most significant prognostic factor among the clinicopathologic variables and metabolic parameters for DFS. Our results demonstrated that adjuvant RT following hysterectomy effectively improves local control. From the subset analysis of preoperative PET/CT, we can consider that metabolic parameters may hold prognostic

  3. Adjuvant chemo-radiotherapy in the "sandwich" method for high risk endometrial cancer--a review of literature.

    Science.gov (United States)

    Bie, Yachun; Zhang, Zhenyu; Wang, Xiaolan

    2015-06-24

    Endometrial cancer is a common female malignancy. Patients with high-risk endometrial cancer have relatively high incidence of metastasis and recurrence. Despite complete resection, patients with stage III or IV are at high risk of local or distant recurrence. Systemic adjuvant treatment includes chemotherapy and radiotherapy. But the optimal scheduling is not known. Recently proposed sequential chemo-radiotherapy as sandwich therapy for high risk endometrial cancer have yielded encouraging results. This article is to review the adjuvant chemo-radiotherapy in the "sandwich" method for high risk endometrial cancer to help clinicians identify the most effective adjuvant treatment for patients with high risks of it. We used MEDLINE, EMBASE, Cochrane Library and CBM databases to search the literature. A systematic review was made. And most data showed "sandwich" therapy is feasible, efficacious, well-tolerated and resulted in excellent long-term progression free and overall survival in the setting of advanced endometrial cancer. Randomized trials are necessary to compare chemo-radio therapy given in the "sandwich" fashion to other means of sequencing these treatment modalities. It is also necessary to define which population is best suited for "sandwich" adjuvant therapy.

  4. Translating innate response into long-lasting antibody response by the intrinsic antigen-adjuvant properties of papaya mosaic virus.

    Science.gov (United States)

    Acosta-Ramírez, Elizabeth; Pérez-Flores, Rebeca; Majeau, Nathalie; Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Ramírez-Saldaña, Maricela; Manjarrez-Orduño, Nataly; Cervantes-Barragán, Luisa; Santos-Argumedo, Leopoldo; Flores-Romo, Leopoldo; Becker, Ingeborg; Isibasi, Armando; Leclerc, Denis; López-Macías, Constantino

    2008-06-01

    Identifying the properties of a molecule involved in the efficient activation of the innate and adaptive immune responses that lead to long-lasting immunity is crucial for vaccine and adjuvant development. Here we show that the papaya mosaic virus (PapMV) is recognized by the immune system as a pathogen-associated molecular pattern (PAMP) and as an antigen in mice (Pamptigen). A single immunization of PapMV without added adjuvant efficiently induced both cellular and specific long-lasting antibody responses. PapMV also efficiently activated innate immune responses, as shown by the induction of lipid raft aggregation, secretion of pro-inflammatory cytokines, up-regulation of co-stimulatory molecules on dendritic cells and macrophages, and long-lasting adjuvant effects upon the specific antibody responses to model antigens. PapMV mixed with Salmonella enterica serovar Typhi (S. typhi) outer membrane protein C increased its protective capacity against challenge with S. typhi, revealing the intrinsic adjuvant properties of PapMV in the induction of immunity. Antigen-presenting cells loaded with PapMV efficiently induced antibody responses in vivo, which may link the innate and adaptive responses observed. PapMV recognition as a Pamptigen might be translated into long-lasting antibody responses and protection observed. These properties could be used in the development of new vaccine platforms.

  5. Neisseria lactamica antigens complexed with a novel cationic adjuvant

    OpenAIRE

    Gaspar, Emanuelle B.; Rosetti, Andreza S.; Lincopan, Nilton; De Gaspari, Elizabeth

    2013-01-01

    Colonization of the nasopharynx by non-pathogenic Neisseria species, including N. lactamica, has been suggested to lead to the acquisition of natural immunity against Neisseria meningitidis in young children. The aim of this study was to identify a model complex of antigens and adjuvant for immunological preparation against N. meningitidis B, based on cross reactivity with N. lactamica outer membrane vesicles (OMV) antigens and the (DDA-BF) adjuvant. Complexes of 25 µg of OMV in 0.1 mM of DDA...

  6. Aluminium: a natural adjuvant in Leishmania transmission via sand flies?

    Science.gov (United States)

    Maingon, Rhayza; Khela, Amandeep; Sampson, Christopher; Ward, Richard; Walker, Karen; Exley, Christopher

    2008-11-01

    Genetically identical Leishmania chagasi/infantum parasites cause both atypical cutaneous leishmaniasis and visceral leishmaniasis. In this report we have tested the first part of a hypothesis that states that the form of this disease that is manifested depends upon the adjuvant-like activity of aluminium of dietary origin accumulated in the salivary gland of the sand fly vector. In sand flies fed aluminium-supplemented sucrose we have used histochemistry to qualitatively identify aluminium in their salivary glands and graphite furnace atomic absorption spectrometry to quantify the aluminium content of dissected salivary glands. Aluminium may be acting as a natural adjuvant in some forms of leishmaniasis.

  7. Immunogenicity of a Bivalent Adjuvanted Glycoconjugate Vaccine against Salmonella Typhimurium and Salmonella Enteritidis

    Science.gov (United States)

    Fiorino, Fabio; Rondini, Simona; Micoli, Francesca; Lanzilao, Luisa; Alfini, Renzo; Mancini, Francesca; MacLennan, Calman A.; Medaglini, Donata

    2017-01-01

    Salmonella enterica serovars Typhimurium and Enteritidis are the predominant causes of invasive non-typhoidal Salmonella (iNTS) disease. Considering the co-endemicity of S. Typhimurium and S. Enteritidis, a bivalent vaccine formulation against both pathogens is necessary for protection against iNTS disease, thus investigation of glycoconjugate combination is required. In the present work, we investigated the immune responses induced by S. Typhimurium and S. Enteritidis monovalent and bivalent glycoconjugate vaccines adjuvanted with aluminum hydroxide (alum) only or in combination with cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG). Humoral and cellular, systemic and local, immune responses were characterized in two different mouse strains. All conjugate vaccines elicited high levels of serum IgG against the respective O-antigens (OAg) with bactericidal activity. The bivalent conjugate vaccine induced systemic production of antibodies against both S. Typhimurium and S. Enteritidis OAg. The presence of alum or alum + CpG adjuvants in vaccine formulations significantly increased the serum antigen-specific antibody production. The alum + CpG bivalent vaccine formulation triggered the highest systemic anti-OAg antibodies and also a significant increase of anti-OAg IgG in intestinal washes and fecal samples, with a positive correlation with serum levels. These data demonstrate the ability of monovalent and bivalent conjugate vaccines against S. Typhimurium and S. Enteritidis to induce systemic and local immune responses in different mouse strains, and highlight the suitability of a bivalent glycoconjugate formulation, especially when adjuvanted with alum + CpG, as a promising candidate vaccine against iNTS disease. PMID:28289411

  8. Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial

    DEFF Research Database (Denmark)

    Pestalozzi, B.C.; Francis, P.; Quinaux, E.

    2008-01-01

    BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the B...

  9. Contamination of DNase Preparations Confounds Analysis of the Role of DNA in Alum-Adjuvanted Vaccines

    OpenAIRE

    Noges, Laura E.; White, Janice; Cambier, John C.; Kappler, John W.; Marrack, Philippa

    2016-01-01

    Aluminum salt (alum) adjuvants have been used for many years as adjuvants for human vaccines because they are safe and effective. Despite its widespread use, the means by which alum acts as an adjuvant remains poorly understood. Recently, it was shown that injected alum is rapidly coated with host chromatin within mice. Experiments suggested that the host DNA in the coating chromatin contributed to alum’s adjuvant activity. Some of the experiments used commercially purchased DNase and showed ...

  10. 75 FR 66766 - NIAID Blue Ribbon Panel Meeting on Adjuvant Discovery and Development

    Science.gov (United States)

    2010-10-29

    ... discovery, development and clinical evaluation of adjuvants for use with preventive vaccines. NIAID has developed a draft Strategic Plan and Research Agenda for Adjuvant Discovery and Development, which... HUMAN SERVICES NIAID Blue Ribbon Panel Meeting on Adjuvant Discovery and Development Notice is...

  11. Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines.

    Science.gov (United States)

    Hayashi, Masayuki; Aoshi, Taiki; Haseda, Yasunari; Kobiyama, Kouji; Wijaya, Edward; Nakatsu, Noriyuki; Igarashi, Yoshinobu; Standley, Daron M; Yamada, Hiroshi; Honda-Okubo, Yoshikazu; Hara, Hiromitsu; Saito, Takashi; Takai, Toshiyuki; Coban, Cevayir; Petrovsky, Nikolai; Ishii, Ken J

    2017-02-01

    Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th)2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV), a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR) 7 knockout mice which are unable to respond to RNA contained in WV antigen. Similarly, no adjuvant effect was seen when Advax was combined with endotoxin-free ovalbumin, a neutral Th0-type antigen. An adjuvant effect was also not seen in tumor necrosis factor (TNF)-α knockout mice, and the adjuvant effect required the presences of dendritic cells (DCs) and phagocytic macrophages. Therefore, unlike other adjuvants, Advax potentiates the intrinsic or in-built adjuvant property of co-administered antigens. Hence, Advax is a unique class of adjuvant which can potentiate the intrinsic adjuvant feature of the vaccine antigens through a yet to be determined mechanism.

  12. Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines

    Directory of Open Access Journals (Sweden)

    Masayuki Hayashi

    2017-02-01

    Full Text Available Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV, a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR 7 knockout mice which are unable to respond to RNA contained in WV antigen. Similarly, no adjuvant effect was seen when Advax was combined with endotoxin-free ovalbumin, a neutral Th0-type antigen. An adjuvant effect was also not seen in tumor necrosis factor (TNF-α knockout mice, and the adjuvant effect required the presences of dendritic cells (DCs and phagocytic macrophages. Therefore, unlike other adjuvants, Advax potentiates the intrinsic or in-built adjuvant property of co-administered antigens. Hence, Advax is a unique class of adjuvant which can potentiate the intrinsic adjuvant feature of the vaccine antigens through a yet to be determined mechanism.

  13. Nickel acts as an adjuvant during cobalt sensitization.

    Science.gov (United States)

    Bonefeld, Charlotte Menné; Nielsen, Morten Milek; Vennegaard, Marie T; Johansen, Jeanne Duus; Geisler, Carsten; Thyssen, Jacob P

    2015-03-01

    Metal allergy is the most frequent form of contact allergy with nickel and cobalt being the main culprits. Typically, exposure comes from metal-alloys where nickel and cobalt co-exist. Importantly, very little is known about how co-exposure to nickel and cobalt affects the immune system. We investigated these effects by using a recently developed mouse model. Mice were epicutaneously sensitized with i) nickel alone, ii) nickel in the presence of cobalt, iii) cobalt alone, or iv) cobalt in the presence of nickel, and then followed by challenge with either nickel or cobalt alone. We found that sensitization with nickel alone induced more local inflammation than cobalt alone as measured by increased ear-swelling. Furthermore, the presence of nickel during sensitization to cobalt led to a stronger challenge response to cobalt as seen by increased ear-swelling and increased B and T cell responses in the draining lymph nodes compared to mice sensitized with cobalt alone. In contrast, the presence of cobalt during nickel sensitization only induced an increased CD8(+) T cell proliferation during challenge to nickel. Thus, the presence of nickel during cobalt sensitization potentiated the challenge response against cobalt more than the presence of cobalt during sensitization to nickel affected the challenge response against nickel. Taken together, our study demonstrates that sensitization with a mixture of nickel and cobalt leads to an increased immune response to both nickel and cobalt, especially to cobalt, and furthermore that the adjuvant effect appears to correlate with the inflammatory properties of the allergen. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. How much survival benefit is necessary for breast cancer patients to opt for adjuvant chemotherapy? Results from a Chilean survey

    Science.gov (United States)

    Acevedo, Francisco; Sanchez, Cesar; Jans, Jaime; Rivera, Solange; Camus, Mauricio; Besa, Pelayo

    2014-01-01

    Background: Breast cancer (BC) is the leading cause of cancer death in Chilean women. Adjuvant chemotherapy decreases recurrence and death from BC. The recommendation to indicate chemotherapy is complex. Adjuvant! Online is a valuable computational tool to predict survival benefit obtained with adjuvant systemic therapy. Previous studies in Caucasian patients with BC showed that they are willing to receive chemotherapy for a small benefit. No studies, to our knowledge, have been done in the Hispanic or Latino populations. Methods: We interviewed females with BC who had previously received adjuvant chemotherapy. Age, stage at presentation, time since last chemotherapy, type of chemotherapy, marital status, number of children, and level of education were recorded. We used the graphic representation from Adjuvant! Online to question each patient on how much survival benefit she required to accept chemotherapy. Results: There were 101 women surveyed. The average age was 55.9 (±10.2), 54.5% had involved lymph nodes, 59.4% were married, and 15.8% did not have parity; 62.3% of females accepted chemotherapy for an absolute survival benefit of 1% or less. In a multivariate analysis, younger (p = 0.02) and less-educated patients (p = 0.018) were associated with lower survival benefit required to opt for chemotherapy. Conclusion: In our study, the acceptance of chemotherapy by the Hispanic population requires minimal survival benefit and is in agreement with the Caucasian population reported elsewhere. To our knowledge, our report is the first study that evaluates the perception of Latino patients regarding the benefit of chemotherapy in early BC. PMID:24678346

  15. Development of a SARS Coronavirus Vaccine from Recombinant Spike Protein Plus Delta Inulin Adjuvant.

    Science.gov (United States)

    McPherson, Clifton; Chubet, Richard; Holtz, Kathy; Honda-Okubo, Yoshikazu; Barnard, Dale; Cox, Manon; Petrovsky, Nikolai

    2016-01-01

    Given periodic outbreaks of fatal human infections caused by coronaviruses, development of an optimal coronavirus vaccine platform capable of rapid production is an ongoing priority. This chapter describes the use of an insect cell expression system for rapid production of a recombinant vaccine against severe acute respiratory syndrome coronavirus (SARS). Detailed methods are presented for expression, purification, and release testing of SARS recombinant spike protein antigen, followed by adjuvant formulation and animal testing. The methods herein described for rapid development of a highly protective SARS vaccine are equally suited to rapid development of vaccines against other fatal human coronavirus infections, e.g., the MERS coronavirus.

  16. Immunological and Antitumor Effects of IL-23 as a Cancer Vaccine Adjuvant1

    OpenAIRE

    Overwijk, Willem W; Karin E de Visser; Tirion, Felicia H.; de Jong, Laurina A.; Pols, Thijs W. H.; van der Velden, Yme U; Boorn, Jasper G. van den; Keller, Anna M.; Buurman, Wim A; Theoret, Marc R.; Blom, Bianca; Restifo, Nicholas P.; Kruisbeek, Ada M.; Kastelein, Robert A.; Haanen, John B. A. G.

    2006-01-01

    The promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory cytokine, IL-23, in gp100 peptide vaccine therapy of established murine melanoma. Neither systemic nor local IL-23 alone had any impact on tumor growth or tumor-specific T cell numbers. Upon specific va...

  17. Lipopolysaccharide contamination in intradermal DNA vaccination : toxic impurity or adjuvant?

    NARCIS (Netherlands)

    Berg, J.H. van den; Quaak, S.G.L.; Beijnen, J.H.; Hennink, W.E.; Storm, G.; Schumacher, T.N.; Haanen, J.B.A.G.; Nuijen, B.

    2010-01-01

    Purpose: Lipopolysaccharides (LPS) are known both as potential adjuvants for vaccines and as toxic impurity in pharmaceutical preparations. The aim of this study was to assess the role of LPS in intradermal DNA vaccination administered by DNA tattooing. Method: Micewere vaccinated with a model DNA v

  18. Postoperative adjuvant chemotherapy in rectal cancer operated for cure

    DEFF Research Database (Denmark)

    Petersen, Sune Høirup; Harling, Henrik; Kirkeby, Lene Tschemerinsky

    2012-01-01

    in Dukes´ C (TNM stage III) colon tumours i.e. tumours with metastases in the regional lymph nodes but no distant metastases. In contrast, the evidence for recommendations of adjuvant therapy in rectal cancer is sparse. In Europe it is generally acknowledged that locally advanced rectal tumours receive...

  19. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy.

    Science.gov (United States)

    Kim, Su-Yeon; Joo, Hong-Gu

    2015-01-01

    Fucoidan is a sulfated polysaccharide derived from brown seaweed, including Fucus vesiculosus. This compound is known to have immunostimulatory effects on various types of immune cells including macrophages and dendritic cells. A recent study described the application of fucoidan as a vaccine adjuvant. Vaccination is regarded as the most efficient prophylactic method for preventing harmful or epidemic diseases. To increase vaccine efficacy, effective adjuvants are needed. In the present study, we determined whether fucoidan can function as an adjuvant using vaccine antigens. Flow cytometric analysis revealed that fucoidan increases the expression of the activation markers major histocompatibility complex class II, cluster of differentiation (CD)25, and CD69 in spleen cells. In combination with Bordetella bronchiseptica antigen, fucoidan increased the viability and tumor necrosis factor-α production of spleen cells. Furthermore, fucoidan increased the in vivo production of antigen-specific antibodies in mice inoculated with Mycoplasma hyopneumoniae antigen. Overall, this study has provided valuable information about the use of fucoidan as a vaccine adjuvant.

  20. Teaching adjuvant endocrine breast cancer treatment to medical students

    NARCIS (Netherlands)

    Visser, M. de; Fluit, C.R.M.G.; Timmer-Bonte, J.N.H.; Ottevanger, P.B.; Verhagen, C.A.H.H.V.M.; Klaassen, T.; Laarhoven, H.W.M. van

    2013-01-01

    Background: In undergraduate medical education, students are supposed to acquire knowledge and understanding about the basic principles of adjuvant breast cancer treatment. The best education method in this context is unknown. In this randomised study we assessed the effect of designing a patient ed

  1. Local anesthetis and adjuvants in pediatric regional anesthesia.

    Science.gov (United States)

    Mossetti, Valeria; Vicchio, Noemi; Ivani, Giorgio

    2012-06-01

    The pediatric loco-regional techniques are considered very safe and effective, first of all because they target the therapy directly to the site of surgery, decreasing the risks of intravenous analgesia. The quality of local anesthesia is influenced by structural and biophysical characteristics of local anesthetics drug, dose, site of injection, mixture of local anesthetics and possible addition of a vasoconstrictor or an adjuvant to prolong the analgesic effect. In children, unlike adults, small nerve diameters and short distance between Ranvier nodes permit to use large volumes and low concentrations of local anesthetics. The clinical practice has shown that in pediatric population, effective analgesia is obtained by 1% mepivacaine, 1% lidocaine and 0.25% bupivacaine or better 0.2% ropivacaine, 0.2-0.25% levobupivacaine. In addition, levobupivacaine and ropivacaine have a better profile in terms of safety in comparison to bupivacaine and are the local anesthetics of choice for the daily clinical practice also in children as in adults. Among the adjuvant, clonidine and ketamine showed the best pharmacokinetic and pharmacodynamic profiles of effective and safety, improving and prolonging the action of associated local anesthetics. Therefore, the use of enantiomers, in association with adjuvants as clonidine or ketamine, using the multimodal approach of integrated anesthesia, makes the clinical practice effective and safe in the pediatric operating rooms. This review focuses on the overview of local anesthetics and adjuvants used today in locoregional pediatric anesthesia, with an emphasis on the advantages and disadvantages of each drug.

  2. Lipopolysaccharide contamination in intradermal DNA vaccination : toxic impurity or adjuvant?

    NARCIS (Netherlands)

    Berg, J.H. van den; Quaak, S.G.L.; Beijnen, J.H.; Hennink, W.E.; Storm, G.; Schumacher, T.N.; Haanen, J.B.A.G.; Nuijen, B.

    Purpose: Lipopolysaccharides (LPS) are known both as potential adjuvants for vaccines and as toxic impurity in pharmaceutical preparations. The aim of this study was to assess the role of LPS in intradermal DNA vaccination administered by DNA tattooing. Method: Micewere vaccinated with a model DNA

  3. Effects of 5-fluorouracil adjuvant treatment of colon cancer

    NARCIS (Netherlands)

    Kelder, Wendy; Hospers, Geke A. P.; Plukker, John T. M.

    2006-01-01

    Since the late 1980s and early 1990s, 5-fluorouracil-based chemotherapy has been the standard adjuvant treatment for Stage III colon cancer. After the initial introduction of 5-fluorouracil in standard treatment protocols, several changes have been made based on results of randomized studies on vari

  4. Postoperative adjuvant chemotherapy in rectal cancer operated for cure.

    Science.gov (United States)

    Petersen, Sune Høirup; Harling, Henrik; Kirkeby, Lene Tschemerinsky; Wille-Jørgensen, Peer; Mocellin, Simone

    2012-03-14

    Colorectal cancer is one of the most common types of cancer in the Western world. Apart from surgery - which remains the mainstay of treatment for resectable primary tumours - postoperative (i.e., adjuvant) chemotherapy with 5-fluorouracil (5-FU) based regimens is now the standard treatment in Dukes' C (TNM stage III) colon tumours i.e. tumours with metastases in the regional lymph nodes but no distant metastases. In contrast, the evidence for recommendations of adjuvant therapy in rectal cancer is sparse. In Europe it is generally acknowledged that locally advanced rectal tumours receive preoperative (i.e., neoadjuvant) downstaging by radiotherapy (or chemoradiotion), whereas in the US postoperative chemoradiotion is considered the treatment of choice in all Dukes' C rectal cancers. Overall, no universal consensus exists on the adjuvant treatment of surgically resectable rectal carcinoma; moreover, no formal systematic review and meta-analysis has been so far performed on this subject. We undertook a systematic review of the scientific literature from 1975 until March 2011 in order to quantitatively summarize the available evidence regarding the impact of postoperative adjuvant chemotherapy on the survival of patients with surgically resectable rectal cancer. The outcomes of interest were overall survival (OS) and disease-free survival (DFS). CCCG standard search strategy in defined databases with the following supplementary search. 1. Rect* or colorect* - 2. Cancer or carcinom* or adenocarc* or neoplasm* or tumour - 3. Adjuv* - 4. Chemother* - 5. Postoper* Randomised controlled trials (RCT) comparing patients undergoing surgery for rectal cancer who received no adjuvant chemotherapy with those receiving any postoperative chemotherapy regimen. Two authors extracted data and a third author performed an independent search for verification. The main outcome measure was the hazard ratio (HR) between the risk of event between the treatment arm (adjuvant chemotherapy

  5. Persistent neurocognitive problems after adjuvant chemotherapy for breast cancer

    NARCIS (Netherlands)

    Kreukels, B.P.C.; van Dam, F.S.A.M.; Ridderinkhof, K.R.; Boogerd, W.; Schagen, S.B.

    2008-01-01

    Background: Neurocognitive problems have been observed in a number of women previously treated with adjuvant chemotherapy for breast cancer. The present study aims to combine the results of neuropsychological and electrophysiological techniques collected in patients with breast cancer treated with c

  6. Adjuvant chemotherapy compliance is not superior after thoracoscopic lobectomy

    DEFF Research Database (Denmark)

    Licht, Peter B; Schytte, Tine; Jakobsen, Erik

    2014-01-01

    BACKGROUND: It is generally assumed that patient compliance with adjuvant chemotherapy is superior after video-assisted thoracoscopic surgery compared with open lobectomy for non-small cell lung cancer (NSCLC). The level of evidence for this assumption, however, is limited to single-institution, ......BACKGROUND: It is generally assumed that patient compliance with adjuvant chemotherapy is superior after video-assisted thoracoscopic surgery compared with open lobectomy for non-small cell lung cancer (NSCLC). The level of evidence for this assumption, however, is limited to single...... histopathology. A clinical oncologist, who was blinded to the surgical approach, reviewed all medical oncology charts for types of adjuvant chemotherapy, reasons for not initiating or stopping treatment, number of cycles delivered, and time interval from surgery to initial chemotherapy. RESULTS: During a 6-year...... adjuvant chemotherapy and 121 (38.7%) completed all four cycles. Ordinal logistic regression revealed that chemotherapy compliance (none, partial, and full chemotherapy) was significantly reduced by the patient's age (p

  7. Adjuvant chemotherapy for the perineural invasion of colorectal cancer.

    Science.gov (United States)

    Suzuki, Toshiaki; Suwa, Katsuhito; Ogawa, Masaichi; Eto, Ken; Kawahara, Hidejiro; Fujita, Tetsuji; Ikegami, Masahiro; Yanaga, Katsuhiko

    2015-11-01

    To evaluate the association of perineural invasion (PNI) with outcomes in patients after colorectal resection of colorectal cancer (CRC) and to assess the effect of PNI on the response to adjuvant chemotherapy. Data were retrospectively reviewed for 178 patients with consecutive stages I-III CRC who underwent curative surgery between January 1999 and December 2004. PNI data were examined, and the overall survival (OS) and disease-free survival rates were analyzed. PNI was detected in 36 of 178 patients (20%) and positively correlated with lymphatic invasion (P = 0.020), venous invasion (P = 0.037), and the incidence of metastasis or recurrence (P = 0.029). Five-year disease-free survival was 46% and 68% (P negative prognostic factor of OS; among PNI-positive patients, median OS with adjuvant chemotherapy was almost twofold higher than that without adjuvant chemotherapy (6 versus 2.8 y; P = 0.017). PNI was a poor predictor of survival among patients with stage III CRC, and adjuvant chemotherapy may attenuate the adverse effects of PNI on survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. An adjuvanted, tetravalent dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against dengue challenge in rhesus macaques.

    Science.gov (United States)

    Fernandez, Stefan; Thomas, Stephen J; De La Barrera, Rafael; Im-Erbsin, Rawiwan; Jarman, Richard G; Baras, Benoît; Toussaint, Jean-François; Mossman, Sally; Innis, Bruce L; Schmidt, Alexander; Malice, Marie-Pierre; Festraets, Pascale; Warter, Lucile; Putnak, J Robert; Eckels, Kenneth H

    2015-04-01

    The immunogenicity and protective efficacy of a candidate tetravalent dengue virus purified inactivated vaccine (TDENV PIV) formulated with alum or an Adjuvant System (AS01, AS03 tested at three different dose levels, or AS04) was evaluated in a 0, 1-month vaccination schedule in rhesus macaques. One month after dose 2, all adjuvanted formulations elicited robust and persisting neutralizing antibody titers against all four dengue virus serotypes. Most of the formulations tested prevented viremia after challenge, with the dengue serotype 1 and 2 virus strains administered at 40 and 32 weeks post-dose 2, respectively. This study shows that inactivated dengue vaccines, when formulated with alum or an Adjuvant System, are candidates for further development.

  9. Chemoradiotherapy, with adjuvant surgery for local control, confers a durable survival advantage in adenocarcinoma and squamous cell carcinoma of the oesophagus.

    LENUS (Irish Health Repository)

    Bass, G A

    2014-04-01

    Oesophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short-term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials.

  10. Adjuvant properties of thermal component of hyperthermia enhanced transdermal immunization: effect on dendritic cells.

    Directory of Open Access Journals (Sweden)

    Neha Joshi

    Full Text Available Hyperthermia enhanced transdermal (HET immunization is a novel needle free immunization strategy employing application of antigen along with mild local hyperthermia (42°C to intact skin resulting in detectable antigen specific Ig in serum. In the present study, we investigated the adjuvant effect of thermal component of HET immunization in terms of maturation of dendritic cells and its implication on the quality of the immune outcome in terms of antibody production upon HET immunization with tetanus toxoid (TT. We have shown that in vitro hyperthermia exposure at 42°C for 30 minutes up regulates the surface expression of maturation markers on bone marrow derived DCs. This observation correlated in vivo with an increased and accelerated expression of maturation markers on DCs in the draining lymph node upon HET immunization in mice. This effect was found to be independent of the antigen delivered and depends only on the thermal component of HET immunization. In vitro hyperthermia also led to enhanced capacity to stimulate CD4+ T cells in allo MLR and promotes the secretion of IL-10 by BMDCs, suggesting a potential for Th2 skewing of T cell response. HET immunization also induced a systemic T cell response to TT, as suggested by proliferation of splenocytes from immunized animal upon in vitro stimulation by TT. Exposure to heat during primary immunization led to generation of mainly IgG class of antibodies upon boosting, similar to the use of conventional alum adjuvant, thus highlighting the adjuvant potential of heat during HET immunization. Lastly, we have shown that mice immunized by tetanus toxoid using HET route exhibited protection against challenge with a lethal dose of tetanus toxin. Thus, in addition to being a painless, needle free delivery system it also has an immune modulatory potential.

  11. Triple negative breast cancer: adjuvant chemotherapy effect on survival.

    Science.gov (United States)

    Steponaviciene, L; Lachej-Mikeroviene, N; Smailyte, G; Aleknavicius, E; Meskauskas, R; Didziapetriene, J

    2011-01-01

    The purpose of this study was to evaluate the overall survival of patients with triple negative breast cancer and the impact of different adjuvant chemotherapy regimens on survival. The study group consisted of 99 breast cancer patients with immunohistochemically confirmed triple negative breast cancer. The impact of various factors as well as the impact of different chemotherapy regimens on survival was evaluated. The overall survival of breast cancer patients was 97.0% (95% CI 90.9-99.0), 84.9% (95% CI 76.1-90.6) and 66.5% (95% CI 55.5-75.3) 10, 30 and 60 months after diagnosis, respectively. Univariate analysis demonstrated that the following were significant risk factors for breast cancer patients survival: patient's age, stage of disease, tumour size, lymph node status, type of surgery and chemotherapy. Better survival was related to younger patients' age, smaller tumour size, lower stage of disease, no lymph nodes involvement. Survival rates were higher among patients who received adjuvant chemotherapy and underwent quadrantectomy. In the multivariate statistical analysis the significant independent prognostic variables influencing survival were lymph node status and adjuvant chemotherapy. Survival rates of the patients, who received adjuvant anthracycline containing chemotherapy were higher, than those in non-anthracycline containing treatment group, but the difference was not statistically significant. Patients who had lymph node status N2-3 and those who did not receive adjuvant chemotherapy showed worse prognosis and survival than other patients. The impact of chemotherapy type (anthracycline containing or non-anthracycline containing) on patients survival was not statistically significant.

