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Sample records for adjuvant therapeutic application

  1. Herbal medicines as adjuvants for cancer therapeutics.

    PubMed

    Wang, Chong-Zhi; Calway, Tyler; Yuan, Chun-Su

    2012-01-01

    In the United States, many patients, including cancer patients, concurrently take prescription drugs and herbal supplements. Co-administration of prescription medicines and herbal supplements may have negative outcomes via pharmacodynamic and pharmacokinetic herb-drug interactions. However, multiple constituents in botanicals may also yield beneficial pharmacological activities. Botanicals could possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity. Herbal medicines, such as ginseng, potentiated the effects of chemotherapeutic agents via synergistic activities, supported by cell cycle evaluations, apoptotic observations, and computer-based docking analysis. Since botanicals are nearly always administrated orally, the role of intestinal microbiota in metabolizing ginseng constituents is presented. Controlled clinical studies are warranted to verify the clinical utility of the botanicals in cancer chemoprevention.

  2. Applications of nanomaterials as vaccine adjuvants.

    PubMed

    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.

  3. Exosome removal as a therapeutic adjuvant in cancer.

    PubMed

    Marleau, Annette M; Chen, Chien-Shing; Joyce, James A; Tullis, Richard H

    2012-06-27

    Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30-100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible

  4. Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer.

    PubMed

    Kim, Nam Deuk; Mehta, Rajendra; Yu, Weiping; Neeman, Ishak; Livney, Talia; Amichay, Akiva; Poirier, Donald; Nicholls, Paul; Kirby, Andrew; Jiang, Wenguo; Mansel, Robert; Ramachandran, Cheppail; Rabi, Thangaiyan; Kaplan, Boris; Lansky, Ephraim

    2002-02-01

    lesion formation induced by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The findings suggest that clinical trials to further assess chemopreventive and adjuvant therapeutic applications of pomegranate in human breast cancer may be warranted.

  5. Therapeutic Effects of PADRE-BAFF Autovaccine on Rat Adjuvant Arthritis

    PubMed Central

    Feng, Guo-dong; Xue, Xiao-chang; Gao, Mei-li; Wang, Xian-feng; Shu, Zhen; Mu, Nan; Gao, Yuan; Wang, Zeng-lu; Hao, Qiang; Li, Wei-na; Li, Meng; Zhang, Cun; Zhang, Wei; Zhang, Ying-qi

    2014-01-01

    B cell activating factor (BAFF) is a cytokine of tumor necrosis factor family mainly produced by monocytes and dendritic cells. BAFF can regulate the proliferation, differentiation, and survival of B lymphocytes by binding with BAFF-R on B cell membrane. Accumulating evidences showed that BAFF played crucial roles and was overexpressed in various autoimmune diseases such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). This suggests that BAFF may be a therapeutic target for these diseases. In the present study, we developed a BAFF therapeutic vaccine by coupling a T helper cell epitope AKFVAAWTLKAA (PADRE) to the N terminus of BAFF extracellular domains (PADRE-BAFF) and expressed this fusion protein in Escherichia coli. The purified vaccine can induce high titer of neutralizing BAFF antibodies and ameliorate the syndrome of complete Freund's adjuvant (CFA) induced rheumatoid arthritis in rats. Our data indicated that the BAFF autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with high level of BAFF. PMID:24791002

  6. Biomaterials and therapeutic applications

    NASA Astrophysics Data System (ADS)

    Ferraro, Angelo

    2016-03-01

    A number of organic and inorganic, synthetic or natural derived materials have been classified as not harmful for the human body and are appropriate for medical applications. These materials are usually named biomaterials since they are suitable for introduction into living human tissues of prosthesis, as well as for drug delivery, diagnosis, therapies, tissue regeneration and many other clinical applications. Recently, nanomaterials and bioabsorbable polymers have greatly enlarged the fields of application of biomaterials attracting much more the attention of the biomedical community. In this review paper I am going to discuss the most recent advances in the use of magnetic nanoparticles and biodegradable materials as new biomedical tools.

  7. Leech Therapeutic Applications

    PubMed Central

    Abdualkader, A. M.; Ghawi, A. M.; Alaama, M.; Awang, M.; Merzouk, A.

    2013-01-01

    Hematophagous animals including leeches have been known to possess biologically active compounds in their secretions, especially in their saliva. The blood-sucking annelids, leeches have been used for therapeutic purposes since the beginning of civilization. Ancient Egyptian, Indian, Greek and Arab physicians used leeches for a wide range of diseases starting from the conventional use for bleeding to systemic ailments, such as skin diseases, nervous system abnormalities, urinary and reproductive system problems, inflammation, and dental problems. Recently, extensive researches on leech saliva unveiled the presence of a variety of bioactive peptides and proteins involving antithrombin (hirudin, bufrudin), antiplatelet (calin, saratin), factor Xa inhibitors (lefaxin), antibacterial (theromacin, theromyzin) and others. Consequently, leech has made a comeback as a new remedy for many chronic and life-threatening abnormalities, such as cardiovascular problems, cancer, metastasis, and infectious diseases. In the 20th century, leech therapy has established itself in plastic and microsurgery as a protective tool against venous congestion and served to salvage the replanted digits and flaps. Many clinics for plastic surgery all over the world started to use leeches for cosmetic purposes. Despite the efficacious properties of leech therapy, the safety, and complications of leeching are still controversial. PMID:24019559

  8. Immune adjuvants as critical guides directing immunity triggered by therapeutic cancer vaccines.

    PubMed

    Schijns, Virgil; Tartour, Eric; Michalek, Jaroslav; Stathopoulos, Apostolos; Dobrovolskienė, Neringa T; Strioga, Marius M

    2014-04-01

    Tumor growth is controlled by natural antitumor immune responses alone or by augmented immune reactivity resulting from different forms of immunotherapy, which has demonstrated clinical benefit in numerous studies, although the overall percentage of patients with durable clinical responses remains limited. This is attributed to the heterogeneity of the disease, the inclusion of late-stage patients with no other treatment options and advanced tumor-associated immunosuppression, which may be consolidated by certain types of chemotherapy. Despite variable responsiveness to distinct types of immunotherapy, therapeutic cancer vaccination has shown meaningful efficacy for a variety of cancers. A key step during cancer vaccination involves the appropriate modeling of the functional state of dendritic cells (DCs) capable of co-delivering four critical signals for proper instruction of tumor antigen-specific T cells. However, the education of DCs, either directly in situ, or ex vivo by various complex procedures, lacks standardization. Also, it is questioned whether ex vivo-prepared DC vaccines are superior to in situ-administered adjuvant-guided vaccines, although both approaches have shown success. Evaluation of these variables is further complicated by a lack of consensus in evaluating vaccination clinical study end points. We discuss the role of signals needed for the preparation of classic in situ and modern ex vivo DC vaccines capable of proper reprogramming of antitumor immune responses in patients with cancer.

  9. Potential therapeutic applications of biosurfactants.

    PubMed

    Gudiña, Eduardo J; Rangarajan, Vivek; Sen, Ramkrishna; Rodrigues, Lígia R

    2013-12-01

    Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface activity, these molecules interact with cell membranes of several organisms and/or with the surrounding environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for therapeutic purposes, providing new directions towards the discovery and development of molecules with novel structures and diverse functions for advanced applications.

  10. Oligonucleotide conjugates for therapeutic applications

    PubMed Central

    Winkler, Johannes

    2013-01-01

    Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake machanisms and pharmacokinetic properties. PMID:23883124

  11. Oligonucleotide conjugates for therapeutic applications.

    PubMed

    Winkler, Johannes

    2013-07-01

    Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake mechanisms and pharmacokinetic properties.

  12. Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination.

    PubMed

    Fernández, Audry; Oliver, Liliana; Alvarez, Rydell; Fernández, Luis E; Lee, Kelvin P; Mesa, Circe

    2014-01-01

    Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines.

  13. Clinical applications of therapeutic phlebotomy

    PubMed Central

    Kim, Kyung Hee; Oh, Ki Young

    2016-01-01

    Phlebotomy is the removal of blood from the body, and therapeutic phlebotomy is the preferred treatment for blood disorders in which the removal of red blood cells or serum iron is the most efficient method for managing the symptoms and complications. Therapeutic phlebotomy is currently indicated for the treatment of hemochromatosis, polycythemia vera, porphyria cutanea tarda, sickle cell disease, and nonalcoholic fatty liver disease with hyperferritinemia. This review discusses therapeutic phlebotomy and the related disorders and also offers guidelines for establishing a therapeutic phlebotomy program. PMID:27486346

  14. Angiotensin II type 2 receptor correlates with therapeutic effects of losartan in rats with adjuvant-induced arthritis.

    PubMed

    Wang, Di; Hu, Shanshan; Zhu, Jie; Yuan, Jun; Wu, Jingjing; Zhou, Aiwu; Wu, Yujing; Zhao, Wendi; Huang, Qiong; Chang, Yan; Wang, Qingtong; Sun, Wuyi; Wei, Wei

    2013-12-01

    The angiotensin II type 1 receptor (AT1R) blocker losartan ameliorates rheumatoid arthritis (RA) in an experimental model. In RA, AT2R mainly opposes AT1R, but the mechanism by which this occurs still remains obscure. In the present study, we investigated the role of AT2R in the treatment of rats with adjuvant-induced arthritis (AIA) by losartan. Adjuvant-induced arthritis rats were treated with losartan (5, 10 and 15 mg/kg) and methotrexate (MTX; 0.5 mg/kg) in vivo from day 14 to day 28. Arthritis was evaluated by the arthritis index and histological examination. Angiotensin II, tumour necrosis factor-α, and VEGF levels were examined by ELISA. The expression of AT1R and AT2R was detected by western blot and immunohistochemistry analysis. After stimulation with interleukin-1β in vitro, the effects of the AT2R agonist CGP42112 (10(-8) -10(-5)  M) on the chemotaxis of monocytes induced by 10% foetal calf serum (FCS) were analysed by using Transwell assay. Subsequently, the therapeutic effects of CGP42112 (5, 10 and 20 μg/kg) were evaluated in vivo by intra-articular injection in AIA rats. After treatment with losartan, the down-regulation of AT1R expression and up-regulation of AT2R expression in the spleen and synovium of AIA rats correlated positively with reduction in the polyarthritis index. Treatment with CGP42112 inhibited the chemotaxis of AIA monocytes in vitro, possibly because of the up-regulation of AT2R expression. Intra-articular injection with CGP42112 (10 and 20 μg/kg) ameliorated the arthritis index and histological signs of arthritis. In summary, the present study strongly suggests that the up-regulation of AT2R might be an additional mechanism by which losartan exerts its therapeutic effects in AIA rats.

  15. Therapeutic efficacy of cancer stem cell vaccines in the adjuvant setting

    PubMed Central

    Hu, Yangyang; Lu, Lin; Xia, Yang; Chen, Xin; Chang, Alfred E.; Hollingsworth, Robert E; Hurt, Elaine; Owen, John; Moyer, Jeffrey S.; Prince, Mark E.P.; Dai, Fu; Bao, Yangyi; Wang, Yi; Whitfield, Joel; Xia, Jian-chuan; Huang, Shiang; Wicha, Max S.; Li, Qiao

    2016-01-01

    Dendritic cell (DC)-based vaccine strategies aimed at targeting cancer stem-like cells (CSC) may be most efficacious if deployed in the adjuvant setting. In this study, we offer preclinical evidence this is the case for a CSC-DC vaccine as tested in murine models of SCC7 squamous cell cancer and D5 melanoma. Vaccination of mice with an ALDHhigh SCC7 CSC-DC vaccine after surgical excision of established SCC7 tumors reduced local tumor relapse and prolonged host survival. This effect was augmented significantly by simultaneous administration of anti-PD-L1, an immune checkpoint inhibitor. In the minimal disease setting of D5 melanoma, treatment of mice with ALDHhigh CSC-DC vaccination inhibited primary tumor growth, reduced spontaneous lung metastases and increased host survival. In this setting, CCR10 and its ligands were downregulated on ALDHhigh D5 CSCs and in lung tissues respectively after vaccination with ALDHhigh D5 CSC-DC. RNAi-mediated attenuation of CCR10 blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from mice vaccinated with ALDHhigh D5 CSC-DC selectively killed ALDHhigh D5 CSCs, with additional evidence of humoral immunological engagement and a reduction in ALDHhigh cells in residual tumors. Overall, our results offered a preclinical proof of concept for the use of ALDHhigh CSC-DC vaccines in the adjuvant setting to more effectively limit local tumor recurrence and spontaneous pulmonary metastasis, as compared with traditional DC vaccines, with increased host survival further accentuated by simultaneous PD-L1 blockade. PMID:27325649

  16. Review of therapeutic options for adjuvant treatment of focal seizures in epilepsy: focus on lacosamide.

    PubMed

    Becerra, Juan Luis; Ojeda, Joaquín; Corredera, Enrique; Ruiz Giménez, Jesús

    2011-12-05

    Epilepsy is one of the most common serious neurological conditions worldwide, with an age-adjusted incidence of approximately 50 per 100,000 persons per year in developed countries. Antiepileptic therapy can result in long-term remission in 60-70% of patients, but many patients will require combination treatment to achieve optimal seizure control, as monotherapy is ineffective at controlling seizures in 30-53% of patients. Despite the increase in available treatment options, patient outcomes have not improved significantly and there is still a need for more effective therapies. Drugs used in the treatment of focal-onset seizures are a diverse range of compounds, and in most cases their mechanism of action is unknown or poorly defined. This review discusses the efficacy and safety of the newer adjuvant antiepileptic therapies that may improve outcomes in patients unresponsive to monotherapy, including clobazam, vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam, oxcarbazepine, pregabalin, zonisamide and eslicarbazepine, with focus on lacosamide. Lacosamide has been shown to exert its anticonvulsant effects predominantly by enhancement of the slow inactivation of voltage-gated sodium channels. Lacosamide is indicated for use as adjuvant treatment of focal-onset seizures in patients with epilepsy, and there is some evidence that it may also be of use in patients with status epilepticus and cancer patients with epilepsy. The efficacy of lacosamide has been assessed in three randomized, double-blind, placebo-controlled clinical trials, all of which have shown lacosamide to be effective at reducing seizure frequency and increasing 50% responder rates in patients with focal-onset seizures. Long-term lacosamide treatment is generally well tolerated and is not associated with significant drug interactions; the availability of an intravenous form of the drug also makes it particularly useful for a broad range of patients.

  17. Therapeutic Vaccination against Adjuvant Arthritis Using Autoimmune T Cells Treated with Hydrostatic Pressure

    NASA Astrophysics Data System (ADS)

    Lider, Ofer; Karin, Nathan; Shinitzky, Meir; Cohen, Irun R.

    1987-07-01

    An ideal treatment for autoimmune diseases would be a nontoxic means of specifically neutralizing the autoreactive lymphocytes responsible for the disease. This goal has been realized in experimental autoimmunity models by immunizing rats or mice against their own autoimmune cells such that the animals generate an immune response specifically repressive to the disease-producing lymphocytes. This maneuver, termed lymphocyte vaccination, was demonstrated to be effective using some, but not all, autoimmune helper T-lymphocyte lines. We now report that T lymphocytes, otherwise incapable of triggering an immune response, can be transformed into effective immunogens by treating the cells in vitro with hydrostatic pressure. Clone A2b, as effector clone that recognized cartilage proteoglycan and caused adjuvant arthritis in Lewis rats, is such a cell. Untreated A2b could not trigger an immune response, but inoculating rats with pressure-treated A2b induced early remission of established adjuvant arthritis as well as resistance to subsequent disease. Specific resistance to arthritis was associated with anti-idiotypic T-cell reactivity to clone A2b and could be transferred from vaccinated rats to naive recipients using donor lymphoid cells. Aggregation of T-lymphocyte membrane components appeared to be important for an immune response because the effects of hydrostatic pressure could be reproduced by treatment of A2b with chemical cross-linkers or with agents disrupting the cytoskeleton. Populations of lymph node cells from antigen-primed rats, when treated with hydrostatic pressure, could also induce suppression of disease. Thus, effective vaccines can be developed without having to isolate the autoimmune T lymphocytes as lines or clones. These results demonstrate that effector T lymphocytes suitably treated may serve as agents for specifically controlling the immune system.

  18. Enzymosomes with surface-exposed superoxide dismutase: in vivo behaviour and therapeutic activity in a model of adjuvant arthritis.

    PubMed

    Gaspar, Maria Manuela; Boerman, Otto C; Laverman, Peter; Corvo, Maria Luísa; Storm, Gert; Cruz, Maria Eugénia Meirinhos

    2007-02-12

    Acylated Superoxide Dismutase (Ac-SOD) enzymosomes, liposomal enzymatic systems expressing catalytic activity in the intact form, were previously characterized. The main scope of the present work was to investigate the biological behaviour of Ac-SOD inserted in the lipid bilayer of liposomes, in comparison with SOD located in the aqueous compartment of liposomes. Two types of liposomes were used: conventional liposomes presenting an unmodified external surface and long circulating liposomes coated with poly (ethylene glycol) (PEG). Liposomal formulations of Ac-SOD and SOD were prepared and labelled with indium-111 and their in vivo fate compared. Data obtained led us to the conclusion that, for liposomes coated with PEG the in vivo fate was not influenced by the insertion of Ac-SOD in the lipid bilayers. The potential therapeutic effect of Ac-SOD enzymosomes was compared with SOD liposomes in a rat model of adjuvant arthritis. A faster anti-inflammatory effect was observed for Ac-SOD enzymosomes by monitoring the volume of the inflamed paws. The present results allowed us to conclude that Ac-SOD enzymosomes are nano-carriers combining the advantages of expressing enzymatic activity in intact form and thus being able to exert therapeutic effect even before liposomes disruption, as well as acting as a sustained release of the enzyme.

  19. Testing a Protocol for a Randomized Controlled Trial of Therapeutic versus Placebo Shoulder Strapping as an Adjuvant Intervention Early after Stroke.

    PubMed

    Appel, Caroline; Perry, Lin; Jones, Fiona

    2015-06-01

    This study tested a protocol for a randomized controlled trial of therapeutic versus placebo shoulder strapping as an adjuvant intervention early after stroke. Despite widespread use, there is little evidence of the efficacy or acceptability of shoulder strapping to improve arm function in patients with shoulder paresis following stroke. This study tested a protocol designed to trial shoulder strapping as an adjuvant therapy in patients with shoulder paresis after stroke and tested its acceptability for patients and clinical staff. A multiple-method design comprised one quantitative randomized, double-blind, placebo-controlled study and two qualitative exploratory investigations entailing patient interviews and staff surveys. Seventeen sub-acute stroke patients with shoulder paresis were recruited in London stroke service settings between November 2007 and December 2009. Outcomes from a 4-week therapeutic strapping protocol were compared with those of placebo strapping as an adjunct to conventional rehabilitation. Minimal adverse events and greater improvement in arm function (Action Research Arm Test) were seen with therapeutic compared with placebo strapping (effect size 0.34). Patients and staff found the strapping acceptable with minimal adverse effects. This study provided data for sample size calculation and demonstrated a workable research protocol to investigate the efficacy of shoulder strapping as an adjuvant intervention to routine rehabilitation for stroke patients. Small-scale findings continue to flag the importance of investigating this topic. The protocol is recommended for a definitive trial of shoulder strapping as an adjuvant intervention.

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

    PubMed Central

    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

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

    PubMed

    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

    2013-12-02

    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.

  2. Therapeutic Applications of Ionizing Radiations

    NASA Astrophysics Data System (ADS)

    Sánchez-Santos, María Elena

    The aim of radiation therapy is to deliver a precisely measured dose of radiation to a defined tumour volume with minimal damage to the surrounding healthy tissue, resulting in the eradication of the tumour, a higher quality of life with palliation of symptoms of the disease, and the prolongation of survival at competitive cost. Together with surgery and pharmacology, radiotherapy is presently one of the most important therapeutical weapons against cancer. This chapter provides an overview of the clinical use of radiation, with emphasis on the optimisation of treatment planning and delivery, and a top level summary of state-of-the-art techniques in radiation therapy.

  3. Metformin as an Adjuvant Drug against Pediatric Sarcomas: Hypoxia Limits Therapeutic Effects of the Drug

    PubMed Central

    Garofalo, Cecilia; Capristo, Mariantonietta; Manara, Maria Cristina; Mancarella, Caterina; Landuzzi, Lorena; Belfiore, Antonino; Lollini, Pier-Luigi; Picci, Piero; Scotlandi, Katia

    2013-01-01

    Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas. PMID:24391834

  4. Application of “Systems Vaccinology” to Evaluate Inflammation and Reactogenicity of Adjuvanted Preventative Vaccines

    PubMed Central

    Lewis, David J. M.; Lythgoe, Mark P.

    2015-01-01

    Advances in “omics” technology (transcriptomics, proteomics, metabolomics, genomics/epigenomics, etc.) allied with statistical and bioinformatics tools are providing insights into basic mechanisms of vaccine and adjuvant efficacy or inflammation/reactogenicity. Predictive biomarkers of relatively frequent inflammatory reactogenicity may be identified in systems vaccinology studies involving tens or hundreds of participants and used to screen new vaccines and adjuvants in in vitro, ex vivo, animal, or human models. The identification of rare events (such as those observed with initial rotavirus vaccine or suspected autoimmune complications) will require interrogation of large data sets and population-based research before application of systems vaccinology. The Innovative Medicine Initiative funded public-private project BIOVACSAFE is an initial attempt to systematically identify biomarkers of relatively common inflammatory events after adjuvanted immunization using human, animal, and population-based models. Discriminatory profiles or biomarkers are being identified, which require validation in large trials involving thousands of participants before they can be generalized. Ultimately, it is to be hoped that the knowledge gained from such initiatives will provide tools to the industry, academia, and regulators to select optimal noninflammatory but immunogenic and effective vaccine adjuvant combinations, thereby shortening product development cycles and identifying unsuitable vaccine candidates that would fail in expensive late stage development or postmarketing. PMID:26380327

  5. [Glucomannan: properties and therapeutic applications].

    PubMed

    González Canga, A; Fernández Martínez, N; Sahagún, A M; García Vieitez, J J; Díez Liébana, M J; Calle Pardo, A P; Castro Robles, L J; Sierra Vega, M

    2004-01-01

    Glucomannan is a dietary fiber employed quite frequently in the western countries since two decades now, as its ingestion plays an important role in human health. However, eastern people have used this fiber for more than a thousand years. This dietary fiber is the main polysaccharide obtain from the tubers of the Amorphophallus konjac plant, a member of the family Araceae found in east Asia. The chemical structure of glucomannan consists, mainly, in mannose and glucose in the ratio 8:5 linked by beta (1-->4) glycosidic bonds. This soluble fiber has a extraordinarily high waterholding capacity, forming highly viscous solutions when dissolved in water. It has the highest molecular weight and viscosity of any known dietary fiber. It has been demonstrated that this product is highly effective in the treatment of obesity due to the satiety sensation that it produces; as a remedy for constipation, because it increases the faeces volume; as hypocholesterolemic agent, interfering in the transport of cholesterol and of bile acids and as hypoglycemic and hypoinsulinemic agent, probably, by delaying gastric emptying and slowering glucose delivery to the intestinal mucosa. To the beneficial properties of this fiber, several disadvantages can be added as the production of flatulence, abdominal pain, esophageal obstruction, lower gastrointestinal obstruction or even the possible modification of the bioavailability of other drugs. This paper reviews the main characteristics of glucomannan, as well as its properties, physiologic effects and therapeutic uses.

  6. Magnetic Microspheres for Therapeutical Applications

    NASA Technical Reports Server (NTRS)

    Mazuruk, K.; Ramachandran, N.; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady. The basic obstacle of the present heating methods are non-uniform thermal properties of the tissue. Our approach is to develop a novel class of magnetic fluids which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as a suitable nano-particle material. The objective is to synthesize, characterize and evaluate the efficacy of TRMF for hyperthermia therapy.

  7. Synthetic biology for therapeutic applications.

    PubMed

    Abil, Zhanar; Xiong, Xiong; Zhao, Huimin

    2015-02-02

    Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders.

  8. Synthetic Biology for Therapeutic Applications

    PubMed Central

    2015-01-01

    Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders. PMID:25098838

  9. Applications of inorganic nanoparticles as therapeutic agents

    NASA Astrophysics Data System (ADS)

    Kim, Taeho; Hyeon, Taeghwan

    2014-01-01

    During the last decade, various functional nanostructured materials with interesting optical, magnetic, mechanical and chemical properties have been extensively applied to biomedical areas including imaging, diagnosis and therapy. In therapeutics, most research has focused on the application of nanoparticles as potential delivery vehicles for drugs and genes, because nanoparticles in the size range of 2-100 nm can interact with biological systems at the molecular level, and allow targeted delivery and passage through biological barriers. Recent investigations have even revealed that several kinds of nanomaterials are intrinsically therapeutic. Not only can they passively interact with cells, but they can also actively mediate molecular processes to regulate cell functions. This can be seen in the treatment of cancer via anti-angiogenic mechanisms as well as the treatment of neurodegenerative diseases by effectively controlling oxidative stress. This review will present recent applications of inorganic nanoparticles as therapeutic agents in the treatment of disease.

  10. Silver nanoparticles: synthesis, properties, and therapeutic applications

    PubMed Central

    Wei, Liuya; Lu, Jingran; Xu, Huizhong; Patel, Atish; Chen, Zhe-Sheng; Chen, Guofang

    2014-01-01

    Silver nanoparticles (AgNPs) have been widely used in biomedical fields because of their intrinsic therapeutic properties. Here, we introduce methods of synthesizing AgNPs and discuss their physicochemical, localized surface plasmon resonance (LSPR) and toxicity properties. We also review the impact of AgNPs on human health and the environment along with the underlying mechanisms. More importantly, we highlight the newly emerging applications of AgNPs as antiviral agents, photosensitizers and/or radiosensitizers, and anticancer therapeutic agents in the treatment of leukemia, breast cancer, hepatocellular carcinoma, lung cancer, and skin and/or oral carcinoma. PMID:25543008

  11. Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

    PubMed

    Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat

    2016-01-01

    Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues.

  12. Therapeutic and diagnostic applications of nanoparticles.

    PubMed

    Youns, Mahmoud; Hoheisel, Jörg D; Efferth, Thomas

    2011-03-01

    Nanoparticles are sphere-like biocompatible materials made of inert silica, metal or crystals of a few nanometers in size. They are emerging as a novel class of therapeutics for cancer treatment. Being more selective and specific toward their targets, nanoparticles have the ability to enhance the anticancer effects and to simultaneously reduce systemic toxicity compared with conventional therapeutics. Furthermore, they offer the potential to overcome drug resistance leading to higher intracellular drug accumulation. Nowadays, nanotechnologies are applied to molecular diagnostics and incorporated in cutting-edge molecular diagnostic methods, such as DNA and protein microarray biochips. Nanotechnologies enable diagnosis at the single-cell and single-molecule levels. Recent progress in cancer nanotechnology raises exciting opportunities for specific drug delivery. The purpose of this review is to give an overview about different types of nanoparticles and to summarize the latest results regarding their diagnostic and therapeutic applications in the clinic with more focus on cancer treatment. Furthermore, we discuss opportunities, limitations, and challenges faced by therapeutic nanoparticles.

  13. A Vaxfectin(®)-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes.

    PubMed

    Veselenak, Ronald L; Shlapobersky, Mark; Pyles, Richard B; Wei, Qun; Sullivan, Sean M; Bourne, Nigel

    2012-11-19

    Here we describe studies in the guinea pig model of genital herpes to evaluate a novel plasmid DNA (pDNA) vaccine encoding the HSV-2 glycoprotein D and UL46 and UL47 genes encoding tegument proteins VP11/12 and VP 13/14 (gD2/UL46/UL47), formulated with a cationic lipid-based adjuvant Vaxfectin(®). Prophylactic immunization with Vaxfectin(®)-gD2/UL46/UL47 significantly reduced viral replication in the genital tract, provided complete protection against both primary and recurrent genital skin disease following intravaginal HSV-2 challenge, and significantly reduced latent HSV-2 DNA in the dorsal root ganglia compared to controls. We also examined the impact of therapeutic immunization of HSV-2 infected animals. Here, Vaxfectin(®)-gD2/UL46/UL47 immunization significantly reduced both the frequency of recurrent disease and viral shedding into the genital tract compared to controls. This novel adjuvanted pDNA vaccine has demonstrated both prophylactic and therapeutic efficacy in the guinea pig model of genital herpes and warrants further development.

  14. Atherosclerosis and Nanotechnology: Diagnostic and Therapeutic Applications.

    PubMed

    Kratz, Jeremy D; Chaddha, Ashish; Bhattacharjee, Somnath; Goonewardena, Sascha N

    2016-02-01

    Over the past several decades, tremendous advances have been made in the understanding, diagnosis, and treatment of coronary artery disease (CAD). However, with shifting demographics and evolving risk factors we now face new challenges that must be met in order to further advance are management of patients with CAD. In parallel with advances in our mechanistic appreciation of CAD and atherosclerosis, nanotechnology approaches have greatly expanded, offering the potential for significant improvements in our diagnostic and therapeutic management of CAD. To realize this potential we must go beyond to recognize new frontiers including knowledge gaps between understanding atherosclerosis to the translation of targeted molecular tools. This review highlights nanotechnology applications for imaging and therapeutic advancements in CAD.

  15. Atherosclerosis and Nanotechnology: Diagnostic and Therapeutic Applications

    PubMed Central

    Kratz, Jeremy D.; Chaddha, Ashish; Bhattacharjee, Somnath

    2016-01-01

    Over the past several decades, tremendous advances have been made in the understanding, diagnosis, and treatment of coronary artery disease (CAD). However, with shifting demographics and evolving risk factors we now face new challenges that must be met in order to further advance are management of patients with CAD. In parallel with advances in our mechanistic appreciation of CAD and atherosclerosis, nanotechnology approaches have greatly expanded, offering the potential for significant improvements in our diagnostic and therapeutic management of CAD. To realize this potential we must go beyond to recognize new frontiers including knowledge gaps between understanding atherosclerosis to the translation of targeted molecular tools. This review highlights nanotechnology applications for imaging and therapeutic advancements in CAD. PMID:26809711

  16. Patented herbal formulations and their therapeutic applications.

    PubMed

    Musthaba, Mohamed; Baboota, Sanjula; Athar, Tanwir M D; Thajudeen, Kamal Y; Ahmed, Sayeed; Ali, Javed

    2010-11-01

    Recently, there is a greater global interest in non synthetic, natural medicines derived from plant sources due to better tolerance and minimum adverse drug reactions as compared to synthetic medicines. Herbal products are also commonly used by the patients with certain chronic medical conditions, including breast cancer, liver disease, human immunodeficiency, asthma and rheumatological disorders. WHO estimates that about three-quarters of the world's population currently uses herbs and other forms of traditional medicines for the treatment of various diseases. The herbs are formulated in different modern dosage forms, such as Tablets, Capsules, Topical cream, Gel, Ointment and even some novel drug delivery forms, like extended release, sustained release, and microencapsules dosage forms. Patenting of herbal formulations has increased over the past few years and scientific evidence of therapeutic activity has been reported by performing various in vitro and in vivo experiments. This manuscript deals with various patented herbal formulations with their therapeutic application against various diseases.