  12. Influenza vaccination in children primed with MF59®-adjuvanted or non-adjuvanted seasonal influenza vaccine

    Science.gov (United States)

    Vesikari, Timo; Forstén, Aino; Arora, Ashwani; Tsai, Theodore; Clemens, Ralf

    2015-01-01

    Routine annual influenza immunization is increasingly recommended in young children. We compared the safety and immunogenicity of vaccination with trivalent inactivated influenza vaccine (TIV) versus MF59-adjuvanted TIV (aTIV) in children who received 2 half or full doses of aTIV or TIV, or non-influenza control vaccine, in an efficacy trial conducted 2 years earlier. 197 healthy children aged 30–96 months were randomized to receive vaccination with aTIV or TIV in 2010. To evaluate responses to the first follow-up seasonal vaccination after priming we excluded children who received influenza vaccine(s) in the 2009 pandemic year leaving 40 children vaccinated with aTIV, 26 children with TIV and 10 children with aTIV after a control vaccine in the parent study. Hemagglutination inhibiting antibodies were assayed on Days 1, 22 and 181. aTIV vaccination produced 6.9 to 8.0-fold higher antibody responses than the reference TIV-TIV regimen against A/H3N2 and B strains, which remained higher 6 months following vaccination. The response to the B/Victoria lineage antigen in the second year's vaccine (the first vaccine contained a B/Yamagata lineage antigen) demonstrated that aTIV primed for an adequate response after a single dose on Day 22 (GMTs 160, 95 to antigens in the 2 lineages, respectively), whereas TIV did not (GMTs 38, 20). Vaccination with aTIV produced slightly higher but acceptable local and systemic reactogenicity compared to TIV-TIV and TIV-aTIV mixed regimens. Within the limitations of a small study, the strong immune responses support the use of aTIV for vaccination in young children. PMID:26091244

  13. Fucoidan can function as an adjuvant in vivo to enhance dendritic cell maturation and function and promote antigen-specific T cell immune responses.

    Directory of Open Access Journals (Sweden)

    Jun-O Jin

    Full Text Available Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, including promoting antigen uptake and enhancing anti-viral and anti-tumor effects. However, the effect of fucoidan in vivo, especially its adjuvant effect on in vivo anti-tumor immune responses, was not fully investigated. In this study, we investigated the effect of fucoidan on the function of spleen dendritic cells (DCs and its adjuvant effect in vivo. Systemic administration of fucoidan induced up-regulation of CD40, CD80 and CD86 expression and production of IL-6, IL-12 and TNF-α in spleen cDCs. Fucoidan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in an IL-12-dependent manner. When used as an adjuvant in vivo with ovalbumin (OVA antigen, fucoidan promoted OVA-specific antibody production and primed IFN-γ production in OVA-specific T cells. Moreover, fucoidan enhanced OVA-induced up-regulation of MHC class I and II on spleen cDCs and strongly prompted the proliferation of OVA-specific CD4 and CD8 T cells. Finally, OVA immunization with fucoidan as adjuvant protected mice from the challenge with B16-OVA tumor cells. Taken together, these results suggest that fucoidan can function as an adjuvant to induce Th1 immune response and CTL activation, which may be useful in tumor vaccine development.

  14. Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial.

    Science.gov (United States)

    Leroux-Roels, Geert; Marchant, Arnaud; Levy, Jack; Van Damme, Pierre; Schwarz, Tino F; Horsmans, Yves; Jilg, Wolfgang; Kremsner, Peter G; Haelterman, Edwige; Clément, Frédéric; Gabor, Julian J; Esen, Meral; Hens, Annick; Carletti, Isabelle; Fissette, Laurence; Tavares Da Silva, Fernanda; Burny, Wivine; Janssens, Michel; Moris, Philippe; Didierlaurent, Arnaud M; Van Der Most, Robbert; Garçon, Nathalie; Van Belle, Pascale; Van Mechelen, Marcelle

    2016-08-01

    Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.

  15. Localized Gastric or Gastroesophageal Cancer – Chemoradiation Is a Pertinent Component of Adjuvant Treatment for Patients at High Risk of Relapse

    Science.gov (United States)

    Callister, Matthew D.; Jaroszewski, Dawn E.; Ross, Helen J.; Borad, Mitesh J.; Gray, Richard J.; Lanza, Louis A.; Harold, Kristi L.; Pockaj, Barbara A.; Trastek, Victor F.

    2009-01-01

    The standard of care for resectable gastric or gastroesophageal (GE) junction cancer for patients who can tolerate a surgical procedure is surgical resection, but surgery alone is not optimal treatment for patients at high risk for relapse. For patients with lower-risk lesions (confined to gastric wall, nodes negative; T1-2N0M0), local-regional relapse risks are low, and adjuvant radiotherapy is usually not recommended, except in select instances. Since both local-regional and systemic relapses are common after resection of high-risk gastric or GE junction cancers (beyond wall, nodes positive, or both; T3-4N0, TanyN+), adjuvant treatment is indicated for these patients. The results of phase III trials that demonstrate a survival benefit for adjuvant preoperative radiotherapy, postoperative chemoradiation, or preoperative chemoradiation vs. surgery alone will be presented and compared with the results of adjuvant perioperative chemotherapy. Results of Surveillance, Epidemiology, and End Results (SEER) analyses and meta-analyses that support the role of adjuvant radiotherapy or chemoradiation will be summarized. PMID:19461920

  16. Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer.

    Science.gov (United States)

    Qi, Fanghua; Li, Anyuan; Inagaki, Yoshinori; Gao, Jianjun; Li, Jijun; Kokudo, Norihiro; Li, Xiao-Kang; Tang, Wei

    2010-12-01

    Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo- or radio-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by chemo- and radio-therapy. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides evidence for use of Chinese herbal medicines as adjuvant cancer treatment during chemo- or radio-therapy. First, Chinese herbal medicines (e.g. Astragalus, Turmeric, Ginseng, TJ-41, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used by cancer patients for treating the cancer and/or reducing the toxicity induced by chemo- or radio-therapy are discussed. Preclinical and clinical studies have shown that these Chinese herbal medicines possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo- and radio-therapeutics, improving an organism's immune system function, and lessening the damage caused by chemo- and radio-therapeutics. Second, clinical trials of Chinese herbal medicines as adjuvant cancer treatment are reviewed. By reducing side effects and complications during chemo- and radio-therapy, these Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving respiratory tract infections and gastrointestinal side effects including diarrhea, nausea, and vomiting, protecting liver function, and even ameliorating the symptoms of cachexia. This review should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs.

  17. Efficacy comparison of adjuvants in PcrV vaccine against Pseudomonas aeruginosa pneumonia.

    Science.gov (United States)

    Hamaoka, Saeko; Naito, Yoshifumi; Katoh, Hideya; Shimizu, Masaru; Kinoshita, Mao; Akiyama, Koichi; Kainuma, Atsushi; Moriyama, Kiyoshi; Ishii, Ken J; Sawa, Teiji

    2017-02-01

    Vaccination against the type III secretion system of P. aeruginosa is a potential prophylactic strategy for reducing the incidence and improving the poor prognosis of P. aeruginosa pneumonia. In this study, the efficacies of three different adjuvants, Freund's adjuvant (FA), aluminum hydroxide (alum) and CpG oligodeoxynucleotide (ODN), were examined from the viewpoint of inducing PcrV-specific immunity against virulent P. aeruginosa. Mice that had been immunized intraperitoneally with recombinant PcrV formulated with one of the above adjuvants were challenged intratracheally with a lethal dose of P. aeruginosa. The PcrV-FA immunized group attained a survival rate of 91%, whereas the survival rates of the PcrV-alum and PcrV-CpG groups were 73% and 64%, respectively. In terms of hypothermia recovery after bacterial instillation, PcrV-alum was the most protective, followed by PcrV-FA and PcrV-CpG. The lung edema index was lower in the PcrV-CpG vaccination group than in the other groups. PcrV-alum immunization was associated with the greatest decrease in myeloperoxidase in infected lungs, and also decreased the number of lung bacteria to a similar number as in the PcrV-FA group. There was less neutrophil recruitment in the lungs of mice vaccinated with PcrV-alum or PcrV-CpG than in those of mice vaccinated with PcrV-FA or PcrV alone. Overall, in terms of mouse survival the PcrV-CpG vaccine, which could be a relatively safe next-generation vaccine, showed a comparable effect to the PcrV-alum vaccine.

  18. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway.

    Science.gov (United States)

    Güven, Esin; Duus, Karen; Laursen, Inga; Højrup, Peter; Houen, Gunnar

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes complement components and activates the complement system. We show that complement activation by Al(OH)3 involves the three major pathways by monitoring complement components in Al(OH)3-treated serum and in Al(OH)3-containing precipitates. Al(OH)3 activation of complement results in deposition of C3 cleavage products and membrane attack complex (MAC) and in generation of the anaphylatoxins C3a and C5a. Complement activation was time dependent and inhibited by chelation with EDTA but not EGTA+Mg(2+). We thus confirm that Al(OH)3 activates the complement system and show that the alternative pathway is of major importance.

  19. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway.

    Directory of Open Access Journals (Sweden)

    Esin Güven

    Full Text Available Al(OH3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH3 treatment of serum depletes complement components and activates the complement system. We show that complement activation by Al(OH3 involves the three major pathways by monitoring complement components in Al(OH3-treated serum and in Al(OH3-containing precipitates. Al(OH3 activation of complement results in deposition of C3 cleavage products and membrane attack complex (MAC and in generation of the anaphylatoxins C3a and C5a. Complement activation was time dependent and inhibited by chelation with EDTA but not EGTA+Mg(2+. We thus confirm that Al(OH3 activates the complement system and show that the alternative pathway is of major importance.

  20. Aluminum Hydroxide Adjuvant Differentially Activates the Three Complement Pathways with Major Involvement of the Alternative Pathway

    Science.gov (United States)

    Güven, Esin; Duus, Karen; Laursen, Inga; Højrup, Peter; Houen, Gunnar

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes complement components and activates the complement system. We show that complement activation by Al(OH)3 involves the three major pathways by monitoring complement components in Al(OH)3-treated serum and in Al(OH)3-containing precipitates. Al(OH)3 activation of complement results in deposition of C3 cleavage products and membrane attack complex (MAC) and in generation of the anaphylatoxins C3a and C5a. Complement activation was time dependent and inhibited by chelation with EDTA but not EGTA+Mg2+. We thus confirm that Al(OH)3 activates the complement system and show that the alternative pathway is of major importance. PMID:24040248

  1. FLT3 Ligand as a Molecular Adjuvant for Naked RNA Vaccines.

    Science.gov (United States)

    Kreiter, Sebastian; Diken, Mustafa; Selmi, Abderraouf; Petschenka, Jutta; Türeci, Özlem; Sahin, Ugur

    2016-01-01

    Intranodal immunization with antigen-encoding naked mRNA has proven to be an efficacious and safe approach to induce antitumor immunity. Thanks to its unique characteristics, mRNA can act not only as a source for antigen but also as an adjuvant for activation of the immune system. The search for additional adjuvants that can be combined with mRNA to further improve the potency of the immunization revealed Fms-like tyrosine kinase 3 (FLT3) ligand as a potent candidate. Systemic administration of the dendritic cell-activating FLT3 ligand prior to or along with mRNA immunization-enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodally administered mRNA. Both compounds demonstrate a successful combination in terms of boosting the immune response. This chapter describes methods for intranodal immunization with naked mRNA by co-administration of FLT3 ligand, which leads to strong synergistic effects.

  2. Functionally fused antibodies--a novel adjuvant fusion system

    DEFF Research Database (Denmark)

    Larsen, Martin; Jensen, Kim Bak; Christensen, Peter Astrup

    2008-01-01

    Antibodies capable of recognizing key molecular targets isolated e.g. by phage display technology have been used in the pursuit of new and improved therapies for prevalent human diseases. These approaches often take advantage of non-immunogenic antibody fragments to achieve specific toxin-, radio...

  3. Plant Viruses as Nanoparticle-Based Vaccines and Adjuvants

    Directory of Open Access Journals (Sweden)

    Marie-Ève Lebel

    2015-08-01

    Full Text Available Vaccines are considered one of the greatest medical achievements in the battle against infectious diseases. However, the intractability of various diseases such as hepatitis C, HIV/AIDS, malaria, tuberculosis, and cancer poses persistent hurdles given that traditional vaccine-development methods have proven to be ineffective; as such, these challenges have driven the emergence of novel vaccine design approaches. In this regard, much effort has been put into the development of new safe adjuvants and vaccine platforms. Of particular interest, the utilization of plant virus-like nanoparticles and recombinant plant viruses has gained increasing significance as an effective tool in the development of novel vaccines against infectious diseases and cancer. The present review summarizes recent advances in the use of plant viruses as nanoparticle-based vaccines and adjuvants and their mechanism of action. Harnessing plant-virus immunogenic properties will enable the design of novel, safe, and efficacious prophylactic and therapeutic vaccines against disease.

  4. Adjuvant postoperative radiotherapy for gastric carcinoma with poor prognostic signs.

    Science.gov (United States)

    Slot, A; Meerwaldt, J H; van Putten, W L; Treurniet-Donker, A D

    1989-12-01

    Fifty-seven patients with poor prognostic factors following resection with curative intent for gastric adenocarcinoma (T3 or T4, positive lymph nodes, positive resection line) received adjuvant radiotherapy. A dose of 30.0-50.0 Gy was given in 10-25 fractions in one course or with a split of 2 weeks after 15 fractions. This was combined with 5-fluorouracil (5-FU) (375 mg/m2) given i.v. as a bolus during the first 4 days of radiation (n = 49). The 5-year survival was 26%; this rate is higher than the figures mentioned in the literature after surgery alone. The only way to prove the role of adjuvant radiotherapy for gastric carcinoma is a prospective randomized trial.

  5. [Stomach carcinoma. Optimizing therapy by neoadjuvant or adjuvant therapy?].

    Science.gov (United States)

    Rosen, H

    1999-01-01

    Despite the decreasing frequency of gastric cancer in most Western countries prognosis could not be improved by surgery alone in the past. Advanced tumor stage due to late diagnosis is one of the reasons for this observation. Contrary to breast and colorectal cancer, postoperative chemotherapy failed to improve prognosis in gastric cancer. Small number of patients in Western studies, insufficient surgical procedures and the high frequency of locoregional relapse may be attributed for this observation. Intraperitoneal, adjuvant chemotherapy showed a positive impact on survival in Asian studies only, but was also used successfully as a part of a multimodality approach in Western phase II trials. Since neoadjuvant therapy proved to create downstaging of tumor size in some patients with advanced gastric cancer some working groups tried to influence prognosis of potentially resectable tumors by preoperative chemotherapy, surgical resection and postoperative, adjuvant therapy in the recent past. However, the efficacy of this therapeutic approach has to be reconfirmed in a controlled, phase III fashion.

  6. Adjuvant postoperative radiotherapy for gastric carcinoma with poor prognostic signs

    Energy Technology Data Exchange (ETDEWEB)

    Slot, A.; Meerwaldt, J.H.; Treurniet-Donker, A.D. (Dr. Daniel Den Hoed Cancer Center, Rotteram (Netherlands). Department of Radiotherapy); Putten, W.L.J. van (Dr. Daniel Den Hoed Cancer Center, Rotterdam (Netherlands). Department of Statistics)

    1989-12-01

    Fifty-seven patients with poor prognostic factors following resection with curative intent for gastric adenocarcinoma T{sub 3} or T{sub 4}, positive lymph nodes, positive resection line received adjuvant radiotherapy. A dose of 30.0-50.0 Gy was given in 10-25 fraction in one course or with a split of 2 weeks after 15 fractions. This was combined with 5-fluorouracil (5-FU) (375 mg/m{sup 2}) given i.v. as a bolus during the first 4 days of radiation (n = 49). The 5-year survival was 26%; this rate is higher than the figures mentioned in the literature after surgery alone. The only way to prove the role of adjuvant radiotherapy for gastric carcinoma is a prospective randomized trial. (author). 11 refs., 2 figs., 6 tabs.

  7. [How I treat colorectal cancer. I. Prevention and adjuvant treatment].

    Science.gov (United States)

    Bours, V; Jerusalem, G; Fillet, G

    1998-04-01

    Colorectal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Belgium and in other western countries. Prevention implies a modification of alimentation and maybe a chronic uptake of acetylsalicylic acid. Treatment of colorectal cancers is based on surgery and the prognosis is determined by the locoregional or metastatic tumor spread. Complete resection of any Astler Coller stage C colorectal malignant tumor has to be followed by a 5-fluorouracil-based adjuvant chemotherapy. In these protocols, 5-fluorouracil is administered together with folinic acid or levamisole. The administration of an adjuvant chemotherapy could also be considered for stage BII diseases. As rectal cancers are characterized by high local relapse rates, their treatment should associate radiotherapy, given either post-surgery or preferentially pre-surgery, with resection and chemotherapy. Appropriate treatment of colorectal cancers thus requires a concerted multidisciplinary approach.

  8. Antibiotic adjuvants - A strategy to unlock bacterial resistance to antibiotics.

    Science.gov (United States)

    González-Bello, Concepción

    2017-09-15

    Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the number of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an 'antibiotic adjuvant' in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compounds that are already in clinical development, namely β-lactamase inhibitors. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  9. Preparation and evaluation of functional foods in adjuvant arthritis

    OpenAIRE

    2012-01-01

    Adjuvant arthritis is an animal model that closely resembles rheumatoid arthritis in humans. It is a successful working model used to study new anti-inflammatory agents. In previous studies (animal and clinical) we have shown that evening primrose oil, fish oil and the methanol extract of date fruits and fenugreek seeds have anti-inflammatory activity and that the methanol extract of dates has an antioxidant effect. Based on these studies, the aim of the present study was to prepare 7 functio...

  10. Adjuvant properties of a simplified C32 monomycolyl glycerol analogue.

    Science.gov (United States)

    Bhowruth, Veemal; Minnikin, David E; Agger, Else Marie; Andersen, Peter; Bramwell, Vincent W; Perrie, Yvonne; Besra, Gurdyal S

    2009-04-01

    A simplified C(32) monomycolyl glycerol (MMG) analogue demonstrated enhanced immunostimulatory activity in a dioctadecyl ammonium bromide (DDA)/Ag85B-ESAT-6 formulation. Elevated levels of IFN-gamma and IL-6 were produced in spleen cells from mice immunised with a C(32) MMG analogue comparable activity to the potent Th1 adjuvant, trehalose 6,6'-di-behenate (TDB).

  11. Hypothesis: Silver Nanoparticles as an Adjuvant for Cancertherapy

    Directory of Open Access Journals (Sweden)

    Ramin Mohammadzadeh

    2012-06-01

    Full Text Available Cytotoxic agents are a main part of therapeutic process against the observed tumors, which lead to some unwished damages, due to drug uptake by normal body cells causing various tissue/organ failures associated with formal administration manners. But nowadays the risk is reduced by new target therapy techniques, of which the observed physical nature of micelles and nanosilver particles, governing their special behavior, could help using micelle-coated silver nanoparticles as a novel adjuvant for cancer target therapy.

  12. Tocotrienols are good adjuvants for developing cancer vaccines

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Ammu

    2010-01-01

    Full Text Available Abstract Background Dendritic cells (DCs have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours. Methods In this study we have used tocotrienol-rich fraction (TRF, a non-toxic natural compound, as an adjuvant to enhance the effectiveness of DC vaccines in treating mouse mammary cancers. In the mouse model, six-week-old female BALB/c mice were injected subcutaneously with DC and supplemented with oral TRF daily (DC+TRF and DC pulsed with tumour lysate from 4T1 cells (DC+TL. Experimental mice were also injected with DC pulsed with tumour lysate and supplemented daily with oral TRF (DC+TL+TRF while two groups of animal which were supplemented daily with carrier oil (control and with TRF (TRF. After three times vaccination, mice were inoculated with 4T1 cells in the mammary breast pad to induce tumour. Results Our study showed that TRF in combination with DC pulsed with tumour lysate (DC+TL+TRF injected subcutaneously significantly inhibited the growth of 4T1 mammary tumour cells as compared to control group. Analysis of cytokines production from murine splenocytes showed significant increased productions of IFN-γ and IL-12 in experimental mice (DC+TL+TRF compared to control, mice injected with DC without TRF, mice injected with DC pulsed with tumour lysate and mice supplemented with TRF alone. Higher numbers of cytotoxic T cells (CD8 and natural killer cells (NK were observed in the peripheral blood of TRF adjuvanted DC pulsed tumour lysate mice. Conclusion Our study show that TRF has the potential to be an adjuvant to augment DC based immunotherapy.

  13. Adjuvants for single droplet application of glyphosate

    DEFF Research Database (Denmark)

    Mathiassen, Solvejg Kopp; Kudsk, Per; Lund, Ivar

    2016-01-01

    Retention and biological activity of droplets of glyphosate deposited onto plant leaves using a Drop on Demand inkjet printer application system, was examined on pot-grown Brassica napus, Solanum nigrum, Chenopodium album, Silene noctiflora and Echinocloa crus-galli plants. Retention was measured...... but the biological activity of glyphosate was not improved....

  14. Adjuvants for single droplet application of glyphosate

    DEFF Research Database (Denmark)

    Mathiassen, Solvejg K.; Kudsk, Per; Lund, Ivar

    2016-01-01

    Retention and biological activity of droplets of glyphosate deposited onto plant leaves using a Drop on Demand inkjet printer application system, was examined on pot-grown Brassica napus, Solanum nigrum, Chenopodium album, Silene noctiflora and Echinocloa crus-galli plants. Retention was measured...... but the biological activity of glyphosate was not improved....

  15. CTA1-DD is an effective adjuvant for targeting anti-chlamydial immunity to the murine genital mucosa.

    Science.gov (United States)

    Cunningham, Kelly A; Carey, Alison J; Lycke, Nils; Timms, Peter; Beagley, Kenneth W

    2009-07-01

    Chlamydia trachomatis is a significant human pathogen with potentially severe disease sequelae in the genital tract, including infertility. A successful vaccine will need to effectively target immunity to the genital mucosa. Intranasal immunisation with cholera toxin (CT) can target immunity to the genital tract, but has the potential to cause neurological side effects. CTA1-DD is a non-toxic potent mucosal adjuvant which combines the enzymatic properties of CT, with a B cell targeting moiety. Here, we demonstrate that intranasal immunisation with CTA1-DD and chlamydial Major Outer Membrane Protein (MOMP) results in the induction of neutralising systemic and mucosal antibodies, and reduces the level of chlamydial shedding following intravaginal challenge with Chlamydia muridarum. Thus, CTA1-DD is an effective adjuvant for vaccine development against Chlamydia trachomatis, and possibly also a range of other genital pathogens.

  16. Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine.

    Directory of Open Access Journals (Sweden)

    Benoît Baras

    Full Text Available BACKGROUND: Unprecedented spread between birds and mammals of highly pathogenic avian influenza viruses (HPAI of the H5N1 subtype has resulted in hundreds of human infections with a high fatality rate. This has highlighted the urgent need for the development of H5N1 vaccines that can be produced rapidly and in sufficient quantities. Potential pandemic inactivated vaccines will ideally induce substantial intra-subtypic cross-protection in humans to warrant the option of use, either prior to or just after the start of a pandemic outbreak. In the present study, we evaluated a split H5N1 A/H5N1/Vietnam/1194/04, clade 1 candidate vaccine, adjuvanted with a proprietary oil-in- water emulsion based Adjuvant System proven to be well-tolerated and highly immunogenic in the human (Leroux-Roels et al. (2007 The Lancet 370:580-589, for its ability to induce intra-subtypic cross-protection against clade 2 H5N1/A/Indonesia/5/05 challenge in ferrets. METHODOLOGY AND PRINCIPAL FINDINGS: All ferrets in control groups receiving non-adjuvanted vaccine or adjuvant alone failed to develop specific or cross-reactive neutralizing antibodies and all died or had to be euthanized within four days of virus challenge. Two doses of adjuvanted split H5N1 vaccine containing >or=1.7 microg HA induced neutralizing antibodies in the majority of ferrets to both clade 1 (17/23 (74% responders and clade 2 viruses (14/23 (61% responders, and 96% (22/23 of vaccinees survived the lethal challenge. Furthermore lung virus loads and viral shedding in the upper respiratory tract were reduced in vaccinated animals relative to controls suggesting that vaccination might also confer a reduced risk of viral transmission. CONCLUSION: These protection data in a stringent challenge model in association with an excellent clinical profile highlight the potential of this adjuvanted H5N1 candidate vaccine as an effective tool in pandemic preparedness.

  17. Cyclic GMP-AMP displays mucosal adjuvant activity in mice.

    Directory of Open Access Journals (Sweden)

    Ivana Škrnjug

    Full Text Available The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice. A characteristic of the cGAMP-induced immune response is the slightly reduced induction of interleukin-17 as a hallmark of Th17 activity--a distinct feature that is not observed with other cyclic di-nucleotide adjuvants. We further characterize the innate immune stimulation activity in vitro on murine bone marrow-derived dendritic cells and human dendritic cells. The observed results suggest the consideration of cGAMP as a candidate mucosal adjuvant for human vaccines.

  18. [Adjuvant chemotherapy in colon cancer. About 119 cases].

    Science.gov (United States)

    Yaich, Asma; Khanfir, Afef; Bayrouti, Mohamed Issam; Frikha, Mounir

    2015-04-01

    colon cancer is a public health problem worldwide and in Tunisia. The prognosis of patients with unresectable colorectal cancer varies according to the stage. The indication for adjuvant chemotherapy is well established in the colon cancer stage III, while it remains a matter of controversy for stage II. The aim of this work is to identify the epidemiological and anatomoclinical assess therapeutic outcomes in terms of overall survival of patients with high-risk stage II and stage III colon cancer treated with surgery and adjuvant chemotherapy. DS: It's a retrospective study based on 119 patients with colon adenocarcinoma from 1996 to 2010. This patients suffering from colon cancer classified stage II and III having them all radical surgery and adjuvant chemotherapy. The average age of our patients was 53 years. The surgery was performed in an emergency situation in 53 patients (44%). Stages II and III, respectively, were observed in 47% and 53% of cases. Three regimens of chemotherapy were used: protocol FUFOL (50%), followed by FOLFOX (34%) and the protocol LV5FU2 (16%). Overall survival of patients all stages combined was 73.4% at 5 years. Stage III of the TNM classification (p = 0.03) and the number of cycles of chemotherapy colon cancer is improving thanks to recent advances that have enabled the integration of new cytogenetic factors in the therapeutic decision.

  19. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    Science.gov (United States)

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy.

  20. A Purified Recombinant Lipopeptide as Adjuvant for Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Ying-Chyi Song

    2014-01-01

    Full Text Available Synthetic lipopeptides have been widely used as vaccine adjuvants to enhance immune responses. The present study demonstrated that the tryptic N-terminal fragment of the lipoprotein rlipo-D1E3 (lipo-Nter induces superior antitumor effects compared to a synthetic lipopeptide. The lipo-Nter was purified and formulated with protein or peptide vaccines to determine if lipo-Nter could be used as a novel adjuvant and could induce antitumor immunity in a cervical cancer model. Purified lipo-Nter activated the maturation of bone marrow-derived dendritic cells (BM-DCs, leading to the secretion of TNF-α through TLR2/6 but not TLR1/2. A recombinant mutant HPV16 E7 (rE7m protein was mixed with lipo-Nter to immunize the mice; the anti-E7 antibody titers were increased, and the T helper cells were skewed toward the Th1 fate (increased IL-2 and decreased IL-5 secretion. Single-dose injection of rE7m and lipo-Nter inhibited tumor growth, but the injection of rE7m alone did not. Accordingly, lipo-Nter also enhanced the antitumor immunity of the E7-derived peptide but not the synthetic lipopeptide (Pam3CSK4. We demonstrated that the lipo-Nter of a bacterial-derived recombinant lipoprotein is a novel adjuvant that could be used for the development of a new generation of vaccines.

  1. Adherence to adjuvant endocrine therapy in women with breast cancer.

    Science.gov (United States)

    Danilak, Melanie; Chambers, Carole R

    2013-06-01

    To determine how many breast cancer patients who initiated adjuvant endocrine therapy discontinued early and to evaluate adherence in patients who persisted with therapy. Secondary objectives were to explore possible trends to see if certain factors may correlate to early discontinuation of therapy. A retrospective review of charts and pharmacy dispensing records was conducted, including patients who initiated adjuvant endocrine therapy for breast cancer at the Cross Cancer Institute from 1 January to 31 December, 2006. Out of 346 patients, 81 (22%) discontinued therapy within 2 years. Adherence rates calculated for the 265 patients who remained on therapy beyond 2 years showed that 247 (93%) of these patients had 80% or better adherence. Patients who did not undergo chemotherapy and patients with Cross Cancer Institute follow-up times of less than 1 year were significantly more likely to discontinue therapy early. The majority of patients who were prescribed adjuvant endocrine therapy for breast cancer at the Cross Cancer Institute remained on therapy for at least 2 years and were adherent. Longer follow-up by Cross Cancer Institute practitioners may help decrease discontinuation rates.

  2. Neisseria lactamica antigens complexed with a novel cationic adjuvant.

    Science.gov (United States)

    Gaspar, Emanuelle B; Rosetti, Andreza S; Lincopan, Nilton; De Gaspari, Elizabeth

    2013-03-01

    Colonization of the nasopharynx by non-pathogenic Neisseria species, including N. lactamica, has been suggested to lead to the acquisition of natural immunity against Neisseria meningitidis in young children. The aim of this study was to identify a model complex of antigens and adjuvant for immunological preparation against N. meningitidis B, based on cross reactivity with N. lactamica outer membrane vesicles (OMV) antigens and the (DDA-BF) adjuvant. Complexes of 25 µg of OMV in 0.1 mM of DDA-BF were colloidally stable, exhibiting a mean diameter and charge optimal for antigen presentation. Immunogenicity tests for these complexes were performed in mice. A single dose of OMV/DDA-BF was sufficient to induce a (DTH) response, while the same result was achieved only after two doses of OMV/alum. In addition, to achieve total IgG levels that are similar to a single immunization with OMV/DDA-BF, it was necessary to give the mice a second dose of OMV/alum. Moreover, the antibodies induced from a single immunization with OMV/DDA-BF had an intermediate avidity, but antibodies with a similar avidity were only induced by OMV/alum after two immunizations. The use of this novel cationic adjuvant for the first time with a N. lactamica OMV preparation revealed good potential for future vaccine design.

  3. Air Pollution and Climate Change Effects on Allergies in the Anthropocene: Abundance, Interaction, and Modification of Allergens and Adjuvants.

    Science.gov (United States)

    Reinmuth-Selzle, Kathrin; Kampf, Christopher J; Lucas, Kurt; Lang-Yona, Naama; Fröhlich-Nowoisky, Janine; Shiraiwa, Manabu; Lakey, Pascale S J; Lai, Senchao; Liu, Fobang; Kunert, Anna T; Ziegler, Kira; Shen, Fangxia; Sgarbanti, Rossella; Weber, Bettina; Bellinghausen, Iris; Saloga, Joachim; Weller, Michael G; Duschl, Albert; Schuppan, Detlef; Pöschl, Ulrich

    2017-04-18

    Air pollution and climate change are potential drivers for the increasing burden of allergic diseases. The molecular mechanisms by which air pollutants and climate parameters may influence allergic diseases, however, are complex and elusive. This article provides an overview of physical, chemical and biological interactions between air pollution, climate change, allergens, adjuvants and the immune system, addressing how these interactions may promote the development of allergies. We reviewed and synthesized key findings from atmospheric, climate, and biomedical research. The current state of knowledge, open questions, and future research perspectives are outlined and discussed. The Anthropocene, as the present era of globally pervasive anthropogenic influence on planet Earth and, thus, on the human environment, is characterized by a strong increase of carbon dioxide, ozone, nitrogen oxides, and combustion- or traffic-related particulate matter in the atmosphere. These environmental factors can enhance the abundance and induce chemical modifications of allergens, increase oxidative stress in the human body, and skew the immune system toward allergic reactions. In particular, air pollutants can act as adjuvants and alter the immunogenicity of allergenic proteins, while climate change affects the atmospheric abundance and human exposure to bioaerosols and aeroallergens. To fully understand and effectively mitigate the adverse effects of air pollution and climate change on allergic diseases, several challenges remain to be resolved. Among these are the identification and quantification of immunochemical reaction pathways involving allergens and adjuvants under relevant environmental and physiological conditions.

  4. Air Pollution and Climate Change Effects on Allergies in the Anthropocene: Abundance, Interaction, and Modification of Allergens and Adjuvants

    Science.gov (United States)

    2017-01-01

    Air pollution and climate change are potential drivers for the increasing burden of allergic diseases. The molecular mechanisms by which air pollutants and climate parameters may influence allergic diseases, however, are complex and elusive. This article provides an overview of physical, chemical and biological interactions between air pollution, climate change, allergens, adjuvants and the immune system, addressing how these interactions may promote the development of allergies. We reviewed and synthesized key findings from atmospheric, climate, and biomedical research. The current state of knowledge, open questions, and future research perspectives are outlined and discussed. The Anthropocene, as the present era of globally pervasive anthropogenic influence on planet Earth and, thus, on the human environment, is characterized by a strong increase of carbon dioxide, ozone, nitrogen oxides, and combustion- or traffic-related particulate matter in the atmosphere. These environmental factors can enhance the abundance and induce chemical modifications of allergens, increase oxidative stress in the human body, and skew the immune system toward allergic reactions. In particular, air pollutants can act as adjuvants and alter the immunogenicity of allergenic proteins, while climate change affects the atmospheric abundance and human exposure to bioaerosols and aeroallergens. To fully understand and effectively mitigate the adverse effects of air pollution and climate change on allergic diseases, several challenges remain to be resolved. Among these are the identification and quantification of immunochemical reaction pathways involving allergens and adjuvants under relevant environmental and physiological conditions. PMID:28326768

  5. Effect of adjuvant lactulose enema therapy on outcome and intestinal mucosal barrier function in patients with acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Ling Gao; Ming-Quan Li

    2016-01-01

    Objective:To analyze the effect of adjuvant lactulose enema therapy on outcome and intestinal mucosal barrier function in patients with acute pancreatitis.Methods: A total of 98 patients with acute pancreatitis were randomly divided into observation group and control group, control group received conventional symptomatic treatment, observation group received symptomatic treatment + adjuvant lactulose enema therapy, and differences in levels of inflammatory cytokines, RAAS system-related molecules and mucosal barrier function-related indexes in serum as well as intestinal flora quantity in stool samples were compared between two groups after treatment.Results:Serum inflammatory cytokines IL-1β, IL-6, IL-8, PCT and TNF-α levels of enema group were significantly lower than those of control group; serum RAAS system molecules R, AngI, AngII and ALD levels were significantly lower than those of control group; serum mucosal barrier function indexes D-lactate, LPS, I-FABP and DAO levels were significantly lower than those of control group; the quantity of bifidobacterium and lactobacillus in stool samples were significantly more than those of control group while the quantity of enterobacterium, enterococcus and E. coli were significantly lower than those of control group.Conclusion:Adjuvant lactulose enema therapy can promote the improvement of acute pancreatitis, and restore patients’ intestinal mucosal barrier function.

  6. Pathogen-Mimicking Polymeric Nanoparticles based on Dopamine Polymerization as Vaccines Adjuvants Induce Robust Humoral and Cellular Immune Responses.

    Science.gov (United States)

    Liu, Qi; Jia, Jilei; Yang, Tingyuan; Fan, Qingze; Wang, Lianyan; Ma, Guanghui

    2016-04-06

    Aiming to enhance the immunogenicity of subunit vaccines, a novel antigen delivery and adjuvant system based on dopamine polymerization on the surface of poly(D,L-lactic-glycolic-acid) nanoparticles (NPs) with multiple mechanisms of immunity enhancement is developed. The mussel-inspired biomimetic polydopamine (pD) not only serves as a coating to NPs but also functionalizes NP surfaces. The method is facile and mild including simple incubation of the preformed NPs in the weak alkaline dopamine solution, and incorporation of hepatitis B surface antigen and TLR9 agonist unmethylated cytosine-guanine (CpG) motif with the pD surface. The as-constructed NPs possess pathogen-mimicking manners owing to their size, shape, and surface molecular immune-activating properties given by CpG. The biocompatibility and biosafety of these pathogen-mimicking NPs are confirmed using bone marrow-derived dendritic cells. Pathogen-mimicking NPs hold great potential as vaccine delivery and adjuvant system due to their ability to: 1) enhance cytokine secretion and immune cell recruitment at the injection site; 2) significantly activate and maturate dendritic cells; 3) induce stronger humoral and cellular immune responses in vivo. Furthermore, this simple and versatile dopamine polymerization method can be applicable to endow NPs with characteristics to mimic pathogen structure and function, and manipulate NPs for the generation of efficacious vaccine adjuvants. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. External validation of Adjuvant! Online breast cancer prognosis tool. Prioritising recommendations for improvement.

    Directory of Open Access Journals (Sweden)

    David Hajage

    Full Text Available BACKGROUND: Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors. PATIENTS AND METHODS: The French data set is composed of 456 women with early breast cancer. The Dutch data set is composed of 295 women less than 52 years of age. Agreement between observation and Adjuvant! Online prediction was checked, and logistic models were performed to estimate the prognostic information added by risk factors to Adjuvant! Online prediction. RESULTS: Adjuvant! Online prediction was overall well-calibrated in the French data set but failed in some subgroups of such high grade and HER2 positive patients. HER2 status, Mitotic Index and Ki67 added significant information to Adjuvant! Online prediction. In the Dutch data set, the overall 10-year survival was overestimated by Adjuvant! Online, particularly in patients less than 40 years old. CONCLUSION: Adjuvant! Online needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider new predictors such as Ki67, HER2 and Mitotic Index.

  8. Comparable quality attributes of hepatitis E vaccine antigen with and without adjuvant adsorption-dissolution treatment.

    Science.gov (United States)

    Zhang, Yue; Li, Min; Yang, Fan; Li, Yufang; Zheng, Zizheng; Zhang, Xiao; Lin, Qingshan; Wang, Ying; Li, Shaowei; Xia, Ningshao; Zhang, Jun; Zhao, Qinjian

    2015-01-01

    Most vaccines require adjuvants for antigen stabilization and immune potentiation. Aluminum-based adjuvants are the most widely used adjuvants for human vaccines. Previous reports demonstrated the preservation of antigen conformation and other antigen characteristics after recovery from adjuvanted Hepatitis B and human papillomavirus vaccines. In this study, we used a combination of various physiochemical and immunochemical methods to analyze hepatitis E vaccine antigen quality attributes after recovery from adjuvants. All biochemical and biophysical methods showed similar characteristics of the p239 protein after recovery from adjuvanted vaccine formulation compared to the antigen in solution which never experienced adsorption/desorption process. Most importantly, we demonstrated full preservation of key antigen epitopes post-recovery from adjuvanted vaccine using a panel of murine monoclonal antibodies as exquisite probes. Antigenicity of p239 was probed with a panel of 9 mAbs using competition/blocking ELISA, surface plasmon resonance and sandwich ELISA methods. These multifaceted analyses demonstrated the preservation of antigen key epitopes and comparable protein thermal stability when adsorbed on adjuvants or of the recovered antigen post-dissolution treatment. A better understanding of the antigen conformation in adjuvanted vaccine will enhanced our knowledge of antigen-adjuvant interactions and facilitate an improved process control and development of stable vaccine formulation.

  9. The Effect of Neoadjuvant Chemotherapy Compared to Adjuvant Chemotherapy in Healing after Nipple-Sparing Mastectomy.

    Science.gov (United States)

    Frey, Jordan D; Choi, Mihye; Karp, Nolan S

    2017-01-01

    Nipple-sparing mastectomy is the latest advancement in the treatment of breast cancer. The authors aimed to investigate the effects of neoadjuvant and adjuvant chemotherapy in nipple-sparing mastectomy. Patients undergoing nipple-sparing mastectomy from 2006 to June of 2015 were identified. Results were stratified by presence of neoadjuvant or adjuvant chemotherapy. A total of 840 nipple-sparing mastectomies were performed. Twenty-eight were in those who received neoadjuvant chemotherapy and 93 were in patients receiving adjuvant chemotherapy. Patients receiving both neoadjuvant and adjuvant chemotherapy were included in the neoadjuvant group. Nipple-sparing mastectomies that received neoadjuvant (with or without adjuvant) chemotherapy were compared to those in patients who received adjuvant chemotherapy. Those with neoadjuvant (with or without adjuvant) chemotherapy were more likely to have explantation (p = 0.0239) and complete nipple-areola complex necrosis (p = 0.0021). Those with neoadjuvant (with or without adjuvant) chemotherapy were more likely to have implant explantation (p = 0.0015) and complete nipple-areola complex necrosis (p = 0.0004) compared to those with no chemotherapy. Compared to nipple-sparing mastectomies in patients with no chemotherapy, those with adjuvant chemotherapy were more likely to have a hematoma (p = 0.0021). Those that received both neoadjuvant and adjuvant chemotherapy were more likely to have complete nipple-areola complex necrosis compared with both the neoadjuvant chemotherapy-only and adjuvant chemotherapy-only groups (p < 0.0001). Nipple-sparing mastectomy is safe to perform in the setting of neoadjuvant and adjuvant chemotherapy. As a whole, neoadjuvant (with or without adjuvant) chemotherapy increases risk of complications. Therapeutic, III.

  10. Clinical impact of PET/CT imaging after adjuvant therapy in patients with oral cavity squamous cell carcinoma.

    Science.gov (United States)

    Lin, Huan-Chun; Kang, Chung-Jan; Huang, Shiang-Fu; Wang, Hung-Ming; Lin, Chien-Yu; Lee, Li-Yu; Liao, Chun-Ta; Yen, Tzu-Chen

    2017-09-01

    This single-center retrospective study of prospectively collected data was aimed at comparing the clinical outcomes of positron emission tomography/computed tomography (PET/CT) for patients with oral cavity squamous cell carcinoma (OSCC) with symptomatic recurrences identified by PET/CT imaging following adjuvant therapy (Group A) versus those of cases with asymptomatic recurrences diagnosed through periodic post-adjuvant therapy PET/CT surveillance (Group B). We also sought to establish the priority of salvage therapy in the two study groups. We identified 111 patients with advanced resected OSCC who developed recurrences following adjuvant therapy (51 in Group A and 60 in Group B). Histopathology served as the gold standard for recurrent lesions. The impact of post-adjuvant therapy PET/CT surveillance was examined with Kaplan-Meier curves and Cox proportional hazards regression models. The 2-year DSS and OS rates were marginally or significantly higher in Group B than in Group A (P = 0.073 and P = 0.025, respectively). Time-dependent ROC curve analysis demonstrated that the optimal cutoff values for time to positive PET/CT findings in relation to OS were 12 months for Group A and 9 months for Group B, respectively. Independent risk factors identified in multivariate analyses were used to devise two prognostic scoring systems for 2-year DSS and OS in each study group (all P PET/CT surveillance is a valuable tool for early detection of recurrent lesion(s) in asymptomatic OSCC patients who bear risk factors for disease recurrence. The presence of clinical symptoms and a short time to positive PET/CT findings were adverse prognostic factors for clinical outcome in patients with advanced OSCC. The priority of salvage therapy is discussed in each patient subgroup according to the devised prognostic scoring systems.

  11. The cost utility and budget impact of adjuvant racecadotril for acute diarrhea in children in Thailand.

    Science.gov (United States)

    Rautenberg, Tamlyn Anne; Zerwes, Ute

    2017-01-01

    To evaluate the cost utility and the budget impact of adjuvant racecadotril for the treatment of acute diarrhea in children in Thailand. A cost utility model has been adapted to the context of Thailand to evaluate racecadotril plus oral rehydration solution (R+ORS) versus oral rehydration solution (ORS) alone for acute diarrhea in children costs and effects (quality-adjusted life years) over a 6-day time horizon from a public health care payer's perspective in Thailand. Deterministic sensitivity analysis and budget impact analysis have been undertaken. According to the cost utility model, the intervention (R+ORS) is less costly and more effective than the comparator (ORS) for the base case with a dominant incremental cost-effectiveness ratio of -2,481,390฿ for the intervention. According to the budget impact analysis (assuming an increase of 5% market share for R+ORS over 5 years), the year-on-year reduction for diarrhea as a percentage of the total health care expenditure is -0.0027%, resulting in potential net cost savings of -35,632,482฿ over 5 years. Subject to the assumptions and limitations of the models, adjuvant racecadotril versus ORS alone is potentially cost-effective for children in Thailand and uptake could translate into savings for the Thailand public health care system.

  12. Zn- and Mg- Containing Tricalcium Phosphates-Based Adjuvants for Cancer Immunotherapy

    Science.gov (United States)

    Wang, Xiupeng; Li, Xia; Onuma, Kazuo; Sogo, Yu; Ohno, Tadao; Ito, Atsuo

    2013-07-01

    Zn-, and Mg-containing tricalcium phosphates (TCPs) loaded with a hydrothermal extract of a human tubercle bacillus (HTB) were prepared by immersing Zn-TCP and Mg-TCP in HTB-containing supersaturated calcium phosphate solutions. The in vitro and in vivo immunogenic activities of the HTB-loaded Zn-, and Mg-TCPs (Zn-Ap-HTB and Mg-Ap-HTB, respectively) were evaluated as potential immunopotentiating adjuvants for cancer immunotherapy. The Zn-Ap-HTB and Mg-Ap-HTB adjuvants showed no obvious cytotoxicity and more effectively stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion by macrophage-like cells than unprocessed HTB or HTB-loaded TCP (T-Ap-HTB) in vitro. Zn-Ap-HTB and Mg-Ap-HTB mixed with liquid-nitrogen-treated tumor tissue markedly inhibited the in vivo development of rechallenged Lewis lung carcinoma (LLC) cells compared with T-Ap-HTB and the unprocessed HTB mixed liquid-nitrogen-treated tumor tissue. Zn-Ap-HTB and Mg-Ap-HTB contributed to eliciting potent systemic antitumor immunity in vivo.

  13. [Subunit vaccines--antigens, carriers, conjugation methods and the role of adjuvants].

    Science.gov (United States)

    Jarząb, Anna; Skowicki, Michał; Witkowska, Danuta

    2013-11-27

    Vaccines are effective tools protecting against the development of infectious diseases caused by pathogenic microorganisms. Currently, we have vaccines protecting against many infections, where standard therapy is not only difficult but often impossible due to the ever-progressive increase in bacterial resistance to many available antibiotics. Among vaccines which have been used in the prevention of infection are the traditional vaccines containing live, killed or attenuated strains of microorganisms. However, it should be noted that such vaccines are not always effective, especially when the expected immune response is directed against specific antigens. Subunit vaccines belong to new generation vaccines and have gained more and more interest in recent years. These vaccines contain fragments of pathogenic microorganisms, which are highly purified and immunogenic antigens. Using these purified antigens excludes the risk of post-vaccination infection. In addition, subunit vaccines minimize side-effects associated with the use of whole bacterial cells. The paper discusses the most promising and the most tested antigens, vaccine carriers, conjugation methods and vaccine delivery systems which are being used in the design of subunit vaccines. This paper also highlights the advantages and disadvantages of adjuvants, which are substances to support the immune response in humans, and the relationship between adjuvants' efficacy and their mechanism of action.

  14. Role of Adjuvant Radiosurgery after Thoracoscopic Microsurgical Resection of a Spinal Schwannoma

    Directory of Open Access Journals (Sweden)

    Toba N. Niazi

    2012-01-01

    Full Text Available Stereotactic radiosurgery to benign tumors of the spine has not been advocated as a primary treatment modality because of the favorable prognosis for these lesions after gross-total resection. There is even less evidence regarding its use as an adjuvant to neurosurgical resection of benign recurrent spinal disease. We describe the case of a 30-year-old man with a thoracic spinal schwannoma who had an interval increase of his lesion five months after thoracoscopic microsurgical resection. The patient opted for noninvasive stereotactic radiosurgery in lieu of additional surgical excision and has had stable disease 15 months after radiosurgical treatment with the linear accelerator (LINAC system. In this setting, stereotactic radiosurgery provided a useful adjunct to thoracoscopic microsurgical resection. Future Class I and II evidence should be sought to evaluate the utility of stereotactic radiosurgery as a primary treatment modality or as an adjuvant for microneurosurgical resection of benign spinal lesions in patients who want noninvasive treatment after disease recurrence or who harbor medical comorbidities that would preclude them from being safe surgical candidates.

  15. Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice.

    Science.gov (United States)

    Paes, Wayne; Brown, Naj; Brzozowski, Andrzej M; Coler, Rhea; Reed, Steve; Carter, Darrick; Bland, Martin; Kaye, Paul M; Lacey, Charles J N

    2016-07-29

    The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmitted Chlamydia trachomatis (Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinical Ct vaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinant Ct polymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designed in silico by modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginal Ct challenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognize Ct EBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinical Ct vaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenital Ct infection. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  16. Small cationic DDA:TDB liposomes as protein vaccine adjuvants obviate the need for TLR agonists in inducing cellular and humoral responses.

    Directory of Open Access Journals (Sweden)

    Anita Milicic

    Full Text Available Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar or multiple (multilamellar phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes--including size, antigen association and addition of TLR agonists--to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs. Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs, but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes.

  17. Small cationic DDA:TDB liposomes as protein vaccine adjuvants obviate the need for TLR agonists in inducing cellular and humoral responses.

    Science.gov (United States)

    Milicic, Anita; Kaur, Randip; Reyes-Sandoval, Arturo; Tang, Choon-Kit; Honeycutt, Jared; Perrie, Yvonne; Hill, Adrian V S

    2012-01-01

    Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes--including size, antigen association and addition of TLR agonists--to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes.

  18. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials.

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    Wenjin Yin

    Full Text Available BACKGROUND: Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors. METHODS: Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data. FINDINGS: With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001 from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018. Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001 but bore a higher incidence of CNS recurrence (P = 0.010, while statistical significance failed to be discerned for either overall survival (P = 0.069 or CNS metastasis (P = 0.374 between the sequential and observation arms. CONCLUSION: This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.

  19. Cost-utility analysis of adjuvant goserelin (Zoladex and adjuvant chemotherapy in premenopausal women with breast cancer

    Directory of Open Access Journals (Sweden)

    Cheng Tsui

    2012-01-01

    Full Text Available Abstract Background Increased health care costs have made it incumbent on health-care facilities and physicians to demonstrate both clinical and cost efficacy when recommending treatments. Though studies have examined the cost-effectiveness of adjuvant goserelin with radiotherapy for locally advanced prostate cancer, few have compared the cost-effectiveness of adjuvant goserelin to adjuvant chemotherapy alone in premenopausal breast cancer. Methods In this retrospective study at one hospital, the records of 152 patients with stage Ia to IIIa ER + breast cancer who received goserelin or chemotherapy were reviewed. Survival analysis was assessed by the Kaplan-Meier method. Patients were interviewed to evaluate their quality of life using the European Organization for Research and Treatment Quality of Life questionnaire (EORTC-QLQ-C30, version 4.0, and to obtain the utility value by the standard gamble (SG and visual scale (VS methods. Total medical cost was assessed from the (National Health Insurance NHI payer's perspective. Results Survival at 11 years was significantly better in the groserelin group (P Conclusions Goserelin therapy results in better survival and higher utility-weighted life-years, and is more cost-effective than TC or TEC chemotherapy.

  20. Gamma ray sterilization of delta inulin adjuvant particles (Advax™) makes minor, partly reversible structural changes without affecting adjuvant activity.

    Science.gov (United States)

    Cooper, P D; Barclay, T G; Ginic-Markovic, M; Petrovsky, N

    2014-01-23

    We earlier identified a developmental series of seven isoforms/polymorphs of microparticulate inulin by comparing non-covalent bonding strengths. Their pharmaceutical utility lies in the modulation of cellular immunity, exploited as vaccine adjuvants (Advax™) especially for delta inulin (DI). As such particles cannot be sterilized by filtration we explore the effect of (60)Co gamma radiation (GR) on inulin isoforms, particularly DI. Its adjuvant activity and overt physical properties were unaffected by normal GR sterilizing doses (up to 25kGy). Heating irradiated isoform suspensions near their critical dissolution temperature revealed increased solubility deduced to reflect a single lethal event in one component of a multi-component structure. Local oxidative effects of GR on DI were not found. The observed DI loss was almost halved by re-annealing at the critical temperature: surviving inulin chains apparently reassemble into smaller amounts of the original type of structure. Colorimetric tetrazolium assay revealed increases in reducing activity after GR of raw inulin powder, which yielded DI with normal physical properties but only 25% normal recovery yet 4× normal reducing ability, implying final retention of some GR-changed inulin chains. These findings suggest minimal inulin chain cleavage and confirm that GR may be a viable strategy for terminal sterilization of microparticulate inulin adjuvants.

  1. Development of a minimal saponin vaccine adjuvant based on QS-21

    Science.gov (United States)

    Fernández-Tejada, Alberto; Chea, Eric K.; George, Constantine; Pillarsetty, Nagavarakishore; Gardner, Jeffrey R.; Livingston, Philip O.; Ragupathi, Govind; Lewis, Jason S.; Tan, Derek S.; Gin, David Y.

    2014-07-01

    Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure-function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.

  2. Effect of Zinc gluconate adjuvant therapy on myocardial damage, immunologic function and serum inflammatory factors in children with rotaviral enteritis

    Institute of Scientific and Technical Information of China (English)

    Jun Zhu

    2015-01-01

    Objective:To analyze the effects of Zinc gluconate adjuvant therapy on Rotavirus myocardial injury, immune function and serum inflammatory factors of children with viral enteritis. Methods:A total of 138 Rotavirus viral enteritis children were enrolled as research objects. According to stochastic indicator method, they were divided into control group (n=69 cases) which received clinical routine treatment, and observation group (n=69 cases) which received Zinc gluconate adjuvant therapy, myocardial enzyme spectrum; serum inflammatory cytokines and immune function of the two groups were compared.Results:(1) LDH, CK, CK-MB, cTnⅠ myocardial enzyme indexes of the observation group were significantly lower than that of the control group (P<0.05). (2) serum zinc gluconate auxiliary CD19+CD5+CD1dhi B cells expression level of the observation group were higher than that of the control group, CD11b and CD40-CD40L stimulus molecule expression levels of the observation group were significantly lower than that of the control group (P<0.05). (3) Serum zinc gluconate auxiliary TRF1, TRF2 expression levels of the observation group were significantly higher than that of the control group but IL-12 level was lower than control group (P<0.05).Conclusion:Zinc gluconate adjuvant therapy could help to avoid the heart of the children with rotavirus virus enteritis loss, enhance immune function,reduce level of systemic inflammation.

  3. Infected dendritic cells are sufficient to mediate the adjuvant activity generated by Venezuelan equine encephalitis virus replicon particles.

    Science.gov (United States)

    Tonkin, Daniel R; Whitmore, Alan; Johnston, Robert E; Barro, Mario

    2012-06-22

    Replicon particles derived from Venezuelan equine encephalitis virus (VEE) are infectious non-propagating particles which act as a safe and potent systemic, mucosal, and cellular adjuvant when delivered with antigen. VEE and VEE replicon particles (VRP) can target multiple cell types including dendritic cells (DCs). The role of these cell types in VRP adjuvant activity has not been previously evaluated, and for these studies we focused on the contribution of DCs to the response to VRP. By analysis of VRP targeting in the draining lymph node, we found that VRP induced rapid recruitment of TNF-secreting monocyte-derived inflammatory dendritic cells. VRP preferentially infected these inflammatory DCs as well as classical DCs and macrophages, with less efficient infection of other cell types. DC depletion suggested that the interaction of VRP with classical DCs was required for recruitment of inflammatory DCs, induction of high levels of many cytokines, and for stable transport of VRP to the draining lymph node. Additionally, in vitro-infected DCs enhanced antigen-specific responses by CD4 and CD8 T cells. By transfer of VRP-infected DCs into mice we showed that these DCs generated an inflammatory state in the draining lymph node similar to that achieved by VRP injection. Most importantly, VRP-infected DCs were sufficient to establish robust adjuvant activity in mice comparable to that produced by VRP injection. These findings indicate that VRP infect, recruit and activate both classical and inflammatory DCs, and those DCs become mediators of the VRP adjuvant activity. Published by Elsevier Ltd.

  4. Effect of Feeding Status on Adjuvant Arthritis Severity, Cachexia, and Insulin Sensitivity in Male Lewis Rats

    Directory of Open Access Journals (Sweden)

    Andrea Stofkova

    2010-01-01

    Full Text Available We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART in the arcuate nucleus (ARC does not play a primary role. The overexpression of IL-1β mRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats.

  5. Effect of incorporation of the adjuvant Quil A on structure and immune stimulatory capacity of liposomes.

    Science.gov (United States)

    Demana, Patrick H; Fehske, Christian; White, Karen; Rades, Thomas; Hook, Sarah

    2004-10-01

    Liposomes have been widely used as drug delivery systems for many years. However, they are of limited use as delivery systems for subunit vaccines due to their low immunogenicity. Here we examine the effect of incorporating the adjuvant Quil A into liposomes on the type of particles produced, on the ability of the different particles to incorporate antigen and on the ability of the different particles to stimulate murine bone-marrow-derived dendritic cells (DC) and lymphocytes. The incorporation of increasing amounts of Quil A, from 20% to 70% of the total lipid into liposomes, reduces the size of the particles that form in aqueous dispersion and decreases antigen incorporation and uptake by DC. Interestingly, the particles with 20% Quil A were more toxic to cells in culture than the particles containing 70% Quil A, and the 20% particles were also more immunostimulatory. Copyright 2004 Australasian Society for Immunology Inc.

  6. Adjuvant Activity of a Novel Metabolizable Lipid Emulsion with Inactivated Viral Vaccines

    Science.gov (United States)

    1980-06-01

    hamsters, sheep, and two species of nonhuman 0 primates which demonstrate the adjuvant activity of a new metabolizable lipid emulsion with marginally...mice, hamsters, sheep, and two species of nonhuman primates . This adjuvant has several 10.000 advantages over other known adjuvant com-cpounds. It is...plaque neutralization method for arboviruses . Proc. Soc. granulomatous reaction was not observed. We Exp. Biol. Med. 125:741-747. closely observed the

  7. Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations

    OpenAIRE

    2016-01-01

    Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al3+ in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, pote...

  8. Characteristics and prognosis of patients with early-stage endometrial cancer who refuse adjuvant radiotherapy.

    Science.gov (United States)

    Koskas, Martin; Huchon, Cyrille; Amant, Frederic

    2016-06-01

    To investigate the risk factors for refusing adjuvant radiotherapy in patients who have undergone surgery for early-stage endometrial cancer, and to compare their survival rates with patients who have undergone adjuvant radiotherapy. Data from the Surveillance, Epidemiology, and End Results database for patients operated on for histologically-proven early-stage endometrioid endometrial cancer, between 1988 and 2012, were screened. Univariate and multivariate logistic regression analyses tested the associations between refusal of adjuvant radiotherapy and demographic, tumoral, and management characteristics. Overall and cancer-related survival rates were compared between 376 patients who refused adjuvant radiotherapy and 752 patients who received adjuvant radiotherapy, matched for demographics (age, race, year of diagnosis, marital status, region), tumoral (grade, FIGO stage, size), and management (lymphadenectomy performed) criteria. 434 of the 16,014 patients (2.7%) who were proposed adjuvant radiotherapy refused this treatment. Older, widowed, divorced, or separated patients, who were recently diagnosed and managed in the Northern plains or Pacific coast (USA), with limited tumoral extension, were more likely to refuse adjuvant radiotherapy. Five-year cancer-related survival was significantly lower in patients who refused adjuvant radiotherapy (88.9% vs. 95.7%, pradiotherapy. Refusing adjuvant radiotherapy increased cancer-related death but probably does not reduce overall survival. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Review on adjuvant chemotherapy for rectal cancer - why do treatment guidelines differ so much?

    Science.gov (United States)

    Poulsen, Laurids Ø; Qvortrup, Camilla; Pfeiffer, Per; Yilmaz, Mette; Falkmer, Ursula; Sorbye, Halfdan

    2015-04-01

    The use of postoperative adjuvant chemotherapy is controversial for rectal adenocarcinoma. Both international and national guidelines display a great span varying from recommending no adjuvant chemotherapy at all, over single drug 5-fluororuacil (5-FU), to combinations of 5-FU/oxaliplatin. A review of the literature was made identifying 24 randomized controlled trials on adjuvant treatment of rectal cancer based on about 10 000 patients. The trials were subdivided into a number of clinically relevant subgroups. As regards patients treated with preoperative (chemo) radiotherapy, four randomized studies were found where use of adjuvant chemotherapy showed no benefit in survival. Three trials were found in which a subset of patients received preoperative (chemo) radiotherapy. Two of these trials showed a statistically significant benefit of adjuvant chemotherapy. Twenty trials were identified in which the patients did not receive preoperative (chemo) radiotherapy, including five Asian studies in which a statistically significant benefit from adjuvant chemotherapy was reported. Most of the data found did not support the use of postoperative adjuvant chemotherapy for patients already treated with preoperative (chemo) radiotherapy. For patients not treated preoperatively, several studies support the use of single agent 5-FU chemotherapy. Treatment guidelines seem to differ according to if preoperative chemoradiation is considered of importance for use of adjuvant chemotherapy and if adjuvant colon cancer studies are considered transferrable to rectal cancer patients regardless of the molecular differences.