  17. Bee Pollen: Chemical Composition and Therapeutic Application

    PubMed Central

    Komosinska-Vassev, Katarzyna; Olczyk, Pawel; Kaźmierczak, Justyna; Olczyk, Krystyna

    2015-01-01

    Bee pollen is a valuable apitherapeutic product greatly appreciated by the natural medicine because of its potential medical and nutritional applications. It demonstrates a series of actions such as antifungal, antimicrobial, antiviral, anti-inflammatory, hepatoprotective, anticancer immunostimulating, and local analgesic. Its radical scavenging potential has also been reported. Beneficial properties of bee pollen and the validity for their therapeutic use in various pathological condition have been discussed in this study and with the currently known mechanisms, by which bee pollen modulates burn wound healing process. PMID:25861358

  18. Therapeutic Effects of Acetone Extract of Saraca asoca Seeds on Rats with Adjuvant-Induced Arthritis via Attenuating Inflammatory Responses

    PubMed Central

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

    Saraca asoca has been traditionally used in Indian system for treatment of uterine, genital, and other reproductive disorders in women, fever, pain, and inflammation. The hypothesis of this study is that acetone extract of Saraca asoca seeds is an effective anti-inflammatory treatment for arthritis in animal experiments. The antiarthritic effect of its oral administration on Freund's adjuvant-induced arthritis has been studied in Wistar albino rats after acute and subacute toxicities. Phytochemical analysis revealed presence of high concentrations of phenolic compounds such as flavonoids and tannins, while no mortality or morbidity was observed up to 1000 mg/kg dose during acute and subacute toxicity assessments. Regular treatment up to 21 days of adjuvant-induced arthritic rats with Saraca asoca acetone extract (at 300 and 500 mg/kg doses) increases RBC and Hb, decreases WBC, ESR, and prostaglandin levels in blood, and restores body weight when compared with control (normal saline) and standard (Indomethacin) groups. Significant (P < 0.05) inhibitory effect was observed especially at higher dose on paw edema, ankle joint inflammation, and hydroxyproline and glucosamine concentrations in urine. Normal radiological images of joint and histopathological analysis of joint, liver, stomach, and kidney also confirmed its significant nontoxic, antiarthritic, and anti-inflammatory effect. PMID:24729890

  19. Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan.

    PubMed

    Nakayama, Takahiro; Noguchi, Shinzaburo

    2010-01-01

    In Japan, the history of postoperative chemotherapy for breast cancer started with 5-fluorouracil (5-FU), launched in the 1980s. Currently, oral fluoropyrimidine-based regimens indicated for the treatment of breast cancer in Japan include tegafur plus uracil (UFT); tegafur, gimeracil, and oteracil (TS-1); doxifluridine; and capecitabine. In particular, UFT represents an important option for long-term treatment because of minimal adverse events and the potential for long-term maintenance of effective plasma concentrations of 5-FU to inhibit micrometastasis after surgery. Therefore, various clinical studies of postoperative adjuvant chemotherapy with UFT have been conducted in patients with completely resected tumors. Recent studies have shown that UFT prolongs survival after tumor resection in patients with gastric cancer, colorectal cancer, and lung cancer. In patients with breast cancer, large clinical trials of UFT-based postoperative chemotherapy conducted in Japan have shown that UFT is useful for the treatment of intermediate-risk patients with no lymph node metastasis. This paper reviews the results of clinical studies of UFT conducted in Japan to assess the therapeutic usefulness of this oral 5-FU. The types of patients most likely to benefit from UFT are discussed on the basis of currently available evidence and a global consensus of treatment recommendations. The optimal timing of endocrine therapy and strategies for postoperative adjuvant chemotherapy with UFT in patients with breast cancer are also discussed.

  20. Protein prenylation: enzymes, therapeutics, and biotechnology applications.

    PubMed

    Palsuledesai, Charuta C; Distefano, Mark D

    2015-01-16

    Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a geranylgeranyl isoprenoid. It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins. Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity. Here, we review the biochemistry of the prenyltransferase enzymes and numerous isoprenoid analogs synthesized to investigate various aspects of prenylation and prenyltransferases. We also give an account of the current status of prenyltransferase inhibitors as potential therapeutics against several diseases including cancers, progeria, aging, parasitic diseases, and bacterial and viral infections. Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.

  1. Meningioma Genomics: Diagnostic, Prognostic, and Therapeutic Applications

    PubMed Central

    Bi, Wenya Linda; Zhang, Michael; Wu, Winona W.; Mei, Yu; Dunn, Ian F.

    2016-01-01

    There has been a recent revolution in our understanding of the genetic factors that drive meningioma, punctuating an equilibrium that has existed since Cushing’s germinal studies nearly a century ago. A growing appreciation that meningiomas share similar biologic features with other malignancies has allowed extrapolation of management strategies and lessons from intra-axial central nervous system neoplasms and systemic cancers to meningiomas. These features include a natural proclivity for invasion, frequent intratumoral heterogeneity, and correlation between biologic profile and clinical behavior. Next-generation sequencing has characterized recurrent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA, which are collectively present in ~80% of sporadic meningiomas. Genomic features of meningioma further associate with tumor location, histologic subtype, and possibly clinical behavior. Such genomic decryption, along with advances in targeted pharmacotherapy, provides a maturing integrated view of meningiomas. We review recent advances in meningioma genomics and probe their potential applications in diagnostic, therapeutic, and prognostic frontiers. PMID:27458586

  2. Therapeutic and prophylactic applications of alphavirus vectors.

    PubMed

    Atkins, Gregory J; Fleeton, Marina N; Sheahan, Brian J

    2008-11-11

    Alphavirus vectors are high-level, transient expression vectors for therapeutic and prophylactic use. These positive-stranded RNA vectors, derived from Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, multiply and are expressed in the cytoplasm of most vertebrate cells, including human cells. Part of the genome encoding the structural protein genes, which is amplified during a normal infection, is replaced by a transgene. Three types of vector have been developed: virus-like particles, layered DNA-RNA vectors and replication-competent vectors. Virus-like particles contain replicon RNA that is defective since it contains a cloned gene in place of the structural protein genes, and thus are able to undergo only one cycle of expression. They are produced by transfection of vector RNA, and helper RNAs encoding the structural proteins. Layered DNA-RNA vectors express the Semliki Forest virus replicon from a cDNA copy via a cytomegalovirus promoter. Replication-competent vectors contain a transgene in addition to the structural protein genes. Alphavirus vectors are used for three main applications: vaccine construction, therapy of central nervous system disease, and cancer therapy.

  3. The Therapeutic Recreation Professional: Microcomputer Applications.

    ERIC Educational Resources Information Center

    Beland, Robert M.

    1984-01-01

    Therapeutic recreation professionals can work with computer specialists to develop uses for microcomputers with special populations. Computers can help sensory-impaired individuals, physically disabled, the aged, and special education students. Computer professionals benefit from receiving feedback from therapeutic recreation professionals on…

  4. Topical dermal application of essential oils attenuates the severity of adjuvant arthritis in Lewis rats

    PubMed Central

    Komeh-Nkrumah, Steva A.; Nanjundaiah, Siddaraju M.; Rajaiah, Rajesh; Yu, Hua; Moudgil, Kamal D.

    2011-01-01

    This study was aimed at examining the effect of an ointment containing essential oils (EO) on the severity of adjuvant arthritis (AA), an experimental model of human rheumatoid arthritis (RA), in Lewis rats and to define the underlying mechanisms. At the onset of AA, rats received topical application twice daily of ointment containing 20% EO or placebo ointment. The synovial fluid (SF) and synovium-infiltrating cells (SIC) of rats were tested for pro-inflammatory cytokines TNF-α and IL-1β. The hind paws and skin were examined histologically. The activity/level of matrix metalloproteinases (MMPs) and anti-mycobacterial heat-shock protein 65 (Bhsp65) antibodies was tested. Arthritic rats treated with ointment containing EO developed less severe clinical arthritis compared to the controls, and this activity was attributable to EO and not the carrier oil. The levels of TNF-α and IL-1β, and the activity of MMPs in SF and SIC-lysate were significantly (p<0.05) reduced in EO-treated arthritic rats compared to the controls. However, the levels of anti-Bhsp65 antibodies were unaffected by treatment. Thus, topical dermal delivery of EO-containing ointment downmodulates the severity of AA in Lewis rats by inhibiting defined mediators of inflammation. Such ointments should be tested in patients with RA and other arthritic conditions. PMID:21544881

  5. Applications of polymeric adjuvants in studying autoimmune responses and vaccination against infectious diseases

    PubMed Central

    Shakya, Akhilesh Kumar; Nandakumar, Kutty Selva

    2013-01-01

    Polymers as an adjuvant are capable of enhancing the vaccine potential against various infectious diseases and also are being used to study the actual autoimmune responses using self-antigen(s) without involving any major immune deviation. Several natural polysaccharides and their derivatives originating from microbes and plants have been tested for their adjuvant potential. Similarly, numerous synthetic polymers including polyelectrolytes, polyesters, polyanhydrides, non-ionic block copolymers and external stimuli responsive polymers have demonstrated adjuvant capacity using different antigens. Adjuvant potential of these polymers mainly depends on their solubility, molecular weight, degree of branching and the conformation of polymeric backbone. These polymers have the ability not only to activate humoral but also cellular immune responses in the host. The depot effect, which involves slow release of antigen over a long duration of time, using different forms (particulate, solution and gel) of polymers, and enhances the co-stimulatory signals for optimal immune activation, is the underlying principle of their adjuvant properties. Possibly, polymers may also interact and activate various toll-like receptors and inflammasomes, thus involving several innate immune system players in the ensuing immune response. Biocompatibility, biodegradability, easy production and purification, and non-toxic properties of most of the polymers make them attractive candidates for substituting conventional adjuvants that have undesirable effects in the host. PMID:23173193

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

    NASA Astrophysics Data System (ADS)

    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.

  7. Refractory heparin induced thrombocytopenia with thrombosis (HITT) treated with therapeutic plasma exchange and rituximab as adjuvant therapy.

    PubMed

    Schell, Amy M; Petras, Melissa; Szczepiorkowski, Zbigniew M; Ornstein, Deborah L

    2013-10-01

    We report a case of refractory heparin-induced thrombocytopenia with thrombosis (HITT) with prolonged thrombocytopenia and multiple thrombotic complications that failed to improve despite aggressive treatment. A 60 year old female with a prior history of venous thromboembolism was admitted with an acute pulmonary embolism, and developed HITT after several days on heparin therapy. She suffered multiple complications including bilateral venous limb gangrene, acute renal failure, and refractory thrombocytopenia, leading us to use multimodality therapy including therapeutic plasma exchange (TPE) and rituximab immunosuppression. The patient had transient improvements in her thrombocytopenia with TPE, and rituximab was added in an attempt to reduce antibody production. She eventually required bilateral limb amputation, and only after removal of the gangrenous limbs did her platelet count show sustained improvement. We discuss the possible contribution of infection to her prolonged course.

  8. Therapeutic effects of total steroid saponin extracts from the rhizome of Dioscorea zingiberensis C.H.Wright in Freund’s complete adjuvant induced arthritis in rats

    PubMed Central

    Zhang, Xin-xin; Ito, Yoichiro; Liang, Jin-ru; Liu, Jian-li; He, Jiao; Sun, Wen-ji

    2014-01-01

    The aim of our present study is to explore the anti-arthritic potential effect of total steroid saponins (TSSN) extracted from the rhizome of Dioscorea zingiberensis C.H.Wright (DZW) and to investigate the underlying mechanisms. This work was performed using adjuvant-induced arthritis (AIA) rats in vivo and lipopolysaccharide (LPS) simulated 264.7 macrophage cells in vitro. In AIA-induced arthritic rats, TSSN significantly alleviated the arthritic progression through evaluating arthritic score, immune organ indexes, paw swelling, and body weight. This phenomenon was well correlated with significant suppression of the overproduction of inflammation cytokines (IL-1, IL-1β, IL-6, and TNF-α), oxidant stress makers (MDA and NO), eicosanoids (LTB4 and PGE2), and inflammatory enzymes (5-LOX and COX-2) versus the AIA rats without treatment. On the contrary, the release of SOD and IL-10 was profoundly increased. What’s more, TSSN could obviously ameliorate the translocation of NF-κB to the nucleus through phosphorylation of the p65 and IκBα in vivo and vitro. The current findings demonstrated that TSSN could protect the injured ankle joint from further deterioration and exert its satisfactory anti-arthritis properties through anti-inflammatory and anti-oxidant effects via inactivating NF-κB signal pathway. This research implies that DZW may be a useful therapeutic agent for the treatment of human arthritis. PMID:25066758

  9. Therapeutic effects of total steroid saponin extracts from the rhizome of Dioscorea zingiberensis C.H.Wright in Freund's complete adjuvant induced arthritis in rats.

    PubMed

    Zhang, Xin-xin; Ito, Yoichiro; Liang, Jin-ru; Liu, Jian-li; He, Jiao; Sun, Wen-ji

    2014-12-01

    The aim of our present study is to explore the anti-arthritic potential effect of total steroid saponins (TSSNs) extracted from the rhizome of Dioscorea zingiberensis C.H.Wright (DZW) and to investigate the underlying mechanisms. This work was performed using adjuvant-induced arthritis (AIA) rats in vivo and lipopolysaccharide (LPS) simulated 264.7 macrophage cells in vitro. In AIA-induced arthritic rats, TSSN significantly alleviated the arthritic progression through evaluating arthritic score, immune organ indexes, paw swelling, and body weight. This phenomenon was well correlated with significant suppression of the overproduction of inflammation cytokines (IL-1, IL-1β, IL-6, and TNF-α), oxidant stress makers (MDA and NO), eicosanoids (LTB4 and PGE2), and inflammatory enzymes (5-LOX and COX-2) versus the AIA rats without treatment. On the contrary, the release of SOD and IL-10 was profoundly increased. What's more, TSSN could obviously ameliorate the translocation of NF-κB to the nucleus through phosphorylation of the p65 and IκBα in vivo and in vitro. The current findings demonstrated that TSSN could protect the injured ankle joint from further deterioration and exert its satisfactory anti-arthritis properties through anti-inflammatory and anti-oxidant effects via inactivating the NF-κB signal pathway. This research implies that DZW may be a useful therapeutic agent for the treatment of human arthritis.

  10. New technologies for application to veterinary therapeutics.

    PubMed

    Riviere, Jim E

    2010-01-01

    The purpose of this contribution is to review new technologies and make an educated prediction as to how they will impact veterinary pharmacology over the coming decades. By examining past developments, it becomes evident that change is incremental and predictable unless either a transforming discovery or a change in societal behaviour occurs. In the last century, both discoveries and behaviours have dramatically changed medicine, pharmacology and therapeutics. In this chapter, the potential effects of six transforming technologies on veterinary therapeutics are examined: continued advances in computer technology, microfluidics, nanotechnology, high-throughput screening, control and targeted drug delivery and pharmacogenomics. These should lead to the more efficacious and safer use of existing medicants, and the development of novel drugs across most therapeutic classes through increases in our knowledge base, as well as more efficient drug development. Although this growth in technology portends major advances over the next few decades, economic and regulatory constraints must still be overcome for these new drugs or therapeutic approaches to become common practise.

  11. Therapeutic cell encapsulation techniques and applications in diabetes.

    PubMed

    Steele, J A M; Hallé, J-P; Poncelet, D; Neufeld, R J

    2014-04-01

    The encapsulation of therapeutic cells permits the implantation of allogeneic and xenogeneic cells for the regulation of certain physiological processes damaged by the death or senescence of host tissues. The encapsulation of pancreatic cells for the treatment of diabetes is emphasized; however, many of the techniques are applicable to a wide array of mammalian cell applications. The summary of both established and novel encapsulation techniques, clinical trials, and commercial product developments highlights the metered but steady pace of therapeutic cell encapsulation towards implementation.

  12. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Five new drift control adjuvants were sele...

  13. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Four new drift control adjuvants were sele...

  14. Neuropsychopharmacological understanding for therapeutic application of morphinans.

    PubMed

    Shin, Eun-Joo; Hong, Jau-Shyong; Kim, Hyoung-Chun

    2010-10-01

    Morphinans are a class of compounds containing the basic structure of morphine. It is well-known that morphinans possess diverse pharmacological effects on the central nervous system. This review will demonstrate novel neuroprotective effects of several morphinans such as, dextromethorphan, its analogs and naloxone on the models of multiple neurodegenerative disease by modulating glial activation associated with the production of a host of proinflammatory and neurotoxic factors, although dextromethorphan possesses neuropsychotoxic potentials. The neuroprotective effects and the therapeutic potential for the treatment of excitotoxic and inflammatory neurodegenerative diseases, and underlying mechanism of morphinans are discussed.

  15. Vasculogenesis and Its Cellular Therapeutic Applications.

    PubMed

    Ratajska, Anna; Jankowska-Steifer, Ewa; Czarnowska, Elżbieta; Olkowski, Radosław; Gula, Grzegorz; Niderla-Bielińska, Justyna; Flaht-Zabost, Aleksandra; Jasińska, Agnieszka

    2017-01-01

    Vasculogenesis was originally defined by Risau in 1997 [Nature 386: 671-674] as the de novo formation of vessels from endothelial progenitor cells (EPCs), so-called angioblasts. Initially, this process was believed to be related only to embryonic life; however, further studies reported vasculogenesis to occur also in adult tissues. This overview presents the current knowledge about the origin, differentiation and significance of EPCs that have been observed in various diseases, tumors, and reparative processes. We also summarize the knowledge of how to activate these cells for therapeutic purposes and the outcomes of the therapies.

  16. Therapeutic applications of extracellular vesicles: clinical promise and open questions.

    PubMed

    György, Bence; Hung, Michelle E; Breakefield, Xandra O; Leonard, Joshua N

    2015-01-01

    This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury.

  17. Lasers and their therapeutic application in chiropractic

    PubMed Central

    Fitz-Ritson, Don

    2001-01-01

    The purpose of this paper is to review some of the applications of laser therapy and its reported effects on tissue healing, pain relief and other effects. Several musculoskeletal and low back pain studies are highlighted to show the efficacy of laser therapy and its' applicability as an adjunct to chiropractic treatment. Information is also presented which highlights the necessary information the clinician should be aware of in order to develop specific protocols for musculoskeletal pathologies. The parameters, which are now available on lasers, include power, frequency, duty cycle and cadence. When these are manipulated, different effects are achieved on tissues, which may enhance chiropractic treatment. Imagesp34-a

  18. Developments in the rat adjuvant arthritis model and its use in therapeutic evaluation of novel non-invasive treatment by SOD in Transfersomes.

    PubMed

    Simões, S I; Delgado, T C; Lopes, R M; Jesus, S; Ferreira, A A; Morais, J A; Cruz, M E M; Corvo, M L; Martins, M B F

    2005-03-21

    The aim of this study was firstly to refine a rat model of arthritis, the adjuvant arthritis (AA) model, by studying the time course of the disease, introducing new evaluation methods such as haematological and biochemical parameters in order to identify the main stages of the disease. An optimisation of treatment schedule and evaluation criteria was developed. This refinement provided novel non-invasive anti-inflammatory treatment of the AA with SOD by using mixed lipid vesicles specially developed for transdermal delivery, Transfersomes (Tfs), this being the second major aim. The time course of AA includes a first stage: 1 day after the disease induction, the induced paw volume more than doubled and the paw circumference increased by approx. 50%. Two weeks later, another stage occurred where the disease shifted from the local arthritis form towards polyarthritis: an additional increase of volume and circumference of the induced and non-induced paws, occurred. The animals also started to loose weight around day 14 after the disease induction. Radiographic observable lesions increased correspondingly. Treatment of animals, started at day 1 after induction, by epicutaneous application of SOD-Tfs showed that 1 mg SOD/kg body weight is more efficient than 0.66 mg SOD /kg body weight. As a positive control, SOD liposomes intravenously injected were used for comparison and confirmed the biological efficiency of epicutaneously applied SOD in Tfs. SOD solution and empty Tfs epicutaneously applied exerted no effect. In addition, epicutaneous application of SOD-Tfs used prophylactically was able to suppress the induced rat paw oedema. Radiographic images showed less joint lesions in SOD-Tfs treated animals in comparison with control and placebo treated rats. It was shown for the first time that SOD incorporated into Tfs and applied onto a skin area not necessarily close to the inflamed tissue is able to promote non-invasive treatment of induced arthritis.

  19. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  20. Vaccine adjuvants as potential cancer immunotherapeutics

    PubMed Central

    Temizoz, Burcu; Kuroda, Etsushi

    2016-01-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund’s adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  1. Recent developments in therapeutic applications of Cyanobacteria.

    PubMed

    Raja, Rathinam; Hemaiswarya, Shanmugam; Ganesan, Venkatesan; Carvalho, Isabel S

    2016-05-01

    The cyanobacteria (blue-green algae) are photosynthetic prokaryotes having applications in human health with numerous biological activities and as a dietary supplement. It is used as a food supplement because of its richness in nutrients and digestibility. Many cyanobacteria (Microcystis sp, Anabaena sp, Nostoc sp, Oscillatoria sp., etc.) produce a great variety of secondary metabolites with potent biological activities. Cyanobacteria produce biologically active and chemically diverse compounds belonging to cyclic peptides, lipopeptides, fatty acid amides, alkaloids and saccharides. More than 50% of the marine cyanobacteria are potentially exploitable for extracting bioactive substances which are effective in killing cancer cells by inducing apoptotic death. Their role as anti-viral, anti-tumor, antimicrobial, anti-HIV and a food additive have also been well established. However, such products are at different stages of clinical trials and only a few compounds have reached to the market.

  2. Therapeutic clinical applications of reactor-produced radioisotopes

    SciTech Connect

    Knapp, F.F. Jr.

    1997-12-01

    One of the most rapidly growing areas of clinical nuclear medicine is the therapeutic use of radioisotopes for applications in oncology, rheumatology and, more recently, interventional cardiology. With the rapidly increasing development and evaluation of new agents, their introduction into clinical use, and commercialization, the availability of high levels of therapeutic reactor-produced neutron-rich radioisotopes is of increasing importance. The goals of this paper are to discuss the issues associated with optimization of the production and processing of reactor-produced radioisotopes for therapy, with special emphasis on {sup 188}W, and the optimization of the use of the {sup 188}W/{sup 188}Re generator. In addition, other key examples of therapeutic radioisotopes of current interest and their specific clinical applications are discussed.

  3. Nanomaterials for Photo-Based Diagnostic and Therapeutic Applications

    PubMed Central

    Menon, Jyothi U.; Jadeja, Parth; Tambe, Pranjali; Vu, Khanh; Yuan, Baohong; Nguyen, Kytai T.

    2013-01-01

    Photo-based diagnosis and treatment methods are gaining prominence due to increased spatial imaging resolution, minimally invasive modalities involved as well as localized treatment. Recently, nanoparticles (NPs) have been developed and used in photo-based therapeutic applications. While some nanomaterials have inherent photo-based imaging capabilities, others including polymeric NPs act as nanocarriers to deliver various fluorescent dyes or photosensitizers for photoimaging and therapeutic applications. These applications can vary from Magnetic Resonance Imaging (MRI) and optical imaging to photothermal therapy (PTT) and chemotherapy. Materials commonly used for development of photo-based NPs ranges from metal-based (gold, silver and silica) to polymer-based (chitosan, dextran, poly ethylene glycol (PEG) and poly lactic-co-glycolic acid (PLGA)). Recent research has paved the way for multi-modal 'theranostic' (a combination of therapy and diagnosis) nano-carriers capable of active targeting using cell-specific ligands and carrying multiple therapeutic and imaging agents for accurate diagnosis and controlled drug delivery. This review summarizes the different materials used today to synthesize photo-based NPs, their diagnostic and therapeutic applications as well as the current challenges faced in bringing these novel nano-carriers into clinical practices. PMID:23471164

  4. Adjuvant effect of Japanese herbal medicines on the mucosal type 1 immune responses to human papillomavirus (HPV) E7 in mice immunized orally with Lactobacillus-based therapeutic HPV vaccine in a synergistic manner.

    PubMed

    Taguchi, Ayumi; Kawana, Kei; Yokoyama, Terufumi; Adachi, Katsuyuki; Yamashita, Aki; Tomio, Kensuke; Kojima, Satoko; Oda, Katsutoshi; Fujii, Tomoyuki; Kozuma, Shiro

    2012-08-03

    The Japanese herbal medicines, Juzen-taiho-to (JTT) and Hochu-ekki-to (HET), have been shown to enhance humoral immune responses to vaccine antigen when used as adjuvants for prophylactic vaccines. However, their adjuvant effect on mucosal cellular immune responses remains unstudied. The precursor lesion of cervical cancer, high-grade CIN that expresses HPV E7 oncoprotein ubiquitously is a target for HPV therapeutic vaccines that elicit mucosal E7-specific type 1 T cell responses. We have demonstrated that oral immunization with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7) is more effective in eliciting mucosal E7-specific IFNγ-producing cells than subcutaneous or intramuscular antigen delivery. Here we report the synergistic effect of an oral Lactobacillus-based vaccine and Japanese herbal medicines on mucosal immune responses. Oral immunization of mice with LacE7 plus either a Japanese herbal medicine (JTT or HET) or a mucosal adjuvant, heated-labile enterotoxin T subunit (LTB), promotes systemic E7-specific type 1 T cell responses but not mucosal responses. Administration of LacE7 plus either Japanese herbal medicine and LTB enhanced mucosal E7-specific type 1 T cell response to levels approximately 3-fold higher than those after administration of LacE7 alone. Furthermore, secretion of IFNγ and IL-2 into the intestinal lumen was observed after oral administration of LacE7 and was enhanced considerably by the addition of Japanese herbal medicines and LTB. Our data indicated that Japanese herbal medicines, in synergy with Lactobacillus and LTB, enhance the mucosal type 1 immune responses to orally immunized antigen. Japanese herbal medicines may be excellent adjuvants for oral Lactobacillus-based vaccines and oral immunization of LacE7, HET and LTB may have the potential to elicit extremely high E7-specific mucosal cytotoxic immune response to HPV-associated neoplastic lesions.

  5. The therapeutic applications of antimicrobial peptides (AMPs): a patent review.

    PubMed

    Kang, Hee-Kyoung; Kim, Cheolmin; Seo, Chang Ho; Park, Yoonkyung

    2017-01-01

    Antimicrobial peptides (AMPs) are small molecules with a broad spectrum of antibiotic activities against bacteria, yeasts, fungi, and viruses and cytotoxic activity on cancer cells, in addition to anti-inflammatory and immunomodulatory activities. Therefore, AMPs have garnered interest as novel therapeutic agents. Because of the rapid increase in drug-resistant pathogenic microorganisms, AMPs from synthetic and natural sources have been developed using alternative antimicrobial strategies. This article presents a broad analysis of patents referring to the therapeutic applications of AMPs since 2009. The review focuses on the universal trends in the effective design, mechanism, and biological evolution of AMPs.

  6. Intradermal application of Aujeszky's disease virus strain Begonia with tocopherol-based adjuvant and a novel design injection device.

    PubMed

    Visser, N; Egger, W; Lütticken, D

    1994-01-01

    Initially the use of intradermal application of Aujeszky's disease vaccines was shown to be very effective. However, for thus far unknown reasons the gI-deleted vaccines were much less efficacious by using this route of vaccination as compared to gI-positive vaccines. By the use of a tocopherol-based adjuvant and an improved design of the intradermal injection device it now appeared feasible to obtain the same efficacy both in specific pathogen free pigs and in pigs with material antibodies as found before when intramuscular administration was performed. With respect to safety we found a complete lack of skin lesions, no adverse systemic reactions (e.g. body temperatures) and no effect on growth rates. Last but not least, the easiness of intradermal injections is of great advantage in large-scale vaccination programs.

  7. Cell-penetrating peptides: Possible transduction mechanisms and therapeutic applications

    PubMed Central

    GUO, ZHENGRONG; PENG, HUANYAN; KANG, JIWEN; SUN, DIANXING

    2016-01-01

    Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse peptides with 5–30 amino acids. CPPs are divided into cationic, amphipathic and hydrophobic CPPs. They are able to carry small molecules, plasmid DNA, small interfering RNA, proteins, viruses, imaging agents and other various nanoparticles across the cellular membrane, resulting in internalization of the intact cargos. However, the mechanisms of CPP internalization remain to be elucidated. Recently, CPPs have received considerable attention due to their high transduction efficiency and low cytotoxicity. These peptides have a significant potential for diagnostic and therapeutic applications, such as delivery of fluorescent or radioactive compounds for imaging, delivery of peptides and proteins for therapeutic application, and delivery of molecules into induced pluripotent stem cells for directing differentiation. The present study reviews the classifications and transduction mechanisms of CPPs, as well as their potential applications. PMID:27123243

  8. Environmental impact of adjuvants in crop protection.

    PubMed

    Ryckaert, B; Spanoghe, P; Steurbaut, W; Heremans, B; Haesaert, G; de Coen, W

    2005-01-01

    The overall performance of chemical and biological plant protection products is enhanced by the use of adjuvants in the formulation (formulation adjuvants) or in the spray tank (spray adjuvants). Both types of adjuvants aim to stabilize the formulation, to improve the efficiency of the active ingredients and to reduce application and environmental risks. As an important part of the formulation, both quantitatively and qualitatively, the environmental impact and toxicology of adjuvants can not always be considered as inert. However, little is known of their impact as part of plant protection products compared with the active substances. Therefore an experimental framework is needed as a tool for a consistent environmental legislation.

  9. Therapeutic applications of hydrogels in oral drug delivery

    PubMed Central

    Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

    2015-01-01

    Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest. PMID:24848309

  10. Overview of Therapeutic Ultrasound Applications and Safety Considerations

    PubMed Central

    Miller, Douglas; Smith, Nadine; Bailey, Michael; Czarnota, Gregory; Hynynen, Kullervo; Makin, Inder

    2013-01-01

    Summary Applications of ultrasound in medicine for therapeutic purposes have been an accepted and beneficial use of ultrasonic biological effects for many years. Low power ultrasound of about 1 MHz frequency has been widely applied since the 1950s for physical therapy in conditions such as tendinitis or bursitis. In the 1980s, high pressure-amplitude shockwaves came into use for mechanically resolving kidney stones, and “lithotripsy” rapidly replaced surgery as the most frequent treatment choice. The use of ultrasonic energy for therapy continues to expand, and approved applications now include uterine fibroid ablation, cataract removal (phacoemulsification), surgical tissue cutting and hemostasis, transdermal drug delivery, and bone fracture healing, among others. Undesirable bioeffects can occur including burns for thermal-based therapies and significant hemorrhage for mechanical-based therapies (e. g. lithotripsy). In all these therapeutic applications for bioeffects of ultrasound, standardization, ultrasound dosimetry, benefits assurance and side-effects risk minimization must be carefully considered in order to insure an optimal benefit to risk ratio for the patient. Therapeutic ultrasound typically has well-defined benefits and risks, and therefore presents a tractable safety problem to the clinician. However, safety information can be scattered, confusing or subject to commercial conflict of interest. Of paramount importance for managing this problem is the communication of practical safety information by authoritative groups, such as the AIUM, to the medical ultrasound community. In this overview, the Bioeffects Committee outlines the wide range of therapeutic ultrasound methods, which are in clinical use or under study, and provides general guidance for assuring therapeutic ultrasound safety. PMID:22441920

  11. Overview of therapeutic ultrasound applications and safety considerations.

    PubMed

    Miller, Douglas L; Smith, Nadine B; Bailey, Michael R; Czarnota, Gregory J; Hynynen, Kullervo; Makin, Inder Raj S

    2012-04-01

    Applications of ultrasound in medicine for therapeutic purposes have been accepted and beneficial uses of ultrasonic biological effects for many years. Low-power ultrasound of about 1 MHz has been widely applied since the 1950s for physical therapy in conditions such as tendinitis and bursitis. In the 1980s, high-pressure-amplitude shock waves came into use for mechanically resolving kidney stones, and "lithotripsy" rapidly replaced surgery as the most frequent treatment choice. The use of ultrasonic energy for therapy continues to expand, and approved applications now include uterine fibroid ablation, cataract removal (phacoemulsification), surgical tissue cutting and hemostasis, transdermal drug delivery, and bone fracture healing, among others. Undesirable bioeffects can occur, including burns from thermal-based therapies and severe hemorrhage from mechanical-based therapies (eg, lithotripsy). In all of these therapeutic applications of ultrasound bioeffects, standardization, ultrasound dosimetry, benefits assurance, and side-effect risk minimization must be carefully considered to ensure an optimal benefit to risk ratio for the patient. Therapeutic ultrasound typically has well-defined benefits and risks and therefore presents a manageable safety problem to the clinician. However, safety information can be scattered, confusing, or subject to commercial conflicts of interest. Of paramount importance for managing this problem is the communication of practical safety information by authoritative groups, such as the American Institute of Ultrasound in Medicine, to the medical ultrasound community. In this overview, the Bioeffects Committee of the American Institute of Ultrasound in Medicine outlines the wide range of therapeutic ultrasound methods, which are in clinical use or under study, and provides general guidance for ensuring therapeutic ultrasound safety.

  12. Diagnostic and Therapeutic Applications of Quantum Dots in Nanomedicine.

    PubMed

    Kamila, Sukanta; McEwan, Conor; Costley, David; Atchison, Jordan; Sheng, Yinjie; Hamilton, Graham R C; Fowley, Colin; Callan, John F

    2016-01-01

    The interest in Quantum Dots as a class of nanomaterials has grown considerably since their discovery by Ekimov and Efros in the early 1980s. Although this early work focussed primarily on CdSe-based nanocrystals, the field has now expanded to include various classes of nanoparticles with different types of core, shell or passivation chemistry. Such differences can have a profound effect on the optical properties and potential biocompatibility of the resulting constructs. Although QDs have predominantly been used for imaging and sensing applications, more examples of their use as therapeutics are beginning to emerge. In this chapter we discuss the progress made over the past decade in developing QDs for imaging and therapeutic applications.

  13. Cationic liposomes as vaccine adjuvants.

    PubMed

    Christensen, Dennis; Korsholm, Karen Smith; Andersen, Peter; Agger, Else Marie

    2011-04-01

    The application of cationic liposomes as vaccine delivery systems and adjuvants has been investigated extensively over the last few decades. However, cationic liposomes are, in general, not sufficiently immunostimulatory, which is why the combination of liposomes with immunostimulating ligands has arisen as a strategy in the development of novel adjuvant systems. Within the last 5 years, two novel adjuvant systems based on cationic liposomes incorporating Toll-like receptor or non-Toll-like receptor immunostimulating ligands have progressed from preclinical testing in smaller animal species to clinical testing in humans. The immune responses that these clinical candidates induce are primarily of the Th1 type for which there is a profound unmet need. Furthermore, a number of new cationic liposome-forming surfactants with notable immunostimulatory properties have been discovered. In this article we review the recent progress on the application of cationic liposomes as vaccine delivery systems/adjuvants.

  14. Emerging Non-Cancer Applications of Therapeutic Ultrasound

    PubMed Central

    O’Reilly, Meaghan A.; Hynynen, Kullervo

    2015-01-01

    Ultrasound therapy has been investigated for over half a century. Ultrasound can act on tissue through a variety of mechanisms, including thermal, shockwave and cavitation mechanisms, and through these can elicit different responses. Ultrasound therapy can provide a non-invasive or minimally invasive treatment option, and ultrasound technology has advanced to the point where devices can be developed to investigate a wide range of applications. This review focuses on non-cancer, clinical applications of therapeutic ultrasound, with an emphasis on treatments that have recently reached clinical investigations, and preclinical research programs that have great potential to impact patient care. PMID:25792225

  15. [Progress of epigenetics and its therapeutic application in hepatocellular carcinoma].

    PubMed

    Lingyun, Sun; Xingyu, Li; Zhiwei, Sun

    2015-06-01

    Liver cancer is a severe harmful disease. It is the fifth most frequently diagnosed cancer and second most frequent cause of cancer deaths worldwide. As the most popular histologic subtype of hepatocellular carcinoma (HCC), primary HCC is a heterogeneous disease whose management requires a multidisciplinary approach combining genetics, genomics and environmental toxicology. Although many molecular targeted therapies such as sorafenib have entered clinical application and proven effective, the cytotoxicity and other negative effects cannot be ignored. There is an urgent need to identify new therapeutic targets and drugs, which can kill HCC cells with high efficiency and specificity. Plenty of evidence suggests that occurrence and development of HCC is closely related with epigenetics. DNA methylation, histone modification, aberrant expression of miRNAs and dysregulated expression of many epigenetic regulatory genes are significantly altered in HCC. Epigenetic therapeutic drugs may reverse abnormal gene expression, thus controlling the occurrence and development of HCC. In this review, we summarize the latest research progresses in epigenetics and its therapeutic application in HCC,and the potential treatments to be used in the future.

  16. Proangiogenic Features of Mesenchymal Stem Cells and Their Therapeutic Applications

    PubMed Central

    Tao, Hongyan; Han, Zhibo; Han, Zhong Chao; Li, Zongjin

    2016-01-01

    Mesenchymal stem cells (MSCs) have shown their therapeutic potency for treatment of cardiovascular diseases owing to their low immunogenicity, ease of isolation and expansion, and multipotency. As multipotent progenitors, MSCs have revealed their ability to differentiate into various cell types and could promote endogenous angiogenesis via microenvironmental modulation. Studies on cardiovascular diseases have demonstrated that transplanted MSCs could engraft at the injured sites and differentiate into cardiomyocytes and endothelial cells as well. Accordingly, several clinical trials using MSCs have been performed and revealed that MSCs may improve relevant clinical parameters in patients with vascular diseases. To fully comprehend the characteristics of MSCs, understanding their intrinsic property and associated modulations in tuning their behaviors as well as functions is indispensable for future clinical translation of MSC therapy. This review will focus on recent progresses on endothelial differentiation and potential clinical application of MSCs, with emphasis on therapeutic angiogenesis for treatment of cardiovascular diseases. PMID:26880933

  17. Protein transduction: cell penetrating peptides and their therapeutic applications.

    PubMed

    Wagstaff, Kylie M; Jans, David A

    2006-01-01

    Cell penetrating proteins or peptides (CPPs) have the ability to cross the plasma membranes of mammalian cells in an apparently energy- and receptor-independent fashion. Although there is much debate over the mechanism by which this "protein transduction" occurs, the ability of CPPs to translocate rapidly into cells is being exploited to deliver a broad range of therapeutics including proteins, DNA, antibodies, oligonucleotides, imaging agents and liposomes in a variety of situations and biological systems. The current review looks at the delivery of many such molecules by various CPPs, and their potential therapeutic application in a wide range of areas. CPP ability to deliver different cargoes in a relatively efficient and non-invasive manner has implications as far reaching as drug delivery, gene transfer, DNA vaccination and beyond. Although many questions remain to be answered and limitations on the use of CPPs exist, it is clear that this emerging technology has much to offer in a clinical setting.

  18. Performance characteristics of a conformal ultra-wideband multilayer applicator (CUMLA) for hyperthermia in veterinary patients: a pilot evaluation of its use in the adjuvant treatment of non-resectable tumours.

    PubMed

    Smrkovski, O A; Koo, Y; Kazemi, R; Lembcke, L M; Fathy, A; Liu, Q; Phillips, J C

    2013-03-01

    Performance and clinical characteristics of a novel hyperthermia antenna operating at 434 MHz were evaluated for the adjuvant treatment of locally advanced superficial tumours in cats, dogs and horses. Electromagnetic simulations were performed to determine electric field characteristics and compared to simulations for a flat microwave antenna with similar dimensions. Simulation results show a reduced skin surface and backfield irradiation and improved directional irradiation (at broadside) compared to a flat antenna. Radiated power and penetration is notably increased with a penetration depth of 4.59 cm compared to 2.74 cm for the flat antenna. Clinical use of the antenna was then evaluated in six animals with locoregionally advanced solid tumours receiving adjuvant chemotherapy. During clinical applications, therapeutic temperatures were achieved at depths ≥4 cm. Objective responses were seen in all patients; tissue toxicity in one case limited further therapy. This antenna provides compact, efficient, focused and deep-penetrating clinical hyperthermia for the treatment of solid tumours in veterinary patients.

  19. Nanoscale porosity in polymer films: fabrication and therapeutic applications

    PubMed Central

    Bernards, Daniel A.; Desai, Tejal A.

    2011-01-01

    This review focuses on current developments in the field of nanostructured bulk polymers and their application in bioengineering and therapeutic sciences. In contrast to well-established nanoscale materials, such as nanoparticles and nanofibers, bulk nanostructured polymers combine nanoscale structure in a macroscopic construct, which enables unique application of these materials. Contemporary fabrication and processing techniques capable of producing nanoporous polymer films are reviewed. Focus is placed on techniques capable of sub-100 nm features since this range approaches the size scale of biological components, such as proteins and viruses. The attributes of these techniques are compared, with an emphasis on the characteristic advantages and limitations of each method. Finally, application of these materials to biofiltration, immunoisolation, and drug delivery are reviewed. PMID:22140398

  20. The effect of adjuvants at high spray pressures for aerial applications

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Controlling droplet size is a critical part of making any successful agrochemical spray application. This is particularly true for higher speed aerial applications where secondary atomization from air shear becomes the most dominate factor driving spray droplet size. Previous research has shown th...

  1. Recent Advances in Therapeutic Applications of Induced Pluripotent Stem Cells.

    PubMed

    Rami, Farzaneh; Beni, Shamsi Naderi; Kahnamooi, Mahboobeh Mojaver; Rahimmanesh, Ilnaz; Salehi, Ahmad Reza; Salehi, Rasoul

    2017-04-01

    Induced pluripotent stem (iPS) cells are generated by reprogramming of differentiated somatic cells. These cells are identical to human embryonic stem cells (hESCs) in gene expression pattern and the ability to differentiate. iPS cells can be used in in vitro modeling of diseases, testing drugs, assessing gene therapy methods, and cell therapy. Yet, the most important and promising application of iPS cells is in regenerative medicine. Regenerative medicine is a novel area in medicine aiming at the treatment of impaired or lost tissues by replacing them with functional and healthy ones. Currently, organ transplantation, which is considered the only treatment and cure for a number of diseases, is limited by shortage of organ donors and availability of the right match. Therefore, utilization of an alternative source of cells and tissues is critical in transplantation therapy. In this study, we review recent advances in therapeutic application of iPS cells in diseases where organ transplantation remains the only solution and will discuss the potential and usage of iPS cells in different areas of regenerative medicine. The primary theory of using iPS cells in regenerative medicine has brought lots of promises due to its potential for solving the immunological, social, and ethical problems of using ESCs. Nevertheless, several issues and problems have to be resolved before applying iPS cells in therapeutic applications.

  2. The natural flavonoid pinocembrin: molecular targets and potential therapeutic applications

    PubMed Central

    Lan, Xi; Wang, Wenzhu; Li, Qiang; Wang, Jian

    2015-01-01

    Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications. PMID:25744566

  3. Bioinspired Composite Materials: Applications in Diagnostics and Therapeutics

    NASA Astrophysics Data System (ADS)

    Prasad, Alisha; Mahato, Kuldeep; Chandra, Pranjal; Srivastava, Ananya; Joshi, Shrikrishna N.; Maurya, Pawan Kumar

    2016-08-01

    Evolution-optimized specimens from nature with inimitable properties, and unique structure-function relationships have long served as a source of inspiration for researchers all over the world. For instance, the micro/nanostructured patterns of lotus-leaf and gecko feet helps in self-cleaning, and adhesion, respectively. Such unique properties shown by creatures are results of billions of years of adaptive transformation, that have been mimicked by applying both science and engineering concepts to design bioinspired materials. Various bioinspired composite materials have been developed based on biomimetic principles. This review presents the latest developments in bioinspired materials under various categories with emphasis on diagnostic and therapeutic applications.

  4. Therapeutic Applications of Herbal Medicines for Cancer Patients

    PubMed Central

    Yin, Shu-Yi; Wei, Wen-Chi; Jian, Feng-Yin; Yang, Ning-Sun

    2013-01-01

    Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines for various cancers and the development of randomized controlled trials (RCTs) in this emerging research area. In addition, we also report recent studies on the biochemical and cellular mechanisms of herbal medicines in specific tumor microenvironments and the potential application of specific phytochemicals in cell-based cancer vaccine systems. This review should provide useful technological support for evidence-based application of herbal medicines in cancer therapy. PMID:23956768

  5. Therapeutic applications of herbal medicines for cancer patients.

    PubMed

    Yin, Shu-Yi; Wei, Wen-Chi; Jian, Feng-Yin; Yang, Ning-Sun

    2013-01-01

    Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines for various cancers and the development of randomized controlled trials (RCTs) in this emerging research area. In addition, we also report recent studies on the biochemical and cellular mechanisms of herbal medicines in specific tumor microenvironments and the potential application of specific phytochemicals in cell-based cancer vaccine systems. This review should provide useful technological support for evidence-based application of herbal medicines in cancer therapy.

  6. Therapeutic application of anti-angiogenic nanomaterials in cancers

    NASA Astrophysics Data System (ADS)

    Mukherjee, Sudip; Patra, Chitta Ranjan

    2016-06-01

    Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clinical perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the

  7. Adjuvant Treatment of Melanoma

    PubMed Central

    Moreno Nogueira, J. A.; Valero Arbizu, M.; Pérez Temprano, R.

    2013-01-01

    Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50–80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-α2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas. PMID:23476798

  8. Examples of adjuvant treatment enhancing the antitumor effect of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Cecic, Ivana; Sun, Jinghai; Chaplin, David J.

    1999-07-01

    Strategies for improving the clinical efficacy of photodynamic therapy (PDT) in treatment of solid cancers include applications of different types of adjuvant treatments in addition to this modality that may result in superior therapeutic outcome. Examples of such an approach investigated using mouse tumor models are presented in this report. It is shown that the cures of PDT treated subcutaneous tumors can be substantially improved by adjuvant therapy with: metoclopramide (enhancement of cancer cell apoptosis), combretastatin A-4 (selective destruction of tumor neovasculature), Roussin's Black Salt (light activated tumor localized release of nitric oxide), or dendritic cell-based adoptive immunotherapy (immune rejection of treated tumor).

  9. Cannabinoids: mechanisms and therapeutic applications in the CNS.

    PubMed

    Drysdale, Alison J; Platt, Bettina

    2003-12-01

    Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and anti-oxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.

  10. Properties and Therapeutic Application of Bromelain: A Review

    PubMed Central

    Pavan, Rajendra; Jain, Sapna; Shraddha

    2012-01-01

    Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action. PMID:23304525

  11. Therapeutic and Prophylactic Applications of Bacteriophage Components in Modern Medicine

    PubMed Central

    Adhya, Sankar; Merril, Carl R.; Biswas, Biswajit

    2014-01-01

    As the interactions of phage with mammalian innate and adaptive immune systems are better delineated and with our ability to recognize and eliminate toxins and other potentially harmful phage gene products, the potential of phage therapies is now being realized. Early efforts to use phage therapeutically were hampered by inadequate phage purification and limited knowledge of phage–bacterial and phage–human relations. However, although use of phage as an antibacterial therapy in countries that require controlled clinical studies has been hampered by the high costs of patient trials, their use as vaccines and the use of phage components such as lysolytic enzymes or lysozymes has progressed to the point of commercial applications. Recent studies concerning the intimate associations between mammalian hosts and bacterial and phage microbiomes should hasten this progress. PMID:24384811

  12. Microbial siderophore-based iron assimilation and therapeutic applications.

    PubMed

    Li, Kunhua; Chen, Wei-Hung; Bruner, Steven D

    2016-06-01

    Siderophores are structurally diverse, complex natural products that bind metals with extraordinary specificity and affinity. The acquisition of iron is critical for the survival and virulence of many pathogenic microbes and diverse strategies have evolved to synthesize, import and utilize iron. There has been a substantial increase of known siderophore scaffolds isolated and characterized in the past decade and the corresponding biosynthetic gene clusters have provided insight into the varied pathways involved in siderophore biosynthesis, delivery and utilization. Additionally, therapeutic applications of siderophores and related compounds are actively being developed. The study of biosynthetic pathways to natural siderophores augments the understanding of the complex mechanisms of bacterial iron acquisition, and enables a complimentary approach to address virulence through the interruption of siderophore biosynthesis or utilization by targeting the key enzymes to the siderophore pathways.

  13. Potential role of bromelain in clinical and therapeutic applications

    PubMed Central

    Rathnavelu, Vidhya; Alitheen, Noorjahan Banu; Sohila, Subramaniam; Kanagesan, Samikannu; Ramesh, Rajendran

    2016-01-01

    Pineapple has been used as part of traditional folk medicine since ancient times and it continues to be present in various herbal preparations. Bromelain is a complex mixture of protease extracted from the fruit or stem of the pineapple plant. Although the complete molecular mechanism of action of bromelain has not been completely identified, bromelain gained universal acceptability as a phytotherapeutic agent due to its history of safe use and lack of side effects. Bromelain is widely administered for its well-recognized properties, such as its anti-inflammatory, antithrombotic and fibrinolytic affects, anticancer activity and immunomodulatory effects, in addition to being a wound healing and circulatory improvement agent. The current review describes the promising clinical applications and therapeutic properties of bromelain. PMID:27602208

  14. Silver Nanoparticles: Synthesis, Characterization, Properties, Applications, and Therapeutic Approaches

    PubMed Central

    Zhang, Xi-Feng; Liu, Zhi-Guo; Shen, Wei; Gurunathan, Sangiliyandi

    2016-01-01

    Recent advances in nanoscience and nanotechnology radically changed the way we diagnose, treat, and prevent various diseases in all aspects of human life. Silver nanoparticles (AgNPs) are one of the most vital and fascinating nanomaterials among several metallic nanoparticles that are involved in biomedical applications. AgNPs play an important role in nanoscience and nanotechnology, particularly in nanomedicine. Although several noble metals have been used for various purposes, AgNPs have been focused on potential applications in cancer diagnosis and therapy. In this review, we discuss the synthesis of AgNPs using physical, chemical, and biological methods. We also discuss the properties of AgNPs and methods for their characterization. More importantly, we extensively discuss the multifunctional bio-applications of AgNPs; for example, as antibacterial, antifungal, antiviral, anti-inflammatory, anti-angiogenic, and anti-cancer agents, and the mechanism of the anti-cancer activity of AgNPs. In addition, we discuss therapeutic approaches and challenges for cancer therapy using AgNPs. Finally, we conclude by discussing the future perspective of AgNPs. PMID:27649147

  15. Iyengar-Yoga Compared to Exercise as a Therapeutic Intervention during (Neo)adjuvant Therapy in Women with Stage I–III Breast Cancer: Health-Related Quality of Life, Mindfulness, Spirituality, Life Satisfaction, and Cancer-Related Fatigue

    PubMed Central

    Lötzke, Désirée; Wiedemann, Florian; Rodrigues Recchia, Daniela; Ostermann, Thomas; Sattler, Daniel; Ettl, Johannes; Kiechle, Marion; Büssing, Arndt

    2016-01-01

    This study aims to test the effects of yoga on health-related quality of life, life satisfaction, cancer-related fatigue, mindfulness, and spirituality compared to conventional therapeutic exercises during (neo)adjuvant cytotoxic and endocrine therapy in women with breast cancer. In a randomized controlled trial 92 women with breast cancer undergoing oncological treatment were randomly enrolled for a yoga intervention (YI) (n = 45) or for a physical exercise intervention (PEI) (n = 47). Measurements were obtained before (t0) and after the intervention (t1) as well as 3 months after finishing intervention (t2) using standardized questionnaires. Life satisfaction and fatigue improved under PEI (p < 0.05) but not under YI (t0 to t2). Regarding quality of life (EORTC QLQ-C30) a direct effect (t0 to t1; p < 0.001) of YI was found on role and emotional functioning, while under PEI only emotional functioning improved. Significant improvements (p < 0.001) were observed at both t1 and t2 also for symptom scales in both groups: dyspnea, appetite loss, constipation, and diarrhea. There was no significant difference between therapies for none of the analyzed variables neither for t1 nor for t2. During chemotherapy, yoga was not seen as more helpful than conventional therapeutic exercises. This does not argue against its use in the recovery phase. PMID:27019663

  16. Design of a shear-thinning recoverable peptide hydrogel from native sequences and application for influenza H1N1 vaccine adjuvant

    SciTech Connect

    Huang, Hongzhou; Shi, Jishu; Laskin, Julia; Liu, Ziyan; McVey, David S.; Sun, Xiuzhi S.

    2011-10-07

    Peptide hydrogels are considered injectable materials for drug delivery and tissue engineering applications. Most published hydrogel-forming sequences contain either alternating-charged and noncharged residues or amphiphilic blocks. Here, we report a self-assembling peptide, h9e (FLIVIGSIIGPGGDGPGGD), designed by rationally combining two native sequences from an elastic segment of spider silk and a trans-membrane segment of human muscle L-type calcium channel. The turning segment GSII of h9e promoted hydrogel formation in both Ca2+ solution and acidic pH conditions at water content greater than 99.5%. Although h9e Ca2+ hydrogel and h9e acidic hydrogel have the same sequence, they have distinct physical properties. The shear-thinning, rapid-strengthrecovering h9e Ca2+ hydrogel was used as an H1N1 influenza vaccine adjuvant. The h9e adjuvant was biologically safe and improved immune response by 70% compared with an oil-based commercial adjuvant.

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

    PubMed

    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.

  18. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior...

  19. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior...

  20. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  1. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  2. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  3. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  4. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  5. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  6. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

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

    PubMed

    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.

  8. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases.

    PubMed

    Prud'homme, Gérald J; Glinka, Yelena; Wang, Qinghua

    2015-11-01

    Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. However, it is also produced in other sites; notably by pancreatic β cells and immune cells. The function of GABA in the immune system is at an early stage of study, but it exerts inhibitory effects that are relevant to autoimmune diseases. The study of GABAergic interactions in the immune system has centered on three main aspects: 1) the expression of GABA and the relevant GABAergic molecular machinery; 2) the in vitro response of immune cells; and 3) therapeutic applications in autoimmune diseases. T cells and macrophages can produce GABA, and express all the components necessary for a GABAergic response. There are two types of GABA receptors, but lymphocytes appear to express only type A (GABAAR); a ligand-gated chloride channel. Other immune cells may also express the type B receptor (GABABR); a G-protein coupled receptor. Activation of GABA receptors on T cells and macrophages inhibits responses such as production of inflammatory cytokines. In T cells, GABA blocks the activation-induced calcium signal, and it also inhibits NF-κB activation. In preclinical models, therapeutic application of GABA, or GABAergic (agonistic) drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and contact dermatitis. In addition, GABA exerts anti-apoptotic and proliferative effects on islet β cells, which may be applicable to islet transplantation. Autoimmunity against glutamic acid decarboxylase 65 (GAD65; synthesizes GABA) occurs in T1D. Antigen therapy of T1D with GAD65 or proinsulin in mice has protective effects, which are markedly enhanced by combined GABA therapy. Clinically, autoantibodies against GAD65 and/or GABA receptors play a pathogenic role in several neurological conditions, including stiff person syndrome (SPS), some forms of encephalitis, and autoimmune epilepsy. GABAergic drugs are widely used in

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

    PubMed

    Deleidi, Michela; Yu, Cong

    2016-05-06

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

  10. Guided Bone Regeneration: biological principle and therapeutic applications.

    PubMed

    Retzepi, Maria; Donos, N

    2010-06-01

    The Guided Bone Regeneration (GBR) treatment concept advocates that regeneration of osseous defects is predictably attainable via the application of occlusive membranes, which mechanically exclude non-osteogenic cell populations from the surrounding soft tissues, thereby allowing osteogenic cell populations originating from the parent bone to inhabit the osseous wound. The present review discusses the evolution of the GBR biological rationale and therapeutic concept over the last two decades. Further, an overview of the GBR research history is provided with specific focus on the evidence available on its effectiveness and predictability in promoting the regeneration of critical size cranio-maxillo-facial defects, the neo-osteogenesis potential and the reconstruction of atrophic alveolar ridges before, or in conjunction with, the placement of dental implants. The authors conclude that future research should focus on (a) the investigation of the molecular mechanisms underlying the wound healing process following GBR application; (b) the identification of site and patient related factors which impact on the effectiveness and predictability of GBR therapy and (c) the evaluation of the pathophysiology of the GBR healing process in the presence of systemic conditions potentially affecting the skeletal system.

  11. Centipede venoms and their components: resources for potential therapeutic applications.

    PubMed

    Hakim, Md Abdul; Yang, Shilong; Lai, Ren

    2015-11-17

    Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components.

  12. Centipede Venoms and Their Components: Resources for Potential Therapeutic Applications

    PubMed Central

    Hakim, Md Abdul; Yang, Shilong; Lai, Ren

    2015-01-01

    Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components. PMID:26593947

  13. Bioengineering natural product biosynthetic pathways for therapeutic applications.

    PubMed

    Wu, Ming-Cheng; Law, Brian; Wilkinson, Barrie; Micklefield, Jason

    2012-12-01

    With the advent of next-generation DNA sequencing technologies, the number of microbial genome sequences has increased dramatically, revealing a vast array of new biosynthetic gene clusters. Genomics data provide a tremendous opportunity to discover new natural products, and also to guide the bioengineering of new and existing natural product scaffolds for therapeutic applications. Notably, it is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. It is imperative therefore to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. Moreover, on the basis of our expanding mechanistic and structural knowledge of biosynthetic assembly-line enzymes, new strategies for re-programming biosynthetic pathways have emerged, resulting in focused libraries of modified products with potentially improved biological properties. In this review we will focus on the latest bioengineering approaches that have been utilised to optimise yields and increase the structural diversity of natural product scaffolds for future clinical applications.