  10. Improved survival with early adjuvant chemotherapy after colonic resection for stage III colonic cancer

    DEFF Research Database (Denmark)

    Klein, Mads; Azaquoun, Najah; Jensen, Benny Vittrup

    2015-01-01

    BACKGROUND AND OBJECTIVES: In stage III colonic cancer, time from surgery to start of adjuvant chemotherapy may influence survival. In this study, we evaluated the effect of timing of adjuvant therapy on survival. METHODS: Database study from the Danish Colorectal Cancer Group's national database....... RESULTS: The final population included 1,827 patients scheduled for adjuvant chemotherapy. Adjuvant therapy started within 4 and 8 weeks improved survival when compared to start later than 8 weeks (HR [95%CI]: 1.7 [1.1-2.6]; P = 0.024 and 1.4 [1.07-1.8]; P = 0.013, respectively), whereas...

  11. Stage IB endometrial cancer. Does lymphadenectomy replace adjuvant radiotherapy?

    Science.gov (United States)

    Bottke, Dirk; Wiegel, Thomas; Kreienberg, Rolf; Kurzeder, Christian; Sauer, Georg

    2007-11-01

    The role of surgical lymph node dissection and adjuvant radiation therapy (RT) in early stage endometrial cancer is no longer clearly defined. The increased appreciation of lymphadenectomy and the absence of survival advantage from adjuvant RT rise controversies how patients should adequately be treated in stage IB endometrial cancer. The aim of this review is to rule out the validity of either treatment option and determine which preference provides the best therapeutic benefit. Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. Based on the available data in the literature, for stage IB grade 1 or 2, the risk of pelvic relapse is considered too low to justify pelvic RT. However, intravaginal RT (IVRT) should be recommended for those >or= 60 years old or with lymphovascular invasion (LVI). For patients with stage IB grade 3 (and IC all grades), the treatment recommendation is mainly based on whether surgical lymph node staging was performed. These patients have--without surgical lymph node staging--a high risk of pelvic recurrence and should therefore primarily undergo relaparotomy for lymphadenectomy or pelvic RT as second choice. If these patients had a surgical lymph node staging, then IVRT alone is a reasonable alternative to pelvic RT. Overall survival may not be the only ideal endpoint for stage IB endometrial cancer since causes of death are mostly other than endometrial cancer. Conventional pelvic RT may be overtreatment in some patients, in particular in those patients with a large number of negative lymph nodes after lymphadenectomy. However, negative surgical staging should not be understood as adjuvant RT can be omitted in all patients.

  12. Adjuvant Ab Interno Tumor Treatment After Proton Beam Irradiation.

    Science.gov (United States)

    Seibel, Ira; Riechardt, Aline I; Heufelder, Jens; Cordini, Dino; Joussen, Antonia M

    2017-06-01

    This study was performed to show long-term outcomes concerning globe preservation in uveal melanoma patients after proton beam therapy with the main focus on outcomes according to different adjuvant ab interno surgical procedures. Retrospective cohort study. All patients treated with primary proton beam therapy for choroidal or ciliary body melanoma between June 1998 and June 2015 were included. A total of 2499 patients underwent primary proton beam therapy, with local tumor control and globe preservation rates of 95.9% and 94.8% after 5 years, respectively. A total of 110 (4.4%) patients required secondary enucleation. Unresponsive neovascular glaucoma was the leading cause of secondary enucleation in 78 of the 2499 patients (3.1%). The 5-year enucleation-free survival rate was 94.8% in the endoresection group, 94.3% in the endodrainage group, and 93.5% in the comparator group. The log-rank test showed P = .014 (comparator group vs endoresection group) and P = .06 (comparator group vs endodrainage-vitrectomy group). Patients treated with endoresection or endodrainage-vitrectomy developed less radiation retinopathy (30.5% and 37.4% after 5 years, P = .001 and P = .048 [Kaplan-Meier], respectively) and less neovascular glaucoma (11.6% and 21.3% after 5 years, P = .001 and P = .01 [Kaplan-Meier], respectively) compared with the comparator group (52.3% radiation retinopathy and 57.8% neovascular glaucoma after 5 years). This study suggests that in larger tumors the enucleation and neovascular glaucoma rates might be reduced by adjuvant surgical procedures. Although endoresection is the most promising adjuvant treatment option, the endodrainage-vitrectomy is recommended in patients who are ineligible for endoresection. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Beryllium, an adjuvant that promotes gamma interferon production.

    Science.gov (United States)

    Lee, J Y; Atochina, O; King, B; Taylor, L; Elloso, M; Scott, P; Rossman, M D

    2000-07-01

    Beryllium is associated with a human pulmonary granulomatosis characterized by an accumulation of CD4(+) T cells in the lungs and a heightened specific lymphocyte proliferative response to beryllium (Be) with gamma interferon (IFN-gamma) release (i.e., a T helper 1 [Th1] response). While an animal model of Be sensitization is not currently available, Be has exhibited adjuvant effects in animals. The effects of Be on BALB/c mice immunized with soluble leishmanial antigens (SLA) were investigated to determine if Be had adjuvant activity for IFN-gamma production, an indicator of the Th1 response. In this strain of Leishmania-susceptible BALB/c mice, a Th2 response is normally observed after in vivo SLA sensitization and in vitro restimulation with SLA. If interleukin-12 (IL-12) is given during in vivo sensitization with SLA, markedly increased IFN-gamma production and decreased IL-4 production are detected. We show here that when beryllium sulfate (BeSO(4)) was added during in vivo sensitization of BALB/c mice with SLA and IL-12, significantly increased IFN-gamma production and decreased IL-4 production from lymph node and spleen cells were detected upon in vitro SLA restimulation. No specific responses were observed to Be alone. Lymph node and spleen cells from all mice proliferated strongly and comparably upon in vitro restimulation with SLA and with SLA plus Be; no differences were noted among groups of mice that received different immunization regimens. In vivo, when Be was added to SLA and IL-12 for sensitization of BALB/c mice, more effective control of Leishmania infection was achieved. This finding has implications for understanding not only the development of granulomatous reactions but also the potential for developing Be as a vaccine adjuvant.

  14. Caffeine as an opioid analgesic adjuvant in fibromyalgia

    OpenAIRE

    Scott JR; Hassett AL; Brummett CM; Harris RE; Clauw DJ; Harte SE

    2017-01-01

    J Ryan Scott,1 Afton L Hassett,1 Chad M Brummett,1 Richard E Harris,1,2 Daniel J Clauw,1,2 Steven E Harte1,2 1Chronic Pain and Fatigue Research Center, Department of Anesthesiology, 2Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA Background: Caffeine’s properties as an analgesic adjuvant with nonsteroidal anti-inflammatory drugs/acetaminophen are well documented. However, little clinical research has explored ca­ffeine&a...

  15. Radiation Recall Reaction Induced by Adjuvant Trastuzumab (Herceptin

    Directory of Open Access Journals (Sweden)

    Caroline Chung

    2009-01-01

    trastuzumab (Herceptin administration, there has been no published case of radiation recall reaction associated with trastuzumab. This case describes a clinical presentation consistent with a radiation recall reaction following administration of adjuvant trastuzumab after neoadjuvant FEC-D chemotherapy and locoregional radiotherapy for HER2-positive, locally advanced breast cancer in a premenopausal woman. Although the mechanism and etiology of radiation recall dermatitis remain unclear, this case raises further hypotheses regarding a possible drug dose-dependence and possible predisposing risk factor for the development of radiation recall reactions.

  16. Adjuvant chemo-radiation for gastric adenocarcinoma: an institutional experience

    Directory of Open Access Journals (Sweden)

    Ghosn Marwan G

    2010-06-01

    Full Text Available Abstract Background Studies have shown that surgery alone is less than satisfactory in the management of early gastric cancer, with cure rates approaching 40%. The role of adjuvant therapy was indefinite until three large, randomized controlled trials showed the survival benefit of adjuvant therapy over surgery alone. Chemoradiation therapy has been criticized for its high toxicity. Methods 24 patients diagnosed between September 2001 and July 2007 were treated with adjuvant chemoradiation. 18 patients had the classical MacDonald regimen of 4500 cGy of XRT and chemotherapy with 5-fluorouracil (5FU and leucovorin, while chemotherapy consisted of 5FU/Cisplatin for 6 patients. Results This series consisted of non-metastatic patients, 17 females and 7 males with a median age of 62.5 years. 23 patients (96% had a performance status of 0 or 1. The full course of radiation therapy (4500 cGy was completed by 22 patients (91.7%. Only 7 patients (36.8% completed the total planned courses of chemotherapy. 2 local relapses (10%, 2 regional relapses (10% and 2 distant relapses (10% were recorded. Time to progression has not been reached. 9 patients (37.5% died during follow-up with a median overall survival of 75 months. Patients lost a mean of 4 Kgs during radiation therapy. We recorded 6 episodes of febrile neutropenia and the most frequent toxicity was gastro-intestinal in 17 patients (70.8% with 9 (36% patients suffering grade 3 or 4 toxicity and 5 patients (20% suffering from grade 3 or 4 neutropenia. 4 (17% patients required total parenteral nutrition for a mean duration of 20 days. 4 patients suffered septic shock (17% and 1 patient developed a deep venous thrombosis and a pulmonary embolus. Conclusions Adjuvant chemo-radiation for gastric cancer is a standard at our institution and has resulted in few relapses and an interesting median survival. Toxicity rates were serious and this remains a harsh regimen with only 36.8% of patients completing the

  17. [Value of adjuvant physiotherapy in postoperative pain management].

    Science.gov (United States)

    Bullmann, V; Weber, T P; Kienle, B; Schulte, T L

    2008-10-01

    In times of limited financial and human resources the application of adjuvant physiotherapy postoperatively in orthopaedic patients requires reevaluation. In the early postoperative course physiotherapy improves the patients' mobility. However, it is not able to reduce the need for pain medication. It is intended to minimize complications and to mobilize and motivate the patients early. In contrast, massages are of minor importance in the immediate postoperative course and are applied only in a few selected cases. Cryotherapy plays a major role especially after shoulder and knee surgery. On the other hand, transcutaneous electrical nerve stimulation (TENS) and acupuncture are applied only in selected patients after orthopaedic surgery, e.g., after limb amputation.

  18. An evaluation of early or delayed adjuvant chemotherapy in premenopausal patients with advances breast cancer undergoing oophorectomy: a later analysis.

    Science.gov (United States)

    Ahmann, D L; Green, S J; Bisel, H F; Ingle, J N; Hahn, R G; Lee, R A; Edmonson, J H

    1982-08-01

    In 1977 we reported our results of an ongoing randomized clinical trial evaluating early or delayed adjuvant chemotherapy utilizing 5-flourouracil, cytoxan and prednisone in premenopausal patients with recurrent or advanced breast cancer. At that time the group receiving early systemic chemotherapy was shown to have an improved progression-free interval and appeared to have a trend toward improved survival. The results of subsequent analysis after over 4 more years of follow-up indicate however, that while early employment of systemic chemotherapy does indeed prolong the progression-free interval, and while this advantage has been maintained, there is no survival advantage shown for either group of patients.

  19. Mucosal vaccination against diphtheria using starch microparticles as adjuvant for cross-reacting material (CRM197) of diphtheria toxin.

    Science.gov (United States)

    Rydell, Niclas; Sjöholm, Ingvar

    2005-04-15

    Mucosal vaccination has the advantage of eliciting a local mucosal immune response as well as a systemic response. In this investigation, polyacryl starch microparticles were conjugated to diphtheria toxin cross-reacting material (CRM197) as a mucosal adjuvant for oral or intranasal immunisation of mice. Various methods of stabilising CRM197 with formaldehyde were investigated. A good systemic and local mucosal immune response was attained with oral immunisation when CRM197 was treated with a relatively low formaldehyde concentration prior to conjugation to the microparticles. No immune response was seen after intranasal immunisation.

  20. Success Predictors of Adjuvant Chemotherapy in Node-Negative Breast Cancer Patients Under 55 years1

    Directory of Open Access Journals (Sweden)

    Emiel A. M. Janssen

    2006-01-01

    Full Text Available Background: Adjuvant systemic chemotherapy (ASCT in lymph node-negative breast (LN− cancers improves survival. The majority of (LN− patients receive ASCT when the St. Gallen criteria or its modifications are used, as accurate identifiers which patients benefit from ASCT are lacking. This may imply over-treatment in many patients. Aim: To evaluate which patients or primary tumor factors predict ASCT success. Material and method: Retrospective analysis by single and multivariate survival analysis of clinical and tumor characteristics in (LN− breast cancers <55 years, related to ASCT (n = 125 or-not (n = 516. Results: The two patient groups did not differ in age, tumor diameter, grade, type, number of mitoses and other factors. Fourteen-year survival for the ASCT and non-ASCT patients was 83% and 74% (Hazard Ratio = HR = 0.33; p < 0.0001, 9% absolute = 12% relative difference. Subgroup analysis showed that the recurrence-free survival = RFS of ASCT treated vs. non-treated patients differed in patients with grade 1 cancers (p = 0.008, grade 2 cancers (p = 0.004, grades 3 (p = 0.02, tumors under and ≧2 cm (p = 0.001 and 0.0002, oestrogen receptor-positive or -negative tumors (p = 0.003, 0.04, MAI < 10 and ≧10 (p = 0.005, 0.003 and fibrotic focus absent (p = 0.002. With multivariate analysis the most important predictor of ASCT effect was the MAI. In patients with slowly proliferating tumors (MAI < 3 no advantage was found between patients treated-or-not with adjuvant chemotherapy (RFS = 92% and 91%, p = 0.13, p = 0.63 for overall survival, contrasting those with MAI ≧ 3 (p = 0.0001; HR = 0.32, 95% CI 0.18–0.58. Conclusion: MAI is the strongest predictor of adjuvant systemic chemotherapy success. In patients with MAI < 3 (31% of all patients, ASCT does not improve survival.

  1. Utilization and impact of adjuvant therapy in anaplastic oligodendroglioma: an analysis on 1692 patients.

    Science.gov (United States)

    Shin, Jacob Y; Diaz, Aidnag Z

    2016-09-01

    The aim of this study was to determine the utilization rates and impact of adjuvant therapy on overall survival (OS) for anaplastic oligodendroglioma (AO). Data were extracted from the National Cancer Data Base (NCDB). Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 1692 patients with AO who underwent surgery were identified. 945 (55.9 %) received adjuvant radiotherapy with concomitant chemotherapy (chemoRT), 102 (6.0 %) adjuvant radiotherapy (RT) sequentially followed by chemotherapy, 244 (14.4 %) adjuvant RT alone, and 401 (23.7 %) received no adjuvant therapy. Patients were more likely to receive adjuvant chemoRT if they were diagnosed in 2009-2013 vs. 2004-2008 (p 70 vs. <70 (p = 0.018), had private insurance vs. Medicaid vs. no insurance (p < 0.001), or had median income ≥$63,000 vs. <$63,000 (p = 0.014). Those who received adjuvant chemoRT (concomitant or sequential) had significantly better 5-year OS than those who received adjuvant RT alone or no adjuvant therapy (59.8 % vs. 65.0 % vs. 44.9 % vs. 45.6 %, p < 0.001). This significant 5-year OS benefit was also observed regardless of age. There was no difference in OS when comparing concomitant chemoRT to sequential RT and chemotherapy (p = 0.481). On multivariate analysis, receipt of adjuvant chemoRT (concomitant or sequential) remained an independent prognostic factor for improved OS. Adjuvant chemoRT (concomitant or sequential) is an independent prognostic factor for improved OS in anaplastic oligodendroglioma and should be considered for all clinically suitable patients who have undergone surgery for the disease.

  2. Choice of adjuvant drug therapy on the basis of the molecular classification of breast cancer

    Directory of Open Access Journals (Sweden)

    N. S. Besova

    2012-01-01

    Full Text Available Molecular genetic analysis identified some biological subtypes of breast cancer (BC: luminal A, luminal B, HER2 positive, and basal-like (including triple negative. The surrogate clinical and morphological criteria including the immunohistochemical determination of estrogen and progesterone receptors, the hyperexpression and/or amplification of HER2, Ki-67, or tumor grade (G are used to identify the biological subtypes of BC in clinical practice. The biological subtypes are distinguished by their biological course and susceptibility to various systemic treatments, which requires different therapeutic tactics. The paper presents tactics of adjuvant therapy for BC in relation to its biological subtype according to the recommendations of the 12th St. Gallen International Breast Cancer Conference (2011 and considers the place of taxans.

  3. Current status of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer.

    Science.gov (United States)

    Rosenberg, Jonathan E

    2007-12-01

    Muscle-invasive transitional cell carcinoma occurs in approximately 30% of patients and is associated with a high risk of distant metastasis. Radical local therapy in the form of cystectomy or radiotherapy is curative in a portion of patients. Systemic therapy to treat occult micrometastasis at the time of local control is necessary to improve outcomes. Neoadjuvant chemotherapy is associated with a 5-6% improvement in overall survival at 5 years, and adjuvant chemotherapy may achieve similar results, although this remains unproven. Operative complications are not increased with neoadjuvant therapy. Perioperative treatment strategies remain underutilized, and many patients are not offered treatment to reduce the risk of relapse. Neoadjuvant strategies are a potent tool for research and should be employed to test new agents for the treatment of transitional cell carcinoma.

  4. Immunoendocrine Interactions during HIV-TB Coinfection: Implications for the Design of New Adjuvant Therapies

    Directory of Open Access Journals (Sweden)

    Guadalupe Veronica Suarez

    2015-01-01

    Full Text Available Worldwide, around 14 million individuals are coinfected with both tuberculosis (TB and human immunodeficiency virus (HIV. In coinfected individuals, both pathogens weaken immunological system synergistically through mechanisms that are not fully understood. During both HIV and TB infections, there is a chronic state of inflammation associated to dramatic changes in immune cytokine and endocrine hormone levels. Despite this, the relevance of immunoendocrine interaction on both the orchestration of an effective immune response against both pathogens and the control of the chronic inflammation induced during HIV, TB, or both infections is still controversial. The present study reviews immunoendocrine interactions occurring during HIV and TB infections. We also expose our own findings on immunoendocrine cross talk in HIV-TB coinfection. Finally, we evaluate the use of adrenal hormones and their derivatives in immune-therapy and discuss the use of some of these compounds like the adjuvant for the prevention and treatment of TB in HIV patients.

  5. Preparation and evaluation of functional foods in adjuvant arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Al-Okbi, S. Y.; Mohamed, D. A.

    2012-07-01

    Adjuvant arthritis is an animal model that closely resembles rheumatoid arthritis in humans. It is a successful working model used to study new anti-inflammatory agents. In previous studies (animal and clinical) we have shown that evening primrose oil, fish oil and the methanol extract of date fruits and fenugreek seeds have anti-inflammatory activity and that the methanol extract of dates has an antioxidant effect. Based on these studies, the aim of the present study was to prepare 7 functional foods containing such bioactive fractions separately or in combination and to evaluate them in adjuvant arthritis in rats, study the stability of bioactive ingredients and evaluate their sensory properties. The studied biochemical parameters were erythrocyte sedimentation rate, erythrocyte superoxide dismutase, glutathione peroxidase and plasma copper, zinc and interlukin 2. Nutritional parameters, including body weight gain, food intake and food efficiency ratio were monitored during the feeding of the functional foods. The bioactive ingredients assessed were total phenolic contents and fatty acids. The results showed improvement in the biochemical parameters, body weight gain and food efficiency ratio of arthritic rats fed on the functional foods with different degrees. All the prepared functional foods were sensory accepted. The active ingredients showed stability during storage. In conclusion, all the tested functional foods showed promising antiinflammatory activity and were determined to be acceptable through sensory evaluation which means that their potential beneficial use as dietary supplements in rheumatoid arthritis patients may be recommended. (Author) 42 refs.

  6. Innate Immune Signaling by, Genetic Adjuvants for, DNA Vaccination

    Directory of Open Access Journals (Sweden)

    Kouji Kobiyama

    2013-07-01

    Full Text Available DNA vaccines can induce both humoral and cellular immune responses. Although some DNA vaccines are already licensed for infectious diseases in animals, they are not licensed for human use because the risk and benefit of DNA vaccines is still controversial. Indeed, in humans, the immunogenicity of DNA vaccines is lower than that of other traditional vaccines. To develop the use of DNA vaccines in the clinic, various approaches are in progress to enhance or improve the immunogenicity of DNA vaccines. Recent studies have shown that immunogenicity of DNA vaccines are regulated by innate immune responses via plasmid DNA recognition through the STING-TBK1 signaling cascade. Similarly, molecules that act as dsDNA sensors that activate innate immune responses through STING-TBK1 have been identified and used as genetic adjuvants to enhance DNA vaccine immunogenicity in mouse models. However, the mechanisms that induce innate immune responses by DNA vaccines are still unclear. In this review, we will discuss innate immune signaling upon DNA vaccination and genetic adjuvants of innate immune signaling molecules.

  7. Effects of 3% trehalose as an adjuvant treatment after LASIK

    Science.gov (United States)

    Mateo Orobia, Antonio J; Casas Pascual, Paula; Cristóbal Bescós, José Á; Perez García, Diana; Peiro Embid, Carlos; del Buey Sayas, M Ángeles; Korobko Kulikova, Valentyna; Lafuente Ojeda, Noelia

    2017-01-01

    Purpose To evaluate the effect of 3% trehalose as an adjuvant in the standard treatment after laser-assisted in situ keratomileusis. Design Interventional prospective comparative single-blind study. Setting Department of Ophthalmology, Hospital Quirón Zaragoza, Spain. Methods A total of 26 eyes (13 patients) were included, of which 12 eyes (group 1) received conventional treatment with lubricant drops of hyaluronic acid (0.15%) and 14 eyes (group 2) received, additionally, an ophthalmic solution of 3% trehalose. Pre- and postoperative quality-of-life tests and vital stains, tear breakup time, and osmolarity measurements were made. Results We obtained statistically significant differences between the groups in the Symptom Assessment in Dry Eye test in all visits with respect to severity, and in the postoperative day 1 visit with respect to frequency, in all cases favoring the trehalose treatment. The values of osmolarity were not significantly different between groups. However, we did find significant differences in the Oxford scale in day 90 for the trehalose treatment (P<0.001), and in the National Eye Institute scale in day 30 (P=0.02). Conclusion The results of this exploratory study indicate that the adjuvant treatment with 3% trehalose could be superior with respect to the standard treatment, with improvements in the objective and subjective parameters of tear quality. PMID:28243058

  8. Use of melatonin as an adjuvant therapy in neonatal sepsis.

    Science.gov (United States)

    El Frargy, M; El-Sharkawy, H M; Attia, G F

    2015-01-01

    The objective of this study is to evaluate the therapeutic efficacy of melatonin as an adjuvant therapy in treating neonatal sepsis. A prospective clinical trial study was conducted on 50 infants with neonatal sepsis diagnosed on the basis of both clinical and laboratory criteria. Enrolled infants were divided into two groups. Intervention group (n = 25) received melatonin and antibiotics, while the control group (n = 25) was treated with antibiotics only. Melatonin was administered as a single oral dose of 20 mg and antibiotics were administered according to a standard protocol. Both groups were compared using a predefined sepsis score utilizing both clinical and laboratory parameters. There was no significant difference in sepsis score between both groups before starting melatonin (p-value = 0.99), while there was significant difference in sepsis score between groups after 24 hours, 48 hours and 72 hours of starting melatonin with (p-value = 0.008, 0.006 and 0.002, respectively). There was significant improvement sepsis score in both groups with more improvement of sepsis score in the intervention group. Administration of melatonin as an adjuvant therapy in the treatment of neonatal sepsis is associated with improvement of clinical and laboratory outcomes.

  9. Ethoxylated rapeseed oil derivatives as novel adjuvants for herbicides.

    Science.gov (United States)

    Müller, Thomas; Brancq, Bernard; Milius, Alain; Okori, Nathalie; Vaille, Claude; Gauvrit, Christian

    2002-12-01

    Ethoxylates of rapeseed oil and of methylated rapeseed oil were synthesized and tested as adjuvants for 2,4-D and phenmedipham. Provided they had less than 6 units of ethylene oxide (EO), 1.0 to 10 g litre(-1) ethoxylates in water induced droplet spreading on barley leaves. In an acetone-based medium all derivatives strongly promoted the foliar uptake of 2,4-D, with no clear influence of the ethoxylation degree. In the same medium there was a negative influence of ethoxylate chain length on the foliar uptake of phenmedipham. In a water-based medium, phenmedipham applied with rapeseed oil emulsified with ethoxylated (20 EO) rapeseed oil displayed uptake rates close to a commercial preparation. The same was true for phenmedipham applied with ethoxylated (2 EO) methylated rapeseed oil. In bioassays, phenmedipham prepared with methylated rapeseed oil emulsified with ethoxylated (20 EO) rapeseed oil was as efficacious on barley as a commercial formulation. The same was true for phenmedipham prepared with ethoxylated (2 EO) methylated rapeseed oil. However, neither rapeseed oil nor methylated rapeseed oil emulsified with ethoxylated (2 EO) methylated rapeseed oil conferred good efficacy to phenmedipham. Hence, ethoxylated rapeseed oil derivatives are promising adjuvants or formulants for herbicides.

  10. Effect of ascorbic acid and other adjuvants on manganese absorption

    Energy Technology Data Exchange (ETDEWEB)

    Papaioannou, R.; Sohler, A.; Pfeiffer, C.C.

    1986-03-01

    Animal experiments have demonstrated that manganese is poorly absorbed from the gut and that it is rapidly removed from the blood by liver uptake and bilary excretion. Zinc supplements which are readily absorbed can induce a Mn deficiency so that Mn supplementation is necessary. Supplementation with a diet rich in Mn (high in legumes, nuts, whole grains, tea) failed to influence blood Mn levels. The present study is concerned with the route of Mn administration and the effect of various adjuvants on the absorption and availability of Mn. Oral and sublingual administration of 20 mgs of Mn as the chloride failed to elicit a blood level rise. A rise was noted after the intramuscular injection of 2.5 mgs Mn as Mn Cl/sub 2/. Blood Mn levels rose to a maximum in thirty minutes and were back to basal levels within three hours. Adjuvants such as arginine, lecithin, taurine, biotin, bioflavinoids, were tested with essentially negative results. Mn orotate also failed to increase absorption. Oral absorption was obtained with ascorbic acid in five female subjects when 20 mgs of Mn as the chloride was given orally with 1 gm of ascorbic acid. This effect was not observed with five male subjects. A 30-40% increase in blood Mn after 2 hours was found when Mn was administered with ascorbic acid in the female subjects.

  11. Innate Immune Signaling by, and Genetic Adjuvants for DNA Vaccination.

    Science.gov (United States)

    Kobiyama, Kouji; Jounai, Nao; Aoshi, Taiki; Tozuka, Miyuki; Takeshita, Fumihiko; Coban, Cevayir; Ishii, Ken J

    2013-01-01

    DNA vaccines can induce both humoral and cellular immune responses. Although some DNA vaccines are already licensed for infectious diseases in animals, they are not licensed for human use because the risk and benefit of DNA vaccines is still controversial. Indeed, in humans, the immunogenicity of DNA vaccines is lower than that of other traditional vaccines. To develop the use of DNA vaccines in the clinic, various approaches are in progress to enhance or improve the immunogenicity of DNA vaccines. Recent studies have shown that immunogenicity of DNA vaccines are regulated by innate immune responses via plasmid DNA recognition through the STING-TBK1 signaling cascade. Similarly, molecules that act as dsDNA sensors that activate innate immune responses through STING-TBK1 have been identified and used as genetic adjuvants to enhance DNA vaccine immunogenicity in mouse models. However, the mechanisms that induce innate immune responses by DNA vaccines are still unclear. In this review, we will discuss innate immune signaling upon DNA vaccination and genetic adjuvants of innate immune signaling molecules.

  12. Development of a novel adjuvanted nasal vaccine: C48/80 associated with chitosan nanoparticles as a path to enhance mucosal immunity.

    Science.gov (United States)

    Bento, D; Staats, H F; Gonçalves, T; Borges, O

    2015-06-01

    In a time in which mucosal vaccines development has been delayed by the lack of safe and effective mucosal adjuvants, the combination of adjuvants has started to be explored as a strategy to obtain potent vaccine formulations. This study describes a novel adjuvant combination as an effective approach for a nasal vaccine - the association of the mast cell activator compound 48/80 with chitosan based nanoparticles. It was hypothesized that mucoadhesive nanoparticles would promote the cellular uptake and prolong the antigen residence time on nasal cavity. Simultaneously, mast cell activation would promote a local microenvironment favorable to the development of an immune response. To test this hypothesis, two different C48/80 loaded nanoparticles (NPs) were prepared: Chitosan-C48/80 NP (Chi-C48/80 NP) and Chitosan/Alginate-C48/80 NP (Chi/Alg-C48/80 NP). The potential as a vaccine adjuvant of the two delivery systems was evaluated and directly compared. Both formulations had a mean size near 500nm and a positive charge; however, Chi-C48/80 NP was a more effective adjuvant delivery system when compared with Chi/Alg-C48/80 NP or C48/80 alone. Chi-C48/80 NP activated mast cells at a greater extent, were better internalized by antigen presenting cells than Chi/Alg-C48/80 NP and successfully enhanced the nasal residence time of a model antigen. Superiority of Chi-C48/80 NP as adjuvant was also observed in vivo. Therefore, nasal immunization of mice with Bacillus anthracis protective antigen (PA) adsorbed on Chi-C48/80 NP elicited high levels of serum anti-PA neutralizing antibodies and a more balanced Th1/Th2 profile than C48/80 in solution or Chi/Alg-C48/80 NP. The incorporation of C48/80 within Chi NP also promoted a mucosal immunity greater than all the other adjuvanted groups tested, showing that the combination of a mast cell activator and chitosan NP could be a promising strategy for nasal immunization.