  14. Classification of Laser Vaccine Adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Poznansky, Mark C

    2016-01-01

    An immunologic adjuvant, which enhances the magnitude and quality of immune responses to vaccine antigens, has become an essential part of modern vaccine practice. Chemicals and biologicals have been typically used for this purpose, but there are an increasing number of studies that are being conducted on the vaccine adjuvant effect of laser light on the skin. Currently, four different types or classes of laser devices have been shown to systemically enhance immune responses to intradermal vaccination: ultra-short pulsed lasers, non-pulsed lasers, non-ablative fractional lasers and ablative fractional lasers. Aside from involving the application of laser light to the skin in a manner that minimizes discomfort and damage, each type of laser vaccine adjuvant involves emission parameters, modes of action and immunologic adjuvant effects that are quite distinct from each other. This review provides a summary of the four major classes of “laser vaccine adjuvant” and clarifies and resolves their characteristics as immunologic adjuvants. These aspects of each adjuvant’s properties will ultimately help define which laser would be most efficacious in delivering a specific clinical benefit with a specific vaccine. PMID:27104047

  15. Therapeutic applications of botulinum neurotoxins in head and neck disorders

    PubMed Central

    Alshadwi, Ahmad; Nadershah, Mohammed; Osborn, Timothy

    2014-01-01

    Objective The aim of this article is to review the mechanism of action, physiological effects, and therapeutic applications of botulinum neurotoxins in the head and neck area. Study design An extensive literature search was performed using keywords. The resulting articles were analyzed for relevance in four areas: overview on botulinum neurotoxins, the role of botulinum neurotoxins in the management of salivary secretory disorders, the role of botulinum neurotoxins in the management of facial pain, and the role of botulinum neurotoxins in head and neck movement disorders. Institutional review board approval was not needed due the nature of the study. Results Botulinum neurotoxin therapy was demonstrated to be a valuable alternative to conventional medical therapy for many conditions affecting the head and neck area in terms of morbidly, mortality, and patient satisfaction with treatment outcomes. Conclusion Botulinum neurotoxin therapy provides viable alternatives to traditional treatment modalities for some conditions affecting the head and neck region that have neurological components. This therapy can overcome some of the morbidities associated with conventional therapy. More research is needed to determine the ideal doses of botulinum neurotoxin to treat different diseases affecting the head and neck regions. PMID:25544809

  16. Lectins, Interconnecting Proteins with Biotechnological/Pharmacological and Therapeutic Applications

    PubMed Central

    Silva, Priscila Marcelino dos Santos

    2017-01-01

    Lectins are proteins extensively used in biomedical applications with property to recognize carbohydrates through carbohydrate-binding sites, which identify glycans attached to cell surfaces, glycoconjugates, or free sugars, detecting abnormal cells and biomarkers related to diseases. These lectin abilities promoted interesting results in experimental treatments of immunological diseases, wounds, and cancer. Lectins obtained from virus, microorganisms, algae, animals, and plants were reported as modulators and tool markers in vivo and in vitro; these molecules also play a role in the induction of mitosis and immune responses, contributing for resolution of infections and inflammations. Lectins revealed healing effect through induction of reepithelialization and cicatrization of wounds. Some lectins have been efficient agents against virus, fungi, bacteria, and helminths at low concentrations. Lectin-mediated bioadhesion has been an interesting characteristic for development of drug delivery systems. Lectin histochemistry and lectin-based biosensors are useful to detect transformed tissues and biomarkers related to disease occurrence; antitumor lectins reported are promising for cancer therapy. Here, we address lectins from distinct sources with some biological effect and biotechnological potential in the diagnosis and therapeutic of diseases, highlighting many advances in this growing field. PMID:28367220

  17. Design and Application of Multifunctional DNA Nanocarriers for Therapeutic Delivery

    PubMed Central

    Charoenphol, Phapanin; Bermudez, Harry

    2013-01-01

    The unique programmability of nucleic acids offers versatility and flexibility in the creation of self-assembled DNA nanostructures. To date, many three-dimensional DNA architectures have been precisely formed of varying sizes and shapes. Their biocompatibility, biodegradability, and high intrinsic stability in physiological environments emphasize their emerging use as carriers for drug and gene delivery. Furthermore, DNA nanocarriers have been shown to enter cells efficiently and without the aid of transfection reagents. A key strength of DNA nanocarriers over other delivery systems is their modularity and their ability to control the spatial distribution of cargoes and ligands. Optimizing DNA nanocarrier properties to dictate their localization, uptake, and intracellular trafficking is also possible. In this review, we present design considerations for DNA nanocarriers and examples of their use in the context of therapeutic delivery applications. The assembly of DNA nanocarriers and approaches for loading and releasing cargo are described. The stability and safety of DNA nanocarriers is also discussed, with particular attention to the in vivo physiological environment. Mechanisms of cellular uptake and intracellular trafficking are examined, and we conclude with strategies to enhance the delivery efficiency of DNA nanocarriers. PMID:23896566

  18. Biosurfactants Produced by Marine Microorganisms with Therapeutic Applications

    PubMed Central

    Gudiña, Eduardo J.; Teixeira, José A.; Rodrigues, Lígia R.

    2016-01-01

    Marine microorganisms possess unique metabolic and physiological features and are an important source of new biomolecules, such as biosurfactants. Some of these surface-active compounds synthesized by marine microorganisms exhibit antimicrobial, anti-adhesive and anti-biofilm activity against a broad spectrum of human pathogens (including multi-drug resistant pathogens), and could be used instead of existing drugs to treat infections caused by them. In other cases, these biosurfactants show anti-cancer activity, which could be envisaged as an alternative to conventional therapies. However, marine biosurfactants have not been widely explored, mainly due to the difficulties associated with the isolation and growth of their producing microorganisms. Culture-independent techniques (metagenomics) constitute a promising approach to study the genetic resources of otherwise inaccessible marine microorganisms without the requirement of culturing them, and can contribute to the discovery of novel biosurfactants with significant biological activities. This paper reviews the most relevant biosurfactants produced by marine microorganisms with potential therapeutic applications and discusses future perspectives and opportunities to discover novel molecules from marine environments. PMID:26901207

  19. GLP-1: physiological effects and potential therapeutic applications.

    PubMed

    Aaboe, Kasper; Krarup, Thure; Madsbad, Sten; Holst, Jens Juul

    2008-11-01

    Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1 stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.

  20. Pycnogenol: a blend of procyanidins with multifaceted therapeutic applications?

    PubMed

    D'Andrea, Gabriele

    2010-10-01

    Great interest is currently centred on the biologic activities of pycnogenol a standardized plant extract obtained from the bark of the French maritime pine Pinus pinaster (formerly known as Pinus maritima), Aiton, subspecies Atlantica des Villar (Pycnogenol, Horphag Research Ltd., UK, Geneve, Switzerland), which grows in the coastal southwest France. The quality of this extract is specified in the United States Pharmacopeia (USP 28). Between 65% and 75% of Pycnogenol are procyanidins comprising of catechin and epicatechin subunits with varying chain lengths. Other constituents are polyphenolic monomers, phenolic or cinnamic acids and their glycosides. As many studies indicate, pycnogenol components are highly bioavailable. Uniquely, pycnogenol displays greater biologic effects as a mixture than its purified components do individually indicating that the components interact synergistically. Pycnogenol is now utilized throughout the world as a nutritional supplement and as a phytochemical remedy for various diseases ranging from chronic inflammation to circulatory dysfunction, including several impaired psycho-physiological functions. Owing to the basic chemical structure of its components, the most obvious feature of pycnogenol is its strong antioxidant activity. In fact, phenolic acids, polyphenols, and in particular flavonoids, are composed of one (or more) aromatic rings bearing one or more hydroxyl groups and are therefore potentially able to quench free radicals by forming resonance-stabilized phenoxyl radicals. In this review, emphasizing the molecular, cellular, and functional bases of therapy, data appearing in the peer-reviewed literature and focussing the main therapeutic applications of pycnogenol will be summarized and critically evaluated.

  1. Chitosan oligosaccharide: Biological activities and potential therapeutic applications.

    PubMed

    Muanprasat, Chatchai; Chatsudthipong, Varanuj

    2017-02-01

    Chitosan oligosaccharide (COS) is an oligomer of β-(1➔4)-linked d-glucosamine. COS can be prepared from the deacetylation and hydrolysis of chitin, which is commonly found in the exoskeletons of arthropods and insects and the cell walls of fungi. COS is water soluble, non-cytotoxic, readily absorbed through the intestine and mainly excreted in the urine. Of particular importance, COS and its derivatives have been demonstrated to possess several biological activities including anti-inflammation, immunostimulation, anti-tumor, anti-obesity, anti-hypertension, anti-Alzheimer's disease, tissue regeneration promotion, drug and DNA delivery enhancement, anti-microbial, anti-oxidation and calcium-absorption enhancement. The mechanisms of actions of COS have been found to involve the modulation of several important pathways including the suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) and the activation of AMP-activated protein kinase (AMPK). This review summarizes the current knowledge of the preparation methods, pharmacokinetic profiles, biological activities, potential therapeutic applications and safety profiles of COS and its derivatives. In addition, future research directions are discussed.

  2. Biosurfactants Produced by Marine Microorganisms with Therapeutic Applications.

    PubMed

    Gudiña, Eduardo J; Teixeira, José A; Rodrigues, Lígia R

    2016-02-18

    Marine microorganisms possess unique metabolic and physiological features and are an important source of new biomolecules, such as biosurfactants. Some of these surface-active compounds synthesized by marine microorganisms exhibit antimicrobial, anti-adhesive and anti-biofilm activity against a broad spectrum of human pathogens (including multi-drug resistant pathogens), and could be used instead of existing drugs to treat infections caused by them. In other cases, these biosurfactants show anti-cancer activity, which could be envisaged as an alternative to conventional therapies. However, marine biosurfactants have not been widely explored, mainly due to the difficulties associated with the isolation and growth of their producing microorganisms. Culture-independent techniques (metagenomics) constitute a promising approach to study the genetic resources of otherwise inaccessible marine microorganisms without the requirement of culturing them, and can contribute to the discovery of novel biosurfactants with significant biological activities. This paper reviews the most relevant biosurfactants produced by marine microorganisms with potential therapeutic applications and discusses future perspectives and opportunities to discover novel molecules from marine environments.

  3. Group 9 organometallic compounds for therapeutic and bioanalytical applications.

    PubMed

    Ma, Dik-Lung; Chan, Daniel Shiu-Hin; Leung, Chung-Hang

    2014-12-16

    CONSPECTUS: Compared with organic small molecules, metal complexes offer several distinct advantages as therapeutic agents or biomolecular probes. Carbon atoms are typically limited to linear, trigonal planar, or tetrahedral geometries, with a maximum of two enantiomers being formed if four different substituents are attached to a single carbon. In contrast, an octahedral metal center with six different substituents can display up to 30 different stereoisomers. While platinum- and ruthenium-based anticancer agents have attracted significant attention in the realm of inorganic medicinal chemistry over the past few decades, group 9 complexes (i.e., iridium and rhodium) have garnered increased attention in therapeutic and bioanalytical applications due to their adjustable reactivity (from kinetically liable to substitutionally inert), high water solubility, stability to air and moisture, and relative ease of synthesis. In this Account, we describe our efforts in the development of group 9 organometallic compounds of general form [M(C(∧)N)2(N(∧)N)] (where M = Ir, Rh) as therapeutic agents against distinct biomolecular targets and as luminescent probes for the construction of oligonucleotide-based assays for a diverse range of analytes. Earlier studies by researchers had focused on organometallic iridium(III) and rhodium(III) half-sandwich complexes that show promising anticancer activity, although their precise mechanisms of action still remain unknown. More recently, kinetically-inert group 9 complexes have arisen as fascinating alternatives to organic small molecules for the specific targeting of enzyme activity. Research in our laboratory has shown that cyclometalated octahedral rhodium(III) complexes were active against Janus kinase 2 (JAK2) or NEDD8-activating enzyme (NAE) activity, or against NO production leading to antivasculogenic activity in cellulo. At the same time, recent interest in the development of small molecules as modulators of protein

  4. Adjuvant chemotherapy for early-stage cervical cancer

    PubMed Central

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-01-01

    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

  5. miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart.

    PubMed

    Bernardo, Bianca C; Ooi, Jenny Y Y; Lin, Ruby C Y; McMullen, Julie R

    2015-01-01

    miRNAs are small non-coding RNAs (ncRNAs), which regulate gene expression. Here, the authors describe the contribution of miRNAs to cardiac biology and disease. They discuss various strategies for manipulating miRNA activity including antisense oligonucleotides (antimiRs, blockmiRs), mimics, miRNA sponges, Tough Decoys and miRNA mowers. They review developments in chemistries (e.g., locked nucleic acid) and modifications (sugar, 'ZEN', peptide nucleic acids) and miRNA delivery tools (viral vectors, liposomes, nanoparticles, pHLIP). They summarize potential miRNA therapeutic targets for heart disease based on preclinical studies. Finally, the authors review current progress of miRNA therapeutics in clinical development for HCV and cancer, and discuss challenges that will need to be overcome for similar therapies to enter the clinic for patients with cardiac disease.

  6. [Therapeutic application of repetitive transcranial magnetic stimulation for major depression].

    PubMed

    Nakamura, Motoaki

    2012-01-01

    , the neuronal level hypothesis includes the induction of neuroplasticity and activation of the dopamine system, and the neuronal circuitry level hypothesis includes the activation of the left DLPFC and inhibition of the right DLPFC and (para) limbic system such as the subgenual cingulate cortex and amygdala. On the therapeutic application of rTMS in clinical psychiatry, neuroethics and low invasiveness should be fully considered along with a negative history of punitive electroconvulsive therapy and prefrontal lobotomy. It is important to investigate the neurobiological mechanism of rTMS treatment and to place rTMS in a suitable position within comprehensive treatment algorithms of major depression.

  7. Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice*

    PubMed Central

    Zhao, Ming; Ding, Xian-feng; Shen, Jian-yu; Zhang, Xi-ping; Ding, Xiao-wen; Xu, Bin

    2017-01-01

    Breast cancer is one of the malignant tumors with the highest morbidity and mortality. It is helpful to reduce the rate of tumor recurrence and metastasis by treating breast cancer with adjuvant chemotherapy, so as to increase the cure rate or survival of patients. In recent years, liposomes have been regarded as a kind of new carrier for targeted drugs. Being effective for enhancing drug efficacy and reducing side effects, they have been widely used for developing anticancer drugs. As a kind of anthracycline with high anticancer activity, doxorubicin can treat or alleviate a variety of malignant tumors effectively when it is used on its own or in combination with other anticancer drugs. Although liposomal doxorubicin has been extensively used in the adjuvant chemotherapy of breast cancer, its exact therapeutic efficacy and side effects have not been definitely proven. Various clinical studies have adopted different combined regimes, dosages, and staging, so their findings differ to certain extent. This paper reviews the clinical application of liposomal doxorubicin in the adjuvant chemotherapy of breast cancer and illustrates therapeutic effects and side effects of pegylated liposomal doxorubicin (PLD) and non-PLD (NPLD) in clinical research, in order to discuss the strategies for applying these drugs in such adjuvant chemotherapy, looking forward to providing references for related research and clinical treatment in terms of dosage, staging, combined regimes, and analysis methods and so on. PMID:28070993

  8. Daily Experience Research: Methods and Applications in Therapeutic Recreation.

    ERIC Educational Resources Information Center

    Voelkl, Judith E.; Baldwin, Cheryl K.

    2000-01-01

    Reviews the major approaches used by social scientists to measure daily experiences, including interval-contingent, signal- contingent, and event-contingent methods. Examples of how these methods have been used in therapeutic recreation and leisure research are provided. The unique challenges and issues of measuring the daily experiences of…

  9. Antibody humanization methods for development of therapeutic applications.

    PubMed

    Ahmadzadeh, Vahideh; Farajnia, Safar; Feizi, Mohammad Ali Hosseinpour; Nejad, Ramezan Ali Khavari

    2014-04-01

    Recombinant antibody technologies are rapidly becoming available and showing considerable clinical success. However, the immunogenicity of murine-derived monoclonal antibodies is restrictive in cancer immunotherapy. Humanized antibodies can overcome these problems and are considered to be a promising alternative therapeutic agent. There are several approaches for antibody humanization. In this article we review various methods used in the antibody humanization process.

  10. Evaluation of locally induced osteoarthritis by the complete and incomplete Freund's adjuvant in mice. The application of DEXA measurements.

    PubMed

    Włodarski, K H; Dickson, G R

    2002-01-01

    The inflammatory reactions elicited in mice by subcutaneous injections of IFA and CFA had opposite effects when tested on local metacarpal shank bones and the distal epiphysis of shank bones. Although the intensity of the immune reactions was similar, IFA induced bone loss, while CFA induced bone formation, which was mostly periosteal in nature. BMC and BMD measurements were assessed by means of high resolution DEXA, using a hologic 4500A bone scanner with software dedicated for the analysis of small animal bones. DEXA scans were evaluated and related to histological and bone ash content analyses. The morphological and quantitative ash weight analyses of bones exposed to the adjuvants were consistent with DEXA bone density scan measurements.

  11. Potential therapeutic applications of hyaluronan in the lung

    PubMed Central

    Cantor, Jerome O

    2007-01-01

    Hyaluronan (HA), a long-chain polysaccharide, is currently being evaluated as a potential therapeutic agent for a number of inflammatory disorders. The effect of HA on inflammation appears to be related to its molecular size, with larger polysaccharide chains having anti-inflammatory activity and smaller ones having proinflammatory properties. This dichotomous behavior is particularly relevant to the work of our laboratory on an aerosolized preparation of HA to treat pulmonary emphysema. The breakdown of inhaled HA into smaller fragments could possibly induce an inflammatory reaction in the lung that counteracts any beneficial effect. Consequently, the proposed therapeutic use of HA will require development of treatment strategies aimed at minimizing its proinflammatory activity. PMID:18229566

  12. 77 FR 43862 - Manufacturer of Controlled Substances, Notice of Application, Nektar Therapeutics

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances, Notice of Application, Nektar Therapeutics... letter to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of...

  13. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

  14. Identification and Reconstruction of Prostate Tumor-Suppressing Exosomes for Therapeutic Applications

    DTIC Science & Technology

    2015-01-01

    Exosomes for Therapeutic Applications PRINCIPAL INVESTIGATOR: Daotai Nie CONTRACTING ORGANIZATION: Southern Illinois University School of Medicine... Exosomes for Therapeutic Applications 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0019 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Daotai Nie email...released by many cell types, exosomes serve as vehicles for long range intercellular communications, with the bioactive contents of exosomes as the

  15. Functional Roles and Therapeutic Applications of Exosomes in Hepatocellular Carcinoma.

    PubMed

    Santangelo, Laura; Battistelli, Cecilia; Montaldo, Claudia; Citarella, Franca; Strippoli, Raffaele; Cicchini, Carla

    2017-01-01

    Exosomes are important in intercellular communication. They assure the horizontal transfer of specific functional contents (i.e., proteins, lipids, RNA molecules, and circulating DNA) from donor to recipient cells. Notably, tumor-derived exosomes (TDEs) appear to be an important vehicle of specific signals in cancer, impacting on tumor growth and metastasis. Recent researches point to the characterization of exosomes in Hepatocellular Carcinoma (HCC), the major adult liver malignancy. In this review, we summarize current findings on HCC exosomes, focusing on the identification of noncoding RNAs as exosome-enriched functional regulators and new potential biomarkers. The great potential of exosomes in future HCC diagnostic and therapeutic approaches is underlined.

  16. Functional Roles and Therapeutic Applications of Exosomes in Hepatocellular Carcinoma

    PubMed Central

    Montaldo, Claudia; Strippoli, Raffaele

    2017-01-01

    Exosomes are important in intercellular communication. They assure the horizontal transfer of specific functional contents (i.e., proteins, lipids, RNA molecules, and circulating DNA) from donor to recipient cells. Notably, tumor-derived exosomes (TDEs) appear to be an important vehicle of specific signals in cancer, impacting on tumor growth and metastasis. Recent researches point to the characterization of exosomes in Hepatocellular Carcinoma (HCC), the major adult liver malignancy. In this review, we summarize current findings on HCC exosomes, focusing on the identification of noncoding RNAs as exosome-enriched functional regulators and new potential biomarkers. The great potential of exosomes in future HCC diagnostic and therapeutic approaches is underlined. PMID:28265569

  17. Therapeutic application of cardiac stem cells and other cell types.

    PubMed

    Hayashi, Emiko; Hosoda, Toru

    2013-01-01

    Various researches on regenerative medicine were carried out experimentally, and selected modalities have been introduced to the clinical arena. Meanwhile, the presence of resident stem cells in the heart and their role in physiological cell turnover were demonstrated. So far skeletal myoblasts, bone marrow-derived cells, mesenchymal stromal cells, and resident cardiac cells have been applied for therapeutic myocardial regeneration. Among them, autologous transplantation of c-kit-positive cardiac stem cells in congestive heart failure patients resulted in an outstanding outcome, with long-lasting beneficial effects without major adverse events. By reviewing these clinical trials, an endeavor was made to seek for an ideal cellular therapy for cardiovascular diseases.

  18. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 182.99 Section...) SUBSTANCES GENERALLY RECOGNIZED AS SAFE General Provisions § 182.99 Adjuvants for pesticide chemicals... pesticide use dilutions by a grower or applicator prior to application to the raw agricultural...

  19. Polyvinylpyrrolidone-Poly(ethylene glycol) Modified Silver Nanorods Can Be a Safe, Noncarrier Adjuvant for HIV Vaccine.

    PubMed

    Liu, Ye; Balachandran, Yekkuni L; Li, Dan; Shao, Yiming; Jiang, Xingyu

    2016-03-22

    One of the biggest obstacles for the development of HIV vaccines is how to sufficiently trigger crucial anti-HIV immunities via a safe manner. We herein integrated surface modification-dependent immunostimulation against HIV vaccine and shape-dependent biosafety and designed a safe noncarrier adjuvant based on silver nanorods coated by both polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG). Such silver nanorods can significantly elevate crucial immunities of HIV vaccine and overcome the toxicity, which is a big problem for other existing adjuvants. This study thus provided a principle for designing a safe and high-efficacy material for an adjuvant and allow researchers to really have a safe and effective prophylaxis against HIV. We expect this material approach to be applicable to other types of vaccines, whether they are preventative or therapeutic.

  20. Ligament-Derived Stem Cells: Identification, Characterisation, and Therapeutic Application

    PubMed Central

    Clegg, Peter David; Comerford, Eithne Josephine; Canty-Laird, Elizabeth Gail

    2017-01-01

    Ligament is prone to injury and degeneration and has poor healing potential and, with currently ineffective treatment strategies, stem cell therapies may provide an exciting new treatment option. Ligament-derived stem cell (LDSC) populations have been isolated from a number of different ligament types with the majority of studies focussing on periodontal ligament. To date, only a few studies have investigated LDSC populations in other types of ligament, for example, intra-articular ligaments; however, this now appears to be a developing field. This literature review aims to summarise the current information on nondental LDSCs including in vitro characteristics of LDSCs and their therapeutic potential. The stem cell niche has been shown to be vital for stem cell survival and function in a number of different physiological systems; therefore, the LDSC niche may have an impact on LDSC phenotype. The role of the LDSC niche on LDSC viability and function will be discussed as well as the therapeutic potential of LDSC niche modulation. PMID:28386284

  1. Packaging protein drugs as bacterial inclusion bodies for therapeutic applications

    PubMed Central

    2012-01-01

    A growing number of insights on the biology of bacterial inclusion bodies (IBs) have revealed intriguing utilities of these protein particles. Since they combine mechanical stability and protein functionality, IBs have been already exploited in biocatalysis and explored for bottom-up topographical modification in tissue engineering. Being fully biocompatible and with tuneable bio-physical properties, IBs are currently emerging as agents for protein delivery into mammalian cells in protein-replacement cell therapies. So far, IBs formed by chaperones (heat shock protein 70, Hsp70), enzymes (catalase and dihydrofolate reductase), grow factors (leukemia inhibitory factor, LIF) and structural proteins (the cytoskeleton keratin 14) have been shown to rescue exposed cells from a spectrum of stresses and restore cell functions in absence of cytotoxicity. The natural penetrability of IBs into mammalian cells (reaching both cytoplasm and nucleus) empowers them as an unexpected platform for the controlled delivery of essentially any therapeutic polypeptide. Production of protein drugs by biopharma has been traditionally challenged by IB formation. However, a time might have arrived in which recombinant bacteria are to be engineered for the controlled packaging of therapeutic proteins as nanoparticulate materials (nanopills), for their extra- or intra-cellular release in medicine and cosmetics. PMID:22686540

  2. Novel therapeutics in multiple sclerosis management: clinical applications.

    PubMed

    Leist, Thomas; Hunter, Samuel F; Kantor, Daniel; Markowitz, Clyde

    2014-01-01

    Multiple sclerosis (MS) affects an estimated 300,000 individuals in the United States. No cure exists and although there is a lack of consensus on management, strategies to modify disease course are available. These strategies involve initiating disease-modifying therapies that have been found to slow disease progression and prevent disability symptoms, thereby improving function for MS patients. The overall goal of early disease management is to intervene prior to irreversible neuronal destruction in order to delay disability progression and improve quality of life. Maintaining a lower level of disability for a longer period of time postpones and ultimately attempts to prevent reaching a level of immobility and irreversible disability. However, due to the complex nature of disease and its unique, individual patient course, no patient can be treated alike and no patient responds to therapy similarly. Therefore, MS research is continuous in its evolution of therapeutic development, focusing on neuroprotective effects and agents with distinctive mechanisms of action allowing for unique safety and efficacy profiles. Investigations include novel oral agents and monoclonal antibodies. Many of the approved agents also are continually being investigated in order to evaluate comparative data, the most appropriate means of implementing subsequent therapy upon failure, responsiveness to therapeutic agent when switched, and long-term safety and efficacy. This multimedia webcast educational activity will cover the current state of MS science, current therapies in MS, emerging treatments in clinical trials for MS as well as differences between physicians in diagnosis and management of MS and their evolving practices.

  3. From miniature to nano robots for diagnostic and therapeutic applications.

    PubMed

    Menciassi, Arianna; Sinibaldi, Edoardo; Pensabene, Virginia; Dario, Paolo

    2010-01-01

    This paper presents the evolution of diagnostic and therapeutic procedures as a process of convergence of technologies coming from different fields and involving different disciplines. In particular, it illustrates how modern surgery evolved thanks to fundamental biology knowledge; thus, with the introduction of imaging techniques intra-operatively and with the introduction of robotics, surgical procedures became much more predictable, precise and effective. Finally, the recent developments of optics (with CMOS and CCD technologies, and with the introduction of fiber optic technologies) allowed to "see" inside the human body, thus reducing the invasiveness of surgical procedures and making diagnostic procedures adequate for an effective early discovery of pathologies. Nowadays, we are assisting to a concrete merging between microrobotics technologies and bioengineering, with the potential to bring therapeutic tools where requested and when requested, with high precision and with very limited side effects. Furthermore, nanotechnology offers the possibility to fully implement this merging, thanks to the development of dedicated theranostic nanotools suitably fitting the considered convergence scenario.

  4. Leveraging biodiversity knowledge for potential phyto-therapeutic applications

    PubMed Central

    Sharma, Vivekanand; Sarkar, Indra Neil

    2013-01-01

    Objective To identify and highlight the feasibility, challenges, and advantages of providing a cross-domain pipeline that can link relevant biodiversity information for phyto-therapeutic assessment. Materials and methods A public repository of clinical trials information (ClinicalTrials.gov) was explored to determine the state of plant-based interventions under investigation. Results The results showed that ∼15% of drug interventions in ClinicalTrials.gov were potentially plant related, with about 60% of them clustered within 10 taxonomic families. Further analysis of these plant-based interventions identified ∼3.7% of associated plant species as endangered as determined from the International Union for the Conservation of Nature Red List. Discussion The diversity of the plant kingdom has provided human civilization with life-sustaining food and medicine for centuries. There has been renewed interest in the investigation of botanicals as sources of new drugs, building on traditional knowledge about plant-based medicines. However, data about the plant-based biodiversity potential for therapeutics (eg, based on genetic or chemical information) are generally scattered across a range of sources and isolated from contemporary pharmacological resources. This study explored the potential to bridge biodiversity and biomedical knowledge sources. Conclusions The findings from this feasibility study suggest that there is an opportunity for developing plant-based drugs and further highlight taxonomic relationships between plants that may be rich sources for bioprospecting. PMID:23518859

  5. Multiple sclerosis: Therapeutic applications of advancing drug delivery systems.

    PubMed

    Dolati, Sanam; Babaloo, Zohreh; Jadidi-Niaragh, Farhad; Ayromlou, Hormoz; Sadreddini, Sanam; Yousefi, Mehdi

    2017-02-01

    Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, which is accompanying with demyelination, neurodegeneration and sensibility to oxidative stress. In MS, auto-reactive lymphocytes cross the blood-brain barrier (BBB) and reside in the perivenous demyelinating lesions which create various distinct inflammatory demyelinated plaques situated predominantly in the white matter. The current MS-related therapeutic approaches can be classified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs suppress circulating immune cells, inhibit passing the BBB and decrease the inflammatory responses. Recent advances have remarkably delayed disease development and improved the quality of life for numerous patients. In spite of major improvements in therapeutic options, there are some limitations regarding the routes of administration and the necessity for repeated and long-term dosing in which cause to systemic disadvantageous consequences and patient non-compliance. Nanotechnology presents promising approaches to improve autoimmune disease treatment with the capability to overcome many of the limitations common to the current immunosuppressive and biological therapies. Here we emphasis on nanomedicine-based drug delivery approaches of biological immunomodulatory mediators for the treatment of multiple sclerosis. This comprehensive review details the most successful drugs in MS therapy and also focuses on conceptions and clinical potential of novel nanomedicine attitudes for inducing immunosuppression and immunological tolerance in MS to modulate abnormal and pathologic immune responses.

  6. Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis

    PubMed Central

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS. PMID:25157751

  7. Sirtuins in dermatology: applications for future research and therapeutics.

    PubMed

    Serravallo, Melissa; Jagdeo, Jared; Glick, Sharon A; Siegel, Daniel M; Brody, Neil I

    2013-05-01

    Sirtuins are a family of seven proteins in humans (SIRT1-SIRT7) that are involved in multiple cellular processes relevant to dermatology. The role of sirtuins in other organ systems is established. However, the importance of these proteins in dermatology is less defined. Recently, sirtuins gained international attention because of their role as "longevity proteins" that may extend and enhance human life. Sirtuins function in the cell via histone deacetylase and/or adenosine diphosphate ribosyltransferase enzymatic activity that target histone and non-histone substrates, including transcription regulators, tumor suppressors, structural proteins, DNA repair proteins, cell signaling proteins, transport proteins, and enzymes. Sirtuins are involved in cellular pathways related to skin structure and function, including aging, ultraviolet-induced photoaging, inflammation, epigenetics, cancer, and a variety of cellular functions including cell cycle, DNA repair and proliferation. This review highlights sirtuin-related cellular pathways, therapeutics and pharmacological targets in atopic dermatitis, bullous dermatoses, collagen vascular disorders, psoriasis, systemic lupus erythematosus, hypertrophic and keloid scars, cutaneous infections, and non-melanoma and melanoma skin cancer. Also discussed is the role of sirtuins in the following genodermatoses: ataxia telangiectasia, Cowden's syndrome, dyskeratosis congenita, Rubenstein-Taybi, Werner syndrome, and xeroderma pigmentosum. The pathophysiology of these inherited diseases is not well understood, and sirtuin-related processes represent potential therapeutic targets for diseases lacking suitable alternative treatments. The goal of this review is to bring attention to the dermatology community, physicians, and scientists, the importance of sirtuins in dermatology and provide a foundation and impetus for future discussion, research and pharmacologic discovery.

  8. Stem Cells Applications in Regenerative Medicine and Disease Therapeutics

    PubMed Central

    2016-01-01

    Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation. PMID:27516776

  9. Stem Cells Applications in Regenerative Medicine and Disease Therapeutics.

    PubMed

    Mahla, Ranjeet Singh

    2016-01-01

    Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.