  13. Comparative Safety and Efficacy Profile of a Novel Oil in Water Vaccine Adjuvant Comprising Vitamins A and E and a Catechin in Protective Anti-Influenza Immunity

    Directory of Open Access Journals (Sweden)

    Sapna Patel

    2017-05-01

    Full Text Available Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more efficacious alternative, we tested whether vaccinations with influenza recombinant hemagglutinin (HA mixed with a novel vegetable oil in water emulsion adjuvant (Natural Immune-enhancing Delivery System, NIDS, based on the immune-enhancing synergy of vitamins A and E and a catechin, could protect against intra-nasal challenge with live influenza virus. Vaccinations of inbred Brag Albino strain c (BALB/c mice, with HA mixed with NIDS compared to other adjuvants, i.e., a squalene oil in water emulsion (Sq. oil, and the Toll Like Receptor 3 (TLR3 agonist Poly (I:C, induced significantly lower select innate pro-inflammatory responses in serum, but induced significantly higher adaptive antibody and splenic T Helper 1 (TH1 or TH2, but not TH17, responses. Vaccinations with NIDS protected against infection, as measured by clinical scores, lung viral loads, and serum hemagglutination inhibition titers. The NIDS exhibited a strong dose sparing effect and the adjuvant action of NIDS was intact in the outbred CD1 mice. Importantly, vaccinations with the Sq. oil, but not NIDS, induced a significantly higher Serum Amyloid P component, an acute phase reactant secreted by hepatocytes, and total serum IgE. Thus, the NIDS may be used as a clinically safer and more efficacious vaccine adjuvant against influenza, and potentially other infectious diseases.

  14. Feasibility of a randomized trial on adjuvant radio-iodine therapy in differentiated thyroid cancer.

    NARCIS (Netherlands)

    Dragoiescu, C.; Hoekstra, O.S.; Kuik, D.J.; Lips, P.T.A.M.; Plaizier, MA; Rodrigus, PT; Huijsmans, DA; Ribot, JG; Kuijpens, J; Coebergh, J.W.; Teule, G.J.J.

    2003-01-01

    BACKGROUND: Justification for adjuvant radio-iodine (I-131) therapy in differentiated thyroid cancer (DTC) is purely based on retrospective data. This is true for ablative therapy and even more so for high-dosage adjuvant schedules. Randomized trials on the latter application are considered impossib

  15. High-risk endometrial cancer may be benefit from adjuvant radiotherapy plus chemotherapy.

    Science.gov (United States)

    Miao, Jin-Wei; Deng, Xiao-Hong

    2012-12-01

    To present patterns of practice and outcomes in the adjuvant treatment of intermediate- and high-risk endometrial cancer. Retrospective data on 224 women with intermediate-risk and high-risk endometrial cancer from 1999 to 2006 were reviewed. All patients underwent surgical staging. Patterns of adjuvant treatment, consisting of pelvic radiotherapy, chemotherapy, and radiotherapy plus chemotherapy, were assessed. The 3- and 5-year disease-specific survival (DSS) rates were calculated using the Kaplan-Meier method. The difference in 5-year DSS rate was statistically significant between adjuvant group and non-adjuvant group (80.65% vs. 63.80%, P=0.040). In 110 high-risk patients who underwent adjuvant treatment, both 5-year DSS rate and recurrent rate were significantly different in combined radiotherapy and chemotherapy group compared with radiotherapy alone and chemotherapy alone groups (DSS rate, P=0.049; recurrent rate, P=0.047). In 83 intermediate-risk women who underwent adjuvant treatment, there was no significant difference in 5-year DSS rate and recurrence rate among the combined radiotherapy and chemotherapy, radiotherapy alone and chemotherapy alone groups (DSS rate, P=0.776; recurrent rate, P=0.937). Adjuvant radiotherapy plus chemotherapy is associated with a higher 5-year DSS rate and lower recurrence rate compared with radiotherapy alone and chemotherapy alone in high-risk endometrial cancer patients. Patients with intermediate-risk endometrial cancer may be not likely to benefit from adjuvant combined radiotherapy and chemotherapy.

  16. Prognostic role of adjuvant radiotherapy in triple-negative breast cancer : A historical cohort study

    NARCIS (Netherlands)

    Bhoo Pathy, Nirmala; Verkooijen, Helena M.; Wong, Fuh-Yong; Pignol, Jean-Philippe; Kwong, Ava; Tan, Ern-Yu; Taib, Nur Aishah; Nei, Wen-Long; Ho, Gwo-Fuang; Tan, Benita; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har; Dent, Rebecca

    2015-01-01

    The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N=1,138) were include

  17. Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens.

    Science.gov (United States)

    Knudsen, Niels Peter H; Olsen, Anja; Buonsanti, Cecilia; Follmann, Frank; Zhang, Yuan; Coler, Rhea N; Fox, Christopher B; Meinke, Andreas; D'Oro, Ugo; Casini, Daniele; Bonci, Alessandra; Billeskov, Rolf; De Gregorio, Ennio; Rappuoli, Rino; Harandi, Ali M; Andersen, Peter; Agger, Else Marie

    2016-01-21

    The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use.

  18. The importance of adjuvant formulation in the development of a TB vaccine

    Science.gov (United States)

    Baldwin, Susan L.; Bertholet, Sylvie; Reese, Valerie A.; Ching, Lance K.; Reed, Steven G.; Coler, Rhea N.

    2011-01-01

    An effective protein based vaccine for tuberculosis (TB) will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including Alum and the oil-in-water (o/w) based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmith Kline Biologics, GSK) AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both Alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A (MPL), a TLR-4 agonist, with Alum. In this study, we compared two adjuvants, an o/w emulsion (SE), and an o/w emulsion incorporating glucopyranosyl lipid adjuvant (GLA), a synthetic TLR-4 agonist, together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2 biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4+ Th1 cell responses (IFN-γ, TNF-α and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against TB. PMID:22291184

  19. The importance of adjuvant formulation in the development of a tuberculosis vaccine.

    Science.gov (United States)

    Baldwin, Susan L; Bertholet, Sylvie; Reese, Valerie A; Ching, Lance K; Reed, Steven G; Coler, Rhea N

    2012-03-01

    An effective protein-based vaccine for tuberculosis will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including alum and the oil-in-water-based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmithKline Biologics), AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A, a TLR-4 agonist, with alum. In this study, we compared two adjuvants: a stable oil-in-water emulsion (SE) and a stable oil-in-water emulsion incorporating glucopyranosyl lipid adjuvant, a synthetic TLR-4 agonist (GLA-SE), each together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2-biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4(+) Th1 cell responses (IFN-γ, TNF-α, and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against tuberculosis.

  20. Aluminium based adjuvants and their effects on mitochondria and lysosomes of phagocytosing cells.

    Science.gov (United States)

    Ohlsson, Lars; Exley, Christopher; Darabi, Anna; Sandén, Emma; Siesjö, Peter; Eriksson, Håkan

    2013-11-01

    Aluminium oxyhydroxide, Al(OH)3 is one of few compounds approved as an adjuvant in human vaccines. However, the mechanism behind its immune stimulating properties is still poorly understood. In vitro co-culture of an aluminium adjuvant and the human monocytic cell line THP-1 resulted in reduced cell proliferation. Inhibition occurred at concentrations of adjuvant several times lower than would be found at the injection site using a vaccine formulation containing an aluminium adjuvant. Based on evaluation of the mitochondrial membrane potential, THP-1 cells showed no mitochondrial rupture after co-culture with the aluminium adjuvant, instead an increase in mitochondrial activity was seen. The THP-1 cells are phagocytosing cells and after co-culture with the aluminium adjuvant the phagosomal pathway was obstructed. Primary or early phagosomes mature into phagolysosomes with an internal pH of 4.5 - 5 and carry a wide variety of hydrolysing enzymes. Co-culture with the aluminium adjuvant yielded a reduced level of acidic vesicles and cathepsin L activity, a proteolytic enzyme of the phagolysosomes, was almost completely inhibited. THP-1 cells are an appropriate in vitro model in order to investigate the mechanism behind the induction of a phagocytosing antigen presenting cell into an inflammatory cell by aluminium adjuvants. Much information will be gained by investigating the phagosomal pathway and what occurs inside the phagosomes and to elucidate the ultimate fate of phagocytosed aluminium particles. © 2013.

  1. Adjuvanted multi-epitope vaccines protect HLA-A*1101 transgenic mice against Toxoplasma gondii

    Science.gov (United States)

    We created and tested multi-epitope DNA or protein vaccines with TLR4 ligand emulsion adjuvant (gluco glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)) for their ability to protect against Toxoplasma gondii in HLA transgenic mice. Our constructs each included five of our best down selecte...

  2. Prognostic role of adjuvant radiotherapy in triple-negative breast cancer : A historical cohort study

    NARCIS (Netherlands)

    Bhoo Pathy, Nirmala; Verkooijen, Helena M.; Wong, Fuh-Yong; Pignol, Jean-Philippe; Kwong, Ava; Tan, Ern-Yu; Taib, Nur Aishah; Nei, Wen-Long; Ho, Gwo-Fuang; Tan, Benita; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har; Dent, Rebecca

    2015-01-01

    The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N=1,138) were

  3. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial

    NARCIS (Netherlands)

    Suter, Thomas M.; Procter, Marion; van Veldhuisen, Dirk J.; Muscholl, Michael; Bergh, Jonas; Carlomagno, Chiara; Perren, Timothy; Passalacqua, Rodolfo; Bighin, Claudia; Klijn, Jan G. M.; Ageev, Fail T.; Hitre, Erika; Groetz, Juergen; Iwata, Hiroji; Knap, Malgorzata; Gnant, Michael; Muehlbauer, Susanne; Spence, Alison; Gelber, Richard D.; Piccart-Gebhart, Martine J.

    2007-01-01

    Purpose The purpose of this analysis was to investigate trastuzumab- associated cardiac adverse effects in breast cancer patients after completion of ( neo) adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant ( HERA) trial is a three- group, multicenter, o

  4. Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

    NARCIS (Netherlands)

    Perez, O.; Batista-Duharte, A.; Gonzalez, E.; Zayas, C.; Balbao, J.; Cuello, M.; Cabrera, O.; Lastre, M.; Schijns, V.E.J.C.

    2012-01-01

    Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past

  5. Long-term heart function after adjuvant epirubicin chemotherapy for breast cancer

    DEFF Research Database (Denmark)

    Appel, Jon M; Zerahn, Bo; Møller, Susanne

    2012-01-01

    Newer studies raise concern that adjuvant anthracycline treatment for breast cancer (BC) causes long-term heart damage. We aimed to examine whether heart failure or impairment could be demonstrated several years after low-dose epirubicin-based adjuvant treatment....

  6. Current adjuvant treatment modalities for gastric cancer:From history to the future

    Institute of Scientific and Technical Information of China (English)

    Leyla Kilic; Cetin Ordu; Ibrahim Yildiz; Fatma Sen; Serkan Keskin; Rumeysa Ciftci; Kezban Nur Pilanci

    2016-01-01

    The discrepancy between the surgical technique and the type of adjuvant chemotherapy used in clinical trials and patient outcomes in terms of overall survival rates has led to the generation of different adjuvant treatment protocols in distinct parts of the world.The adjuvant treatment recommendation is generally chemoradiotherapy in the United States,perioperative chemotherapy in the United Kingdom and parts of Europe,and chemotherapy in Asia.These options mainly rely on the United States Intergroup-0116,United Kingdom British Medical Research Council Adjuvant Gastric Infusional Chemotherapy,and the Asian Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer trials.However,the benefits were evident for only certain patients,which were not very homogeneous regarding the type of surgery,chemotherapy regimens,and stage of disease.Whether the dissimilarities in survival are attributable to surgical technique or intrinsic biological differences is a subject of debate.Regardless of the extent of surgery,multimodal therapy may offer modest survival advantage at least for diseases with lymph node involvement.Moreover,in the era of individualized treatment for most of the other cancer types,identification of special subgroups comprising those who will derive more or no benefit from adjuvant therapy merits further investigation.The aim of this review is to reveal the historical evolution and future reflections of adjuvant treatment modalities for resected gastric cancer patients.

  7. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway

    DEFF Research Database (Denmark)

    Güven, Esin; Duus, Karen; Laursen, Inga

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes c...

  8. The effect of immediate breast reconstruction on the timing of adjuvant chemotherapy: a systematic review

    NARCIS (Netherlands)

    J. Xavier Harmeling; C.A.E. Kouwenberg (Casimir A. E.); E. Bijlard (Eveline); K.N.J. Burger (Koert N. J.); A. Jager (Agnes); M.A.M. Mureau (Marc)

    2015-01-01

    textabstractAdjuvant chemotherapy is often needed to achieve adequate breast cancer control. The increasing popularity of immediate breast reconstruction (IBR) raises concerns that this procedure may delay the time to adjuvant chemotherapy (TTC), which may negatively impact oncological outcome. The

  9. Antibody-antigen-adjuvant conjugates enable co-delivery of antigen and adjuvant to dendritic cells in cis but only have partial targeting specificity.

    Directory of Open Access Journals (Sweden)

    Martin Kreutz

    Full Text Available Antibody-antigen conjugates, which promote antigen-presentation by dendritic cells (DC by means of targeted delivery of antigen to particular DC subsets, represent a powerful vaccination approach. To ensure immunity rather than tolerance induction the co-administration of a suitable adjuvant is paramount. However, co-administration of unlinked adjuvant cannot ensure that all cells targeted by the antibody conjugates are appropriately activated. Furthermore, antigen-presenting cells (APC that do not present the desired antigen are equally strongly activated and could prime undesired responses against self-antigens. We, therefore, were interested in exploring targeted co-delivery of antigen and adjuvant in cis in form of antibody-antigen-adjuvant conjugates for the induction of anti-tumour immunity. In this study, we report on the assembly and characterization of conjugates consisting of DEC205-specific antibody, the model antigen ovalbumin (OVA and CpG oligodeoxynucleotides (ODN. We show that such conjugates are more potent at inducing cytotoxic T lymphocyte (CTL responses than control conjugates mixed with soluble CpG. However, our study also reveals that the nucleic acid moiety of such antibody-antigen-adjuvant conjugates alters their binding and uptake and allows delivery of the antigen and the adjuvant to cells partially independently of DEC205. Nevertheless, antibody-antigen-adjuvant conjugates are superior to antibody-free antigen-adjuvant conjugates in priming CTL responses and efficiently induce anti-tumour immunity in the murine B16 pseudo-metastasis model. A better understanding of the role of the antibody moiety is required to inform future conjugate vaccination strategies for efficient induction of anti-tumour responses.

  10. Quality of adjuvant CMF chemotherapy for node-positive primary breast cancer : a population-based study

    NARCIS (Netherlands)

    Schaapveld, M; de Vries, EGE; van der Graaf, WTA; Otter, R; Willemse, PHB

    2004-01-01

    Purpose: Adjuvant 'classical' oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) has long been the mainstay of adjuvant chemotherapy for premenopausal breast cancer patients. The Comprehensive Cancer Center North Netherlands (CCCN) breast cancer working group performed a retrospective

  11. Narcolepsy, 2009 A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants.

    Science.gov (United States)

    Ahmed, S Sohail; Schur, Peter H; MacDonald, Noni E; Steinman, Lawrence

    2014-05-01

    The vaccine safety surveillance system effectively detected a very rare adverse event, narcolepsy, in subjects receiving AS03-adjuvanted A(H1N1) pandemic vaccine made using the European inactivation/purification protocol. The reports of increased cases of narcolepsy in non-vaccinated subjects infected with wild A(H1N1) pandemic influenza virus suggest a role for the viral antigen(s) in disease development. However, additional investigations are needed to better understand what factor(s) in wild influenza infection trigger(s) narcolepsy in susceptible hosts. An estimated 31 million doses of European AS03-adjuvanted A(H1N1) pandemic vaccine were used in more than 47 countries. The Canadian AS03-adjuvanted A(H1N1) pandemic vaccine was used with high coverage in Canada where an estimated 12 million doses were administered. As no similar narcolepsy association has been reported to date with the AS03-adjuvanted A(H1N1) pandemic vaccine made using the Canadian inactivation/purification protocol, this suggests that the AS03 adjuvant alone may not be responsible for the narcolepsy association. To date, no narcolepsy association has been reported with the MF59®-adjuvanted A(H1N1) pandemic vaccine. This review article provides a brief background on narcolepsy, outlines the different types of vaccine preparations including the ones for influenza, reviews the accumulated evidence for the safety of adjuvants, and explores the association between autoimmune diseases and natural infections. It concludes by assimilating the historical observations and recent clinical studies to formulate a feasible hypothesis on why vaccine-associated narcolepsy may not be solely linked to the AS03 adjuvant but more likely be linked to how the specific influenza antigen component of the European AS03-adjuvanted pandemic vaccine was prepared. Careful and long-term epidemiological studies of subjects who developed narcolepsy in association with AS03-adjuvanted A(H1N1) pandemic vaccine prepared with

  12. An observer-blind, randomized, multi-center trial assessing long-term safety and immunogenicity of AS03-adjuvanted or unadjuvanted H1N1/2009 influenza vaccines in children 10-17 years of age.

    Science.gov (United States)

    Poder, Airi; Simurka, Pavol; Li, Ping; Roy-Ghanta, Sumita; Vaughn, David

    2014-02-19

    Vaccination is an effective strategy to prevent influenza. This observer-blind, randomized study in children 10-17 years of age assessed whether the hemagglutination inhibition (HI) antibody responses elicited by H1N1/2009 vaccines adjuvanted with AS03 (an adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion) or without adjuvant, met the European regulatory immunogenicity criteria at Days 21 and 182. Three hundred and ten healthy children were randomized (3:3:3:5) to receive one dose of 3.75 μg hemagglutinin (HA) AS03A-adjuvanted vaccine, one or two doses of 1.9 μg HA AS03B-adjuvanted vaccine, or one dose of 15 μg HA pandemic vaccine. All children received a booster dose of the allocated vaccine at Day 182. Serum samples were tested for HI antibody response at Days 21, 42, 182 and 189. All vaccination regimens elicited HI antibody responses that met the European regulatory criteria at Days 21 and 42. HI antibody responses fulfilling European regulatory criteria were still observed six months after the first vaccine dose in all study vaccines groups. Two doses of 1.9 μg HA AS03B-adjuvanted vaccine elicited the strongest HI antibody response throughout the study. The non-adjuvanted 15 μg HA vaccine elicited a lower HI antibody response than the AS03-adjuvanted vaccines. At Day 189, the European regulatory criteria were met for all vaccines with baseline HI antibody titers as reference. An anamnestic response for all vaccines was suggested at Day 189, based on the rapid increase in HI antibody geometric mean titers (1.5-2.5-fold increase). Injection site reactogenicity was higher following the AS03-adjuvanted vaccines compared with the non-adjuvanted vaccine. No safety concerns were identified for any study vaccine. All study vaccines elicited HI antibody responses that persisted at purported protective levels through six months after vaccination and fulfilled the European regulatory criteria. Copyright © 2013 The Authors. Published

  13. Preliminary results of capecitabine metronomic chemotherapy in operable triple-negative breast cancer after standard adjuvant therapy – A single-arm phase II study

    Directory of Open Access Journals (Sweden)

    Hanan Shawky

    2014-12-01

    Conclusion: One year of capecitabine metronomic therapy preceded by standard adjuvant chemotherapy, is active and well-tolerated in TNBC patients previously treated with standard adjuvant chemotherapy.

  14. A synthetic adjuvant to enhance and expand immune responses to influenza vaccines.

    Science.gov (United States)

    Coler, Rhea N; Baldwin, Susan L; Shaverdian, Narek; Bertholet, Sylvie; Reed, Steven J; Raman, Vanitha S; Lu, Xiuhua; DeVos, Joshua; Hancock, Kathy; Katz, Jacqueline M; Vedvick, Thomas S; Duthie, Malcolm S; Clegg, Christopher H; Van Hoeven, Neal; Reed, Steven G

    2010-10-27

    Safe, effective adjuvants that enhance vaccine potency, including induction of neutralizing Abs against a broad range of variant strains, is an important strategy for the development of seasonal influenza vaccines which can provide optimal protection, even during seasons when available vaccines are not well matched to circulating viruses. We investigated the safety and ability of Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE), a synthetic Toll-like receptor (TLR)4 agonist formulation, to adjuvant Fluzone® in mice and non-human primates. The GLA-SE adjuvanted Fluzone vaccine caused no adverse reactions, increased the induction of T helper type 1 (T(H)1)-biased cytokines such as IFNγ, TNF and IL-2, and broadened serological responses against drifted A/H1N1 and A/H3N2 influenza variants. These results suggest that synthetic TLR4 adjuvants can enhance the magnitude and quality of protective immunity induced by influenza vaccines.

  15. A synthetic adjuvant to enhance and expand immune responses to influenza vaccines.

    Directory of Open Access Journals (Sweden)

    Rhea N Coler

    Full Text Available Safe, effective adjuvants that enhance vaccine potency, including induction of neutralizing Abs against a broad range of variant strains, is an important strategy for the development of seasonal influenza vaccines which can provide optimal protection, even during seasons when available vaccines are not well matched to circulating viruses. We investigated the safety and ability of Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE, a synthetic Toll-like receptor (TLR4 agonist formulation, to adjuvant Fluzone® in mice and non-human primates. The GLA-SE adjuvanted Fluzone vaccine caused no adverse reactions, increased the induction of T helper type 1 (T(H1-biased cytokines such as IFNγ, TNF and IL-2, and broadened serological responses against drifted A/H1N1 and A/H3N2 influenza variants. These results suggest that synthetic TLR4 adjuvants can enhance the magnitude and quality of protective immunity induced by influenza vaccines.

  16. Saponins from the Spanish saffron Crocus sativus are efficient adjuvants for protein-based vaccines.

    Science.gov (United States)

    Castro-Díaz, Nathaly; Salaun, Bruno; Perret, Rachel; Sierro, Sophie; Romero, Jackeline F; Fernández, Jose-Antonio; Rubio-Moraga, Angela; Romero, Pedro

    2012-01-05

    Protein and peptide-based vaccines provide rigorously formulated antigens. However, these purified products are only weakly immunogenic by themselves and therefore require the addition of immunostimulatory components or adjuvants in the vaccine formulation. Various compounds derived from pathogens, minerals or plants, possess pro-inflammatory properties which allow them to act as adjuvants and contribute to the induction of an effective immune response. The results presented here demonstrate the adjuvant properties of novel saponins derived from the Spanish saffron Crocus sativus. In vivo immunization studies and tumor protection experiments unambiguously establish the value of saffron saponins as candidate adjuvants. These saponins were indeed able to increase both humoral and cellular immune responses to protein-based vaccines, ultimately providing a significant degree of protection against tumor challenge when administered in combination with a tumor antigen. This preclinical study provides an in depth immunological characterization of a new saponin as a vaccine adjuvant, and encourages its further development for use in vaccine formulations.

  17. The Effect of Adjuvants on Penetration of beta-cypermethrin Through the Epidermis of Cabbage Leaf

    Institute of Scientific and Technical Information of China (English)

    WANG Yi; ZHANG Li-ta; ZHENG Fei-neng; CHEN Fu-liang; LIANG Wen-ping

    2002-01-01

    The effects of three types of adjuvant (mineral oil, higher aliphatic acid and nonionic surfactant) on the penetration of beta-cypermethrin through the cabbage leaf surface were studied. The results showed that the penetration was positively correlated with both the concentration of adjuvant and the time after application, in a given range of treatment. A synergistic effect of two types of adjuvant on the penetration was found. Some physical properties of emulsions were determined. The change of the structures of the cabbage leaf surface by these adjuvants was observed from photomicrographs. The mechanism concerned with the effect of these adjuvants on the penetration of beta-cypermethrin through the cabbage leaf surface was tentatively discussed.

  18. Pseudo-Mannosylated DC-SIGN Ligands as Potential Adjuvants for HIV Vaccines

    Directory of Open Access Journals (Sweden)

    Angela Berzi

    2014-01-01

    Full Text Available The development of new and effective adjuvants may play a fundamental role in improving HIV vaccine efficacy. New classes of vaccine adjuvants activate innate immunity receptors, notably toll like receptors (TLRs. Adjuvants targeting the C-Type lectin receptor DC-SIGN may be alternative or complementary to adjuvants based on TRL activation. Herein we evaluate the ability of the glycomimetic DC-SIGN ligand Polyman 19 (PM 19 to modulate innate immune responses. Results showed that PM 19 alone, or in combination with TLR agonists, induces the expression of cytokines, β chemokines and co-stimulatory molecules that may, in turn, modulate adaptive immunity and exert anti-viral effects. These results indicate that the suitability of this compound as a vaccine adjuvant should be further evaluated.

  19. Adjuvant chemoradiotherapy for adenocarcinoma of the stomach. A new progress?; Chimioradiotherapie dans le traitement adjuvant des adenocarcinomes gastriques: reelle avancee?

    Energy Technology Data Exchange (ETDEWEB)

    Mineur, L. [Institut Sainte Catherine, 84 - Avignon (France); Lacaine, F. [Hopital Tenon, 75 - Paris (France); Ychou, M. [Centre Regional de Lutte Contre le Cancer Val d' Aurelle, Service d' Oncologie, 34 - Montpellier (France); Bosset, J.F. [Centre Hospitalier Universitaire, Service de Radiotherapie, 25 - Besancon (France); Daban, A. [Centre Hospitalier Universitaire, Service de Radiotherapie, 86 - Poitiers (France)

    2002-11-01

    Frequency of local and distant failures after gastrectomy has led to extended lymph nodes dissection to obtain a better locoregional control. However, five year survival rates were not significantly different between patients undergoing D2 and D1 lymphadenectomy, and higher morbidity and post operative deaths were reported in large randomized trials (respectively 25% vs 48% and 4 vs 13%). Additionally, several met-analysis failed to demonstrate a significant survival advantage with adjuvant chemotherapy. The results of the first trial demonstrating one advantage to adjuvant post-operative chemoradiotherapy should modify the standard care. Disease free and overall survival after surgery alone and after surgery and concurrent chemoradiotherapy were respectively 31% vs 48% and 41% vs 50%. The inter-group trial demonstrate that better local control improve survival if radiation fields include stamps, tumour bed, proximal nodal chains and nodes corresponding to D2 extended lymph nodes dissection. Treatment was feasible with few severe toxic effects (1%). Of the 281 patients, 17% stopped treatment because toxic effects. Technical modalities of radiotherapy and post-operative nutrition support which are critical points of interest for this treatment, are also discussed. (authors)

  20. Pilot scale production of the vaccine adjuvant Proteoliposome derived Cochleates (AFCo1) from Neisseria meningitidis serogroup B

    OpenAIRE

    Zayas, Caridad; González, Domingo; Acevedo, Reinaldo; del Campo, Judith; Lastre, Miriam; González, Elizabeth; Romeu, Belkis; Cuello, Maribel; Balboa, Julio; Cabrera, Osmir; Guilherme, Luisa; Pérez, Oliver

    2013-01-01

    The use of new adjuvants in vaccine formulations is a subject of current research. Only few parenteral adjuvants have been licensed. We have developed a mucosal and parenteral adjuvant known as AFCo1 (Adjuvant Finlay Cochleate 1, derived from proteoliposomes of N. meningitidis B) using a dialysis procedure to produce them on lab scale. The immunogenicity of the AFCo1 produced by dialysis has been already evaluated, but it was necessary to demonstrate the feasibility of a larger-scale manufact...

  1. Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice

    Science.gov (United States)

    Russell, Ryan F.; McDonald, Jacqueline U.; Lambert, Laura

    2016-01-01

    ABSTRACT Neonates are at a high risk of infection, but vaccines are less effective in this age group; tailored adjuvants could potentially improve vaccine efficacy. Increased understanding about danger sensing by the innate immune system has led to the rational design of novel adjuvants. But differences in the neonatal innate immune response, for example, to Toll-like receptor (TLR) agonists, can reduce the efficacy of these adjuvants in early life. We therefore targeted alternative danger-sensing pathways, focusing on a range of compounds described as inflammasome agonists, including nanoscale silicon dioxide (NanoSiO2), calcium pyrophosphate dihydrate (CPPD) crystals, and muramyl tripeptide (M-Tri-DAP), for their ability to act as adjuvants. In vitro, these compounds induced an interleukin 1-beta (IL-1β) response in the macrophage-like cell line THP1. In vivo, adult CB6F1 female mice were immunized intramuscularly with H1N1 influenza vaccine antigens in combination with NanoSiO2, CPPD, or M-Tri-DAP and subsequently challenged with H1N1 influenza virus (A/England/195/2009). The adjuvants boosted anti-hemagglutinin IgG and IgA antibody levels. Both adult and neonatal animals that received NanoSiO2-adjuvanted vaccines lost significantly less weight and recovered earlier after infection than control animals treated with antigen alone. Administration of the adjuvants led to an influx of activated inflammatory cells into the muscle but to little systemic inflammation measured by serum cytokine levels. Blocking IL-1β or caspase 1 in vivo had little effect on NanoSiO2 adjuvant function, suggesting that it may work through pathways other than the inflammasome. Here we demonstrate that NanoSiO2 can act as an adjuvant and is effective in early life. IMPORTANCE Vaccines can fail to protect the most at-risk populations, including the very young, the elderly, and the immunocompromised. There is a gap in neonatal immunity between the waning of maternal protection and routine

  2. Incorporation of a synthetic mycobacterial monomycoloyl glycerol analogue stabilizes dimethyldioctadecylammonium liposomes and potentiates their adjuvant effect in vivo.