  10. Preparation, Surface Properties, and Therapeutic Applications of Gold Nanoparticles in Biomedicine.

    PubMed

    Panahi, Yunes; Mohammadhosseini, Majid; Nejati-Koshki, Kazem; Abadi, Azam Jafari Najaf; Moafi, Hadi Fallah; Akbarzadeh, Abolfazl; Farshbaf, Masoud

    2017-02-01

    Gold nanoparticles (AuNPs) due to their unique properties and manifold surface functionalities have been applied in bio-nanotechnology. The application of GNPs in recent medical and biological research is very extensive. Especially it involves applications such as detection and photothermalysis of microorganisms and cancer stem cells, biosensors; optical bio-imaging and observing of cells and these nanostructures also serve as practical platforms for therapeutic agents. In this review we studied all therapeutic applications of gold nanoparticles in biomedicine, synthesis methods, and surface properties.

  11. Inorganic-Organic Hybrid Nanomaterials for Therapeutic and Diagnostic Imaging Applications

    PubMed Central

    Vivero-Escoto, Juan L.; Huang, Yu-Tzu

    2011-01-01

    Nanotechnology offers outstanding potential for future biomedical applications. In particular, due to their unique characteristics, hybrid nanomaterials have recently been investigated as promising platforms for imaging and therapeutic applications. This class of nanoparticles can not only retain valuable features of both inorganic and organic moieties, but also provides the ability to systematically modify the properties of the hybrid material through the combination of functional elements. Moreover, the conjugation of targeting moieties on the surface of these nanomaterials gives them specific targeted imaging and therapeutic properties. In this review, we summarize the recent reports in the synthesis of hybrid nanomaterials and their applications in biomedical areas. Their applications as imaging and therapeutic agents in vivo will be highlighted. PMID:21747714

  12. 78 FR 64018 - Manufacturer of Controlled Substances, Notice of Application, Nektar Therapeutics

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-25

    ... Enforcement Administration Manufacturer of Controlled Substances, Notice of Application, Nektar Therapeutics... (9801), a basic class of controlled substance listed in schedule II. The company plans to manufacture the listed controlled substance in support of product development. Any other such applicant, and...

  13. Therapeutic applications of reconstituted HDL: When structure meets function.

    PubMed

    Darabi, Maryam; Guillas-Baudouin, Isabelle; Le Goff, Wilfried; Chapman, M John; Kontush, Anatol

    2016-01-01

    Reconstituted forms of HDL (rHDL) are under development for infusion as a therapeutic approach to attenuate atherosclerotic vascular disease and to reduce cardiovascular risk following acute coronary syndrome and ischemic stroke. Currently available rHDL formulations developed for clinical use contain apolipoprotein A-I (apoA-I) and one of the major lipid components of HDL, either phosphatidylcholine or sphingomyelin. Recent data have established that quantitatively minor molecular constituents of HDL particles can strongly influence their anti-atherogenic functionality. Novel rHDL formulations displaying enhanced biological activities, including cellular cholesterol efflux, may therefore offer promising prospects for the development of HDL-based, anti-atherosclerotic therapies. Indeed, recent structural and functional data identify phosphatidylserine as a bioactive component of HDL; the content of phosphatidylserine in HDL particles displays positive correlations with all metrics of their functionality. This review summarizes current knowledge of structure-function relationships in rHDL formulations, with a focus on phosphatidylserine and other negatively-charged phospholipids. Mechanisms potentially underlying the atheroprotective role of these lipids are discussed and their potential for the development of HDL-based therapies highlighted.

  14. Therapeutic applications of TRAIL receptor agonists in cancer and beyond

    PubMed Central

    Amarante-Mendes, Gustavo P.; Griffith, Thomas S.

    2016-01-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings — ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  15. Antimicrobial bacteriophage-derived proteins and therapeutic applications

    PubMed Central

    Roach, Dwayne R; Donovan, David M

    2015-01-01

    Antibiotics have the remarkable power to control bacterial infections. Unfortunately, widespread use, whether regarded as prudent or not, has favored the emergence and persistence of antibiotic resistant strains of human pathogenic bacteria, resulting in a global health threat. Bacteriophages (phages) are parasites that invade the cells of virtually all known bacteria. Phages reproduce by utilizing the host cell's machinery to replicate viral proteins and genomic material, generally damaging and killing the cell in the process. Thus, phage can be exploited therapeutically as bacteriolytic agents against bacteria. Furthermore, understanding of the molecular processes involved in the viral life cycle, particularly the entry and cell lysis steps, has led to the development of viral proteins as antibacterial agents. Here we review the current preclinical state of using phage-derived endolysins, virion-associated peptidoglycan hydrolases, polysaccharide depolymerases, and holins for the treatment of bacterial infection. The scope of this review is a focus on the viral proteins that have been assessed for protective effects against human pathogenic bacteria in animal models of infection and disease. PMID:26442196

  16. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  17. Magnetic Microspheres and Tissue Model Studies for Therapeutical Applications

    NASA Technical Reports Server (NTRS)

    Ramachandran, N.; Mazuruk, K.

    2003-01-01

    Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia breast therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady for an extended period (2-3 hours). The basic shortcomings of the presently utilized heating methods stem from the non-uniform thermal properties of the tissue and the point heating characteristics of the techniques without any thermal control. Our approach is to develop a novel class of magnetic fluids, which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as suitable nano to micron-size particle material. The objective is to synthesize, characterize and evaluate the efficacy of Thermo Regulating

  18. Therapeutic application of hydrogen sulfide donors: the potential and challenges.

    PubMed

    Wu, Dan; Hu, Qingxun; Zhu, Yizhun

    2016-03-01

    Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been considered a toxic gas and environment hazard. However, evidences show that H2S plays a great role in many physiological and pathological activities, and it exhibits different effects when applied at various doses. In this review, we summarize the chemistry and biomedical applications of H2S-releasing compounds, including inorganic salts, phosphorodithioate derivatives, derivatives of Allium sativum extracts, derivatives of thioaminoacids, and derivatives of antiinflammatory drugs.

  19. Dispersion and evaporation of droplets amended with adjuvants on soybeans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Increased use of adjuvants to improve pesticide spray application efficiency is hindered by a lack of knowledge to enhance droplet adhesion. Dispersion and evaporation of single 300 µm droplets amended with four different spray adjuvants deposited at four different soybean plant locations were inves...

  20. Adjuvant Effects on Evaporation Time and Wetted Area of Droplets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Appropriate adjuvant selection for pesticide applications is central to improve spray performances on waxy leaves and to reduce off-target losses. Evaporation and deposition patterns of 500 µm sessile droplets with five classes of adjuvants on five different waxy plants were investigated. Droplets g...

  1. Acoustic droplet vaporization for diagnostic and therapeutic applications

    NASA Astrophysics Data System (ADS)

    Kripfgans, Oliver Daniel

    A technology, termed Acoustic Droplet Vaporization (ADV), is developed whereby superheated droplets are caused to vaporize by application of an ultrasonic field. The droplet emulsion (90% <6 um diameter) is made by mixing saline, albumin, and perfluorocarbon at high speed. It has been observed that an acoustic pressure threshold exists above which the droplets vaporize into bubbles approximately 25-times the original droplet diameter. For frequencies between 1.5 and 8 MHz, the threshold decreases from 4.5 to 0.75 MPa peak rarefactional pressure. The single pulse efficiency of ADV has been measured as 26%. This technology might be useful for tissue occlusion in cancer treatment as well as for aberration correction in acoustic imaging. To demonstrate these potential applications, gas bubbles were made in vivo in animal models by ADV. It was found that ADV could be used to temporarily form large gas bubbles (>30 um) in vivo, which at large number density occluded targeted tissues and reduced the blood flow by 34%. Alternatively, for a very sparse droplet population, gas bubbles could serve as potential point beacons for phase aberration correction given their backscatter amplitudes of 24 dB above tissue background. Other possible applications include drug delivery, indicator for cryo therapy, pressure/radiation beacons, hyperthermia, and cavitation nuclei. ADV of individual droplets showed that during acoustic irradiation, droplets perform dipole-type oscillations and that such oscillations increased in amplitude with acoustic intensity. Smaller droplets required more acoustic intensity for vaporization than larger droplets; however, independent of droplet diameter, a maximum oscillation amplitude of 1.3 um, was required. This threshold corresponds to a Reynolds number of ˜5 x 104. Vaporization started either as a spot on the axis of oscillation close to a pole of the droplet, or homogeneously throughout the droplet's imaged cross-section. It is concluded that

  2. Actinium-225 in targeted alpha-particle therapeutic applications.

    PubMed

    Scheinberg, David A; McDevitt, Michael R

    2011-10-01

    Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium- 225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day halflife; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer.

  3. Vaccines, adjuvants and autoimmunity.

    PubMed

    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.

  4. Using adjuvants and environmental factors to modulate the activity of antimicrobial peptides.

    PubMed

    Walkenhorst, William F

    2016-05-01

    The increase in antibiotic resistant and multi-drug resistant bacterial infections has serious implications for the future of health care. The difficulty in finding both new microbial targets and new drugs against existing targets adds to the concern. The use of combination and adjuvant therapies are potential strategies to counter this threat. Antimicrobial peptides (AMPs) are a promising class of antibiotics (ABs), particularly for topical and surface applications. Efforts have been directed toward a number of strategies, including the use of conventional ABs combined with AMPs, and the use of potentiating agents to increase the performance of AMPs. This review focuses on combination strategies such as adjuvants and the manipulation of environmental variables to improve the efficacy of AMPs as potential therapeutic agents. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

  5. Therapeutic application of melatonin in mild cognitive impairment

    PubMed Central

    Cardinali, Daniel P; Vigo, Daniel E; Olivar, Natividad; Vidal, María F; Furio, Analía M; Brusco, Luis I

    2012-01-01

    Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome defined by cognitive impairment in advance of dementia. We previously reported in a retrospective analysis that daily 3 - 9 mg of a fast-release melatonin preparation given p. o. at bedtime for up to 3 years significantly improved cognitive and emotional performance and daily sleep/wake cycle in MCI patients. In a follow up of that study we now report data from another series of 96 MCI outpatients, 61 of who had received daily 3 - 24 mg of a fast-release melatonin preparation p. o. at bedtime for 15 to 60 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin exhibited significantly better performance in Mini–Mental State Examination and the cognitive subscale of the Alzheimer’s disease Assessment Scale. After application of a neuropsychological battery comprising a Mattis´ test, Digit-symbol test, Trail A and B tasks and the Rey´s verbal test, better performance was found in melatonin-treated patients for every parameter tested. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with the improvement in the quality of sleep and wakefulness. The comparison of the medication profile in both groups of MCI patients indicated that 9.8% in the melatonin group received benzodiazepines vs. 62.8% in the non-melatonin group. The results further support that melatonin can be a useful add-on drug for treating MCI in a clinic environment. PMID:23383398

  6. Analysis of volumetric response of pituitary adenomas receiving adjuvant CyberKnife stereotactic radiosurgery with the application of an exponential fitting model

    PubMed Central

    Yu, Yi-Lin; Yang, Yun-Ju; Lin, Chin; Hsieh, Chih-Chuan; Li, Chiao-Zhu; Feng, Shao-Wei; Tang, Chi-Tun; Chung, Tzu-Tsao; Ma, Hsin-I; Chen, Yuan-Hao; Ju, Da-Tong; Hueng, Dueng-Yuan

    2017-01-01

    Abstract Tumor control rates of pituitary adenomas (PAs) receiving adjuvant CyberKnife stereotactic radiosurgery (CK SRS) are high. However, there is currently no uniform way to estimate the time course of the disease. The aim of this study was to analyze the volumetric responses of PAs after CK SRS and investigate the application of an exponential decay model in calculating an accurate time course and estimation of the eventual outcome. A retrospective review of 34 patients with PAs who received adjuvant CK SRS between 2006 and 2013 was performed. Tumor volume was calculated using the planimetric method. The percent change in tumor volume and tumor volume rate of change were compared at median 4-, 10-, 20-, and 36-month intervals. Tumor responses were classified as: progression for >15% volume increase, regression for ≤15% decrease, and stabilization for ±15% of the baseline volume at the time of last follow-up. For each patient, the volumetric change versus time was fitted with an exponential model. The overall tumor control rate was 94.1% in the 36-month (range 18–87 months) follow-up period (mean volume change of −43.3%). Volume regression (mean decrease of −50.5%) was demonstrated in 27 (79%) patients, tumor stabilization (mean change of −3.7%) in 5 (15%) patients, and tumor progression (mean increase of 28.1%) in 2 (6%) patients (P = 0.001). Tumors that eventually regressed or stabilized had a temporary volume increase of 1.07% and 41.5% at 4 months after CK SRS, respectively (P = 0.017). The tumor volume estimated using the exponential fitting equation demonstrated high positive correlation with the actual volume calculated by magnetic resonance imaging (MRI) as tested by Pearson correlation coefficient (0.9). Transient progression of PAs post-CK SRS was seen in 62.5% of the patients receiving CK SRS, and it was not predictive of eventual volume regression or progression. A three-point exponential model is of potential predictive value

  7. Nanoparticles as conjugated delivery agents for therapeutic applications

    NASA Astrophysics Data System (ADS)

    Muroski, Megan Elizabeth

    a molecular beacon. The development of non-viral transfection approaches using gold nanoparticles (AuNP) as a gene carrier allows the implementation of advanced biophysical tools to follow the transfection cycle by utilizing nanometal surface energy transfer (NSET) molecular beacon methods coupled to delivery of a gene that induces a fluorescent protein. The change in photoluminescence of an appended dye following gene release from the AuNP surface within endosomes can be tempo-rally and spatially followed. The ability to correlate the release events with the protein expression event by simultaneously monitoring fluorescent protein production provides insight into package uptake, nanoparticle disassembly, and final gene expression. Employing AuNP transfection constructs and then monitoring the stages of the transfection cycle via NSET, indicates delivery of the constructs leads to gene release from the AuNP surface within the endosome followed by slow cytosolic diffusion. The slow diffusion is the limiting step for transfection and impacts the protein yield due to competing degradation processes. Chapter 4 aims to improve the NP conjugate through the use of cell penetrating peptides (CPP) to Transfect Primary Cells. All future clinical applications of mesenchymal stem cell (MSC) therapies must allow the MSC to be harvested, transfected, and induced to express a desired protein or selection of proteins to have medical benefit. For the full potential of MSC cell therapy to be realized, it is desirable to be able to systematically alter the protein expression in harvested MSC cells with high fidelity in a single transfection event. We have developed a bimodal delivery platform based on the use of a solid gold core nanoparticle that has been surface modified to produce a chimera containing a protein transduction domain (PTD) sequence to enhance cellular uptake and a linearized expression vector to induce protein production. The transfection chimera is observed to be an

  8. Probiotics as an adjuvant treatment in Helicobacter pylori eradication therapy.

    PubMed

    Zhu, Xinyan; Liu, Fei

    2017-03-10

    Over 80% population with Helicobacter pylori (H. pylori) infection is asymptomatic. H. pylori was considered as a primary reason for various natural gastric physiopathology. Increased antibiotic resistance and less medication compliance lead to the failure of antibiotic eradication therapy. Probiotics have been applied as a supplementary treatment in H. pylori eradication therapy in recent years. They have direct and indirect inhibitory effects on H. pylori in both animal models and clinical trials. Because of the improvement in eradication rates and therapy-related side effects, probiotics have been considered as the useful supplementation to current eradication therapy although the treatment outcomes were controversial due to the heterogeneity of probiotics in species, strains, doses and therapeutic duration. Despite the positive role of probiotics, several factors need to be further considered during the application of probiotics. At last, the adverse effects of probiotics are notable. Further investigation into the safety of adjuvant probiotics to present H. pylori eradication therapy is still needed.

  9. Peptide hormones and lipopeptides: from self-assembly to therapeutic applications.

    PubMed

    Hutchinson, J A; Burholt, S; Hamley, I W

    2017-02-01

    This review describes the properties and activities of lipopeptides and peptide hormones and how the lipidation of peptide hormones could potentially produce therapeutic agents combating some of the most prevalent diseases and conditions. The self-assembly of these types of molecules is outlined, and how this can impact on bioactivity. Peptide hormones specific to the uptake of food and produced in the gastrointestinal tract are discussed in detail. The advantages of lipidated peptide hormones over natural peptide hormones are summarised, in terms of stability and renal clearance, with potential application as therapeutic agents. © 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

  10. Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes

    PubMed Central

    2015-01-01

    Adjuvants improve the adaptive immune response to a vaccine antigen by modulating innate immunity or facilitating transport and presentation. The selection of an appropriate adjuvant has become vital as new vaccines trend toward narrower composition, expanded application, and improved safety. Functionally, adjuvants act directly or indirectly on antigen presenting cells (APCs) including dendritic cells (DCs) and are perceived as having molecular patterns associated either with pathogen invasion or endogenous cell damage (known as pathogen associated molecular patterns [PAMPs] and damage associated molecular patterns [DAMPs]), thereby initiating sensing and response pathways. PAMP-type adjuvants are ligands for toll-like receptors (TLRs) and can directly affect DCs to alter the strength, potency, speed, duration, bias, breadth, and scope of adaptive immunity. DAMP-type adjuvants signal via proinflammatory pathways and promote immune cell infiltration, antigen presentation, and effector cell maturation. This class of adjuvants includes mineral salts, oil emulsions, nanoparticles, and polyelectrolytes and comprises colloids and molecular assemblies exhibiting complex, heterogeneous structures. Today innovation in adjuvant technology is driven by rapidly expanding knowledge in immunology, cross-fertilization from other areas including systems biology and materials sciences, and regulatory requirements for quality, safety, efficacy and understanding as part of the vaccine product. Standardizations will aid efforts to better define and compare the structure, function and safety of adjuvants. This article briefly surveys the genesis of adjuvant technology and then re-examines polyionic macromolecules and polyelectrolyte materials, adjuvants currently not known to employ TLR. Specific updates are provided for aluminum-based formulations and polyelectrolytes as examples of improvements to the oldest and emerging classes of vaccine adjuvants in use. PMID:25648619

  11. Cytotoxic T cell adjuvant effects of three Salmonella enterica flagellins

    PubMed Central

    Braga, Catarina J.M.; Massis, Liliana M.; Alencar, Bruna C.G.; Rodrigues, Maurício M.; Sbrogio-Almeida, M.E.; Ferreira, Luís C.S.

    2008-01-01

    Bacterial flagellins are important virulence-associated factors and strong inducers of inflammatory responses in mammalian hosts. Flagellins have also been investigated as potential vaccine adjuvants, either for induction of humoral or cellular immune responses, to different target antigens. In this study we investigated the adjuvant properties of three Salmonella enterica flagellins types (FliCd, FliCi and FljB) to an ovalbumin-derived CD8+ T cell-restricted epitope (OVA257–264). Although mice immunized with the three tested flagellins elicited antigen-specific activated CD8+ T cells, only animals immunized with FliCi and FliCd flagellins admixed with ovalbumin mounted specific in vivo cytotoxic responses to peptide-pulsed target cells. The present results indicate that Salmonella flagellins are endowed with type-specific adjuvant effects toward murine CD8+ T cells, a feature that may impact their use as adjuvants for prophylatic or therapeutic vaccines. PMID:24031176

  12. [Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?].

    PubMed

    Hupe, M C; Kramer, M W; Kuczyk, M A; Merseburger, A S

    2015-05-01

    Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients, the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). For second-line treatment, vinflunine is the only approved therapeutic agent.

  13. The application of adjuvant autologous antravesical macrophage cell therapy vs. BCG in non-muscle invasive bladder cancer: a multicenter, randomized trial

    PubMed Central

    2010-01-01

    Introduction While adjuvant immunotherapy with Bacille Calmette Guérin (BCG) is effective in non-muscle-invasive bladder cancer (BC), adverse events (AEs) are considerable. Monocyte-derived activated killer cells (MAK) are discussed as essential in antitumoural immunoresponse, but their application may imply risks. The present trial compared autologous intravesical macrophage cell therapy (BEXIDEM®) to BCG in patients after transurethral resection (TURB) of BC. Materials and methods This open-label trial included 137 eligible patients with TaG1-3, T1G1-2 plurifocal or unifocal tumours and ≥ 2 occurrences within 24 months and was conducted from June 2004 to March 2007. Median follow-up for patients without recurrence was 12 months. Patients were randomized to BCG or mononuclear cells collected by apheresis after ex vivo cell processing and activation (BEXIDEM). Either arm treatment consisted of 6 weekly instillations and 2 cycles of 3 weekly instillations at months 3 and 6. Toxicity profile (primary endpoint) and prophylactic effects (secondary endpoint) were assessed. Results Patient characteristics were evenly distributed. Of 73 treated with BCG and 64 with BEXIDEM, 85% vs. 45% experienced AEs and 26% vs. 14% serious AEs (SAE), respectively (p < 0.001). Recurrence occurred significantly less frequent with BCG than with BEXIDEM (12% vs. 38%; p < 0.001). Discussion This initial report of autologous intravesical macrophage cell therapy in BC demonstrates BEXIDEM treatment to be safe. Recurrence rates were significantly lower with BCG however. As the efficacy of BEXIDEM remains uncertain, further data, e.g. marker lesions studies, are warranted. Trial registration The trial has been registered in the ISRCTN registry http://isrctn.org under the registration number ISRCTN35881130. PMID:20529333

  14. New horizons for focused ultrasound (FUS) - therapeutic applications in neurodegenerative diseases.

    PubMed

    Miller, Diane B; O'Callaghan, James P

    2017-04-01

    Access to the CNS and delivery of therapeutics across the blood-brain barrier remains a challenge for most treatments of major neurological diseases such as AD or PD. Focused ultrasound represents a potential approach for overcoming these barriers to treating AD and PD and perhaps other neurological diseases. Ultrasound (US) is best known for its imaging capabilities of organs in the periphery, but various arrangements of the transducers producing the acoustic signal allow the energy to be precisely focused (F) within the skull. Using FUS in combination with MRI and contrast agents further enhances accuracy by providing clear information on location. Varying the acoustic power allows FUS to be used in applications ranging from imaging, stimulation of brain circuits, to ablation of tissue. In several transgenic mouse models of AD, the use of FUS with microbubbles reduces plaque load and improves cognition and suggests the need to investigate this technology for plaque removal in AD. In PD, FUS is being explored as a way to non-invasively ablate the brain areas responsible for the tremor and dyskinesia associated with the disease, but has yet to be utilized for non-invasive delivery of putative therapeutics. The FUS approach also greatly increases the range of possible CNS therapeutics as it overcomes the issues of BBB penetration. In this review we discuss how the characteristics and various applications of FUS may advance the therapeutics available for treating or preventing neurodegenerative disorders with an emphasis on treating AD and PD.

  15. Opioid and adjuvant analgesics: compared and contrasted.

    PubMed

    Khan, Mohammed Ilyas Ahmed; Walsh, Declan; Brito-Dellan, Norman

    2011-08-01

    An adjuvant (or co-analgesic) is a drug that in its pharmacological characteristic is not necessarily primarily identified as an analgesic in nature but that has been found in clinical practice to have either an independent analgesic effect or additive analgesic properties when used with opioids. The therapeutic role of adjuvant analgesics (AAs) is to increase the therapeutic index of opioids by a dose-sparing effect, add a unique analgesic action in opioid-resistant pain, or reduce opioid side effects. A notable difference between opioids and AAs is that unlike opioids some AAs are associated with permanent organ toxicity, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) and renal failure. It is impossible to predict in advance in a given individual what opioid dose they may require to control cancer pain. Most AAs have a ceiling effect for their analgesic actions, but often with continued dose-related toxicities and side effects (with the exception of glucocorticoids). The blood levels of opioids (and their metabolites) can be measured with great precision and accuracy. There is sometimes a role for drug blood levels of certain AAs, like tricyclic antidepressants or anticonvulsants when used for neuropathic pain. Age affects metabolism of most opioids. The therapeutic window of opioids is wide, with no ceiling effect. Most AAs (except corticosteroids) have a narrow therapeutic window. Naloxone is a pure opioid antagonist that competes and displaces opioids from their receptor sites. All clinically useful opioids are mu opioid receptor agonists. Not all routes of administration are available to all opioids. Adjuvant analgesics lack the versatility in routes of administration that opioids possess. Dosing flexibility is a major advantage when treating cancer-related pain with opioids. Dose flexibility is much less with AAs than opioids. Unlike opioids, the analgesic response is usually observed within hours to days of attaining an adequate dose with most

  16. Engineered magnetic core shell nanoprobes: Synthesis and applications to cancer imaging and therapeutics

    PubMed Central

    Mandal, Samir; Chaudhuri, Keya

    2016-01-01

    Magnetic core shell nanoparticles are composed of a highly magnetic core material surrounded by a thin shell of desired drug, polymer or metal oxide. These magnetic core shell nanoparticles have a wide range of applications in biomedical research, more specifically in tissue imaging, drug delivery and therapeutics. The present review discusses the up-to-date knowledge on the various procedures for synthesis of magnetic core shell nanoparticles along with their applications in cancer imaging, drug delivery and hyperthermia or cancer therapeutics. Literature in this area shows that magnetic core shell nanoparticle-based imaging, drug targeting and therapy through hyperthermia can potentially be a powerful tool for the advanced diagnosis and treatment of various cancers. PMID:26981204

  17. Site-specific functionalization of proteins and their applications to therapeutic antibodies

    PubMed Central

    van Vught, Remko; Pieters, Roland J; Breukink, Eefjan

    2014-01-01

    Protein modifications are often required to study structure and function relationships. Instead of the random labeling of lysine residues, methods have been developed to (sequence) specific label proteins. Next to chemical modifications, tools to integrate new chemical groups for bioorthogonal reactions have been applied. Alternatively, proteins can also be selectively modified by enzymes. Herein we review the methods available for site-specific modification of proteins and their applications for therapeutic antibodies. PMID:24757499

  18. Biotechnology approaches to produce potent, self-adjuvanting antigen-adjuvant fusion protein subunit vaccines.

    PubMed

    Moyle, Peter Michael

    Traditional vaccination approaches (e.g. live attenuated or killed microorganisms) are among the most effective means to prevent the spread of infectious diseases. These approaches, nevertheless, have failed to yield successful vaccines against many important pathogens. To overcome this problem, methods have been developed to identify microbial components, against which protective immune responses can be elicited. Subunit antigens identified by these approaches enable the production of defined vaccines, with improved safety profiles. However, they are generally poorly immunogenic, necessitating their administration with potent immunostimulatory adjuvants. Since few safe and effective adjuvants are currently used in vaccines approved for human use, with those available displaying poor potency, or an inability to stimulate the types of immune responses required for vaccines against specific diseases (e.g. cytotoxic lymphocytes (CTLs) to treat cancers), the development of new vaccines will be aided by the availability of characterized platforms of new adjuvants, improving our capacity to rationally select adjuvants for different applications. One such approach, involves the addition of microbial components (pathogen-associated molecular patterns; PAMPs), that can stimulate strong immune responses, into subunit vaccine formulations. The conjugation of PAMPs to subunit antigens provides a means to greatly increase vaccine potency, by targeting immunostimulation and antigen to the same antigen presenting cell. Thus, methods that enable the efficient, and inexpensive production of antigen-adjuvant fusions represent an exciting mean to improve immunity towards subunit antigens. Herein we review four protein-based adjuvants (flagellin, bacterial lipoproteins, the extra domain A of fibronectin (EDA), and heat shock proteins (Hsps)), which can be genetically fused to antigens to enable recombinant production of antigen-adjuvant fusion proteins, with a focus on their

  19. Chinese advances in the research of photobiomodulation and its therapeutic applications

    NASA Astrophysics Data System (ADS)

    Liu, Cheng-Yi T.; Cheng, Lei; Liu, Jiang; Xu, Xiao-Yang; Wang, Xian-ju; Liu, Song-hao

    2005-07-01

    Photobiomodulation, once called biostimulation, has been studied as the mechanism of low intensity laser therapy since 1982, and it has been studied in China since 1987. Chinese therapeutic applications began in low intensity laser acupuncture in 1970s, in intravascular low intensity laser therapy in 1990s, in endonasal low intensity laser therapy in 1998, in high intensity laser acupuncture in 2000, and in laser surgery in 2001. As Chinese therapeutic applications of photobiomodulation were the most widely in the world, the research of photobiomodulation and its therapeutic applications was very progressive in China. Although the specific pathways mediating photobiomodulation were put forward and studied by foreign experts such as Karu et al, the non-specific pathways were put forward for the first time and were also studied very deeply by Chinese experts such as Liu TCY et al. Moreover, basic research of intravascular low intensity laser therapy, such as in vitro blood research and animal model research, was also very progressive in China.

  20. Therapeutic Application of Human Wharton Jelly Mesenchymal Stem Cells in Skin Injury of SCID.

    PubMed

    Sabapathy, Vikram; Sundaram, Balasubramanian; Kumar, Sanjay

    2017-01-01

    Mesenchymal stem cells (MSCs) are blossoming as a credible source for regenerative medical applications. The use of fetal MSCs is gaining momentum for therapeutic use. The ease of isolation, enhanced characteristics, and immunomodulation properties renders the utilization of fetal MSCs for numerous clinical applications. In this article, we will demonstrate a step-by-step protocol for isolation of Wharton's jelly MSCs (WJMSCs) from the human umbilical cord matrix, preparation of human platelet lysate, fabricating amniotic membrane scaffold and mice model to study skin regeneration using a combination of MSCs and decellularized amniotic membrane scaffold.

  1. The child's right to an open future: is the principle applicable to non-therapeutic circumcision?

    PubMed

    Darby, Robert J L

    2013-07-01

    The principle of the child's right to an open future was first proposed by the legal philosopher Joel Feinberg and developed further by bioethicist Dena Davis. The principle holds that children possess a unique class of rights called rights in trust-rights that they cannot yet exercise, but which they will be able to exercise when they reach maturity. Parents should not, therefore, take actions that permanently foreclose on or pre-empt the future options of their children, but leave them the greatest possible scope for exercising personal life choices in adulthood. Davis particularly applies the principle to genetic counselling, arguing that parents should not take deliberate steps to create physically abnormal children, and to religion, arguing that while parents are entitled to bring their children up in accordance with their own values, they are not entitled to inflict physical or mental harm, neither by omission nor commission. In this paper, I aim to elucidate the open future principle, and consider whether it is applicable to non-therapeutic circumcision of boys, whether performed for cultural/religious or for prophylactic/health reasons. I argue that the principle is highly applicable to non-therapeutic circumcision, and conclude that non-therapeutic circumcision would be a violation of the child's right to an open future, and thus objectionable from both an ethical and a human rights perspective.