    Science.gov (United States)

    Nordly, Pernille; Korsholm, Karen Smith; Pedersen, Esra Alici; Khilji, Tayba Sajid; Franzyk, Henrik; Jorgensen, Lene; Nielsen, Hanne Mørck; Agger, Else Marie; Foged, Camilla

    2011-01-01

    The combination of delivery systems such as cationic liposomes and immunopotentiating molecules is a promising approach for the rational design of vaccine adjuvants. In this study, a synthetic analogue of the mycobacterial lipid monomycoloyl glycerol (MMG), referred to as MMG-1, was synthesized and combined with the cationic surfactant dimethyldioctadecylammonium (DDA). The purpose of the study was to provide a thorough pharmaceutical characterization of the resulting DDA/MMG-1 binary system and to evaluate how incorporation of MMG-1 affected the adjuvant activity of DDA liposomes. Thermal analyses demonstrated that MMG-1 was incorporated into the DDA lipid bilayers, and cryo-transmission electron microscopy (TEM) confirmed that liposomes were formed. The particles had a polydisperse size distribution and an average diameter of approximately 400 nm. Evaluation of the colloidal stability indicated that at least 18 mol% MMG-1 was required to stabilize the DDA liposomes as the average particle size remained constant during storage for 6 months. The improved colloidal stability is most likely caused by increased hydration of the lipid bilayer. This was demonstrated by studying Langmuir-Blodgett monolayers of DDA and MMG-1 which revealed an increased surface pressure in the presence of high concentrations of MMG-1 when the DDA/MMG-1 monolayers were fully compressed, indicating an increased interaction with water due to enhanced hydration of the lipid head groups. Finally, immunization of mice with the tuberculosis fusion antigen Ag85B-ESAT-6 and DDA/MMG-1 liposomes induced a strong cell-mediated immune response characterized by a mixed Th1/Th17 profile and secretion of IgG1 and IgG2c antibodies. The Th1/Th17-biased immunostimulatory effect was increased in an MMG-1 concentration-dependent manner with maximal observed effect at 31 mol% MMG-1. Thus, incorporation of 31 mol% MMG-1 into DDA liposomes results in an adjuvant system with favorable physical as well as

  3. The role of postoperative adjuvant radiotherapy in resected esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Chang Geol; Kim, Choong Bae; Chung, Kyung Young; Lee, Doo Yun; Seong Jin Sil; Kim, Gwi Eon; Suh, Chang Ok [Yonsei University College of Medicine, Yonsei Cancer Center, Seoul (Korea, Republic of)

    2002-12-15

    A retrospective study was performed to evaluate whether postoperative adjuvant radiotherapy can improve survival and decrease recurrence as compared with surgery alone in resected esophageal cancer. From Jan. 1985 to Dec. 1993, among 94 esophageal cancer patients treated with surgery, fifty-one patients were included in this study. Transthoracic esophagectomy was performed in 35 patients and transhiatal esophagectomy in 16. Postoperative adjuvant radiotherapy was performed 4 weeks after surgery in 26 among 38 patients in stage II and III. A total dose of 30 {approx} 60 Gy in 1.8 Gy daily fraction, median 54 Gy over 6 weeks, was delivered in the mediastinum + both supraclavicular lymph nodes or celiac lymph nodes according to the tumor location. Forty-seven patients (92%) had squamous histology. The median follow-up period was 38 months. The overall 2-year and 5-year survival and median survival were 56.4%, 36.8% and 45 months. Two-year and 5-year survival and median survival by stage were 92%, 60.3% for stage I, 63%, 42% and 51 months for stage II and 34%, 23% and 19 months for stage III ({rho} = 0.04). For stage II and III patients, 5-year survival and median survival were 22.8%. 45 months for the surgery alone group and 37.8%, 22 months for the postoperative RT group ({rho} = 0.89). For stage III patients, 2-year survival and median survival were 0%, 11 months for the surgery alone group and 36.5%, 20 months for the postoperative RT group ({rho} = 0.14). Local and distant failure rates for stage II and III were 50%, 16% for the surgery alone and 39%, 31% for the postoperative RT group. For N1 patients, local failure rate was 71% for the surgery alone group and 37% for the postoperative RT group ({rho} = 0.19). Among 10 local failures in the postoperative RT group, in-field failures were 2, marginal failures 1, out-field 5 and anastomotic site failures 2. There were no statistically significant differences in either the overall survival or the patterns of failure

  4. CCR5 small interfering RNA ameliorated joint inflammation in rats with adjuvant-induced arthritis.

    Science.gov (United States)

    Duan, Hongmei; Yang, Pingting; Fang, Fang; Ding, Shuang; Xiao, Weiguo

    2014-12-01

    Rheumatoid arthritis (RA) is a systemic inflammatory disease. C-C chemokine receptor type 5 (CCR5) is found in inflamed synovium of RA patients and is necessary for formation of RA. We aimed to check whether delivery of CCR5-specific small interfering RNA (siRNA) via electroporation suppresses local inflammation in arthritis rats. Vectors encoding siRNA that target CCR5 or negative control siRNA were constructed for gene silencing and the silencing effects of suppressing CCR5 expression in synovium examined by western blot. The vector with strongest effect was delivered into the knee joint of adjuvant-induced arthritis (AIA) rats by the in vivo electroporation method 7, 10, 13, and 16 days after immunization with Complete Freund's adjuvant. During an observation of 28 days, behavior, paw swelling, arthritis and histopathologic scoring were estimated. The expression level of CCR5 in synovium was evaluated by western blot and real-time PCR. Anti-CCR5 D1 siRNA was effectively inhibited CCR5 expression in vitro. Moreover, delivery of the siRNA into inflammatory joint also suppressed the expression of CCR5 in vivo and markedly suppressed paw swelling and inflammation. Local electroporation of anti-CCR5 siRNA into the left inflamed joints could achieve the silencing of CCR5 gene and alleviate local inflammation just in the knee joint injected with siRNA other than the opposite joint. Inhibition of CCR5 expression may provide a potential for treatment of RA.

  5. Evidence-based adjuvant therapy for gliomas: Current concepts and newer developments

    Directory of Open Access Journals (Sweden)

    M K Khan

    2009-01-01

    Full Text Available The incidence of gliomas is increasing worldwide, including India. Of the 18,820 new cases of primary central nervous system (CNS tumors diagnosed annually in the United States, gliomas account for over 60% with 30-40% of them being glioblastoma multiforme (GBM, 10% being anaplastic astrocytoma (AA, and 10% being low grade gliomas (LGGs. This is in contrast to one study from West Bengal, India, in which only 7.9% of the brain tumors were GBMs, while 46.8% were astrocytomas. Of all adult primary CNS tumors, GBM is the most common and the most malignant with about 7,000 to 8,000 new cases annually in the United States. Given poor outcomes, a number of treatment approaches have been investigated. Common to these approaches is the use of adjuvant radiation therapy, even as surgery alone, with or without chemotherapy, may be the mainstay for some lower grade and low-risk gliomas. Today, treatment typically involves external beam radiation, with concurrent and adjuvant chemotherapy for more aggressive histologies. Although gliomas are relatively uncommon, active research is ongoing. Results of landmark trials along with some of the recently published trials are presented. These trials and management strategies as well as evolving concepts are found by reviewing over 200 articles in the National Library Medical (NLM database, PubMed, more than 60 of which are refrenced. Specifically, the database is searched using the following keywords, with various combinations: glioma, low-grade, anaplastic, astrocytoma, oligodendroglioma, oligoastrocytoma, glioblastoma multiforme, chemotherapy, radiation, new concepts, phase III, MGMT, CDX-110 (Celldex, temozolomide, 1p/19q deletion, and bevacizumab.

  6. Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: a comparative metabolomic study.

    Directory of Open Access Journals (Sweden)

    Norbert W Lutz

    Full Text Available Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE and adjuvant arthritis (AA in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA and spinal-cord homogenate (SC-H, whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group. Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N-acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE or extra-cerebral (AA inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and

  7. Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

    Science.gov (United States)

    Rios, Adan; Hsu, Sigmund H.; Blanco, Angel; Buryanek, Jamie; Day, Arthur L.; McGuire, Mary F.; Brown, Robert E.

    2016-01-01

    Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID:27489862

  8. Adjusted Particle Size Eliminates the Need of Linkage of Antigen and Adjuvants for Appropriated T Cell Responses in Virus-Like Particle-Based Vaccines

    Science.gov (United States)

    Gomes, Ariane C.; Flace, Anna; Saudan, Philippe; Zabel, Franziska; Cabral-Miranda, Gustavo; Turabi, Aadil El; Manolova, Vania; Bachmann, Martin F.

    2017-01-01

    Since the discovery of the first virus-like particle (VLP) derived from hepatitis B virus in 1980 (1), the field has expanded substantially. Besides successful use of VLPs as safe autologous virus-targeting vaccines, the powerful immunogenicity of VLPs has been also harnessed to generate immune response against heterologous and even self-antigens (2–4). Linking adjuvants to VLPs displaying heterologous antigen ensures simultaneous delivery of all vaccine components to the same antigen-presenting cells. As a consequence, antigen-presenting cells, such as dendritic cells, will process and present the antigen displayed on VLPs while receiving costimulatory signals by the VLP-incorporated adjuvant. Similarly, antigen-specific B cells recognizing the antigen linked to the VLP are simultaneously exposed to the adjuvant. Here, we demonstrate in mice that physical association of antigen, carrier (VLPs), and adjuvant is more critical for B than T cell responses. As a model system, we used the E7 protein from human papilloma virus, which spontaneously forms oligomers with molecular weight ranging from 158 kDa to 10 MDa at an average size of 50 nm. E7 oligomers were either chemically linked or simply mixed with VLPs loaded with DNA rich in non-methylated CG motifs (CpGs), a ligand for toll-like receptor 9. E7-specific IgG responses were strongly enhanced if the antigen was linked to the VLPs. In contrast, both CD4+ and CD8+ T cell responses as well as T cell-mediated protection against tumor growth were comparable for linked and mixed antigen formulations. Therefore, our data show that B cell but not T cell responses require antigen-linkage to the carrier and adjuvant for optimal vaccination outcome. PMID:28321220

  9. Comparison between a conventional subunit vaccine and the MF59-adjuvanted subunit influenza vaccine in the elderly: an evaluation of the safety, tolerability and immunogenicity.

    Science.gov (United States)

    Sindoni, D; La Fauci, V; Squeri, R; Cannavò, G; Bacilieri, S; Panatto, D; Gasparini, R; Amicizia, D

    2009-06-01

    The objective of this study was to evaluate and compare the safety, tolerability and immunogenicity for two seasonal influenza subunit vaccines, one with MF59 adjuvant (Fluad) and one without an adjuvant (Agrippal). A total of 195 subjects aged > or = 65 years were enrolled to receive one dose of vaccine intramuscularly, 96 were vaccinated with Fluad, 99 received Agrippal. Blood samples were taken from all subjects in order to assess their antibody titre by the haemagglutination inhibition assay (HI), before (Time 0) and after (Time 1: 28 +/- 7 days) vaccination, against the A/H3N2 (A/Moscow/10/99), A/H1N1 (A/New Caledonia/20/99) and B/Shandong/7/97 antigens contained in the influenza vaccine in the 2002/2003 influenza season for the northern hemisphere. A good humoral antibody response was detected for both vaccines, meeting all the criteria of EMEA. The number of subjects in whom > or = 4-fold increase in antibody titre was recorded, in comparison with the pre-vaccination value, proved to be lower in the group vaccinated with AgrippaPl than in those vaccinated with the adjuvated preparation. Fluad" exhibited better immunogenicity than Agrippal. This difference was probably linked to the potentiated immune stimulation exerted by the adjuvant molecules. These results take on a particular importance if we consider that the immune system is weaker in the elderly; the administration of an adjuvated vaccine in such subjects is clearly preferable in that it provides greater and more prolonged protection. Both vaccines were generally well tolerated; no severe adverse events occurred in any of the subjects vaccinated, confirming the excellent safety profile of Fluad and Agrippal.

  10. Uncaria tomentosa—Adjuvant Treatment for Breast Cancer: Clinical Trial

    Directory of Open Access Journals (Sweden)

    Maria do Carmo Santos Araújo

    2012-01-01

    Full Text Available Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma—Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide, were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.

  11. Uncaria tomentosa—Adjuvant Treatment for Breast Cancer: Clinical Trial

    Science.gov (United States)

    Santos Araújo, Maria do Carmo; Farias, Iria Luiza; Gutierres, Jessie; Dalmora, Sergio L.; Flores, Nélia; Farias, Julia; de Cruz, Ivana; Chiesa, Juarez; Morsch, Vera Maria; Chitolina Schetinger, Maria Rosa

    2012-01-01

    Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma—Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer. PMID:22811748

  12. Uncaria tomentosa-Adjuvant Treatment for Breast Cancer: Clinical Trial.

    Science.gov (United States)

    Santos Araújo, Maria do Carmo; Farias, Iria Luiza; Gutierres, Jessie; Dalmora, Sergio L; Flores, Nélia; Farias, Julia; de Cruz, Ivana; Chiesa, Juarez; Morsch, Vera Maria; Chitolina Schetinger, Maria Rosa

    2012-01-01

    Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma-Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.

  13. Hypofractionated Adjuvant Whole Breast Radiotherapy: Progress and Prospects

    Energy Technology Data Exchange (ETDEWEB)

    Yarnold, John (Section of Radiotherapy, Inst. of Cancer Research, Royal Marsden Hospital, Sutton (United Kingdom)), E-mail: john.yarnold@icr.ac.uk; Haviland, Joanne (Clinical Trials and Statistics Unit (ICR-CTSU), Section of Clinical Trials, Inst. of Cancer Research, Sutton (United Kingdom))

    2010-11-15

    Published results of randomised trials involving >7000 women confirm the safety and efficacy of hypofractionated schedules of adjuvant radiotherapy for women with early breast cancer using fraction sizes between 2 and 3 Gy assuming appropriate downward adjustments to total dose. Unnecessary concerns relating to heart tolerance, suboptimal dose distribution and duration of follow up need not discourage the routine adoption of 15- or 16-fraction schedules in women treated by breast conservation surgery for early breast cancer. Regardless of fractionation regimen, dose escalation to the index quadrant in high risk subgroups will result in a greater relative increase in late adverse effects than tumour control, a therapeutic disadvantage that can only be overcome by exploiting a marked dose-volume effect. A 15-fraction schedule of whole breast radiotherapy is unlikely to represent the lower limits of hypofractionation, and the preliminary results of a 5-fraction regimen are encouraging

  14. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

    DEFF Research Database (Denmark)

    Eggermont, Alexander M M; Chiarion-Sileni, Vanna; Grob, Jean-Jacques;

    2016-01-01

    Background On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had...... undergone complete resection of stage III melanoma. Methods After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months...... patients (1.1%) died owing to immune-related adverse events. Conclusions As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo...

  15. Cardiotoxicity in Asymptomatic Patients Receiving Adjuvant 5-fluorouracil

    DEFF Research Database (Denmark)

    Nielsen, Karin; Polk, Anne; Nielsen, Dorte Lisbet

    2014-01-01

    Evolving evidence of cardiotoxicity in cancer patients treated with 5-fluorouracil (5-FU) has been reported. We report two different clinical manifestations of asymptomatic 5-FU-associated cardiotoxicity in patients operated for colorectal cancer and treated with adjuvant chemotherapy of 5-FU...... (bolus-injection and continuous infusion for 46 hours), folinic acid and oxaliplatin (FOLFOX). For a research study evaluating cardiac events during 5-FU treatment, Holter monitoring, electrocardiogram (ECG) and echocardiography were done and cardiac markers monitored before and during the first...... and hyperlipidemia as well as an incidental finding of negative T-waves in electrocardiogram years before 5-FU treatment. No subjective cardiac symptoms were described during infusion, but approximately 12 hours after infusion she suffered from cardiac arrest but was revived. Subsequent analysis of the Holter...

  16. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

    DEFF Research Database (Denmark)

    Eggermont, Alexander M M; Chiarion-Sileni, Vanna; Grob, Jean-Jacques

    2016-01-01

    Background On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had...... undergone complete resection of stage III melanoma. Methods After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months...... patients (1.1%) died owing to immune-related adverse events. Conclusions As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo...

  17. Lactic acid bacteria as adjuvants for sublingual allergy vaccines.

    Science.gov (United States)

    Van Overtvelt, Laurence; Moussu, Helene; Horiot, Stéphane; Samson, Sandrine; Lombardi, Vincent; Mascarell, Laurent; van de Moer, Ariane; Bourdet-Sicard, Raphaëlle; Moingeon, Philippe

    2010-04-01

    We compared immunomodulatory properties of 11 strains of lactic acid bacteria as well as their capacity to enhance sublingual immunotherapy efficacy in a murine asthma model. Two types of bacterial strains were identified, including: (i) potent inducers of IL-12p70 and IL-10 in dendritic cells, supporting IFN-gamma and IL-10 production in CD4+ T cells such as Lactobacillus helveticus; (ii) pure Th1 inducers such as L. casei. Sublingual administration in ovalbumin-sensitized mice of L. helveticus, but not L. casei, reduced airways hyperresponsiveness, bronchial inflammation and proliferation of specific T cells in cervical lymph nodes. Thus, probiotics acting as a Th1/possibly Treg, but not Th1 adjuvant, potentiate tolerance induction via the sublingual route.

  18. Vaccination of mice for research purpose: alum is as effective as and safer than complete Freund adjuvant

    Directory of Open Access Journals (Sweden)

    L. Punzi

    2012-12-01

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disease involving many organ systems. Glomerulonephritis (GLN is one of the major causes of morbidity and mortality in SLE. It has recently been demonstrated that adjuvants of vaccines could cause the so called ASIA syndrome. The study aimed to assess the effects of Complete Freund’s Adjuvant (CFA vs alum injections in NZB/NZWF1 mice. Mice (n=10 each group were injected with a total volume of 200 μL of: CFA in PBS (group 1, alum in PBS (group 2, PBS (group 3 as controls, PTX3/CFA (group 4, PTX3/alum (group 5, 3 times, 3 weeks apart /given in each injection, three weeks apart from ten weeks of age. Urine samples were collected weekly to evaluate proteinuria. Blood samples were collected before every injection, at 21 weeks of age, and at death to evaluate levels of anti-PTX3 and anti-dsDNA. Proteinuria free survival and survival rates were analyzed by the Kaplan-Meier method using Mantel-Cox’s test for comparisons. CFA-treated mice developed both anti-dsDNA antibodies and proteinuria earlier and at higher levels than alumtreated and PBS-injected mice, starting from 13 weeks of age. Proteinuria free survival rates (proteinuria ≥300 mg/dL and survival rates were lower in CFA-treated mice than those treated with alum or injected with PBS (P<0.001 for all. No difference was observed between the alum-treated group and PBS-injected mice. Notably, groups 4 and 5, immunized with PTX3, developed anti-PTX3 antibodies and no significant difference was observed. Alum seems to be as effective as and safer than CFA as adjuvant, since it did not affect disease progression in immunized NZB/NZWF1 mice.

  19. Eccentric exercise as an adjuvant to influenza vaccination in humans.

    Science.gov (United States)

    Edwards, Kate M; Burns, Victoria E; Allen, Louise M; McPhee, Jamie S; Bosch, Jos A; Carroll, Douglas; Drayson, Mark; Ring, Christopher

    2007-02-01

    The immune response to vaccination in animals can be enhanced by exposure to acute stress at the time of vaccination. The efficacy of this adjuvant strategy for vaccination in humans requires investigation. The current study employed a randomised controlled trial design to examine the effects of eccentric exercise prior to influenza vaccination on the antibody and cell-mediated responses. Sixty young healthy adults (29 men, 31 women) performed eccentric contractions of the deltoid and biceps brachii muscles of the non-dominant arm (exercise group) or rested quietly (control group), and were vaccinated 6h later in the non-dominant arm. Change in arm circumference and pain were measured to assess the physiological response to exercise. Antibody titres were measured pre-vaccination and at 6- and 20-week follow-ups. Interferon-gamma in response to in vitro stimulation by the whole vaccine, an index of the cell-mediated response, was measured 8 weeks post-vaccination. Interferon-gamma responses were enhanced by exercise in men, whereas antibody titres were enhanced by eccentric exercise in women but not in men. Men showed greater increase in arm circumference after eccentric exercise than women but there was no difference in reported pain. The interferon-gamma response was positively associated with the percentage increase in arm circumference among the exercise group. Eccentric exercise exerted differential effects on the response to vaccination in men and women, with enhancement of the antibody response in women, but enhancement of the cell-mediated response in men. Eccentric exercise of the muscle at the site of vaccine administration should be explored further as a possible behavioural adjuvant to vaccination.

  20. Caffeine as an opioid analgesic adjuvant in fibromyalgia.

    Science.gov (United States)

    Scott, J Ryan; Hassett, Afton L; Brummett, Chad M; Harris, Richard E; Clauw, Daniel J; Harte, Steven E

    2017-01-01

    Caffeine's properties as an analgesic adjuvant with nonsteroidal anti-inflammatory drugs/acetaminophen are well documented. However, little clinical research has explored caffeine's effects on opioid analgesia. This study assessed the effects of caffeine consumption on pain and other symptoms in opioid-using and nonusing chronic pain patients meeting the survey criteria for fibromyalgia. Patients presenting to a university-based pain clinic completed validated self-report questionnaires assessing symptoms. Patients (N=962) meeting the fibromyalgia survey criteria were stratified by opioid use and further split into groups based on caffeine amount consumed per day (no caffeine, or low, moderate, high caffeine). Analysis of covariance with Dunnett's post hoc testing compared pain and symptom severity between the no caffeine group and the caffeine consuming groups. In opioid users, caffeine consumption had modest but significant effects on pain, catastrophizing, and physical function. Lower levels of pain interference were associated with low and moderate caffeine use compared to no caffeine intake. Lower pain catastrophizing and higher physical function were observed in all caffeine dose groups, relative to the no caffeine group. Lower pain severity and depression were observed only in the moderate caffeine group. In opioid nonusers, low caffeine intake was associated with higher physical function; however, no other significant effects were observed. Caffeine consumption was associated with decreased pain and symptom severity in opioid users, but not in opioid nonusers, indicating caffeine may act as an opioid adjuvant in fibromyalgia-like chronic pain patients. These data suggest that caffeine consumption concomitant with opioid analgesics could provide therapeutic benefits not seen with opioids or caffeine alone.

  1. Adjuvant Intraoperative Photodynamic Therapy in Head and Neck Cancer

    Science.gov (United States)

    Rigual, Nestor R.; Shafirstein, Gal; Frustino, Jennifer; Seshadri, Mukund; Cooper, Michele; Wilding, Gregory; Sullivan, Maureen A.; Henderson, Barbara

    2015-01-01

    IMPORTANCE There is an immediate need to develop local intraoperative adjuvant treatment strategies to improve outcomes in patients with cancer who undergo head and neck surgery. OBJECTIVES To determine the safety of photodynamic therapy with 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) in combination with surgery in patients with head and neck squamous cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS Nonrandomized, single-arm, single-site, phase 1 study at a comprehensive cancer center among 16 adult patients (median age, 65 years) with biopsy-proved primary or recurrent resectable head and neck squamous cell carcinoma. INTERVENTIONS Intravenous injection of HPPH (4.0 mg/m2), followed by activation with 665-nm laser light in the surgical bed immediately after tumor resection. MAIN OUTCOMES AND MEASURES Adverse events and highest laser light dose. RESULTS Fifteen patients received the full course of treatment, and 1 patient received HPPH without intraoperative laser light because of an unrelated myocardial infarction. Disease sites included larynx (7 patients), oral cavity (6 patients), skin (1 patient), ear canal (1 patient), and oropharynx (1 patient, who received HPPH only). The most frequent adverse events related to photodynamic therapy were mild to moderate edema (9 patients) and pain (3 patients). One patient developed a grade 3 fistula after salvage laryngectomy, and another patient developed a grade 3 wound infection and mandibular fracture. Phototoxicity reactions included 1 moderate photophobia and 2 mild to moderate skin burns (2 due to operating room spotlights and 1 due to the pulse oximeter). The highest laser light dose was 75 J/cm2. CONCLUSIONS AND RELEVANCE The adjuvant use of HPPH-photodynamic therapy and surgery for head and neck squamous cell carcinoma seems safe and deserves further study. PMID:23868427

  2. Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands

    Directory of Open Access Journals (Sweden)

    Deana N. Toussi

    2014-04-01

    Full Text Available Vaccine efficacy is optimized by addition of immune adjuvants. However, although adjuvants have been used for over a century, to date, only few adjuvants are approved for human use, mostly aimed at improving vaccine efficacy and antigen-specific protective antibody production. The mechanism of action of immune adjuvants is diverse, depending on their chemical and molecular nature, ranging from non-specific effects (i.e., antigen depot at the immunization site to specific activation of immune cells leading to improved host innate and adaptive responses. Although the detailed molecular mechanism of action of many adjuvants is still elusive, the discovery of Toll-like receptors (TLRs has provided new critical information on immunostimulatory effect of numerous bacterial components that engage TLRs. These ligands have been shown to improve both the quality and the quantity of host adaptive immune responses when used in vaccine formulations targeted to infectious diseases and cancer that require both humoral and cell-mediated immunity. The potential of such TLR adjuvants in improving the design and the outcomes of several vaccines is continuously evolving, as new agonists are discovered and tested in experimental and clinical models of vaccination. In this review, a summary of the recent progress in development of TLR adjuvants is presented.

  3. STRAP Is a Strong Predictive Marker of Adjuvant Chemotherapy Benefit in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Martin Buess

    2004-11-01

    Full Text Available BACKGROUND: Molecular predictors for the effectiveness of adjuvant chemotherapy in colorectal cancer are of considerable clinical interest. To this aim, we analyzed the serine threonine receptor-associated protein (STRAP, an inhibitor of TGF-βsignaling, with regard to prognosis and prediction of adjuvant 5-FU chemotherapy benefit. i The gene copy status of STRAP was determined using quantitative realtime polymerase chain reaction in 166 colorectal tumor biopsies, which had been collected from a randomized multicenter trial of 5-fluorouracil (5-FU/mitomycin C (MMC adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK. RESULTS: Amplification of STRAP was found in 22.8% of the tumors. When left without adjuvant chemotherapy, patients bearing tumors with a STRAP amplification had a significantly better prognosis (hazard ratio for death: 0.26; P = .004. Interestingly, these patients, when receiving adjuvant treatment, had a worse survival (hazard ratio for death: 3.48; P = .019 than without chemotherapy, whereas patients carrying tumors with diploidy or deletion of STRAP benefited from the treatment (hazard ratio for death: 0.44; P = .052. This suggests the amplification of STRAP as a strong predictor of an unfavorable effect of 5-FU-based adjuvant chemotherapy. CONCLUSION: If confirmed, the STRAP gene copy status might provide a parameter to decide about the use of 5-FU-based adjuvant chemotherapy.

  4. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: Adjuvant 5-FU/cisplatin and chemoradiation with capecitabine

    Institute of Scientific and Technical Information of China (English)

    Hyung-Sik Lee; Min-Chan Kim; Youngmin Choi; Won-Joo Hur; Hyo-Jin Kim; Hyuk-Chan Kwon; Sung-Hyun Kim; Jae-Seok Kim; Jong-Hoon Lee; Ghap-Joong Jung

    2006-01-01

    AIM: To evaluate the efficacy and toxicity of postoperative chemoradiation using FP chemotherapy and oral capecitabine during radiation for advanced gastric cancer following curative resection.METHODS: Thirty-one patients who had underwent a potentially curative resection for Stage Ⅲ and Ⅳ (MO) gastric cancer were enrolled. Therapy consists of one cycle of FP (continuous infusion of 5-FU 1000 mg/m2 on d 1 to 5 and cisplatin 60 mg/m2 on d 1) followed by 4500 cGy (180 cGy/d) with capecitabine (1650 mg/m2 daily throughout radiotherapy). Four wk after completion of the radiotherapy, patients received three additional cycles of FP every three wk. The median follow-up duration was 22.2 mo.RESULTS: The 3-year disease free and overall survival in this study were 82.7% and 83.4%, respectively. Four patients (12.9%) showed relapse during follow-up. Eight patients did not complete all planned adjuvant therapy.Grade 3/4 toxicities included neutropenia in 50.2%, anemia in 12.9%, thrombocytopenia in 3.2% and nausea/vomiting in 3.2%. Neither grade 3/4 hand foot syndrome nor treatment related febrile neutropenia or death were observed.CONCLUSION: These preliminary results suggest that this postoperative adjuvant chemoradiation regimen of FP before and after capecitabine and concurrent radiotherapy appears well tolerated and offers a comparable toxicity profile to the chemoradiation regimen utilized in INT-0116. This treatment modality allowed successful loco-regional control rate and 3-year overall survival.

  5. Adjuvant treatment for Stage I seminoma: Why radiotherapy is better than carboplatin.

    Science.gov (United States)

    Yathiraj, Prahlad H; Sharan, Krishna; Fernandes, Donald J; Vidyasagar, M S

    2016-01-01

    Adjuvant treatment options for Stage I seminoma include active surveillance, chemotherapy, and radiotherapy. Active surveillance may not be ideal for the average Indian patient. Of the two accepted adjuvant therapy options, namely single-dose carboplatin chemotherapy and radiotherapy to the retroperitoneal nodes, though it intuitively appears more appealing, a deeper review reveals the potential drawbacks of chemotherapy. This article highlights the misconceptions regarding carboplatin and provides reasons for an argument why radiotherapy is better when a patient with Stage I seminoma chooses to undergo adjuvant treatment.

  6. Adjuvant chemotherapy for completely resected non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Toyooka,Shinichi

    2009-10-01

    Full Text Available For many years, surgery alone was the standard treatment for patients with stage I-IIIA non-small-cell lung cancer (NSCLC. However, recent studies have demonstrated that adjuvant chemotherapy provides a survival benefit. The first adjuvant chemotherapy for NSCLC was performed in the 1960s using a key drug known as cyclophosphamide. In the 1980s and early 1990s, a new anti-cancer drug, cisplatin, was developed. The first meta-analysis of this drug was conducted by the Non-small Cell Lung Cancer Collaborative Group in 1995. This analysis comparing surgery with surgery plus chemotherapy containing cisplatin produced a hazard ratio of 0.87 and suggested an absolute benefit of chemotherapy of 5% at 5 years;this difference was not statistically significant (p0.08. Several clinical trials of adjuvant chemotherapy were planned after the meta-analysis conducted in 1995, but the efficacy of adjuvant chemotherapy remained a matter of controversy. However, useful evidence was reported after 2003. The International Adjuvant Lung Cancer Collaborative Group Trial (IALT demonstrated a 4.1% improvement in survival for patients with stage I to III NSCLC. The JBR. 10 trial demonstrated a 15% improvement in 5-year survival for the adjuvant chemotherapy arm in stage IB or II (excluding T3N0 patients. The Adjuvant Navelbine International Trialist Association (ANITA trial reported that the overall survival at 5 years improved by 8.6% in the chemotherapy arm and that this survival rate was maintained at 7 years (8.4% in stage II and IIIA patients. A meta-analysis based on collected and pooled individual patient data from the 5 largest randomized trials was conducted by the Lung Adjuvant Cisplatin Evaluation (LACE. This analysis demonstrated that cisplatin-based adjuvant chemotherapy improved survival in patients with stage II or III cancer. Alterna-tively, uracil-tegafur has been developed and tested in Japan. The Japan Lung Cancer Research Group (JLCRG on Postsurgical

  7. U-Omp19 from Brucella abortus Is a Useful Adjuvant for Vaccine Formulations against Salmonella Infection in Mice

    Science.gov (United States)

    Risso, Gabriela S.; Carabajal, Marianela V.; Bruno, Laura A.; Ibañez, Andrés E.; Coria, Lorena M.; Pasquevich, Karina A.; Lee, Seung-Joo; McSorley, Stephen J.; Briones, Gabriel; Cassataro, Juliana

    2017-01-01

    Most pathogens infect through mucosal surfaces, and parenteral immunization typically fails to induce effective immune responses at these sites. Development of oral-administered vaccines capable of inducing mucosal as well as systemic immunity while bypassing the issues of antigen degradation and immune tolerance could be crucial for the control of enteropathogens. This study demonstrates that U-Omp19, a bacterial protease inhibitor with immunostimulatory features, coadministered with Salmonella antigens by the oral route, enhances mucosal and systemic immune responses in mice. U-Omp19 was able to increase antigen-specific production of IFN-γ and IL-17 and mucosal (IgA) antibody response. Finally, oral vaccination with U-Omp19 plus Salmonella antigens conferred protection against virulent challenge with Salmonella Typhimurium, with a significant reduction in bacterial loads. These findings prove the efficacy of this novel adjuvant in the Salmonella infection model and support the potential of U-Omp19 as a suitable adjuvant in oral vaccine formulations against mucosal pathogens requiring T helper (Th)1–Th17 protective immune responses.

  8. Nano-Delivery Vehicles/Adjuvants for DNA Vaccination Against HIV.

    Science.gov (United States)

    Dong, Yaqiong; Yang, Jun; Zhang, Jinchao; Zhang, Xin

    2016-03-01

    More than 75 million people has been infected HIV and it is responsible for nearly 36 million deaths on a global scale. As one of the deadliest infectious diseases, HIV is becoming the urgent issue of the global epidemic to tackle. In order to settle this problem from the source, some effective prevention strategies should be developed to control the pandemic of HIV. Vaccines, especially DNA vaccines, could be the optimal way to control the spread of HIV due to the unparalleled superiority that DNA vaccines could generate long-term humoral and cellular immune responses which could provide protective immunity for HIV. But the naked DNA could hardly enter into cells and is easily degraded by DNases and lysosomes, so designing effective delivery system is a promising strategy. Since delivery system could be constructed to promote efficient delivery of DNA into mammalian cells, protect them from degradation, and also could be established to be a target system to arrive at certain position of expectation. The current review discusses the potential of various nano-delivery vehicles/adjuvants such as polymer, lipid, liposome, peptide and inorganic material in improving efficiency of diverse modalities available for HIV DNA vaccines.

  9. Tratamento adjuvante nos GISTs Adjuvant treatment in GISTs

    Directory of Open Access Journals (Sweden)

    Laercio Gomes Lourenço

    2011-09-01

    Full Text Available INTRODUÇÃO: O tumor estromal gastrointestinal (GIST é o sarcoma mais comum do aparelho digestivo. Essa neoplasia ocorre devido à mutação do gene KIT com consequente ativação constitutiva da proteína KIT. O tratamento primário é cirúrgico e consiste na sua ressecção completa. Entretanto, alguns grupos de pacientes apresentam risco elevado de recorrência mesmo após operação com ressecção completa (R0, indicando diferenças no comportamento biológico. Estudos clínicos comprovaram a atividade clínica do mesilato de imatinibe, fazendo dele a primeira linha de tratamento padrão nos GISTs metastáticos ou irressecáveis, mudando muito o desfecho clínico dessa doença em relação aos benefícios anteriormente obtidos com a quimioterapia antineoplásica. MÉTODO: Foi realizada revisão da literatura com consulta nos periódicos das bases Medline/Pubmed, Scielo e Lilacs cruzando os descritores: tumor estromal gastrointestinal, Gist, tratamento, adjuvância. Além desta revisão foi adicionada a experiência pessoal dos autores. CONCLUSÃO: Melhor refinamento dos critérios de prognóstico tem permitido selecionar de forma mais adequada pacientes para o tratamento adjuvante com imatinibe. Os resultados de maior evidência até o momento respaldam o tratamento adjuvante por um ano, o que produz benefício significativo na sobrevida livre de recidiva, mas não na sobrevida global desses pacientes.INTRODUCTION: Gastrointestinal stromal tumor (GIST is the most common sarcoma of the digestive tract. This cancer occurs due to mutation of the KIT gene resulting in constitutive activation of KIT protein. The primary treatment is surgical and consists of complete resection. However, some groups of patients at high risk of recurrence even after surgery with complete resection (R0, indicate differences in biological behavior. Clinical studies have demonstrated the clinical activity of imatinib mesylate, making it the standard first

  10. Effect of tramadol as an adjuvant to local anesthetics for brachial plexus block: A systematic review and meta-analysis.

    Science.gov (United States)

    Shin, Hye Won; Ju, Bum Jun; Jang, Yoo Kyung; You, Hae Seun; Kang, Hyun; Park, Ji Yong

    2017-01-01

    Tramadol, a 4-phenyl-piperidine analog of codeine, has a unique action in that it has a central opioidergic, noradrenergic, serotonergic analgesic, and peripheral local anesthetic (LA) effect. Many studies have reported contradictory findings regarding the peripheral analgesic effect of tramadol as an adjuvant to LA in brachial plexus block (BPB). This meta-analysis aimed to evaluate the effects of tramadol as an adjunct to LA in BPB during shoulder or upper extremity surgery. We searched the PubMed, EMBASE, Cochrane, KoreaMed databases, and Google Scholar for eligible randomized controlled trials (RCTs) that compared BPB with LA alone and BPB with LA and tramadol. Primary outcomes were the effects of tramadol as an adjuvant on duration of sensory block, motor block, and analgesia. Secondary outcomes were the effects of tramadol as an adjuvant on time to onset of sensory block and motor block and on adverse effects. We performed the meta-analysis using Review Manager 5.3 software. We identified 16 RCTs with 751 patients. BPB with tramadol prolonged the duration of sensory block (mean difference [MD], -61.5 min; 95% CI, -95.5 to -27.6; P = 0.0004), motor block (MD, -65.6 min; 95% CI, -101.5 to -29.7; P = 0.0003), and analgesia (MD, -125.5 min; 95% CI, -175.8 to -75.3; P tramadol. Tramadol also shortened the time to onset of sensory block (MD, 2.1 min; 95% CI, 1.1 to 3.1; P tramadol 100 mg (P tramadol 50 mg. The quality of evidence was high for duration of analgesia according to the GRADE system. Adverse effects were comparable between the studies. In upper extremity surgery performed under BPB, use of tramadol 100 mg as an adjuvant to LA appears to prolong the duration of sensory block, motor block, and analgesia, and shorten the time to onset of sensory and motor blocks without altering adverse effects.

  11. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials.

    Science.gov (United States)

    Mitry, Emmanuel; Fields, Anthony L A; Bleiberg, Harry; Labianca, Roberto; Portier, Guillaume; Tu, Dongsheng; Nitti, Donato; Torri, Valter; Elias, Dominique; O'Callaghan, Chris; Langer, Bernard; Martignoni, Giancarlo; Bouché, Olivier; Lazorthes, Franck; Van Cutsem, Eric; Bedenne, Laurent; Moore, Malcolm J; Rougier, Philippe

    2008-10-20

    Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive [FFCD] Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia [ENG] trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials. After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil [FU] 400 mg/m(2) administered intravenously [IV] once daily plus dl-leucovorin 200 mg/m(2) [FFCD] x 5 days or FU 370 mg/m(2) plus l-leucovorin 100 mg/m(2) IV x 5 days [ENG] for six cycles at 28-day intervals) or to surgery alone (S arm). A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis. This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus-based regimen after complete resection of colorectal cancer metastases.

  12. Effects of 3% trehalose as an adjuvant treatment after LASIK

    Directory of Open Access Journals (Sweden)

    Mateo Orobia AJ

    2017-02-01

    Full Text Available Antonio J Mateo Orobia,1–3 Paula Casas Pascual,1,4 José Á Cristóbal Bescós,1 Diana Perez García,1,4 Carlos Peiro Embid,1,4 M Ángeles del Buey Sayas,1,4 Valentyna Korobko Kulikova,1 Noelia Lafuente Ojeda5 1Department of Ophthalmology, Hospital Quirón, 2Department of Ophthalmology, Hospital Universitario Miguel Servet, 3Instituto de Investigación Sanitaria de Aragón (IIS, 4Department of Ophthalmology, Hospital Clínico Universitario Lozano-Blesa, 5Department of Anesthesiology, Hospital Universitario Miguel Servet, Zaragoza, Spain Purpose: To evaluate the effect of 3% trehalose as an adjuvant in the standard treatment after laser-assisted in situ keratomileusis.Design: Interventional prospective comparative single-blind study.Setting: Department of Ophthalmology, Hospital Quirón Zaragoza, Spain.Methods: A total of 26 eyes (13 patients were included, of which 12 eyes (group 1 received conventional treatment with lubricant drops of hyaluronic acid (0.15% and 14 eyes (group 2 received, additionally, an ophthalmic solution of 3% trehalose. Pre- and postoperative quality-of-life tests and vital stains, tear breakup time, and osmolarity measurements were made.Results: We obtained statistically significant differences between the groups in the Symptom Assessment in Dry Eye test in all visits with respect to severity, and in the postoperative day 1 visit with respect to frequency, in all cases favoring the trehalose treatment. The values of osmolarity were not significantly different between groups. However, we did find significant differences in the Oxford scale in day 90 for the trehalose treatment (P<0.001, and in the National Eye Institute scale in day 30 (P=0.02.Conclusion: The results of this exploratory study indicate that the adjuvant treatment with 3% trehalose could be superior with respect to the standard treatment, with improvements in the objective and subjective parameters of tear quality. Keywords: dry eye syndrome, trehalose

  13. Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer

    DEFF Research Database (Denmark)

    Lund, C M; Nielsen, D; Dehlendorff, C

    2016-01-01

    BACKGROUND: Elderly patients with primary colorectal cancer (CRC) are less frequently treated with adjuvant chemotherapy than younger patients due to concerns regarding toxicity and efficiency. We investigated how age, performance status (PS) and comorbidity influence treatment outcomes. PATIENTS...

  14. [Caprine arthritis-encephalitis: trial of an adjuvant vaccine preparation. I. Clinical and virological study].

    Science.gov (United States)

    Russo, P; Vitu, C; Fontaine, J J; Vignoni, M

    1993-04-01

    In purpose to protect goats against caprine arthritis encephalitis virus (CAEV), the first group of kids (I) was inoculated with purified, inactivated and adjuvant-treated virions, the second group (II) with adjuvant and the third one (III) with culture medium. 2-4 months later, the three groups were challenged with virulent CAEV by intraarticular route. On the clinical level, vaccinated and challenged kids show more early and severe arthritis than other groups. On the virological level, isolation of lentivirus from white blood cells and different organs is more important in group I than groups II and III. Therefore, vaccinations with inactivated and adjuvant-treated virions do not protect against a virulent challenge; there is an enhancement of lesions. We note that the adjuvant elicits a mild non-specific protection against virulent challenge.

  15. Efficacy and safety of oxaliplatin chemotherapy programs as adjuvant treatment in colorectal cancer after surgery

    Institute of Scientific and Technical Information of China (English)

    杨莉萍

    2013-01-01

    Objective To compare the efficacy and safety of 5-fluorouracil and calcium folinatc combined with oxaliplatin(FOLFOX) program with capecitabine regimen combined oxaliplatin(XELOX) program as adjuvant chemotherapy in advanced colorectal cancer after surgery.

  16. Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC

    DEFF Research Database (Denmark)

    Sorensen, Steffen Filskov; Carus, Andreas; Meldgaard, Peter

    2015-01-01

    OBJECTIVES: Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We...... assessed the overall survival (OS) and disease-free survival (DFS) of patients treated with adjuvant i.v. vinorelbine or p.o. vinorelbine, in combination with i.v. cisplatin. MATERIALS AND METHODS: We reviewed two time-separated cohorts of patients referred to the Department of Oncology at Aarhus...... University Hospital (Denmark) from 2005 to 2012 for adjuvant chemotherapy after surgery for NSCLC. RESULTS AND CONCLUSION: Of the 265 patients included in this study, 126 patients received i.v. and 139 received p.o. vinorelbine/cisplatin. The two groups were comparable with respect to important baseline...

  17. POLYPRENYL PHOSPHATES AS ADJUVANTS, POLARIZING THE IMMUNE RESPONSE TO Th1

    Directory of Open Access Journals (Sweden)

    A. V. Pronin

    2012-01-01

    Full Text Available Abstract. The attempts to decrease a toxic action of Freund complete adjuvant have led to development of new emulsion adjuvant compositions. More often they are based on metabolizable oil (squalene with addition the Tween 80 (Polisorbate 80 as an emulsifier. The third component is an immunomodulator. Adjuvants, intended for prevention of virus infections, should include the immunomodulators polarizing the immune response to Th1. From this point of view adjuvant based on a colloidal solution prepared by means of the Tween 80 from polyprenyl phasphates of fir needles (Phosprenyl can be rather perspective. The last one, as well as squalene, is constructed by isoprene links, but has them not 6, but 16 that essentially reduces its toxicity. The obtained data shows that Phosprenyl essentially enhances efficiency of vaccination in such virus infections as tick born encephalitis, bird flu, poliomyelitis and polarizes the immune response to Th1.

  18. Psidium guajava leaves decrease arthritic symptoms in adjuvant-induced arthritic rats

    Directory of Open Access Journals (Sweden)

    Hanif Nasiatul Baroroh

    2016-04-01

    Psidium guajava leaf extract is effective in decreasing the inflammatory response and arthritic symptoms in rats with adjuvant-induced arthritis. Psidium guajava leaves can be developed into an alternative anti-arthritis treatment.

  19. Physician Beliefs and Practices for Adjuvant and Salvage Radiation Therapy After Prostatectomy

    Energy Technology Data Exchange (ETDEWEB)

    Showalter, Timothy N., E-mail: timothy.showalter@jeffersonhospital.org [Department of Radiation Oncology, Jefferson Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Ohri, Nitin; Teti, Kristopher G. [Department of Radiation Oncology, Jefferson Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Foley, Kathleen A. [Strategic Consulting, Thomson Reuters Healthcare, Cambridge, MA (United States); Keith, Scott W. [Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (United States); Trabulsi, Edouard J.; Lallas, Costas D. [Department of Urology, Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Dicker, Adam P. [Department of Radiation Oncology, Jefferson Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Hoffman-Censits, Jean [Department of Medical Oncology, Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); Pizzi, Laura T. [School of Pharmacy, Thomas Jefferson University, Philadelphia, PA (United States); Gomella, Leonard G. [Department of Urology, Jefferson Medical College and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States)

    2012-02-01

    Purpose: Despite results of randomized trials that support adjuvant radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer with adverse pathologic features (APF), many clinicians favor selective use of salvage RT. This survey was conducted to evaluate the beliefs and practices of radiation oncologists (RO) and urologists (U) regarding RT after RP. Methods and Materials: We designed a Web-based survey of post-RP RT beliefs and policies. Survey invitations were e-mailed to a list of 926 RO and 591 U. APF were defined as extracapsular extension, seminal vesicle invasion, or positive surgical margin. Differences between U and RO in adjuvant RT recommendations were evaluated by comparative statistics. Multivariate analyses were performed to evaluate factors predictive of adjuvant RT recommendation. Results: Analyzable surveys were completed by 218 RO and 92 U (overallresponse rate, 20%). Adjuvant RT was recommended based on APF by 68% of respondents (78% RO, 44% U, p <0.001). U were less likely than RO to agree that adjuvant RT improves survival and/or biochemical control (p < 0.0001). PSA thresholds for salvage RT were higher among U than RO (p < 0.001). Predicted rates of erectile dysfunction due to RT were higher among U than RO (p <0.001). On multivariate analysis, respondent specialty was the only predictor of adjuvant RT recommendations. Conclusions: U are less likely than RO to recommend adjuvant RT. Future research efforts should focus on defining the toxicities of post-RP RT and on identifying the subgroups of patients who will benefit from adjuvant vs. selective salvage RT.

  20. Survival after adjuvant chemoradiotherapy or surgery alone in resectable adenocarcinoma at the gastro-esophageal junction

    DEFF Research Database (Denmark)

    Kofoed, Steen Christian; Muhic, A; Jensen, Lene Bæksgaard;

    2012-01-01

    Longterm survival after curative resection for adenocarcinoma at the gastro-esophageal junction (GEJ) range between 18% and 50%. In the pivotal Intergroup-0116 Phase III trial by Macdonald et all, adjuvant chemoradiotherapy improved both disease-free and overall survival in curatively resected...... patients with mainly gastric adenocarcinoma. We compared survival data for curatively resected patients with adeno-carcinoma solely at the gastro-esophageal junction (GEJ), treated with surgery alone or surgery and adjuvant chemoradio-therapy....

  1. The impact of chronic illnesses on the use and effectiveness of adjuvant chemotherapy for colon cancer.

    Science.gov (United States)

    Gross, Cary P; McAvay, Gail J; Guo, Zhenchao; Tinetti, Mary E

    2007-06-15

    It is unclear how noncancer conditions affect the use or effectiveness of adjuvant therapy among older patients with colon cancer. The authors conducted a cohort study of older patients with stage III colon cancer who were diagnosed from 1993 to 1999 in the Surveillance, Epidemiology, and End Results-Medicare database. The correlations between receipt of adjuvant chemotherapy and heart failure, diabetes, and chronic obstructive pulmonary disease (COPD) were assessed. Multivariable regression analysis was used to assess the risk of death and hospitalization as a function of treatment and comorbidity status. The study sample consisted of 5330 patients (median age, 76 years). The use of adjuvant therapy was related significantly to heart failure (36.2% vs 64.9% of patients with vs without heart failure, respectively; adjusted odds ratio [OR], 0.49; 95% confidence interval [95% CI], 0.40-0.60). More moderate correlations were observed for COPD (OR, 0.83; 95% CI, 0.70-0.99) and diabetes (OR, 0.81; 95% CI, 0.68-0.97). Among patients who had heart failure, the 5-year survival was significantly higher among those who received adjuvant chemotherapy (adjusted 5-year survival rate, 43%; 95% CI, 40-47%) than among those who did not receive adjuvant chemotherapy (30%; 95% CI, 27-34%). Among patients without heart failure, the 5-year survival estimates among treated and untreated patients were 54% (95% CI, 52-56%) and 41% (95% CI, 38-44%), respectively. The probability of all-cause, condition-specific, or toxicity-related hospitalization associated with adjuvant therapy was not altered by the presence of any of the 3 conditions. Although chronic conditions appeared to be a strong barrier to the receipt of adjuvant chemotherapy, adjuvant therapy appeared to provide a significant survival benefit to patients who had colon cancer with the conditions studied. Copyright 2007 American Cancer Society.

  2. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA)

    DEFF Research Database (Denmark)

    Goldhirsch, Aron; Gelber, Richard D; Piccart-Gebhart, Martine J

    2013-01-01

    Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatmen......, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial....

  3. Vaccine adjuvants – Current status and prospects on controlled release adjuvancity

    OpenAIRE

    Sivakumar, S.M.; Safhi, Mohammed M.; Kannadasan, M.; Sukumaran, N.

    2011-01-01

    The strategy of World Health Organization is to develop efficient and inexpensive vaccine against various infectious diseases amongst children’s population. Vaccination is considered as the most cost effective health intervention known to public. Since 90 years various substances have been added in vaccine formulation but still alum is considered as the safest adjuvant for human use licensed by United States Food and Drug Administration. MF 59 and ASO4 are the adjuvants were developed recentl...

  4. High-risk endometrial cancer may be benefit from adjuvant radiotherapy plus chemotherapy

    Institute of Scientific and Technical Information of China (English)

    Jin-Wei Miao; Xiao-Hong Deng

    2012-01-01

    Objective:To present patterns of practice and outcomes in the adjuvant treatment of intermediate-and high-risk endometrial cancer.Methods:Retrospective data on 224 women with intermediate-risk and high-risk endometrial cancer from 1999 to 2006 were reviewed.All patients underwent surgical staging.Patterns of adjuvant treatment,consisting of pelvic radiotherapy,chemotherapy,and radiotherapy plus chemotherapy,were assessed.The 3-and 5-year disease-specific survival (DSS) rates were calculated using the Kaplan-Meier method.Results:The difference in 5-year DSS rate was statistically significant between adjuvant group and non-adjuvant group (80.65% vs.63.80%,P=0.040).In 110 high-risk patients who underwent adjuvant treatment,both 5-year DSS rate and recurrent rate were significantly different in combined radiotherapy and chemotherapy group compared with radiotherapy alone and chemotherapy alone groups (DSS rate,P=0.049; recurrent rate,P=0.047).In 83 intermediate-risk women who underwent adjuvant treatment,there was no significant difference in 5-year DSS rate and recurrence rate among the combined radiotherapy and chemotherapy,radiotherapy alone and chemotherapy alone groups (DSS rate,P=0.776; recurrent rate,P=0.937).Conclusions:Adjuvant radiotherapy plus chemotherapy is associated with a higher 5-year DSS rate and lower recurrence rate compared with radiotherapy alone and chemotherapy alone in high-risk endometrial cancer patients.Patients with intermediate-risk endometrial cancer may be not likely to benefit from adjuvant combined radiotherapy and chemotherapy.

  5. [The role of Lactobacillus acidophilus in the prevention and adjuvant therapy of certain infectious diseases].

    Science.gov (United States)

    Halmy, C; Halmy, L

    1998-09-27

    Authors call attention to the role of lactic acid bacteria in the prevention and adjuvant therapy of certain infective diseases. It has special importance in the prevention and adjuvant therapy of new-born and childhood enteritis, different urogenital inflammations and antibiotic associated diarrhoea. Administration of lactic acid bacteria create eubiosis between the human organism and the world of bacteria, that is, eubacteriosis is developed instead of a pathogen flora, assuring normal physiologic functions for the well-being of the organism.

  6. Unequivocal identification of intracellular aluminium adjuvant in a monocytic THP-1 cell line.

    OpenAIRE

    2014-01-01

    Aluminium-based adjuvants (ABA) are the predominant adjuvants used in human vaccinations. While a consensus is yet to be reached on the aetiology of the biological activities of ABA several studies have identified shape, crystallinity and size as critical factors affecting their adjuvanticity. In spite of recent advances, the fate of ABA following their administration remains unclear. Few if any studies have demonstrated the unequivocal presence of intracellular ABA. Herein we demonstrate for...

  7. Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy

    OpenAIRE

    2014-01-01

    Sub-cutaneous immunotherapy is an effective treatment for allergy. It works by helping to modify or re-balance an individual’s immune response to allergens and its efficacy is greatly improved by the use of adjuvants, most commonly, aluminium hydroxide. Aluminium salts have been used in allergy therapy for many decades and are assumed to be safe with few established side-effects. This assumption belies their potency as adjuvants and their potential for biological reactivity both at injection ...

  8. Natural killer T cell and TLR9 agonists as mucosal adjuvants for sublingual vaccination with clade C HIV-1 envelope protein.

    Science.gov (United States)

    Singh, Shailbala; Yang, Guojun; Byrareddy, Siddappa N; Barry, Michael A; Sastry, K Jagannadha

    2014-12-05

    The vast majority of HIV-1 infections occur at mucosa during sexual contact. It may therefore be advantageous to provide mucosal barrier protection against this entry by mucosal vaccination. While a number of mucosal routes of vaccination are possible, many like enteric oral vaccines or intranasal vaccines have significant impediments that limit vaccine efficacy or pose safety risks. In contrast, immunogens applied to the sublingual region of the mouth could provide a simple route for mucosal vaccination. While sublingual immunization is appealing, this site does not always drive strong immune responses, particularly when using protein antigens. To address this issue, we have tested the ability of two mucosal adjuvants: alpha-galactosylceramide (αGalCer) that is a potent stimulator of natural killer T cells and CpG-oligodeoxynucleotide (CpG-ODN) a TLR9 agonist for their ability to amplify immune responses against clade C gp140 HIV-1 envelope protein antigen. Immunization with envelope protein alone resulted in a weak T cell and antibody responses. In contrast, CD4(+) and CD8(+) T cells responses in systemic and mucosal tissues were significantly higher in mice immunized with gp140 in the presence of either αGalCer or CpG-ODN and these responses were further augmented when the two adjuvants were used together. While both the adjuvants effectively increased gp140-specific serum IgG and vaginal IgA antibody levels, combining both significantly improved these responses. Memory T cell responses 60 days after immunization revealed αGalCer to be more potent than CpG-ODN and the combination of the αGalCer and CpG-ODN adjuvants was more effective than either alone. Serum and vaginal washes collected 60 days after immunization with gp140 with both αGalCer and CpG-ODN adjuvants had significant neutralization activity against Tier 1 and Tier 2 SHIVs. These data support the utility of the sublingual route for mucosal vaccination particularly in combination with

  9. Study protocol of the SACURA trial: a randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer

    Directory of Open Access Journals (Sweden)

    Ishiguro Megumi

    2012-07-01

    Full Text Available Abstract Background Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy, but the usefulness of adjuvant chemotherapy for stage II colon cancer remains controversial. The major Western guidelines recommend adjuvant chemotherapy for “high-risk stage II” cancer, but this is not clearly defined and the efficacy has not been confirmed. Methods/design SACURA trial is a multicenter randomized phase III study which aims to evaluate the superiority of 1-year adjuvant treatment with UFT to observation without any adjuvant treatment after surgery for stage II colon cancer in a large population, and to identify “high-risk factors of recurrence/death” in stage II colon cancer and predictors of efficacy and adverse events of the chemotherapy. Patients aged between 20 and 80 years with curatively resected stage II colon cancer are randomly assigned to a observation group or UFT adjuvant therapy group (UFT at 500–600 mg/day as tegafur in 2 divided doses after meals for 5 days, followed by 2-day rest. This 1-week treatment cycle is repeated for 1 year. The patients are followed up for 5 years until recurrence or death. Treatment delivery and adverse events are entered into a web-based case report form system every 3 months. The target sample size is 2,000 patients. The primary endpoint is disease-free survival, and the secondary endpoints are overall survival, recurrence-free survival, and incidence and severity of adverse events. In an additional translational study, the mRNA expression of 5-FU-related enzymes, microsatellite instability and chromosomal instability, and histopathological factors including tumor budding are assessed to evaluate correlation with recurrences, survivals and adverse events. Discussion A total of 2,024 patients were enrolled from October 2006 to July 2010. The results of this study will provide important information that help to improve the

  10. Factors that Influence the Immunological Adjuvant Effect of Lactobacillus fermentum PC1 on Specific Immune Responses in Mice to Orally Administered Antigens

    Directory of Open Access Journals (Sweden)

    Meera Esvaran

    2016-07-01

    Full Text Available This study examined the influences of the dosage of the adjuvant, the nature of the antigen and the host genetics on the capacity of L. fermentum PC1 (PC1 to function as an oral adjuvant. BALB/c and DBA/1 mice were vaccinated with either ovalbumin (OVA or Salmonella Typhimurium on days 0 and 14, Mice were also dosed with the PC1 (108 CFU or 1011 CFU per dose per mouse with the antigens (days 0 and 14 and alone (days −1 and 13. The higher PC1 dose elicited a greater specific serum IgG2a response than IgG1 for both antigens and mice strains, indicating a Th1-biased humoral immune response. The Th1 bias was also observed at the cellular level with greater specific IFN-γ levels than IL-4 and IL-10 with both antigen types and mouse strains. With the particulate antigen, the lower dose of PC1 elicited a Th1 bias at the cellular level, but a balanced Th1/Th2 response at the systemic humoral level. With the soluble antigen, a strong Th1-biased response occurred at the cellular level while the systemic humoral response was Th2-biased. In conclusion, PC1 at the higher dose was an excellent Th1 adjuvant, which was unaffected by the nature of the antigen or the host’s genetic background.

  11. Intranasal immunization with fusion protein MrpH·FimH and MPL adjuvant confers protection against urinary tract infections caused by uropathogenic Escherichia coli and Proteus mirabilis.

    Science.gov (United States)

    Habibi, Mehri; Asadi Karam, Mohammad Reza; Shokrgozar, Mohammad Ali; Oloomi, Mana; Jafari, Anis; Bouzari, Saeid

    2015-04-01

    Urinary tract infections (UTIs) caused by Uropathogenic Escherichia coli (UPEC) and Proteus mirabilis are among the most common infections in the world. Currently there are no vaccines available to confer protection against UTI in humans. In this study, the immune responses and protection of FimH of UPEC with MrpH antigen of P. mirabilis in different vaccine formulations with and without MPL adjuvant were assessed. Mice intranasally immunized with the novel fusion protein MrpH·FimH induced a significant increase in IgG and IgA in serum, nasal wash, vaginal wash, and urine samples. Mice immunized with fusion MrpH·FimH also showed a significant boost in cellular immunity. Addition of MPL as the adjuvant enhanced FimH and MrpH specific humoral and cellular responses in both systemic and mucosal samples. Vaccination with MrpH·FimH alone or in combination with MPL showed the highest efficiency in clearing bladder and kidney infections in mice challenged with UPEC and P. mirabilis. These findings may indicate that the protection observed correlates with the systemic, mucosal and cellular immune responses induced by vaccination with these preparations. Our data suggest MrpH·FimH fusion protein with or without MPL as adjuvant could be potential vaccine candidates for elimination of UPEC and P. mirabilis. These data altogether are promising and these formulations are good candidates for elimination of UPEC and P. mirabilis.

  12. Adjuvant formulation structure and composition are critical for the development of an effective vaccine against tuberculosis.

    Science.gov (United States)

    Orr, Mark T; Fox, Christopher B; Baldwin, Susan L; Sivananthan, Sandra J; Lucas, Elyse; Lin, Susan; Phan, Tony; Moon, James J; Vedvick, Thomas S; Reed, Steven G; Coler, Rhea N

    2013-11-28

    One third of the world is infected with Mycobacterium tuberculosis (Mtb) with eight million new cases of active tuberculosis (TB) each year. Development of a new vaccine to augment or replace the only approved TB vaccine, BCG, is needed to control this disease. Mtb infection is primarily controlled by TH1 cells through the production of IFN-γ and TNF which activate infected macrophages to kill the bacterium. Here we examine an array of adjuvant formulations containing the TLR4 agonist GLA to identify candidate adjuvants to pair with ID93, a lead TB vaccine antigen, to elicit protective TH1 responses. We evaluate a variety of adjuvant formulations including alum, liposomes, and oil-in-water emulsions to determine how changes in formulation composition alter adjuvant activity. We find that alum and an aqueous nanosuspension of GLA synergize to enhance generation of ID93-specific TH1 responses, whereas neither on their own are effective adjuvants for generation of ID93-specific TH1 responses. For GLA containing oil-in-water emulsions, the selection of the oil component is critical for adjuvant activity, whereas a variety of lipid components may be used in liposomal formulations of GLA. The composition of the liposome formulation of ID93/GLA does alter the magnitude of the TH1 response. These results demonstrate that there are multiple solutions for an effective formulation of a novel TB vaccine candidate that enhances both TH1 generation and protective efficacy. © 2013.