  2. Significance of antioxidant potential of plants and its relevance to therapeutic applications.

    PubMed

    Kasote, Deepak M; Katyare, Surendra S; Hegde, Mahabaleshwar V; Bae, Hanhong

    2015-01-01

    Oxidative stress has been identified as the root cause of the development and progression of several diseases. Supplementation of exogenous antioxidants or boosting endogenous antioxidant defenses of the body is a promising way of combating the undesirable effects of reactive oxygen species (ROS) induced oxidative damage. Plants have an innate ability to biosynthesize a wide range of non-enzymatic antioxidants capable of attenuating ROS- induced oxidative damage. Several in vitro methods have been used to screen plants for their antioxidant potential, and in most of these assays they revealed potent antioxidant activity. However, prior to confirming their in vivo therapeutic efficacy, plant antioxidants have to pass through several physiopharmacological processes. Consequently, the findings of in vitro and in vivo antioxidant potential assessment studies are not always the same. Nevertheless, the results of in vitro assays have been irrelevantly extrapolated to the therapeutic application of plant antioxidants without undertaking sufficient in vivo studies. Therefore, we have briefly reviewed the physiology and redox biology of both plants and humans to improve our understanding of plant antioxidants as therapeutic entities. The applications and limitations of antioxidant activity measurement assays were also highlighted to identify the precise path to be followed for future research in the area of plant antioxidants.

  3. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application.

    PubMed

    Yuan, Xun; Wu, Hua; Han, Na; Xu, Hanxiao; Chu, Qian; Yu, Shiying; Chen, Yuan; Wu, Kongming

    2014-12-05

    Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung cancer (NSCLC). Correspondingly, blocking of Notch signaling inhibits NSCLC migration and tumor growth by reversing EMT. Clinical trials have showed promising effect in some cancer patients received treatment with Notch1 inhibitor. This review attempts to provide an overview of the Notch signal in NSCLC: its biological significance and therapeutic application.

  4. A Readily Applicable Strategy to Convert Peptides to Peptoid-based Therapeutics

    PubMed Central

    Park, Minyoung; Wetzler, Modi; Jardetzky, Theodore S.; Barron, Annelise E.

    2013-01-01

    Incorporation of unnatural amino acids and peptidomimetic residues into therapeutic peptides is highly efficacious and commonly employed, but generally requires laborious trial-and-error approaches. Previously, we demonstrated that C20 peptide has the potential to be a potential antiviral agent. Herein we report our attempt to improve the biological properties of this peptide by introducing peptidomimetics. Through combined alanine, proline, and sarcosine scans coupled with a competitive fluorescence polarization assay developed for identifying antiviral peptides, we enabled to pinpoint peptoid-tolerant peptide residues within C20 peptide. The synergistic benefits of combining these (and other) commonly employed methods could lead to a easily applicable strategy for designing and refining therapeutically-attractive peptidomimetics. PMID:23555603

  5. Peptide hormones and lipopeptides: from self‐assembly to therapeutic applications

    PubMed Central

    Hutchinson, J. A.; Burholt, S.

    2017-01-01

    This review describes the properties and activities of lipopeptides and peptide hormones and how the lipidation of peptide hormones could potentially produce therapeutic agents combating some of the most prevalent diseases and conditions. The self‐assembly of these types of molecules is outlined, and how this can impact on bioactivity. Peptide hormones specific to the uptake of food and produced in the gastrointestinal tract are discussed in detail. The advantages of lipidated peptide hormones over natural peptide hormones are summarised, in terms of stability and renal clearance, with potential application as therapeutic agents. © 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID:28127868

  6. Applications of metabolomics for kidney disease research: from biomarkers to therapeutic targets.

    PubMed

    Wettersten, Hiromi I; Weiss, Robert H

    2013-01-01

    Metabolomics is one of the relative newcomers of the omics techniques and is likely the one most closely related to actual real-time disease pathophysiology. Hence, it has the power to yield not only specific biomarkers but also insight into the pathophysiology of disease. Despite this power, metabolomics as applied to kidney disease is still in its early adolescence and has not yet reached the mature stage of clinical application, i.e., specific biomarker and therapeutic target discovery. On the other hand, the insight gained from hints into what makes these diseases tick, as is evident from the metabolomics pathways which have been found to be altered in kidney cancer, are now beginning to bear fruit in leading to potential therapeutic targets. It is quite likely that, with greater numbers of clinical materials and with more investigators jumping into the field, metabolomics may well change the course of kidney disease research.

  7. Therapeutic application of mesenchymal stem cell-derived exosomes: A promising cell-free therapeutic strategy in regenerative medicine.

    PubMed

    Motavaf, M; Pakravan, K; Babashah, S; Malekvandfard, F; Masoumi, M; Sadeghizadeh, M

    2016-06-30

    Mesenchymal stem cells have emerged as promising therapeutic candidates in regenerative medicine. The mechanisms underlying mesenchymal stem cells regenerative properties were initially attributed to their engraftment in injured tissues and their subsequent transdifferentiation to repair and replace damaged cells. However, studies in animal models and patients indicated that the low number of transplanted mesenchymal stem cells localize to the target tissue and transdifferentiate to appropriate cell lineage. Instead the regenerative potential of mesenchymal stem cells has been found - at least in part - to be mediated via their paracrine actions. Recently, a secreted group of vesicles, called "exosome" has been identified as major mediator of mesenchymal stem cells therapeutic efficacy. In this review, we will summarize the current literature on administration of exosomes released by mesenchymal stem cells in regenerative medicine and suggest how they could help to improve tissue regeneration following injury.

  8. Mass Spectrometry in Clinical Laboratory: Applications in Therapeutic Drug Monitoring and Toxicology.

    PubMed

    Garg, Uttam; Zhang, Yan Victoria

    2016-01-01

    Mass spectrometry (MS) has been used in research and specialized clinical laboratories for decades as a very powerful technology to identify and quantify compounds. In recent years, application of MS in routine clinical laboratories has increased significantly. This is mainly due to the ability of MS to provide very specific identification, high sensitivity, and simultaneous analysis of multiple analytes (>100). The coupling of tandem mass spectrometry with gas chromatography (GC) or liquid chromatography (LC) has enabled the rapid expansion of this technology. While applications of MS are used in many clinical areas, therapeutic drug monitoring, drugs of abuse, and clinical toxicology are still the primary focuses of the field. It is not uncommon to see mass spectrometry being used in routine clinical practices for those applications.

  9. Therapeutic application of dysprosium-165-FHMA in the treatment of rheumatoid knee effusions

    SciTech Connect

    English, R.J.; Zalutsky, M.; Venkatesan, P.; Sledge, C.B.

    1986-03-01

    Radiation synovectomy utilizing a variety of radionuclides has proven to be an effective technique in the treatment of rheumatoid arthritis. The recent introduction of the short-lived radionuclide, Dysprosium-165 (/sup 165/Dy), as a replacement for the longer-lived radiocolloids has reduced nontarget dosimetry caused by leakage of the agent from the articular cavity. A review of the methods and status of radiation synovectomy, and the application of /sup 165/Dy-ferric hydroxide macroaggregates (FHMA) as an alternative therapeutic agent is described.

  10. Sugar-based amphiphilic polymers for biomedical applications: from nanocarriers to therapeutics.

    PubMed

    Gu, Li; Faig, Allison; Abdelhamid, Dalia; Uhrich, Kathryn

    2014-10-21

    Various therapeutics exhibit unfavorable physicochemical properties or stability issues that reduce their in vivo efficacy. Therefore, carriers able to overcome such challenges and deliver therapeutics to specific in vivo target sites are critically needed. For instance, anticancer drugs are hydrophobic and require carriers to solubilize them in aqueous environments, and gene-based therapies (e.g., siRNA or pDNA) require carriers to protect the anionic genes from enzymatic degradation during systemic circulation. Polymeric micelles, which are self-assemblies of amphiphilic polymers (APs), constitute one delivery vehicle class that has been investigated for many biomedical applications. Having a hydrophobic core and a hydrophilic shell, polymeric micelles have been used as drug carriers. While traditional APs are typically comprised of nondegradable block copolymers, sugar-based amphiphilic polymers (SBAPs) synthesized by us are comprised of branched, sugar-based hydrophobic segments and a hydrophilic poly(ethylene glycol) chain. Similar to many amphiphilic polymers, SBAPs self-assemble into polymeric micelles. These nanoscale micelles have extremely low critical micelle concentrations offering stability against dilution, which occurs with systemic administration. In this Account, we illustrate applications of SBAPs for anticancer drug delivery via physical encapsulation within SBAP micelles and chemical conjugation to form SBAP prodrugs capable of micellization. Additionally, we show that SBAPs are excellent at stabilizing liposomal delivery systems. These SBAP-lipid complexes were developed to deliver hydrophobic anticancer therapeutics, achieving preferential uptake in cancer cells over normal cells. Furthermore, these complexes can be designed to electrostatically complex with gene therapies capable of transfection. Aside from serving as a nanocarrier, SBAPs have also demonstrated unique bioactivity in managing atherosclerosis, a major cause of cardiovascular

  11. Reactor production and processing of radioisotopes for therapeutic applications in nuclear medicine

    SciTech Connect

    Knapp, F.F. Jr.; Mirzadeh, S.; Beets, A.L.

    1995-02-01

    Nuclear reactors continue to play an important role in providing radioisotopes for nuclear medicine. Many reactor-produced radioisotopes are ``neutron rich`` and decay by beta-emission and are thus of interest for therapeutic applications. This talk discusses the production and processing of a variety of reactor-produced radioisotopes of current interest, including those produced by the single neutron capture process, double neutron capture and those available from beta-decay of reactorproduced radioisotopes. Generators prepared from reactorproduced radioisotopes are of particular interest since repeated elution inexpensively provides many patient doses. The development of the alumina-based W-188/Re-188 generator system is discussed in detail.

  12. Application of Disposable Bag Bioreactors in Tissue Engineering and for the Production of Therapeutic Agents

    NASA Astrophysics Data System (ADS)

    Eibl, R.; Eibl, D.

    In order to increase process efficiency, many pharmaceutical and biotechnology companies have introduced disposable bag technology over the last 10 years. Because this technology also greatly reduces the risk of cross-contamination, disposable bags are preferred in applications in which an absolute or improved process safety is a necessity, namely the production of functional tissue for implantation (tissue engineering), the production of human cells for the treatment of cancer and immune system diseases (cellular therapy), the production of viruses for gene therapies, the production of therapeutic proteins, and veterinary as well as human vaccines.

  13. RNAi therapeutics and applications of microRNAs in cancer treatment.

    PubMed

    Uchino, Keita; Ochiya, Takahiro; Takeshita, Fumitaka

    2013-06-01

    RNA interference-based therapies are proving to be powerful tools for combating various diseases, including cancer. Scientists are researching the development of safe and efficient systems for the delivery of small RNA molecules, which are extremely fragile in serum, to target organs and cells in the human body. A dozen pre-clinical and clinical trials have been under way over the past few years involving biodegradable nanoparticles, lipids, chemical modification and conjugation. On the other hand, microRNAs, which control the balance of cellular biological processes, have been studied as attractive therapeutic targets in cancer treatment. In this review, we provide an overview of RNA interference-based therapeutics in clinical trials and discuss the latest technology for the systemic delivery of nucleic acid drugs. Furthermore, we focus on dysregulated microRNAs in human cancer, which have progressed in pre-clinical trials as therapeutic targets, and describe a wide range of strategies to control the expression levels of endogenous microRNAs. Further development of RNA interference technologies and progression of clinical trials will contribute to the achievement of practical applications of nucleic acid drugs.

  14. Potential therapeutic applications of plant toxin-ricin in cancer: challenges and advances.

    PubMed

    Tyagi, Nikhil; Tyagi, Monika; Pachauri, Manendra; Ghosh, Prahlad C

    2015-11-01

    Cancer is one of the most common devastating disease affecting millions of people per year worldwide. To fight against cancer, a number of natural plant compounds have been exploited by researchers to discover novel anti-cancer therapeutics with minimum or no side effects and plants have proved their usefulness in anti-cancer therapy in past few years. Ricin, a cytotoxic plant protein isolated from castor bean seeds, is a ribosome-inactivating protein which destroys the cells by inhibiting proteins synthesis. Ricin presents great potential as anti-cancer agent and exerts its anti-cancer activity by inducing apoptosis in cancer cells. In this review, we summarize the current information on anti-cancer properties of plant toxin ricin, its potential applications in cancer therapy, challenges associated with its use as therapeutic agent and the recent advances made to overcome these challenges. Nanotechnology could open the doors for quick development of ricin-based anti-cancer therapeutics. Conceivably, ricin may serve as a chemotherapeutic agent against cancer by utilizing nanocarriers for its targeted delivery to cancer cells.

  15. Applicability of predictive toxicology methods for monoclonal antibody therapeutics: status Quo and scope.

    PubMed

    Kizhedath, Arathi; Wilkinson, Simon; Glassey, Jarka

    2017-04-01

    Biopharmaceuticals, monoclonal antibody (mAb)-based therapeutics in particular, have positively impacted millions of lives. MAbs and related therapeutics are highly desirable from a biopharmaceutical perspective as they are highly target specific and well tolerated within the human system. Nevertheless, several mAbs have been discontinued or withdrawn based either on their inability to demonstrate efficacy and/or due to adverse effects. Approved monoclonal antibodies and derived therapeutics have been associated with adverse effects such as immunogenicity, cytokine release syndrome, progressive multifocal leukoencephalopathy, intravascular haemolysis, cardiac arrhythmias, abnormal liver function, gastrointestinal perforation, bronchospasm, intraocular inflammation, urticaria, nephritis, neuropathy, birth defects, fever and cough to name a few. The advances made in this field are also impeded by a lack of progress in bioprocess development strategies as well as increasing costs owing to attrition, wherein the lack of efficacy and safety accounts for nearly 60 % of all factors contributing to attrition. This reiterates the need for smarter preclinical development using quality by design-based approaches encompassing carefully designed predictive models during early stages of drug development. Different in vitro and in silico methods are extensively used for predicting biological activity as well as toxicity during small molecule drug development; however, their full potential has not been utilized for biological drug development. The scope of in vitro and in silico tools in early developmental stages of monoclonal antibody-based therapeutics production and how it contributes to lower attrition rates leading to faster development of potential drug candidates has been evaluated. The applicability of computational toxicology approaches in this context as well as the pitfalls and promises of extending such techniques to biopharmaceutical development has been highlighted.

  16. Molecular signatures of vaccine adjuvants.

    PubMed

    Olafsdottir, Thorunn; Lindqvist, Madelene; Harandi, Ali M

    2015-09-29

    Mass vaccination has saved millions of human lives and improved the quality of life in both developing and developed countries. The emergence of new pathogens and inadequate protection conferred by some of the existing vaccines such as vaccines for tuberculosis, influenza and pertussis especially in certain age groups have resulted in a move from empirically developed vaccines toward more pathogen tailored and rationally engineered vaccines. A deeper understanding of the interaction of innate and adaptive immunity at molecular level enables the development of vaccines that selectively target certain type of immune responses without excessive reactogenicity. Adjuvants constitute an imperative element of modern vaccines. Although a variety of candidate adjuvants have been evaluated in the past few decades, only a limited number of vaccine adjuvants are currently available for human use. A better understanding of the mode of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in shaping a desired immune response. Recent advancement in systems biology powered by the emerging cutting edge omics technology has led to the identification of molecular signatures rapidly induced after vaccination in the blood that correlate and predict a later protective immune response or vaccine safety. This can pave ways to prospectively determine the potency and safety of vaccines and adjuvants. This review is intended to highlight the importance of big data analysis in advancing our understanding of the mechanisms of actions of adjuvants to inform rational development of future human vaccines.

  17. Preventive and therapeutic application of molecular hydrogen in situations with excessive production of free radicals.

    PubMed

    Slezák, J; Kura, B; Frimmel, K; Zálešák, M; Ravingerová, T; Viczenczová, C; Okruhlicová, Ľ; Tribulová, N

    2016-09-19

    Excessive production of oxygen free radicals has been regarded as a causative common denominator of many pathological processes in the animal kingdom. Hydroxyl and nitrosyl radicals represent the major cause of the destruction of biomolecules either by a direct reaction or by triggering a chain reaction of free radicals. Scavenging of free radicals may act preventively or therapeutically. A number of substances that preferentially react with free radicals can serve as scavengers, thus increasing the internal capacity/activity of endogenous antioxidants and protecting cells and tissues against oxidative damage. Molecular hydrogen (H(2)) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals, in the cells, that enables utilization of its potential for preventive and therapeutic applications. H(2) rapidly diffuses into tissues and cells without affecting metabolic redox reactions and signaling reactive species. H(2) reduces oxidative stress also by regulating gene expression, and functions as an anti-inflammatory and anti-apoptotic agent. There is a growing body of evidence based on the results of animal experiments and clinical observations that H(2) may represent an effective antioxidant for the prevention of oxidative stress-related diseases. Application of molecular hydrogen in situations with excessive production of free radicals, in particular, hydroxyl and nitrosyl radicals is relatively simple and effective, therefore, it deserves special attention.

  18. Application of disposable bag bioreactors in tissue engineering and for the production of therapeutic agents.

    PubMed

    Eibl, R; Eibl, D

    2009-01-01

    In order to increase process efficiency, many pharmaceutical and biotechnology companies have introduced disposable bag technology over the last 10 years. Because this technology also greatly reduces the risk of cross-contamination, disposable bags are preferred in applications in which an absolute or improved process safety is a necessity, namely the production of functional tissue for implantation (tissue engineering), the production of human cells for the treatment of cancer and immune system diseases (cellular therapy), the production of viruses for gene therapies, the production of therapeutic proteins, and veterinary as well as human vaccines.Bioreactors with a pre-sterile cultivation bag made of plastic material are currently used in both development and manufacturing processes primarily operating with animal and human cells at small- and middle-volume scale. Because of their scalability, hydrodynamic expertise and the convincing results of oxygen transport efficiency studies, wave-mixed bioreactors are the most used, together with stirred bag bioreactors and static bags, which have the longest tradition.Starting with a general overview of disposable bag bioreactors and their main applications, this chapter summarizes the working principles and engineering aspects of bag bioreactors suitable for cell expansion, formation of functional tissue and production of therapeutic agents. Furthermore, results from selected cultivation studies are presented and discussed.

  19. Advances in aluminum hydroxide-based adjuvant research and its mechanism.

    PubMed

    He, Peng; Zou, Yening; Hu, Zhongyu

    2015-01-01

    In the past few decades, hundreds of materials have been tried as adjuvant; however, only aluminum-based adjuvants continue to be used widely in the world. Aluminum hydroxide, aluminum phosphate and alum constitute the main forms of aluminum used as adjuvants. Among these, aluminum hydroxide is the most commonly used chemical as adjuvant. In spite of its wide spread use, surprisingly, the mechanism of how aluminum hydroxide-based adjuvants exert their beneficial effects is still not fully understood. Current explanations for the mode of action of aluminum hydroxide-based adjuvants include, among others, the repository effect, pro-phagocytic effect, and activation of the pro-inflammatory NLRP3 pathway. These collectively galvanize innate as well as acquired immune responses and activate the complement system. Factors that have a profound influence on responses evoked by aluminum hydroxide-based adjuvant applications include adsorption rate, strength of the adsorption, size and uniformity of aluminum hydroxide particles, dosage of adjuvant, and the nature of antigens. Although vaccines containing aluminum hydroxide-based adjuvants are beneficial, sometimes they cause adverse reactions. Further, these vaccines cannot be stored frozen. Until recently, aluminum hydroxide-based adjuvants were known to preferentially prime Th2-type immune responses. However, results of more recent studies show that depending on the vaccination route, aluminum hydroxide-based adjuvants can enhance both Th1 as well as Th2 cellular responses. Advances in systems biology have opened up new avenues for studying mechanisms of aluminum hydroxide-based adjuvants. These will assist in scaling new frontiers in aluminum hydroxide-based adjuvant research that include improvement of formulations, use of nanoparticles of aluminum hydroxide and development of composite adjuvants.

  20. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

    PubMed

    Savelkoul, Huub F J; Ferro, Valerie A; Strioga, Marius M; Schijns, Virgil E J C

    2015-03-05

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines.

  1. The application of DNA and RNA G-quadruplexes to therapeutic medicines.

    PubMed

    Collie, Gavin W; Parkinson, Gary N

    2011-12-01

    The intriguing structural diversity in folded topologies available to guanine-rich nucleic acid repeat sequences have made four-stranded G-quadruplex structures the focus of both basic and applied research, from cancer biology and novel therapeutics through to nanoelectronics. Distributed widely in the human genome as targets for regulating gene expression and chromosomal maintenance, they offer unique avenues for future cancer drug development. In particular, the recent advances in chemical and structural biology have enabled the construction of bespoke selective DNA based aptamers to be used as novel therapeutic agents and access to detailed structural models for structure based drug discovery. In this critical review, we will explore the important underlying characteristics of G-quadruplexes that make them functional, stable, and predictable nanoscaffolds. We will review the current structural database of folding topologies, molecular interfaces and novel interaction surfaces, with a consideration to their future exploitation in drug discovery, molecular biology, supermolecular assembly and aptamer design. In recent years the number of potential applications for G-quadruplex motifs has rapidly grown, so in this review we aim to explore the many future challenges and highlight where possible successes may lie. We will highlight the similarities and differences between DNA and RNA folded G-quadruplexes in terms of stability, distribution, and exploitability as small molecule targets. Finally, we will provide a detailed review of basic G-quadruplex geometry, experimental tools used, and a critical evaluation of the application of high-resolution structural biology and its ability to provide meaningful and valid models for future applications (255 references).

  2. Characterization of holmium loaded alginate microspheres for multimodality imaging and therapeutic applications.

    PubMed

    Zielhuis, S W; Seppenwoolde, J H; Bakker, C J G; Jahnz, U; Zonnenberg, B A; van het Schip, A D; Hennink, W E; Nijsen, J F W

    2007-09-15

    In this paper the preparation and characterization of holmium-loaded alginate microspheres is described. The rapid development of medical imaging techniques offers new opportunities for the visualisation of (drug-loaded) microparticles. Therefore, suitable imaging agents have to be incorporated into these particles. For this reason, the element holmium was used in this study in order to utilize its unique imaging characteristics. The paramagnetic behaviour of this element allows visualisation with MRI and holmium can also be neutron-activated resulting in the emission of gamma-radiation, allowing visualisation with gamma cameras, and beta-radiation, suitable for therapeutic applications. Almost monodisperse alginate microspheres were obtained by JetCutter technology where alginate droplets of a uniform size were hardened in an aqueous holmium chloride solution. Ho(3+) binds via electrostatic interactions to the carboxylate groups of the alginate polymer and as a result alginate microspheres loaded with holmium were obtained. The microspheres had a mean size of 159 microm and a holmium loading of 1.3 +/- 0.1% (w/w) (corresponding with a holmium content based on dry alginate of 18.3 +/- 0.3% (w/w)). The binding capacity of the alginate polymer for Ho(3+) (expressed in molar amounts) is equal to that for Ca(2+), which is commonly used for the hardening of alginate. This indicates that Ho(3+) has the same binding affinity as Ca(2+). In line herewith, dynamic mechanical analyses demonstrated that alginate gels hardened with Ca(2+) or Ho(3+) had similar viscoelastic properties. The MRI relaxation properties of the microspheres were determined by a MRI phantom experiment, demonstrating a strong R(2)* effect of the particles. Alginate microspheres could also be labelled with radioactive holmium by adding holmium-166 to alginate microspheres, previously hardened with calcium (labelling efficiency 96%). The labelled microspheres had a high radiochemical stability (94% after

  3. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  4. Photothermal therapeutic application of gold nanorods-porphyrin-trastuzumab complexes in HER2-positive breast cancer

    PubMed Central

    Kang, Xinmei; Guo, Ximing; An, Weiwei; Niu, Xingjian; Li, Suhan; Liu, Zhaoliang; Yang, Yue; Wang, Na; Jiang, Qicheng; Yan, Caichuan; Wang, Hui; Zhang, Qingyuan

    2017-01-01

    Gold nanorods are effective photothermal agents in diagnosis and treatment of cancer due to their specific near-infrared laser absorption. However, tumor photothermal therapy by nanorods alone is lack of targeting. Here, we described a novel nanocomplex made up of gold nanorods, porphyrin, and trastuzumab, called TGNs and investigated the TGN-mediated photothermal therapy as a potential alternative treatment of targeting HER2-positive breast cancers. By conjugating trastuzumab and porphyrin to the surface of gold nanorods, we have increased the targeting specificity and amplified the detecting effectiveness at the same time. TGN-mediated photothermal ablation by near-infrared laser led to a selective destruction of HER2-positive cancer cells and significantly inhibited tumor growth in mouse models bearing HER2 over-expressed breast cancer xenograft with less toxicity. Moreover, TGNs provided better therapeutic efficacy in comparison with the conventional molecule targeted therapy. Our current data suggest a highly promising future of TGNs for its therapeutic application in trastuzumab-resistant breast cancers. PMID:28155894

  5. A reduced-order, single-bubble cavitation model with applications to therapeutic ultrasound

    PubMed Central

    Kreider, Wayne; Crum, Lawrence A.; Bailey, Michael R.; Sapozhnikov, Oleg A.

    2011-01-01

    Cavitation often occurs in therapeutic applications of medical ultrasound such as shock-wave lithotripsy (SWL) and high-intensity focused ultrasound (HIFU). Because cavitation bubbles can affect an intended treatment, it is important to understand the dynamics of bubbles in this context. The relevant context includes very high acoustic pressures and frequencies as well as elevated temperatures. Relative to much of the prior research on cavitation and bubble dynamics, such conditions are unique. To address the relevant physics, a reduced-order model of a single, spherical bubble is proposed that incorporates phase change at the liquid-gas interface as well as heat and mass transport in both phases. Based on the energy lost during the inertial collapse and rebound of a millimeter-sized bubble, experimental observations were used to tune and test model predictions. In addition, benchmarks from the published literature were used to assess various aspects of model performance. Benchmark comparisons demonstrate that the model captures the basic physics of phase change and diffusive transport, while it is quantitatively sensitive to specific model assumptions and implementation details. Given its performance and numerical stability, the model can be used to explore bubble behaviors across a broad parameter space relevant to therapeutic ultrasound. PMID:22088026

  6. Photothermal therapeutic application of gold nanorods-porphyrin-trastuzumab complexes in HER2-positive breast cancer

    NASA Astrophysics Data System (ADS)

    Kang, Xinmei; Guo, Ximing; An, Weiwei; Niu, Xingjian; Li, Suhan; Liu, Zhaoliang; Yang, Yue; Wang, Na; Jiang, Qicheng; Yan, Caichuan; Wang, Hui; Zhang, Qingyuan

    2017-02-01

    Gold nanorods are effective photothermal agents in diagnosis and treatment of cancer due to their specific near-infrared laser absorption. However, tumor photothermal therapy by nanorods alone is lack of targeting. Here, we described a novel nanocomplex made up of gold nanorods, porphyrin, and trastuzumab, called TGNs and investigated the TGN-mediated photothermal therapy as a potential alternative treatment of targeting HER2-positive breast cancers. By conjugating trastuzumab and porphyrin to the surface of gold nanorods, we have increased the targeting specificity and amplified the detecting effectiveness at the same time. TGN-mediated photothermal ablation by near-infrared laser led to a selective destruction of HER2-positive cancer cells and significantly inhibited tumor growth in mouse models bearing HER2 over-expressed breast cancer xenograft with less toxicity. Moreover, TGNs provided better therapeutic efficacy in comparison with the conventional molecule targeted therapy. Our current data suggest a highly promising future of TGNs for its therapeutic application in trastuzumab-resistant breast cancers.

  7. Recent advances in food biopeptides: production, biological functionalities and therapeutic applications.

    PubMed

    Saadi, Sami; Saari, Nazamid; Anwar, Farooq; Hamid, Azizah Abdul; Mohd Ghazali, Hasanah

    2015-01-01

    The growing momentum of several common life-style diseases such as myocardial infarction, cardiovascular disorders, stroke, hypertension, diabetes, and atherosclerosis has become a serious global concern. Recent developments in the field of proteomics offering promising solutions to solving such health problems stimulates the uses of biopeptides as one of the therapeutic agents to alleviate disease-related risk factors. Functional peptides are typically produced from protein via enzymatic hydrolysis under in vitro or in vivo conditions using different kinds of proteolytic enzymes. An array of biological activities, including antioxidative, antihypertensive, antidiabetic and immunomodulating has been ascribed to different types of biopeptides derived from various food sources. In fact, biopeptides are nutritionally and functionally important for regulating some physiological functions in the body; however, these are yet to be extensively addressed with regard to their production through advance strategies, mechanisms of action and multiple biological functionalities. This review mainly focuses on recent biotechnological advances that are being made in the field of production in addition to covering the mode of action and biological activities, medicinal health functions and therapeutic applications of biopeptides. State-of-the-art strategies that can ameliorate the efficacy, bioavailability, and functionality of biopeptides along with their future prospects are likewise discussed.

  8. New developments in the application of optimal control theory to therapeutic protocols.

    PubMed

    Bayón, L; Otero, J A; Suárez, P M; Tasis, C

    2016-02-01

    Optimal control theory is one of the most important tools in the development of new therapeutic protocols for treating infections. In this work, we present an algorithm able to deal with high-dimensional problems with bounded controls. The optimal solution is obtained by minimizing a positive-definite treatment cost function. Our method, based on Pontryagin's Minimum Principle and the coordinate cyclic descent method, allows solving problems of varied nature. In this paper, and by way of example, therapeutic enhancement of the immune response to invasion by pathogenic attack is addressed as an optimal control problem. The generic mathematical model used describes the evolution of the disease by means of four non-linear, ordinary differential equations. The model is characterized by the concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of an organ damaged by disease. From a system theory point of view, drugs can be interpreted as control inputs. Therapies based on separate application of the agents are presented in previous studies. We shall present the more general problem in this paper, considering combined therapies and bounded controls. Finally, we present several numerical simulations.