  13. Nipple-sparing mastectomy in breast cancer patients: The role of adjuvant radiotherapy (Review).

    Science.gov (United States)

    Janssen, Stefan; Holz-Sapra, Edna; Rades, Dirk; Moser, Alexander; Studer, Gabriela

    2015-06-01

    The present study aimed to evaluate the role of adjuvant radiotherapy (RT) following nipple-sparing mastectomy (NSM) for patients with ductal carcinoma in situ and invasive breast cancer, based on the published literature. Currently, there is no standard for RT following NSM. NSM aims to spare the nipple areola complex (NAC) without compromising locoregional control. Long-term follow-up studies have begun to show promising results. A search of the English literature was performed using the Medline database and Cochrane central library, with the keywords 'nipple/areola-sparing mastectomy', 'whole skin mastectomy' and 'NAC preservation'. A total of 32 original studies with data on NSM in terms of locoregional control, NAC control, NAC necrosis and adjuvant RT were identified. The median locoregional and NAC recurrence rates were 3.2 and 1.4% (range, 0-28.4% and 0-3.7%), respectively. The volume of remaining breast tissue following NSM was reported inconsistently. In 15 studies, RT was not mentioned. In the remaining 17 studies, RT was administered in 0-100% of patients. Only 7 studies provided detailed information regarding the use of adjuvant RT. Adjuvant thoracic wall irradiation was not used in certain studies, not even for locoregionally advanced tumors. Overall, NSM appears a feasible treatment without increased risk of locoregional recurrence for selected patients. The role of adjuvant RT following NSM requires further clarification. The decision regarding adjuvant RT must be made in interdisciplinary tumor boards and with consideration of the individual situation of the patient.

  14. Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations.

    Science.gov (United States)

    Mold, Matthew; Shardlow, Emma; Exley, Christopher

    2016-08-12

    Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al(3+) in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain.

  15. Improved immunogenicity of tetanus toxoid by Brucella abortus S19 LPS adjuvant.

    Science.gov (United States)

    Mohammadi, Mohsen; Kianmehr, Zahra; Kaboudanian Ardestani, Sussan; Gharegozlou, Behnaz

    2014-09-01

    Adjuvants are used to increase the immunogenicity of new generation vaccines, especially those based on recombinant proteins. Despite immunostimulatory properties, the use of bacterial lipopolysaccharide (LPS) as an adjuvant has been hampered due to its toxicity and pyrogenicity. Brucella abortus LPS is less toxic and has no pyrogenic properties compared to LPS from other gram negative bacteria. To evaluate the adjuvant effect of B. abortus (vaccine strain, S19) LPS for tetanus toxoid antigen (TT) and to investigate the protective effect of different tetanus vaccine preparations. LPS was extracted and purified from B. abortus S19 and KDO, glycan, phosphate content, and protein contamination were measured. Adipic acid dihydrazide (ADH) was used as a linker for conjugation of TT to LPS. Different amounts of B. abortus LPS, TT, TT conjugated with LPS, and TT mixed with LPS or complete Freund's adjuvant (CFA) were injected into mice and antibody production against TT was measured. The protective effect of induced antibodies was determined by LD50. Immunization of mice with TT+LPS produced the highest anti-TT antibody titer in comparison to the group immunized with TT without any adjuvant or the groups immunized with TT-LPS or TT+CFA. Tetanus toxid-S19 LPS also produced a 100% protective effect against TT in immunized mice. These data indicate that B. abortus LPS enhances the immune responses to TT and suggest the possible use of B. abortus LPS as an adjuvant in vaccine preparations.

  16. Orthotopic ileal neobladder reconstruction for bladder cancer: is adjuvant chemotherapy safe?

    Directory of Open Access Journals (Sweden)

    Murugesan Manoharan

    2006-10-01

    Full Text Available OBJECTIVE: We examined our database of patients undergoing radical cystectomy (RC with orthotopic neobladder (NB to determine whether adjuvant chemotherapy in this group is safe. MATERIALS AND METHODS: We performed a retrospective analysis of patients who underwent radical cystectomy and urinary diversion between 1992 and 2004. Relevant clinical and therapeutic data were entered into a database. High-risk bladder cancer patients who underwent NB were identified. They were stratified into 2 groups, those who received adjuvant chemotherapy and those who did not. The incidence of complications between the 2 groups was analyzed and compared. RESULTS: Over the 12-year period, 136 patients underwent RC and NB construction for bladder cancer. Of these, 83 patients were at high risk for recurrence. Nineteen patients received adjuvant chemotherapy and 64 did not. The complication rate in the adjuvant chemotherapy group was 53% and it was 23% in those who did not receive chemotherapy. There were no perioperative or treatment related death. There were 2 patients with grade 4 toxicity in the adjuvant chemotherapy group. There was a statistical difference between these two groups with regard to the incidence of complications. However, none of these complications was life-threatening, required only conservative treatment and caused no long-term disability. CONCLUSIONS: Adjuvant chemotherapy is a safe treatment for patients undergoing RC and NB substitution. Hence, the option of orthotopic NB should not be denied in selected bladder cancer patients with high risk for recurrent disease.

  17. Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations

    Science.gov (United States)

    Mold, Matthew; Shardlow, Emma; Exley, Christopher

    2016-08-01

    Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al3+ in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain.

  18. Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy.

    Science.gov (United States)

    Exley, Christopher

    2014-01-20

    Sub-cutaneous immunotherapy is an effective treatment for allergy. It works by helping to modify or re-balance an individual's immune response to allergens and its efficacy is greatly improved by the use of adjuvants, most commonly, aluminium hydroxide. Aluminium salts have been used in allergy therapy for many decades and are assumed to be safe with few established side-effects. This assumption belies their potency as adjuvants and their potential for biological reactivity both at injection sites and elsewhere in the body. There are very few data purporting to the safety of aluminium adjuvants in allergy immunotherapy and particularly so in relation to longer term health effects. There are, if only few, published reports of adverse events following allergy immunotherapy and aluminium adjuvants are the prime suspects in the majority of such incidents. Aluminium adjuvants are clearly capable of initiating unwanted side effects in recipients of immunotherapy and while there is as yet no evidence that such are commonplace it is complacent to consider aluminium salts as harmless constituents of allergy therapies. Future research should establish the safety of the use of aluminium adjuvants in sub-cutaneous allergy immunotherapy.

  19. Adjuvant Teriparatide Therapy for Surgical Treatment of Femoral Fractures; Does It Work?

    Science.gov (United States)

    Kim, Jung Taek; Jeong, Hyung Jun; Lee, Soong Joon; Kim, Hee Joong

    2016-01-01

    Purpose Atypical femoral fracture (AFF), periprosthetic femoral fracture (PPFF) and femoral nonunion (FNU) are recalcitrant challenges for orthopedic surgeons. Teriparatide (TPTD) had been demonstrated to have anabolic effects on bone in various studies. We postulated that adjuvant TPTD after operation would enhance biologic stimulation for bone formation. We investigated (1) whether the adjuvant TPTD could achieve satisfactory union rate of surgically challenging cases such as displaced AFF, PPFF and FNU; (2) whether the adjuvant TPTD could promote development of abundant callus after surgical fixation; (3) whether the adjuvant TPTD had medically serious adverse effects. Materials and Methods Thirteen patients who agreed to off label use of TPTD in combination of operation were included in this retrospective case series. Median patients' age was 68.7 years, and there were three male and ten female patients. Their diagnoses were nonunion in six patients and acute fracture in seven. Medical records and radiographic images were reviewed. Results Twelve of thirteen fractures were united both clinically and radiologically within a year after adjuvant TPTD. Union completed radiologically median 5.4 months and clinically 5.7 months after the medication, respectively. Callus appeared abundantly showing median 1.4 of fracture healing response postoperatively. There was no serious adverse reaction of medication other than itching, muscle cramp, or nausea. Conclusion Even appropriate surgical treatment is a mainstay of treatment for AFF, PPFF, and FNU, the current report suggested that adjuvant TPTD combined with stable fixation results in satisfactory outcome for the challenging fractures of femur. PMID:27777917

  20. Pushing the limits of hypofractionation for adjuvant whole breast radiotherapy.

    Science.gov (United States)

    Yarnold, John; Haviland, Joanne

    2010-06-01

    Randomised trials report no disadvantages for hypofractionation based on 2.67 Gy fractions of adjuvant whole breast radiotherapy in terms of local tumour control and late adverse effects. Current 15- or 16-fraction schedules may not represent the limits of this approach, and limited data suggest that fewer larger fractions can be delivered safely provided appropriate downward adjustments are made to the total dose. Therapeutic gain will be undermined if breast cancer proves to be, on average, significantly less sensitive to fraction size than the dose-limiting late reacting normal tissues. If so, shortening overall treatment time might wholly or partially offset these limitations, and these uncertainties are addressed in ongoing or planned trials. Meanwhile, the experience of accelerated partial breast irradiation suggests a strong volume effect for late normal tissue damage. Schedules that may be safe when delivered to small partial volumes cannot be assumed to be safe if delivered to larger partial volumes or to the whole breast. Based on current evidence, testing the effectiveness of a 5-fraction schedule of hypofractionated whole breast radiotherapy appears to be a realisable research objective.

  1. Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats.

    Science.gov (United States)

    Taksande, Brijesh G; Gawande, Dinesh Y; Chopde, Chandrabhan T; Umekar, Milind J; Kotagale, Nandkishor R

    2017-02-01

    The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis. Day 8 onwards of CFA administration, rats were injected daily with agmatine for next 7days, and arthritis score, body weights and food intake were monitored daily (g). Since cachexia is known to produce severe inflammation, malnutrition and inhibition of albumin gene expression, we have also monitored the total proteins, albumin, TNF-α and IL-6 levels in arthritic rats and its modulation by agmatine. In the present study, CFA treated rats showed a progressive reduction in both food intake and body weight. In addition analysis of blood serum of arthritis animals showed a significant reduction in proteins and albumin and significant elevation in tumor necrosis factor (TNF)-α and Interleukins (IL)-6. Chronic agmatine (20-40mg/kg, ip) treatment not only attenuated the signs of arthritis but also reverses anorexia and body weight loss in CFA treated rats. In addition, agmatine restored total protein and albumin and reduces TNF-α and IL-6 levels in arthritis rats. These results suggest that agmatine administration can prevent the body weights loss and symptoms of arthritis via inhibition of inflammatory cytokines.

  2. INTRASITE VANCOMYCIN POWDER AS A PROPHYLACTIC ADJUVANT IN LUMBAR FUSION

    Directory of Open Access Journals (Sweden)

    Jorge Álvaro González Ross

    2016-03-01

    Full Text Available ABSTRACT Objective: To identify whether the use of prophylactic intrasite vancomycin as an adjuvant is a protective factor against deep tissue infection of the surgical site. Methods: Retrospective, descriptive, case-control study evaluating 210 patients, of whom 70 received intrasite vancomycin (case group and 140 were controls. It was made a follow up for at least one year, reviewing the physical and electronic records. Data were tabulated in spreadsheets (Excel including all variables and the statistical analysis was made with Epi InfoTM 7 to calculate the odds ratio. Results: Seven cases of deep infection occurred in the control group and none was found in the case group (odds ratio [95% confidence interval]: 0.1262 [0.007-2.24], P = 0.1585. Among the predisposing factors, diabetes and surgical time were the most relevant. Conclusions: Intrasite use of vancomycin has a protective effect against deep infection in patients undergoing lumbar fusion surgery without presenting considerable side effects.

  3. On the adjuvant effect of aluminum hydroxide for mice

    Directory of Open Access Journals (Sweden)

    Nelson M. Vaz

    1981-03-01

    Full Text Available Linear relationships were found between the dose of A1(OH3 adjuvant and the titer of anti-OVA antibodies formed by BDF1 mice. Mice immunized with OVA, DNP-KLH and then boosted with DNP-OVA formed anti-DNP antibodies only when A1(OH3 was added to the injection of DNP-KLH; addition of A1(OH3 to the priming injection of OVA decreased, rather than increased antibody formation.Há relações lineares entre a dose de Al (OH3 usado como adjuvante imunológico e o título de anticorpos anti-ovoalbumina (anti-OVA formado por camundongos BDFI. Camundongos que receberam OVA, depois uma imunização acessoria com dinitrofenil-hemocianina (DNP-KLH e então uma imunização secundária com DNP-OVA, só formaram anticorpos anti-DNP quando havia Al (OH3 incluído na injeção de DNP-KLH; a inclusão de Al (OH3 na injeção primária de OVA baixou em vez de elevar o título de anticorpos anti-DNP. E sugerido que a ação adjuvante do Al(OH3 se deva a ações sobre linfócitos B.

  4. Outcomes after primary or adjuvant radiotherapy for salivary gland carcinoma.

    Science.gov (United States)

    Holtzman, Adam; Morris, Christopher G; Amdur, Robert J; Dziegielewski, Peter T; Boyce, Brian; Mendenhall, William M

    2017-03-01

    We report long-term outcomes of patients treated with primary radiotherapy (RT) or surgery and adjuvant RT for salivary gland malignancies. From 1964 to 2012, 291 patients received primary RT (n = 67) or RT combined with surgery (n = 224). The 5-, 10-, and 15-year local control, local-regional control, distant metastasis-free survival, cause-specific survival and overall survival rates were 82%, 77% and 73%; 77%, 72% and 67%; 74%, 70% and 70%; 70%, 59% and 54%; and 63%, 47% and 38%, respectively. Per multivariate analysis, combined surgery and RT and T stage impacted local control; overall stage and combined surgery and RT impacted local-regional control; overall stage impacted distant metastasis-free survival; and overall stage, node positivity, clinical nerve invasion, and surgery and RT impacted cause-specific and overall survival. Five percent of patients experienced grade 3 or worse toxicity. Combined surgery and RT improves local control, local-regional control, and cause-specific survival compared with primary RT for salivary tumors.

  5. Ketamine as an adjuvant to opioids for cancer pain.

    Science.gov (United States)

    Bell, Rae F; Eccleston, Christopher; Kalso, Eija A

    2017-06-28

    This is an update of a review first published in 2003 and updated in 2012.Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects. To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults. For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017. The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre-existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial. Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient-reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update.Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The

  6. Teaching adjuvant endocrine breast cancer treatment to medical students.

    Science.gov (United States)

    de Visser, M; Fluit, C; Timmer-Bonte, J; Ottevanger, P; Verhagen, C; Klaassen, T; van Laarhoven, H W M

    2013-05-01

    In undergraduate medical education, students are supposed to acquire knowledge and understanding about the basic principles of adjuvant breast cancer treatment. The best education method in this context is unknown. In this randomised study we assessed the effect of designing a patient education poster on knowledge, perceived participation and students' satisfaction compared with case-oriented education concerning endocrine therapy for breast cancer patients. This study was conducted in the Bachelor Oncology Course for undergraduate students in Medical Science of the Radboud University Nijmegen Medical Centre. In the experimental group, students designed and created a patient education poster in small groups. In the control group, students answered case-based questions in small groups. Knowledge was tested at different moments using multiple-choice questions. To assess perceived participation and satisfaction, students filled out questionnaires. 329 students participated in the study. No difference in knowledge was observed between the experimental and control group. However, students in the control group reported a higher perceived participation and satisfaction compared with the students in the experimental group (pstudents' perceived participation and satisfaction. Working on case-based questions may be appreciated by medical students as most relevant for their future profession. We advocate more attention to the importance of patient education in the medical curriculum, to help students realise the relevance of this aspect of medical profession.

  7. A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog

    DEFF Research Database (Denmark)

    Christensen, Dennis; Henriksen-Lacey, Malou; Kamath, Arun T;

    2012-01-01

    Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune...

  8. Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Arnulf; Vaupel, Peter; Stockinger, Marcus; Schmidberger, Heinz [University Medical Center, Department of Radiooncology and Radiotherapy, Mainz (Germany); Struss, Hans-Garlich [University Medical Center, Department of Laboratory Medicine, Mainz (Germany); Giese, Alf [University Medical Center, Department of Neurosurgery, Mainz (Germany)

    2014-10-15

    In comparison to normal brain tissue, glioblastomas exhibit significantly increased glucose uptake. Brain edema is a common complication during adjuvant chemoradiotherapy, leading to a requirement for glucocorticoid treatment. Glucocorticoid treatment frequently causes considerable deregulation of blood glucose levels. Therefore, episodes of hyperglycemia may contribute to radio- and/or chemoresistance. This study comprises a retrospective analysis of the influence of hyperglycemic episodes (HEs) during adjuvant therapy on the overall survival of 106 glioblastoma multiforme patients. The occurrence of one or more deregulated blood glucose value(s) > 10 mM is associated with a reduction in median overall survival from 16.7 to 8.8 months. A significantly poorer overall survival of patients with hyperglycemia could also be detected in subgroup analyses of patients with complete tumor resection and complete treatment according to the EORTC 22891/26891 trial protocol, as well as in a multivariate Cox proportional hazards analysis. A history of diabetes mellitus had no influence on prognosis. Our data suggest that the observed negative impact of elevated blood glucose levels on overall survival may not solely be explained by the patients' poorer general condition; the elevated blood glucose concentration itself may play a pathogenetic role. This could be due to increased activity of antioxidant systems, elevated expression of DNA damage response proteins and protection of hypoxic tumor cells against apoptosis combined with hypoxia-mediated radioresistance. A possible prognostic impact of elevated blood glucose levels during the period of adjuvant (chemo-) radiotherapy of glioblastoma should be evaluated in a prospective clinical trial. (orig.) [German] Glioblastome zeigen im Vergleich mit normalem Gehirngewebe eine deutlich vermehrte Glukoseaufnahme. Im Rahmen der adjuvanten Radio(chemo)therapie von Glioblastomen treten vielfach Hirnoedeme auf, die eine

  9. A CpG-Ficoll Nanoparticle Adjuvant for Anthrax Protective Antigen Enhances Immunogenicity and Provides Single-Immunization Protection against Inhaled Anthrax in Monkeys.

    Science.gov (United States)

    Kachura, Melissa A; Hickle, Colin; Kell, Sariah A; Sathe, Atul; Calacsan, Carlo; Kiwan, Radwan; Hall, Brian; Milley, Robert; Ott, Gary; Coffman, Robert L; Kanzler, Holger; Campbell, John D

    2016-01-01

    Nanoparticulate delivery systems for vaccine adjuvants, designed to enhance targeting of secondary lymphoid organs and activation of APCs, have shown substantial promise for enhanced immunopotentiation. We investigated the adjuvant activity of synthetic oligonucleotides containing CpG-rich motifs linked to the sucrose polymer Ficoll, forming soluble 50-nm particles (DV230-Ficoll), each containing >100 molecules of the TLR9 ligand, DV230. DV230-Ficoll was evaluated as an adjuvant for a candidate vaccine for anthrax using recombinant protective Ag (rPA) from Bacillus anthracis. A single immunization with rPA plus DV230-Ficoll induced 10-fold higher titers of toxin-neutralizing Abs in cynomolgus monkeys at 2 wk compared with animals immunized with equivalent amounts of monomeric DV230. Monkeys immunized either once or twice with rPA plus DV230-Ficoll were completely protected from challenge with 200 LD50 aerosolized anthrax spores. In mice, DV230-Ficoll was more potent than DV230 for the induction of innate immune responses at the injection site and draining lymph nodes. DV230-Ficoll was preferentially colocalized with rPA in key APC populations and induced greater maturation marker expression (CD69 and CD86) on these cells and stronger germinal center B and T cell responses, relative to DV230. DV230-Ficoll was also preferentially retained at the injection site and draining lymph nodes and produced fewer systemic inflammatory responses. These findings support the development of DV230-Ficoll as an adjuvant platform, particularly for vaccines such as for anthrax, for which rapid induction of protective immunity and memory with a single injection is very important.

  10. Exosome-based tumor antigens-adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA.

    Science.gov (United States)

    Morishita, Masaki; Takahashi, Yuki; Matsumoto, Akihiro; Nishikawa, Makiya; Takakura, Yoshinobu

    2016-12-01

    For cancer immunotherapy via tumor antigen vaccination in combination with an adjuvant, major challenges include the identification of a particular tumor antigen and efficient delivery of the antigen as well as adjuvant to antigen-presenting cells. In this study, we proposed an efficient exosome-based tumor antigens-adjuvant co-delivery system using genetically engineered tumor cell-derived exosomes containing endogenous tumor antigens and immunostimulatory CpG DNA. Murine melanoma B16BL6 cells were transfected with a plasmid vector encoding a fusion streptavidin (SAV; a protein that binds to biotin with high affinity)-lactadherin (LA; an exosome-tropic protein) protein, yielding genetically engineered SAV-LA-expressing exosomes (SAV-exo). SAV-exo were combined with biotinylated CpG DNA to prepare CpG DNA-modified exosomes (CpG-SAV-exo). Fluorescent microscopic observation revealed the successful modification of exosomes with CpG DNA by SAV-biotin interaction. CpG-SAV-exo showed efficient and simultaneous delivery of exosomes with CpG DNA to murine dendritic DC2.4 cells in culture. Treatment with CpG-SAV-exo effectively activated DC2.4 cells and enhanced tumor antigen presentation capacity. Immunization with CpG-SAV-exo exhibited stronger in vivo antitumor effects in B16BL6 tumor-bearing mice than simple co-administration of exosomes and CpG DNA. Thus, genetically engineered CpG-SAV-exo is an effective exosome-based tumor antigens-adjuvant co-delivery system that will be useful for cancer immunotherapy.

  11. An adjuvant role of in situ dendritic cells (DCs) in linking innate and adaptive immunity.

    Science.gov (United States)

    Shimizu, Kanako; Fujii, Shin-ichiro

    2008-05-01

    Dendritic cells (DCs) work as a natural adjuvant to elicit T cell immunity. Though DCs have been widely used in immunotherapy, little is known about their number and function in patients with cancer or autoimmune disease. In recent studies, antigen has been targeted to DCs through DC-specific receptors, such as DEC205, the mannose receptor and dying cell receptors. However, antigen captured by DCs in the absence of danger signals induces tolerance. Therefore, the duration and/or magnitude of danger signals plays a crucial role in generating an immunogeneic response. Various danger signals, i.e., pathogen-associated molecular pattern (PAMP), damage-associated molecular pattern (DAMP) and the activation of innate lymphocytes, serve as maturation signals for DCs. An immunotherapeutic approach which delivers both maturation signals and antigen to DCs would link the innate and adaptive arms of the immune system for a more effective and global immune response. It is therefore crucial to determine optimal conditions for antigen delivery to DCs in an environment suited to maximally stimulate the immune system.

  12. Lipid-Core Nanocapsules Improved Antiedematogenic Activity of Tacrolimus in Adjuvant-Induced Arthritis Model.

    Science.gov (United States)

    Friedrich, Rossana B; Coradini, Karine; Fonseca, Francisco N; Guterres, Silvia S; Beck, Ruy C R; Pohlmann, Adriana R

    2016-02-01

    Despite significant technological advances, rheumatoid arthritis remains an incurable disease with great impact on the life quality of patients. We studied the encapsulation of tacrolimus in lipidcore nanocapsules (TAC-LNC) as a strategy to enhance its systemic anti-arthritic properties. TAC-LNC presented unimodal distribution of particles with z-average diameter of 212 +/- 11, drug content close to the theoretical value (0.80 mg mL(-1)), and 99.43% of encapsulation efficiency. An in vitro sustained release was determined for TAC-LNC with anomalous transport mechanism (n = 0.61). In vivo studies using an arthritis model induced by Complete Freund's Adjuvant demonstrated that the animals treated with TAC-LNC presented a significantly greater inhibition of paw oedema after intraperitoneal administration. Furthermore, the encapsulation of TAC in lipid-core nanocapsules was potentially able to prevent hyperglycemia in the animals. In conclusion, TAC-LNC was prepared with 100% yield of nanoscopic particles having satisfactory characteristics for systemic use. This formulation represents a promising strategy to the treatment of rheumatoid arthritis in the near future.

  13. Patterns of Care in the Administration of Neo-adjuvant Chemotherapy for Breast Cancer. A Population-Based Study.

    Science.gov (United States)

    Vugts, Guusje; Maaskant-Braat, Adriana J G; Nieuwenhuijzen, Grard A P; Roumen, Rudi M H; Luiten, Ernest J T; Voogd, Adri C

    2016-05-01

    Neo-adjuvant chemotherapy (NAC) is used to facilitate radical surgery for initially irresectable or locally advanced breast cancer. The indication for NAC has been extended to clinically node negative (cN0) patients in whom adjuvant systemic therapy is foreseen. A population-based study was conducted to evaluate the increasing use of NAC, breast conserving surgery (BCS) after NAC and timing of the sentinel node biopsy (SNB). All female breast cancer patients, treated in 10 hospitals in the Eindhoven Cancer Registry area in the Netherlands between January 2003 and June 2012 were included (N = 18,427). In total, 1,402 patients (7.6%) received NAC. The administration increased from 2.5% in 2003 to 13.0% in 2011 (p 20% (p < 0.001). Of the 1,402 patients with NAC, 495 patients underwent SNB, 91.5% of whom prior to NAC. In the Netherlands up to one in eight patients receive NAC. The administration of NAC and the percentage of BCS increased over the past decade, especially in cT2 tumors. Considerable hospital variation in the administration of NAC exists.

  14. Immune adjuvant effect of V. cholerae O1 derived Proteoliposome coadministered by intranasal route with Vi polysaccharide from Salmonella Typhi.

    Science.gov (United States)

    Acevedo, Reinaldo; Callicó, Adriana; Aranguren, Yisabel; Zayas, Caridad; Valdés, Yolanda; Pérez, Oliver; García, Luis; Ferro, Valerie A; Pérez, José Luis

    2013-01-01

    The proteoliposome derived from Vibrio cholerae O1 (PLc) is a nanoscaled structure obtained by a detergent extraction process. Intranasal (i.n) administration of PLc was immunogenic at mucosal and systemic level vs. V. cholerae; however the adjuvant potential of this structure for non-cholera antigens has not been proven yet. The aim of this work was to evaluate the effect of coadministering PLc with the Vi polysaccharide antigen (Poli Vi) of S. Typhi by the i.n route. The results showed that Poli Vi coadministered with PLc (PLc+Poli Vi) induce a higher IgA response in saliva (p0.05) to that induced in a group of mice immunised by the parenteral route with the Cuban anti-typhoid vaccine vax-TyVi, although this vaccine did not induce a mucosal response. In conclusion, this work demonstrates that PLc can be used as a mucosal adjuvant to potentiate the immune response against a polysaccharide antigen like Poli Vi.

  15. Development of new therapeutical/adjuvant molecules by pepscan mapping of autophagy and IFN inducing determinants of rhabdoviral G proteins.

    Science.gov (United States)

    Ortega-Villaizan, M; Chico, V; Martinez-Lopez, A; Garcia-Valtanen, P; Coll, J M; Estepa, A

    2016-02-01

    Surface glycoproteins of enveloped virus are potent elicitors of both innate and adaptive host immune responses. Therefore, the identification of viral glycoprotein determinants directly implicated in the induction of these responses might be of special interest for designing new therapeutical/adjuvant molecules. In this work we review the contribution of the "pepscan" approach to the screening of viral functions in the sequence of glycoprotein G (gpG) of the fish rhabdovirus of viral hemorrhagic septicemia (VHSV). Among others, by scanning gpG peptides, it has been possible to identify and validate minimal determinants for gpG directly implicated in initiating the fish type I Interferon-associated immune responses as well as in the antiviral autophagy program. Further fine-tunning of the identified peptides in the gpG of VHSV has allowed designing novel adjuvants that decrease DNA vaccine requirements and identify possible innovative antiviral molecules. In addition, these results have also contributed to improve our knowledge on how to stimulate the fish immune system.

  16. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    Science.gov (United States)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

    In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

  17. Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole.

    Science.gov (United States)

    Carlson, Robert W; Henderson, I Craig

    2003-01-01

    The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that

  18. Antibody-antigen-adjuvant conjugates enable co-delivery of antigen and adjuvant to dendritic cells in cis but only have partial targeting specificity

    NARCIS (Netherlands)

    Kreutz, M.; Giquel, B.; Hu, Q.; Abuknesha, R.; Uematsu, S.; Akira, S.; Nestle, F.O.; Diebold, S.S.

    2012-01-01

    Antibody-antigen conjugates, which promote antigen-presentation by dendritic cells (DC) by means of targeted delivery of antigen to particular DC subsets, represent a powerful vaccination approach. To ensure immunity rather than tolerance induction the co-administration of a suitable adjuvant is par

  19. Simultaneous adjuvant radiotherapy and chemotherapy for stage I and II breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lamb, D.; Dady, P. [Wellington Hospital, Wellington, (New Zealand); Atkinson, C. [Christchurch Hospital, Christchurch, (New Zealand); Joseph, D. [Sir Charles Gairdner Hospital, Nedlands, Perth, (Australia); O`Brien, P.; Ackland, S.; Bonaventura, A.; Hamilton, C.; Stewart, J.; Denham, J. [Newcastle Mater Misericordiae Hospital, Waratah, NSW (Australia); Spry, N. [Geelong Hospital, Geelong, VIC (Australia)

    1999-05-01

    The purpose of the present paper was to evaluate treatment outcome after conservative breast surgery or mastectomy followed by simultaneous adjuvant radiotherapy and cyclophosphamide, methotrexate and fluorouracil (CMF) therapy. Two hundred and sixty eight (268) patients were treated at two Australian and two New Zealand centres between 1981 and July 1995. One hundred and sixty-nine patients underwent conservation surgery and 99 had mastectomies. Median follow-up was 53 months. Conventionally fractionated radiation was delivered simultaneously during the first two cycles of CMF, avoiding radiation on the Fridays that the intravenous components of CMF were delivered. In conservatively treated patients, 5-year actuarial rates of any recurrence, distant recurrence and overall survival were 34.5 {+-} 5.2%, 25.4 {+-} 4.5% and 75.5 {+-} 4.8%, respectively. Crude incidence of local relapse at 4 years was 6.3% and at regional/distant sites was 26.3%. Highest grades of granulocyte toxicity (< 0.5 x 10{sup 9}/L), moist desquamation, radiation pneumonitis and persistent breast oedema were recorded in 10.7, 8.5, 8.9 and 17.2%, respectively. In patients treated by mastectomy, 5-year actuarial rates of any recurrence, distant recurrence and overall survival were 59.7 {+-} 7.3%, 56.7 {+-} 7.4% and 50.1 {+-} 7%. The crude incidence o