  9. Therapeutic effects of topical application of ozone on acute cutaneous wound healing.

    PubMed

    Kim, Hee Su; Noh, Sun Up; Han, Ye Won; Kim, Kyoung Moon; Kang, Hoon; Kim, Hyung Ok; Park, Young Min

    2009-06-01

    This study was undertaken to evaluate the therapeutic effects of topical ozonated olive oil on acute cutaneous wound healing in a guinea pig model and also to elucidate its therapeutic mechanism. After creating full-thickness skin wounds on the backs of guinea pigs by using a 6 mm punch biopsy, we examined the wound healing effect of topically applied ozonated olive oil (ozone group), as compared to the pure olive oil (oil group) and non-treatment (control group). The ozone group of guinea pig had a significantly smaller wound size and a residual wound area than the oil group, on days 5 (P<0.05) and 7 (P<0.01 and P<0.05) after wound surgery, respectively. Both hematoxylin-eosin staining and Masson-trichrome staining revealed an increased intensity of collagen fibers and a greater number of fibroblasts in the ozone group than that in the oil group on day 7. Immunohistochemical staining demonstrated upregulation of platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) expressions, but not fibroblast growth factor expression in the ozone group on day 7, as compared with the oil group. In conclusion, these results demonstrate that topical application of ozonated olive oil can accelerate acute cutaneous wound repair in a guinea pig in association with the increased expression of PDGF, TGF-beta, and VEGF.

  10. Therapeutic Effects of Topical Application of Ozone on Acute Cutaneous Wound Healing

    PubMed Central

    Kim, Hee Su; Noh, Sun Up; Han, Ye Won; Kim, Kyoung Moon; Kang, Hoon; Kim, Hyung Ok

    2009-01-01

    This study was undertaken to evaluate the therapeutic effects of topical ozonated olive oil on acute cutaneous wound healing in a guinea pig model and also to elucidate its therapeutic mechanism. After creating full-thickness skin wounds on the backs of guinea pigs by using a 6 mm punch biopsy, we examined the wound healing effect of topically applied ozonated olive oil (ozone group), as compared to the pure olive oil (oil group) and non-treatment (control group). The ozone group of guinea pig had a significantly smaller wound size and a residual wound area than the oil group, on days 5 (P<0.05) and 7 (P<0.01 and P<0.05) after wound surgery, respectively. Both hematoxylin-eosin staining and Masson-trichrome staining revealed an increased intensity of collagen fibers and a greater number of fibroblasts in the ozone group than that in the oil group on day 7. Immunohistochemical staining demonstrated upregulation of platelet derived growth factor (PDGF), transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) expressions, but not fibroblast growth factor expression in the ozone group on day 7, as compared with the oil group. In conclusion, these results demonstrate that topical application of ozonated olive oil can accelerate acute cutaneous wound repair in a guinea pig in association with the increased expression of PDGF, TGF-β, and VEGF. PMID:19543419

  11. Preventive and therapeutic applications of neutralizing antibodies to Human Immunodeficiency Virus Type 1 (HIV-1)

    PubMed Central

    Ringe, Rajesh

    2013-01-01

    The development of a preventive vaccine to neutralize the highly variable and antigenically diverse human immunodeficiency virus type 1 (HIV-1) has been an indomitable goal. The recent discovery of a number of cross-neutralizing and potent monoclonal antibodies from elite neutralizers has provided important insights in this field. Neutralizing antibodies (NAbs) are useful in identifying neutralizing epitopes of vaccine utility and for understanding the mechanism of potent and broad cross-neutralization thus providing a modality of preventive and therapeutic value. In this article we review the current understanding on the potential use of broadly neutralizing antibodies (bNAbs) in their full-length IgG structure, engineered domain antibody or bispecific versions towards preventive and therapeutic applications. The potential implications of NAbs are discussed in the light of the recent developments as key components in vaccination against HIV-1. The development of a vaccine immunogen which elicits bNAbs and confers protective immunity remains a real challenge. PMID:24757516

  12. A reduced-order, single-bubble cavitation model with applications to therapeutic ultrasound.

    PubMed

    Kreider, Wayne; Crum, Lawrence A; Bailey, Michael R; Sapozhnikov, Oleg A

    2011-11-01

    Cavitation often occurs in therapeutic applications of medical ultrasound such as shock-wave lithotripsy (SWL) and high-intensity focused ultrasound (HIFU). Because cavitation bubbles can affect an intended treatment, it is important to understand the dynamics of bubbles in this context. The relevant context includes very high acoustic pressures and frequencies as well as elevated temperatures. Relative to much of the prior research on cavitation and bubble dynamics, such conditions are unique. To address the relevant physics, a reduced-order model of a single, spherical bubble is proposed that incorporates phase change at the liquid-gas interface as well as heat and mass transport in both phases. Based on the energy lost during the inertial collapse and rebound of a millimeter-sized bubble, experimental observations were used to tune and test model predictions. In addition, benchmarks from the published literature were used to assess various aspects of model performance. Benchmark comparisons demonstrate that the model captures the basic physics of phase change and diffusive transport, while it is quantitatively sensitive to specific model assumptions and implementation details. Given its performance and numerical stability, the model can be used to explore bubble behaviors across a broad parameter space relevant to therapeutic ultrasound.

  13. Have adjuvant tyrosine kinase inhibitors lost their shine?

    PubMed Central

    Sabari, Joshua K.

    2016-01-01

    Despite broad advances in molecularly targeted therapies, lung cancer remains the leading cause of cancer related mortality in the United States. Epidermal growth factor receptor (EGFR) mutations occur in approximately 17% of advanced non-small cell lung cancer (NSCLC) in the US population. The remarkable efficacy of small-molecule EGFR tyrosine kinase inhibitors (TKIs) in this unique subset of patients has revolutionized the therapeutic approach to lung cancer. The success of these agents in the metastatic setting leads to the logical question of what role these drugs may have in the adjuvant setting for patients with earlier stage disease. RADIANT, an international randomized, double-blind, placebo controlled phase III study in patients with completely resected stage IB to IIIA NSLC whose tumors expressed EGFR by IHC and EGFR amplification by FISH, attempted to answer the question of whether erlotinib would improve disease free survival and overall survival in the adjuvant setting. While RADIANT does not conclude for or against adjuvant use of EGFR-TKIs, all data points towards benefit in a selected population. As clinicians, we must continue to enroll to potentially practice changing therapeutic neoadjuvant and adjuvant chemotherapy studies internationally. PMID:27568486

  14. Exploring the Hybridization Thermodynamics of Spherical Nucleic Acids to Tailor Probes for Diagnostic and Therapeutic Applications

    NASA Astrophysics Data System (ADS)

    Randeria, Pratik Shailesh

    Spherical nucleic acids (SNAs), three-dimensional nanoparticle conjugates composed of densely packed and highly oriented oligonucleotides around organic or inorganic nanoparticles, are an emergent class of nanostructures that show promise as single-entity agents for intracellular messenger RNA (mRNA) detection and gene regulation. SNAs exhibit superior biocompatibility and biological properties compared to linear oligonucleotides, enabling them to overcome many of the limitations of linear oligonucleotides for use in biomedical applications. However, the origins of these biologically attractive properties are not well understood. In this dissertation, the chemistry underlying one such property is studied in detail, and the findings are applied towards the rational design of more effective SNAs for diagnostic and therapeutic applications. Chapter 1 introduces the synthesis of SNAs, the unique properties that make them superior to linear nucleic acids for biomedicine, and previously studied applications of these structures. Chapter 2 focuses on quantitatively studying the impact of the chemical structure of the SNA on its ability to hybridize multiple complementary nucleic acids. This chapter lays the groundwork for understanding the factors that govern SNA hybridization thermodynamics and how to tailor SNAs to increase their binding affinity to target mRNA strands. Chapters 3 and 4 capitalize on this knowledge to engineer probes for intracellular mRNA detection and gene regulation applications. Chapter 3 reports the development of an SNA-based probe that can simultaneously report the expression level of two different mRNA transcripts in live cells and differentiate diseased cells from non-diseased cells. Chapter 4 investigates the use of topically-applied SNAs to down-regulate a critical mediator of impaired wound healing in diabetic mice to accelerate wound closure. This study represents the first topical therapeutic application of SNA nanotechnology to treat open

  15. The ex utero intrapartum treatment (EXIT) procedure: application of a new therapeutic paradigm.

    PubMed

    Taghavi, Kiarash; Beasley, Spencer

    2013-09-01

    The ex utero intrapartum treatment (EXIT) procedure is a term given to a technique that can transform a potentially fatal neonatal emergency to a controlled intervention with an improved outcome. It has revolutionised the care of prenatally diagnosed congenital malformations in which severe upper airway obstruction is anticipated. An extended period of utero-placental circulation can be utilised to avoid profound cardiopulmonary compromise. Its therapeutic applications have been broadened to include fetuses with congenital diaphragmatic hernia after tracheal plugging, high-risk intrathoracic masses, severe cardiac malformations and conjoined twins. It requires the co-ordination of a highly skilled and experienced multidisciplinary team. The recent enthusiasm for the EXIT procedure needs to be balanced against maternal morbidity. Specific indications and guidelines are likely to be refined as a consequence of ongoing advances in fetal intervention and antenatal imaging.

  16. Elucidation of the mTOR Pathway and Therapeutic Applications in Dermatology.

    PubMed

    Salido-Vallejo, R; Garnacho-Saucedo, G; Vélez, A

    2016-06-01

    The member of the phosphatidylinositol 3-kinase family, mammalian target of rapamycin, is involved in modulating inflammatory response and regulating cellular processes associated with growth, differentiation, and angiogenesis. Recent years have seen major advances in our understanding of the mammalian target of rapamycin signaling pathway and the implication of this pathway in multiple genetic and inflammatory diseases and tumors. The development of the mammalian target of rapamycin inhibitors has given rise to new treatment approaches that have led to substantially improved outcomes in many diseases. In this article, we review the role of the mammalian target of rapamycin signaling pathway in the different skin diseases with which it has been associated, examine the therapeutic applications of drugs targeting this pathway, and provide an overview of current trends and future directions in research.

  17. Mammalian MicroRNAs: Post-Transcriptional Gene Regulation in RNA Virus Infection and Therapeutic Applications

    PubMed Central

    Tsunetsugu-Yokota, Yasuko; Yamamoto, Takuya

    2010-01-01

    RNA silencing mediated by microRNAs (miRNAs) is a recently discovered gene regulatory mechanism involved in various aspects of biology, such as development, cell differentiation and proliferation, and innate immunity against viral infections. miRNAs, which are a class of small (21–25 nucleotides) RNAs, target messenger RNA (mRNA) through incomplete base-pairing with their target sequences resulting in mRNA degradation or translational repression. Although studies of miRNAs have led to numerous sensational discoveries in biology, many fundamental questions about their expression and function still remain. In this review, we discuss the dynamics of the mammalian miRNA machinery and the biological function of miRNAs, focusing on RNA viruses and the various therapeutic applications of miRNAs against viral infections. PMID:21607080

  18. Therapeutic applications of ghrelin to cachexia utilizing its appetite-stimulating effect.

    PubMed

    Akamizu, Takashi; Kangawa, Kenji

    2011-11-01

    Ghrelin, which is a natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), stimulates food intake in both animals and humans. Ghrelin is the only circulating hormone known to stimulate appetite in humans. Ghrelin also stimulates GH secretion and inhibits the production of anorectic proinflammatory cytokines. As GH is an anabolic hormone, protein stores are spared at the expense of fat during conditions of caloric restriction. Thus, ghrelin exhibits anti-cachectic actions via both GH-dependent and -independent mechanisms. Several studies are evaluating the efficacy of ghrelin in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will hopefully lead to the development of novel therapeutic applications for ghrelin in the future. This review summarizes the recent advances in this area of research.

  19. Inflence of air shear and adjuvants on spray atomization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Droplet size is critical to maximizing pesticide efficacy and mitigating off-target movement and correct selection and adjustment of nozzles and application equipment, as well as the use of adjuvants can aid in this process. However, in aerial applications air shear tends to be the dominate factor ...

  20. Cationic liposomal vaccine adjuvants in animal challenge models: overview and current clinical status.

    PubMed

    Korsholm, Karen Smith; Andersen, Peter Lawætz; Christensen, Dennis

    2012-05-01

    Cationic liposome formulations can function as efficient vaccine adjuvants. However, due to the highly diverse nature of lipids, cationic liposomes have different physical-chemical characteristics that influence their adjuvant mechanisms and their relevance for use in different vaccines. These characteristics can be further manipulated by incorporation of additional lipids or stabilizers, and inclusion of carefully selected immunostimulators is a feasible strategy when tailoring cationic liposomal adjuvants for specific disease targets. Thus, cationic liposomes present a plasticity, which makes them promising adjuvants for future vaccines. This versatility has also led to a vast amount of literature on different experimental liposomal formulations in combination with a wide range of immunostimulators. Here, we have compiled information about the animal challenge models and administration routes that have been used to study vaccine adjuvants based on cationic liposomes and provide an overview of the applicability, progress and clinical status of cationic liposomal vaccine adjuvants.

  1. Metallic ions as therapeutic agents in tissue engineering scaffolds: an overview of their biological applications and strategies for new developments

    PubMed Central

    Mouriño, Viviana; Cattalini, Juan Pablo; Boccaccini, Aldo R.

    2012-01-01

    This article provides an overview on the application of metallic ions in the fields of regenerative medicine and tissue engineering, focusing on their therapeutic applications and the need to design strategies for controlling the release of loaded ions from biomaterial scaffolds. A detailed summary of relevant metallic ions with potential use in tissue engineering approaches is presented. Remaining challenges in the field and directions for future research efforts with focus on the key variables needed to be taken into account when considering the controlled release of metallic ions in tissue engineering therapeutics are also highlighted. PMID:22158843

  2. How to define green adjuvants.

    PubMed

    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.

  3. Translational research and therapeutic applications of stem cell transplantation in periodontal regenerative medicine.

    PubMed

    Lu, Hong; Xie, Cheng; Zhao, Yi-Min; Chen, Fa-Ming

    2013-01-01

    Stem cells have received a great deal of interest from the research community as potential therapeutic "tools" for a variety of chronic debilitating diseases that lack clinically effective therapies. Stem cells are also of interest for the regeneration of tooth-supporting tissues that have been lost to periodontal disease. Indeed, substantial data have demonstrated that the exogenous administration of stem cells or their derivatives in preclinical animal models of periodontal defects can restore damaged tissues to their original form and function. As we discuss here, however, considerable hurdles must be overcome before these findings can be responsibly translated to novel clinical therapies. Generally, the application of stem cells for periodontal therapy in clinics will not be realized until the best cell(s) to use, the optimal dose, and an effective mode of administration are identified. In particular, we need to better understand the mechanisms of action of stem cells after transplantation in the periodontium and to learn how to preciously control stem cell fates in the pathological environment around a tooth. From a translational perspective, we outline the challenges that may vary across preclinical models for the evaluation of stem cell therapy in situations that require periodontal reconstruction and the safety issues that are related to clinical applications of human stem cells. Although clinical trials that use autologous periodontal ligament stem cells have been approved and have already been initiated, proper consideration of the technical, safety, and regulatory concerns may facilitate, rather than inhibit, the clinical translation of new therapies.

  4. Novel applications of ubiquinone biopolymer nanocarriers for preventive and regenerative therapeutics: The Saccharomyces cerevisiae paradigm.

    PubMed

    Hoennscheidt, Christoph; Margaritis, Argyrios; Krull, Rainer

    2015-01-15

    Since the last decade, nanodispersed drug delivery systems gain increasingly more importance for therapeutic research fields. The forced transport to the centers of inflammation is supposed to take advantage as a novel strategic approach. Thus, the focus of this study was to investigate the applicability of ubiquinone nanoformulations against oxidative stress. The physiological reduction of reactive oxygen species (ROS) seems to be a promising treatment to point out the potential effects of these sophisticated nano-constructs. Therefore, the yeast strain Saccharomyces cerevisiae N34 was used for in vitro studies as a representative for eukaryotic organisms. Growth parameters during sequential fed batch-cultivation were monitored online using focused beam reflectance measurement (FBRM) method. The ability to control diverse cellular processes makes this yeast strain to a valuable tool for the initial investigation by understanding the fundamental mechanisms of nanoparticulate formulations onto eukaryotic cells. Furthermore, the characteristic stress response of yeast cell culture was examined, so that drug effects could be determined quantitatively. As a chemical stressor, diamide was tested in the range of 1-1000 mg diamide per g cell dry weight (CDW). The ubiquinone nanoformulation demonstrated a total stress reduction of approximately 14% in the yeast culture, confirming the potential applicability of ubiquinone.

  5. MRI-guided therapeutic ultrasound: Temperature feedback control for extracorporeal and endoluminal applicators

    NASA Astrophysics Data System (ADS)

    Salomir, Rares

    2005-09-01

    Therapeutic ultrasound is a mini-invasive and promising tool for in situ ablation of non-resectable tumors in uterus, breast, esophagus, kidney, liver, etc. Extracorporeal, endoluminal, and interstitial applicators have been successfully tested to date. Magnetic resonance imaging (MRI) is the only available technique providing non-invasive temperature mapping, together with excellent contrast of soft tissue. Coupling of these two technologies offers the advantage of both: (1) on line spatial guidance to the target region, and (2) thermal dose control during the treatment. This talk will provide an overview of the author's experience with automatic, active feedback control of the temperature evolution in tissues, which has been demonstrated with MRI compatible extracorporeal transducers (focused beam) or endoluminal applicators (plane waves). The feedback loop is based on fast switching capabilities of the driving electronics and real time data transfer out of the MR scanner. Precision of temperature control was typically better than 1°C. This approach is expected to improve the efficacy of the treatment (complete tumor ablation) and the thermal security of the critical regions crossed by the acoustic beam. It also permits one to reach an under-lethal heating regime for local drug delivery using thermosensitive liposomes or gene expression control based on hsp promoters.

  6. Delivery systems and adjuvants for oral vaccines.

    PubMed

    Lavelle, Ed C; O'Hagan, D T

    2006-11-01

    The oral route is the ideal means of delivering prophylactic and therapeutic vaccines, offering significant advantages over systemic delivery. Most notably, oral delivery is associated with simple administration and improved safety. In addition, unlike systemic immunisation, oral delivery can induce mucosal immune responses. However, the oral route of vaccine delivery is the most difficult because of the numerous barriers posed by the gastrointestinal tract. To facilitate effective immunisation with peptide and protein vaccines, antigens must be protected, uptake enhanced and the innate immune response activated. Numerous delivery systems and adjuvants have been evaluated for oral vaccine delivery, including live vectors, inert particles and bacterial toxins. Although developments in oral vaccines have been disappointing so far, in terms of the generation of products, the availability of a range of novel delivery systems offers much greater hope for the future development of improved oral vaccines.

  7. Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications.

    PubMed

    Jones, Russell G A; Martino, Angela

    2016-01-01

    Therapeutic antibodies provide important tools in the "medicine chest" of today's clinician for the treatment of a range of disorders. Typically monoclonal or polyclonal antibodies are administered in large doses, either directly or indirectly into the circulation, via a systemic route which is well suited for disseminated ailments. Diseases confined within a specific localized tissue, however, may be treated more effectively and at reduced cost by a delivery system which targets directly the affected area. To explore the advantages of the local administration of antibodies, we reviewed current alternative, non-systemic delivery approaches which are in clinical use, being trialed or developed. These less conventional approaches comprise: (a) local injections, (b) topical and (c) peroral administration routes. Local delivery includes intra-ocular injections into the vitreal humor (i.e. Ranibizumab for age-related macular degeneration), subconjunctival injections (e.g. Bevacizumab for corneal neovascularization), intra-articular joint injections (i.e. anti-TNF alpha antibody for persistent inflammatory monoarthritis) and intratumoral or peritumoral injections (e.g. Ipilimumab for cancer). A range of other strategies, such as the local use of antibacterial antibodies, are also presented. Local injections of antibodies utilize doses which range from 1/10th to 1/100th of the required systemic dose therefore reducing both side-effects and treatment costs. In addition, any therapeutic antibody escaping from the local site of disease into the systemic circulation is immediately diluted within the large blood volume, further lowering the potential for unwanted effects. Needle-free topical application routes become an option when the condition is restricted locally to an external surface. The topical route may potentially be utilized in the form of eye drops for infections or corneal neovascularization or be applied to diseased skin for psoriasis, dermatitis, pyoderma

  8. Adjuvant Effects on Evaporation Rates and Wetted Area of Droplets on Waxy Leaves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of an appropriate adjuvant for pesticide applications is a critical process to improve spray deposit characteristics on waxy leaves and to reduce off-target losses. After deposition and evaporation, residue patterns of 500 µm sessile droplets that incorporated four classes of adjuvants on fi...

  9. Recent Progress Toward Hydrogen Medicine: Potential of Molecular Hydrogen for Preventive and Therapeutic Applications

    PubMed Central

    Ohta, Shigeo

    2011-01-01

    Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H2) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H2 has a number of advantages as a potential antioxidant: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H2. There are several methods to ingest or consume H2, including inhaling hydrogen gas, drinking H2-dissolved water (hydrogen water), taking a hydrogen bath, injecting H2-dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H2 by bacteria. Since the publication of the first H2 paper in Nature Medicine in 2007, the biological effects of H2 have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H2 shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. H2 regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H2 remain elusive. PMID:21736547

  10. Clinical Therapeutic Effects of the Application of Doxycycline in the Treatment of Periodontal Disease

    PubMed Central

    Spasovski, Spiro; Belazelkoska, Zlatanka; Popovska, Mirjana; Atanasovska-Stojanovska, Aneta; Radojkova-Nikolovska, Vera; Muratovska, Ilijana; Toseska-Spasova, Natasa; Dzipunova, Biljana; Nikolovski, Bruno

    2016-01-01

    OBJECTIVE: To compare the therapeutic effects of the application of doxycycline-full dose (100 mg) and sub-dose (20 mg) in the treatment of periodontal disease. MATERIAL AND METHODS: A total of 60 patients with periodontal disease were examined. Patients are divided into two groups: A) treated with antimicrobial dose of 100 mg doxycycline once daily for 30 days, and B) treated with 2 x 20 mg/day. doxycycline, during 75 days. Among all patients a conservative treatment was carried out and ordinated the proper dose doxycycline in total dose during treatment from 3 gr. Index of dental plaque by Löe-Sillness, index of gingival inflammation and gingival bleeding by Cowell were followed. RESULTS: Values of dental plaque in relation first examination, 10th, 20th day, 1 month and 2.5 months, showed that after 2.5 months, average value (x = 0.83) of dental plaque in second group is slightly less than the value (x = 0.93) of dental plaque in the first group. The average value (x = 0.17) of gingival inflammation in second group is significantly less than the value (x = 0.50) of gingival inflammation in the first group. The average value (x = 0.97) of gingival bleeding in patients from the first group was significantly higher than value(x = 0.37) of gingival bleeding in the second group. CONCLUSION: Patients whose therapy was helped by a sub-dose doxycycline demonstrated positive therapeutic effects on gingival inflammation and bleeding. PMID:27275351

  11. The ultrastructure of tomatine adjuvant.

    PubMed

    Yang, Ya-Wun; Sheikh, Nadeem A; Morrow, W J W

    2002-12-01

    The tomatine adjuvant, consisting of tomatine, n-octyl-beta-D-glucopyranoside, phosphatidylethanolamine, cholesterol, and ovalbumin, has recently been shown to potentiate the immunogenicity of protein antigen and elicit cytotoxic T-lymphocyte responses in immunized animals. The physicochemical properties of tomatine adjuvant have not been characterized. The aim of this study was to examine the microstructure of this complex formulation, as directly related to its physicochemical properties. To elucidate the micromorphology of this system, the tomatine adjuvant was separated by isopycnic ultracentrifugation, followed by freeze fracturing and examination by transmission and scanning electron microscopy. The adjuvant mixture was shown to be composed of several micro- and nano-structures. The major fraction obtained from isopycnic separation was shown to consist of flaky needle-like microcrystals, approximately 80-160 nm in width and 2-4 microm in length. The tomatine crystals alone in 0.9% NaCl, on the other hand, were shown to be elongated hollow tubular crystals of hundreds of nanometers up to a few microns in length, along which n-octyl-beta-glucopyranoside was speculated to serve as a seeding microtemplate for gel crystallization of protein complexes. Indented marks within the gel phase were observed in the freeze fractured replicas of the adjuvant, suggesting that protein complexes may have been crystallized or precipitated within the gels. Several other forms of micro- and nano-structures were also observed, showing multiple-dispersion features with gel characteristics. The presence of gel crystalline and multiple-dispersed phases is postulated to contribute to the sustained immunopotentiation effect of tomatine adjuvant.

  12. Adjuvant therapy in pancreatic cancer.

    PubMed

    Jones, Owain Peris; Melling, James Daniel; Ghaneh, Paula

    2014-10-28

    Pancreatic cancer remains one of the leading causes of cancer related death worldwide with an overall five-year survival of less than 5%. Potentially curative surgery, which alone can improve 5-year survival to 10%, is an option for only 10%-20% of patients at presentation owing to local invasion of the tumour or metastatic disease. Adjuvant chemotherapy has been shown to improve 5-year survival to 20%-25% but conflicting evidence remains with regards to chemoradiation. In this article we review the current evidence available from published randomised trials and discuss ongoing phase III trials in relation to adjuvant therapy in pancreatic cancer.

  13. Dielectric Characterization of PCL-Based Thermoplastic Materials for Microwave Diagnostic and Therapeutic Applications

    PubMed Central

    Aguilar, Suzette M.; Shea, Jacob D.; Al-Joumayly, Mudar A.; Van Veen, Barry D.; Behdad, Nader; Hagness, Susan C.

    2011-01-01

    We propose the use of a polycaprolactone (PCL)-based thermoplastic mesh as a tissue-immobilization interface for microwave imaging and microwave hyperthermia treatment. An investigation of the dielectric properties of two PCL-based thermoplastic materials in the frequency range of 0.5 – 3.5 GHz is presented. The frequency-dependent dielectric constant and effective conductivity of the PCL-based thermoplastics are characterized using measurements of microstrip transmission lines fabricated on substrates comprised of the thermoplastic meshes. We also examine the impact of the presence of a PCL-based thermoplastic mesh on microwave breast imaging. We use a numerical test bed comprised of a previously reported three-dimensional anatomically realistic breast phantom and a multi-frequency microwave inverse scattering algorithm. We demonstrate that the PCL-based thermoplastic material and the assumed biocompatible medium of vegetable oil are sufficiently well matched such that the PCL layer may be neglected by the imaging solution without sacrificing imaging quality. Our results suggest that PCL-based thermoplastics are promising materials as tissue immobilization structures for microwave diagnostic and therapeutic applications. PMID:21622068

  14. Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation.

    PubMed

    Hersh, David S; Kim, Anthony J; Winkles, Jeffrey A; Eisenberg, Howard M; Woodworth, Graeme F; Frenkel, Victor

    2016-11-01

    : Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for using FUS in neuro-oncology.

  15. In vitro methods to study bubble-cell interactions: Fundamentals and therapeutic applications

    PubMed Central

    Lajoinie, Guillaume; De Cock, Ine; Coussios, Constantin C.; Le Gac, Séverine; Versluis, Michel

    2016-01-01

    Besides their use as contrast agents for ultrasound imaging, microbubbles are increasingly studied for a wide range of therapeutic applications. In particular, their ability to enhance the uptake of drugs through the permeabilization of tissues and cell membranes shows great promise. In order to fully understand the numerous paths by which bubbles can interact with cells and the even larger number of possible biological responses from the cells, thorough and extensive work is necessary. In this review, we consider the range of experimental techniques implemented in in vitro studies with the aim of elucidating these microbubble-cell interactions. First of all, the variety of cell types and cell models available are discussed, emphasizing the need for more and more complex models replicating in vivo conditions together with experimental challenges associated with this increased complexity. Second, the different types of stabilized microbubbles and more recently developed droplets and particles are presented, followed by their acoustic or optical excitation methods. Finally, the techniques exploited to study the microbubble-cell interactions are reviewed. These techniques operate over a wide range of timescales, or even off-line, revealing particular aspects or subsequent effects of these interactions. Therefore, knowledge obtained from several techniques must be combined to elucidate the underlying processes. PMID:26865903

  16. Dielectric characterization of PCL-based thermoplastic materials for microwave diagnostic and therapeutic applications.

    PubMed

    Aguilar, Suzette M; Shea, Jacob D; Al-Joumayly, Mudar A; Van Veen, Barry D; Behdad, Nader; Hagness, Susan C

    2012-03-01

    We propose the use of a polycaprolactone (PCL)-based thermoplastic mesh as a tissue-immobilization interface for microwave imaging and microwave hyperthermia treatment. An investigation of the dielectric properties of two PCL-based thermoplastic materials in the frequency range of 0.5-3.5 GHz is presented. The frequency-dependent dielectric constant and effective conductivity of the PCL-based thermoplastics are characterized using measurements of microstrip transmission lines fabricated on substrates comprised of the thermoplastic meshes. We also examine the impact of the presence of a PCL-based thermoplastic mesh on microwave breast imaging. We use a numerical test bed comprised of a previously reported 3-D anatomically realistic breast phantom and a multi-frequency microwave inverse scattering algorithm. We demonstrate that the PCL-based thermoplastic material and the assumed biocompatible medium of vegetable oil are sufficiently well matched such that the PCL layer may be neglected by the imaging solution without sacrificing imaging quality. Our results suggest that PCL-based thermoplastics are promising materials as tissue immobilization structures for microwave diagnostic and therapeutic applications.

  17. ADULT NEURAL STEM CELLS: RESPONSE TO STROKE INJURY AND POTENTIAL FOR THERAPEUTIC APPLICATIONS

    PubMed Central

    Barkho, Basam Z.; Zhao, Xinyu

    2011-01-01

    The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection. Here we review the current state of our knowledge about endogenous adult and exogenous neural stem/progenitor cells as potential therapeutic agents for central nervous system injuries. PMID:21466483

  18. Clinical use of adjuvants in allergen-immunotherapy.

    PubMed

    Klimek, L; Schmidt-Weber, C B; Kramer, M F; Skinner, M A; Heath, M D

    2017-02-04

    Introduction Allergen-specific Immunotherapy (AIT) is the only available treatment aimed to tackle the underlying causes of allergy. The active components of subcutaneous vaccines traditionally consist of natural or modified allergen extracts which can be combined with adjuvant platforms. In recent years new targets have been further developed in an attempt to raise the safety and efficacy profile of AIT. Areas Covered In this review, we discuss the desirable attributes of adjuvants and delivery systems from empiricism to rational design, for current and future clinical applications in AIT. Expert Summary The introduction of novel adjuvants, in combination with active targets, has been demonstrated to reduce side-effects of AIT, increase clinical efficacy of allergy treatment and reduce the number of doses. The evolution of vaccine development for AIT is entering a phase of scientific progress that challenges dogmas. Over the past century the traditional concept of immunotherapy, entailing long-course administration of native extract preparations and first generation adjuvants has seen evolution in the past decade from proof-of-concept to clinical development pipelines encompassing the advent of second generation adjuvants and delivery systems that form essential components of modern AIT development.

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

    PubMed

    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.

  20. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

    NASA Astrophysics Data System (ADS)

    Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang

    2016-10-01

    A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

  1. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

    PubMed Central

    Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang

    2016-01-01

    A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours. PMID:27767031

  2. Synthesis of Biocompatible Nanoparticulate Coordination Polymers for Diagnostic and Therapeutic Applications

    NASA Astrophysics Data System (ADS)

    Kandanapitiye, Murthi S.

    The combination of nanotechnology with medicinal chemistry has developed into a burgeoning research area. Nanomaterials (NMs) could be seamlessly interfaced with various facets in biology, biochemistry, medicinal chemistry and environmental chemistry that may not be available to the same material in the bulk scale. This dissertation research has focused on the development of nanoparticulate coordination polymers for diagnostic and therapeutic applications. Modern imaging techniques include X-ray computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). We have successfully developed several types of nanoparticulate diagnostics and therapeutics that have some potential usefulness in biomedicine. Synthesis and characterization of nanoparticulate based PET (Positron emission tomography)/SPECT (Single photon emission computed tomography) are discussed in chapter 3. In chapter 4, preparation and potential utility of non-gadolinium based MRI contrast agent are reported for T1-weighted application. As far as the solely effectiveness of relaxation is concerned, Gd-based T 1-weighted MRI contrast agents have excellent enhancement of image contrast but they have risks of biological toxicity. Consequently, the search for T 1-weighted CAs with high efficacy and low toxicity has gained attention toward the Mn(II) and Fe(III). Fe(III) is considered to be more toxic to cells because free ferric or ferrous ions can catalyze the production of reactive oxygen species via the Fenton reactions. Paramagnetic chelates of Mn(II) could be employed as T1-weighted CAs. However, it is challenging to design and synthesize highly stable Mn(II) complexes that could maintain the integrity when administered to living system. Chapter 4 describes the synthesis and utility of nanoparticulate Mn analogue of Prussian blue (K2Mn 3[FeII(CN)6]2) as an effective T1 MRI contrast agent for cellular imaging X

  3. Key roles of adjuvants in modern vaccines.

    PubMed

    Reed, Steven G; Orr, Mark T; Fox, Christopher B

    2013-12-01

    Vaccines containing novel adjuvant formulations are increasingly reaching advanced development and licensing stages, providing new tools to fill previously unmet clinical needs. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of effectiveness, unacceptable levels of tolerability or safety concerns. This Review outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against devastating infectious diseases.

  4. Generation of "virtual" control groups for single arm prostate cancer adjuvant trials.

    PubMed

    Jia, Zhenyu; Lilly, Michael B; Koziol, James A; Chen, Xin; Xia, Xiao-Qin; Wang, Yipeng; Skarecky, Douglas; Sutton, Manuel; Sawyers, Anne; Ruckle, Herbert; Carpenter, Philip M; Wang-Rodriguez, Jessica; Jiang, Jun; Deng, Mingsen; Pan, Cong; Zhu, Jian-Guo; McLaren, Christine E; Gurley, Michael J; Lee, Chung; McClelland, Michael; Ahlering, Thomas; Kattan, Michael W; Mercola, Dan

    2014-01-01

    It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, … 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies.

  5. Application of Emerging Pharmaceutical Technologies for Therapeutic Challenges of Space Exploration Missions

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi

    2011-01-01

    An important requirement of therapeutics for extended duration exploration missions beyond low Earth orbit will be the development of pharmaceutical technologies suitable for sustained and preventive health care in remote and adverse environmental conditions. Availability of sustained, stable and targeted delivery pharmaceuticals for preventive health of major organ systems including gastrointestinal, hepato-renal, musculo-skeletal and immune function are essential to offset adverse effects of space environment beyond low Earth orbit. Specifically, medical needs may include multi-drug combinations for hormone replacement, radiation protection, immune enhancement and organ function restoration. Additionally, extended stability of pharmaceuticals dispensed in space must be also considered in future drug development. Emerging technologies that can deliver stable and multi-therapy pharmaceutical preparations and delivery systems include nanotechnology based drug delivery platforms, targeted-delivery systems in non-oral and non-parenteral formulation matrices. Synthetic nanomaterials designed with molecular precision offer defined structures, electronics, and chemistries to be efficient drug carriers with clear advantages over conventional materials of drug delivery matricies. Nano-carrier materials like the bottle brush polymers may be suitable for systemic delivery of drug cocktails while Superparamagnetic Iron Oxide Nanoparticles or (SPIONS) have great potential to serve as carriers for targeted drug delivery to a specific site. These and other emerging concepts of drug delivery and extended shelf-life technologies will be reviewed in light of their application to address health-care challenges of exploration missions. Innovations in alternate treatments for sustained immune enhancement and infection control will be also discussed.

  6. Current therapeutic paradigms in glioblastoma.

    PubMed

    Quick, Allison; Patel, Disha; Hadziahmetovic, Mersiha; Chakravarti, Arnab; Mehta, Minesh

    2010-01-01

    Glioblastoma (GBM), a WHO grade IV malignant glioma, is the most common and lethal adult primary brain tumor. Median survival rates range from 12-15 months. The current standard of care for GBM has evolved from resection followed by adjuvant radiotherapy to resection, concurrent adjuvant chemotherapy (temozolomide) and radiation, and additional adjuvant chemotherapy. The expression of specific molecular biomarkers, especially O-6-methylguanine methyltransferase (MGMT) status, may determine the response of the tumor to treatment, and helps in identifying the magnitude of benefit from this regimen. By identifying further biological subtypes of GBM at the molecular level, specific targeted therapies could be developed and used in the future for more individualized therapeutic regimens. This article will review the current therapies for GBM and the investigation of new molecular and targeted therapies, such as EGFR inhibitors, mTOR/PI3Kinase inhibitors, and anti-angiogenesis agents.

  7. CpG oligodeoxynucleotides as mucosal adjuvants

    PubMed Central

    Iho, Sumiko; Maeyama, Jun-ichi; Suzuki, Fumiko

    2015-01-01

    Bacterial DNA comprising palindromic sequences and containing unmethylated CpG is recognized by toll-like receptor 9 of plasmacytoid dendritic cells (pDCs) and induces the production of interferon-α and chemokines, leading to the activation of a Th1 immune response. Therefore, synthetic equivalents of bacterial DNA (CpG oligodeoxynucleotides) have been developed for clinical applications. They are usually phosphorothioated for in vivo use; this approach also leads to adverse effects as reported in mouse models.Mucosal vaccines that induce both mucosal and systemic immunity received substantial attention in recent years. For their development, phosphodiester-linked oligodeoxynucleotides, including the sequence of a palindromic CpG DNA may be advantageous as adjuvants because their target pDCs are present right there, in the mucosa of the vaccination site. In addition, the probability of adverse effects is believed to be low. Here, we review the discovery of such CpG oligodeoxynucleotides and their possible use as mucosal adjuvants. PMID:25751765

  8. Applications of RNA interference in cancer therapeutics as a powerful tool for suppressing gene expression.

    PubMed

    He, Song; Zhang, Dechun; Cheng, Fang; Gong, Fanghong; Guo, Yanan

    2009-11-01

    Cancer poses a tremendous therapeutic challenge worldwide, highlighting the critical need for developing novel therapeutics. A promising cancer treatment modality is gene therapy, which is a form of molecular medicine designed to introduce into target cells genetic material with therapeutic intent. The history of RNA interference (RNAi) has only a dozen years, however, further studies have revealed that it is a potent method of gene silencing that has developed rapidly over the past few years as a result of its extensive importance in the study of genetics, molecular biology and physiology. RNAi is a natural process by which small interfering RNA (siRNA) duplex directs sequence specific post-transcriptional silencing of homologous genes by binding to its complementary mRNA and triggering its elimination. RNAi has been extensively used as a novel and effective gene silencing tool for the fundamental research of cancer therapeutics, and has displayed great potential in clinical treatment.

  9. Development of RNA interference-based therapeutics and application of multi-target small interfering RNAs.

    PubMed

    Li, Tiejun; Wu, Meihua; Zhu, York Yuanyuan; Chen, Jianxin; Chen, Li

    2014-08-01

    RNA interference (RNAi) has been proven in recent years to be a newly advanced and powerful tool for development of therapeutic agents toward various unmet medical needs such as cancer, in particular, a great attention has been paid to the development of antineoplastic agents. Recent success in clinical trials related to RNAi-based therapeutics on cancer and ocular disease has validated that small interfering RNAs (siRNAs) constitute a new promising class of therapeutics. Currently, a great wealth of multi-target based siRNA structural modifications is available for promoting siRNA-mediated gene silencing with low side effects. Here, the latest developments in RNAi-based therapeutics and novel structural modifications described for siRNAs--in particular multi-target siRNAs--are reviewed.

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

    PubMed

    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.

  11. Vaccine Adjuvants: Mode of Action

    PubMed Central

    De Gregorio, Ennio; Caproni, Elena; Ulmer, Jeffrey B.

    2013-01-01

    Vaccines were first introduced more than 200 years ago and have since played a key role in the reduction of morbidity and mortality caused by infectious diseases. Many of the safest and most effective vaccines in use today are based on attenuated live viruses, as they mimic a live infection without causing disease. However, it is not always practical to take this approach, such as when it may not be safe to do so (e.g., for viruses that cause chronic infections such as HIV) or may not be feasible to manufacture (e.g., for viruses that do not grow well in cell culture such as HCV). In addition, it may preferable in some cases to target immune responses toward specific antigens from the pathogen, rather than the entirety of the genome. In these cases, subunit vaccines consisting of antigens purified from the pathogen or produced by recombinant DNA technology are being developed. However, highly purified proteins are typically not inherently immunogenic, as they usually lack the means to directly stimulate the innate immune system, and often require the addition of adjuvants to enhance vaccine potency. Despite more than a century of human use, only a few adjuvants are licensed today. However many adjuvants have been tested in humans and are in advanced stages of development. Much of the early work on adjuvants discovery and development was empirical producing safe and effective products, but without a clear understanding of how they worked. Recent insight into the functioning of the innate immune system has demonstrated its important role in triggering and shaping the adaptive immune response to vaccines. PMID:23914187

  12. Transdermal scopolamine for prevention of motion sickness : clinical pharmacokinetics and therapeutic applications.

    PubMed

    Nachum, Zohar; Shupak, Avi; Gordon, Carlos R

    2006-01-01

    A transdermal therapeutic system for scopolamine (TTS-S) was developed to counter the adverse effects and short duration of action that has restricted the usefulness of scopolamine when administered orally or parenterally. The plaster contains a reservoir of 1.5 mg of scopolamine programmed to deliver 0.5 mg over a 3-day period. A priming dose (140 microg) is incorporated into the adhesive layer to saturate certain binding sites within the skin and to accelerate the achievement of steady-state blood levels. The remainder is released at a constant rate of approximately 5 microg/hour. The protective plasma concentration of scopolamine is estimated to be 50 pg/mL. TTS-S attains that concentration after 6 hours; a steady state of about 100 pg/mL is achieved 8-12 hours after application. Yet 20-30% of subjects failed to attain the estimated protective concentration, and plasma concentrations measured in subjects who failed to respond to TTS-S were lower than in responders. These findings may explain some of the treatment failures. Overall, the product appears to be the approximate functional equivalent of a 72-hour slow intravenous infusion. A combination of transdermal and oral scopolamine (0.3 or 0.6 mg) was effective and well tolerated in producing desired plasma concentrations 1-hour post-treatment. TTS-S has proved to be significantly superior to placebo in reducing the incidence and severity of motion sickness by 60-80%. It was more effective than oral meclizine or cinnarizine, similar to oral scopolamine 0.6 mg or promethazine plus ephedrine, and the same as or superior to dimenhydrinate. The addition of ephedrine or the use of two patches did not improve its efficacy, but rather increased the rate of adverse effects. TTS-S was most effective against motion sickness 8-12 hours after application. Despite previous evidence to the contrary, a recent bioavailability study demonstrated similar intraindividual absorption and sustained clinical efficacy with long

  13. BOOK REVIEW: Therapeutic Applications of Monte Carlo Calculations in Nuclear Medicine

    NASA Astrophysics Data System (ADS)

    Coulot, J.

    2003-08-01

    H Zaidi and G Sgouros (eds) Bristol: Institute of Physics Publishing (2002) £70.00, ISBN: 0750308168 Monte Carlo techniques are involved in many applications in medical physics, and the field of nuclear medicine has seen a great development in the past ten years due to their wider use. Thus, it is of great interest to look at the state of the art in this domain, when improving computer performances allow one to obtain improved results in a dramatically reduced time. The goal of this book is to make, in 15 chapters, an exhaustive review of the use of Monte Carlo techniques in nuclear medicine, also giving key features which are not necessary directly related to the Monte Carlo method, but mandatory for its practical application. As the book deals with `therapeutic' nuclear medicine, it focuses on internal dosimetry. After a general introduction on Monte Carlo techniques and their applications in nuclear medicine (dosimetry, imaging and radiation protection), the authors give an overview of internal dosimetry methods (formalism, mathematical phantoms, quantities of interest). Then, some of the more widely used Monte Carlo codes are described, as well as some treatment planning softwares. Some original techniques are also mentioned, such as dosimetry for boron neutron capture synovectomy. It is generally well written, clearly presented, and very well documented. Each chapter gives an overview of each subject, and it is up to the reader to investigate it further using the extensive bibliography provided. Each topic is discussed from a practical point of view, which is of great help for non-experienced readers. For instance, the chapter about mathematical aspects of Monte Carlo particle transport is very clear and helps one to apprehend the philosophy of the method, which is often a difficulty with a more theoretical approach. Each chapter is put in the general (clinical) context, and this allows the reader to keep in mind the intrinsic limitation of each technique

  14. Taiwanofungus camphoratus (Syn Antrodia camphorata) extract and amphotericin B exert adjuvant effects via mitochondrial apoptotic pathway.

    PubMed

    Chen, Ling-Yi; Sheu, Ming-Thau; Liao, Chuh-Kai; Tsai, Feng-Chou; Kao, Woei-Yao; Su, Ching-Hua

    2013-03-01

    The use of multiple drugs in cancer therapy increases the efficacy of the potential therapeutic effects. In this study, the authors investigated the adjuvant effects of an ethanol extract of solid-state cultivated Taiwanofungus camphoratus (TCEE) and amphotericin B (AmB) in the human cancer cell lines RPMI7951 and MG63. Taiwanofungus camphoratus is a well-known Chinese medicine in Taiwan, and AmB is a widely used antifungal agent. The authors demonstrated that TCEE pretreatment followed by AmB treatment effectively inhibited cell growth. The combination of sublethal doses of TCEE and AmB revealed a significant growth inhibitory effect in both cell lines. The combination of TCEE and AmB but not AmB alone induced phosphatidylserine externalization and loss of mitochondrial membrane potential. Cell cycle analyses revealed that combination of TCEE and AmB triggered G2/M arrest and significant apoptosis after 48 hours. These effects were greater than those achieved using TCEE or AmB alone. Furthermore, the authors demonstrated that the drugs increased the levels of p21(Cip1/Waf1) and pro-apoptotic protein Bax and reduced the level of anti-apoptotic protein Bcl-2. Taken together, the results showed that the combination treatment of TCEE and AmB displays strong adjuvant effects, which are indicated by the inhibition of cell proliferation in 2 human cancer cell lines, RPMI7951 and MG63. These findings suggest possible therapeutic applications and alternative medicines using this drug combination.

  15. Application of FRET Technology to the In Vivo Evaluation of Therapeutic Nucleic Acids (ANTs)

    NASA Astrophysics Data System (ADS)

    Benítez-Hess, María Luisa; Alvarez-Salas, Luis Marat

    2007-02-01

    Developing applications for therapeutic nucleic acids (TNAs) (i.e. ribozymes, antisense oligodeoxynucleotides (AS-ODNs), siRNA and aptamers) requires a reporter system designed to rapidly evaluate their in vivo effect. To this end we designed a reporter system based on the fluorescence resonance energy transfer (FRET) engineered to release the FRET effect produced by two green fluorescent protein (GFP) variants linked by a TNA target site. Because the FRET effect occurs instantaneously when two fluorophores are very close to each other (>100nm) stimulating emission of the acceptor fluorophore by the excitation of the donor fluorophore it has been widely use to reveal interactions between molecules. The present system (FRET2) correlates the FRET effect with the in vivo activity of distinct types of TNAs based on a model consisting of RNA from human papillomavirus type 16 (HPV-16) previously shown accessible to TNAs. HPV-16 is the most common papillomavirus associated with cervical cancer, the leading cause of death by cancer in México. The FRET2 system was first tested in vitro and then used in bacteria in which transcription is linked to translation allowing controlled expression and rapid evaluation of the FRET2 protein. To assure accessibility of the target mRNA to TNAs, the FRET2 mRNA was probed by RNaseH assays prior FRET testing. The fluorescence features of the FRET2 system was tested with different FRET-producing GFP donor-acceptor pairs leading to selection of green (donor) and yellow (acceptor) variants of GFP as the most efficient. Modifications in aminoacid composition and linker length of the target sequence did not affect FRET efficiency. In vivo AS-ODN-mediated destruction of the chimerical FRET2 reporter mRNA resulted in the recovery of GFP fluorescent spectrum in a concentration and time dependent manner. Reported anti-HPV ribozymes were also tested with similar results. Therefore, we conclude that the FRET effect can be a useful tool in the

  16. Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins

    PubMed Central

    Ha, Ji-Hee; Kim, Jung-Eun; Kim, Yong-Sung

    2016-01-01

    The monospecific and bivalent characteristics of naturally occurring immunoglobulin G (IgG) antibodies depend on homodimerization of the fragment crystallizable (Fc) regions of two identical heavy chains (HCs) and the subsequent assembly of two identical light chains (LCs) via disulfide linkages between each HC and LC. Immunoglobulin Fc heterodimers have been engineered through modifications to the CH3 domain interface, with different mutations on each domain such that the engineered Fc fragments, carrying the CH3 variant pair, preferentially form heterodimers rather than homodimers. Many research groups have adopted different strategies to generate Fc heterodimers, with the goal of high heterodimerization yield, while retaining biophysical and biological properties of the wild-type Fc. Based on their ability to enforce heterodimerization between the two different HCs, the established Fc heterodimers have been extensively exploited as a scaffold to generate bispecific antibodies (bsAbs) in full-length IgG and IgG-like formats. These have many of the favorable properties of natural IgG antibodies, such as high stability, long serum half-life, low immunogenicity, and immune effector functions. As of July 2016, more than seven heterodimeric Fc-based IgG-format bsAbs are being evaluated in clinical trials. In addition to bsAbs, heterodimeric Fc technology is very promising for the generation of Fc-fused proteins and peptides, as well as cytokines (immunocytokines), which can present the fusion partners in the natural monomeric or heterodimeric form rather than the artificial homodimeric form with wild-type Fc. Here, we present relevant concepts and strategies for the generation of heterodimeric Fc proteins, and their application in the development of bsAbs in diverse formats for optimal biological activity. In addition, we describe wild-type Fc-fused monomeric and heterodimeric proteins, along with the difficulties associated with their preparations, and discuss the

  17. Neurocognitive therapeutics: from concept to application in the treatment of negative attention bias.

    PubMed

    Schnyer, David M; Beevers, Christopher G; deBettencourt, Megan T; Sherman, Stephanie M; Cohen, Jonathan D; Norman, Kenneth A; Turk-Browne, Nicholas B

    2015-01-01

    There is growing interest in the use of neuroimaging for the direct treatment of mental illness. Here, we present a new framework for such treatment, neurocognitive therapeutics. What distinguishes neurocognitive therapeutics from prior approaches is the use of precise brain-decoding techniques within a real-time feedback system, in order to adapt treatment online and tailor feedback to individuals' needs. We report an initial feasibility study that uses this framework to alter negative attention bias in a small number of patients experiencing significant mood symptoms. The results are consistent with the promise of neurocognitive therapeutics to improve mood symptoms and alter brain networks mediating attentional control. Future work should focus on optimizing the approach, validating its effectiveness, and expanding the scope of targeted disorders.

  18. Applications of lipid based formulation technologies in the delivery of biotechnology-based therapeutics.

    PubMed

    du Plessis, Lissinda H; Marais, Etienne B; Mohammed, Faruq; Kotzé, Awie F

    2014-01-01

    In the last decades several new biotechnologically-based therapeutics have been developed due to progress in genetic engineering. A growing challenge facing pharmaceutical scientists is formulating these compounds into oral dosage forms with adequate bioavailability. An increasingly popular approach to formulate biotechnology-based therapeutics is the use of lipid based formulation technologies. This review highlights the importance of lipid based drug delivery systems in the formulation of oral biotechnology based therapeutics including peptides, proteins, DNA, siRNA and vaccines. The different production procedures used to achieve high encapsulation efficiencies of the bioactives are discussed, as well as the factors influencing the choice of excipient. Lipid based colloidal drug delivery systems including liposomes and solid lipid nanoparticles are reviewed with a focus on recent advances and updates. We further describe microemulsions and self-emulsifying drug delivery systems and recent findings on bioactive delivery. We conclude the review with a few examples on novel lipid based formulation technologies.

  19. Antitumor therapeutic application of self-assembled RNAi-AuNP nanoconstructs: Combination of VEGF-RNAi and photothermal ablation

    PubMed Central

    Son, Sejin; Kim, Namho; You, Dong Gil; Yoon, Hong Yeol; Yhee, Ji Young; Kim, Kwangmeyung; Kwon, Ick Chan; Kim, Sun Hwa

    2017-01-01

    Nucleic acid-directed self-assembly provides an attractive method to fabricate prerequisite nanoscale structures for a wide range of technological applications due to the remarkable programmability of DNA/RNA molecules. In this study, exquisite RNAi-AuNP nanoconstructs with various geometries were developed by utilizing anti-VEGF siRNA molecules as RNAi-based therapeutics in addition to their role as building blocks for programmed self-assembly. In particular, the anti-VEGF siRNA-functionalized AuNP nanoconstructs can take additional advantage of gold-nanoclusters for photothermal cancer therapeutic agent. A noticeable technical aspect of self-assembled RNAi-AuNP nanoconstructs in this study is the precise conjugation and separation of designated numbers of therapeutic siRNA onto AuNP to develop highly sophisticated RNA-based building blocks capable of creating various geometries of RNAi-AuNP nano-assemblies. The therapeutic potential of RNAi-AuNP nanoconstructs was validated in vivo as well as in vitro by combining heat generation capability of AuNP and anti-angiogenesis mechanism of siRNA. This strategy of combining anti-VEGF mechanism for depleting angiogenesis process at initial tumor progression and complete ablation of residual tumors with photothermal activity of AuNP at later tumor stage showed effective tumor growth inhibition and tumor ablation with PC-3 tumor bearing mice. PMID:28042312

  20. Mode of action of immunological adjuvants: some physicochemical factors influencing the effectivity of polyacrylic adjuvants.

    PubMed Central

    Kreuter, J; Haenzel, I

    1978-01-01

    The adjuvant effects of different polyacrylic products and monomers were tested. Influenza vaccine was used as a model antigen. Addition of monomers resulted in a decrease in the antibody response, though adjuvant activity of the monomers should be expected according to some theories on adjuvant action. The particle size of the polymer adjuvants proved to be a very important parameter for adjuvant activity. Particles of 0.1 to 0.2 micron yielded a good adjuvant effect, whereas conglomerates or particles bigger than 0.5 micron yielded only poor or no adjuvant effects. The adjuvant effect of 0.1- to 0.2-micron particles was much more reproducible than rat of Al(OH)3. Attention is drawn to the importance of using physiochemically reproducible materials, such as polymer particles, for experimental work. Images PMID:631894

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

    PubMed

    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.

  2. Novel adjuvant therapies for pancreatic adenocarcinoma

    PubMed Central

    Oyasiji, Tolutope

    2015-01-01

    Contemporary adjuvant therapy for pancreatic cancer patients following surgical resection includes chemotherapy and chemoradiotherapy. However, the median survival remains approximately 20 months despite multi-modality treatment using gemcitabine or fluoropyrimidine systemic chemotherapy. Adjuvant randomized trials are currently underway to evaluate cytotoxic combinations found to be active in advanced disease including FOLFIRINOX, gemcitabine/nab-paclitaxel and gemcitabine/capecitabine. Immunotherapy using genetically engineered cell-based vaccines had shown promise in resected pancreatic cancer patients during early phase trials, and algenpantucel-L vaccine is currently being evaluated in adjuvant setting in a randomized trial. This review focuses on novel adjuvant therapies currently in clinical evaluation. PMID:26261729

  3. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    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.

  4. Design of a shear-thinning recoverable peptide hydrogel from native sequences and application for influenza H1N1 vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peptide hydrogels are considered injectable materials for drug delivery and tissue engineering applications. Most published hydrogel-forming sequences contain either alternating-charged and noncharged residues or amphiphilic blocks. Here, we report a self-assembling peptide, h9e (FLIVIGSIIGPGGDGPGGD...

  5. Mechanical clearance of red blood cells by the human spleen: Potential therapeutic applications of a biomimetic RBC filtration method.

    PubMed

    Duez, J; Holleran, J P; Ndour, P A; Pionneau, C; Diakité, S; Roussel, C; Dussiot, M; Amireault, P; Avery, V M; Buffet, P A

    2015-08-01

    During their lifespan, circulating RBC are frequently checked for their deformability. This mechanical quality control operates essentially in the human spleen. RBC unable to squeeze though narrow splenic slits are retained and cleared from the blood circulation. Under physiological conditions this prevents microvessels from being clogged by senescent, rigid RBC. Retention of poorly deformable RBC is an important determinant of pathogenesis in malaria and may also impact the clinical benefit of transfusion. Modulating the splenic retention of RBC has already been proposed to support therapeutic approaches in these research fields. To this aim, the development of microplates for high throughput filtration of RBC through microsphere layers (microplate-based microsphiltration) has been undertaken. This review focuses on potential therapeutic applications provided by this technology in malaria chemotherapy and transfusion.

  6. Bismuth-213 and actinium-225 -- generator performance and evolving therapeutic applications of two generator-derived alpha-emitting radioisotopes.

    PubMed

    Morgenstern, Alfred; Bruchertseifer, Frank; Apostolidis, Christos

    2012-07-01

    The alpha emitters (225)Ac and (213)Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. Both alpha emitters are available with high specific activity from established radionuclide generators. Their favourable chemical and physical properties have led to the conduction of a large number of preclinical studies and several clinical trials, demonstrating the feasibility, safety and therapeutic efficacy of targeted alpha therapy with (225)Ac and (213)Bi. This review describes methods for the production of (225)Ac and (213)Bi and gives an overview of (225)Ac/(213)Bi radionuclide generator systems. Selected preclinical studies are highlighted and the current clinical experience with (225)Ac and (213)Bi is summarized.

  7. Discovery and Development of Synthetic and Natural Biomaterials for Protein Therapeutics and Medical Device Applications

    NASA Astrophysics Data System (ADS)

    Keefe, Andrew J.

    Controlling nonspecific protein interactions is important for applications from medical devices to protein therapeutics. The presented work is a compilation of efforts aimed at using zwitterionic (ionic yet charge neutral) polymers to modify and stabilize the surface of sensitive biomedical and biological materials. Traditionally, when modifying the surface of a material, the stability of the underlying substrate. The materials modified in this dissertation are unique due to their unconventional amorphous characteristics which provide additional challenges. These are poly(dimethyl siloxane) (PDMS) rubber, and proteins. These materials may seem dissimilar, but both have amorphous surfaces, that do not respond well to chemical modification. PDMS is a biomaterial extensively used in medical device manufacturing, but experiences unacceptably high levels of non-specific protein fouling when used with biological samples. To reduce protein fouling, surface modification is often needed. Unfortunately conventional surface modification methods, such as Poly(ethylene glycol) (PEG) coatings, do not work for PDMS due to its amorphous state. Herein, we demonstrate how a superhydrophilic zwitterionic material, poly(carboxybetaine methacrylate) (pCBMA), can provide a highly stable nonfouling coating with long term stability due to the sharp the contrast in hydrophobicity between pCBMA and PDMS. Biological materials, such as proteins, also require stabilization to improve shelf life, circulation time, and bioactivity. Conjugation of proteins with PEG is often used to increase protein stability, but has a detrimental effect on bioactivity. Here we have shown that pCBMA conjugation improves stability in a similar fashion to PEG, but also retains, or even improves, binding affinity due to enhanced protein-substrate hydrophobic interactions. Recognizing that pCBMA chemically resembles the combination of lysine (K) and glutamic acid (E) amino acids, we have shown how zwitterionic

  8. Mucosal application of cationic poly(D,L-lactide-co-glycolide) microparticles as carriers of DNA vaccine and adjuvants to protect chickens against infectious bursal disease.

    PubMed

    Negash, Tamiru; Liman, Martin; Rautenschlein, Silke

    2013-08-12

    Infectious bursal disease virus (IBDV) is an immunosuppressive virus of chickens. The virus protein (VP) 2 induces neutralizing antibodies, which protect chickens against the disease. The aim of this study was to develop a cationic poly(d,l-lactide-co-glycolide) (PLGA) microparticle (MP) based IBDV-VP2 DNA vaccine (MP-IBDV-DNA) for chickens to be delivered orally and by eye drop route. The tested IBDV-VP2 DNA vaccines were immunogenic for specific-pathogen-free chickens and induced an antibody response after intramuscular application. Co-inoculation with a plasmid encoding chicken IL-2 (chIL-2) or CpG-ODN did not significantly improve protection against IBDV challenge. However, the application of a MP-IBDV-DNA vaccine alone or in combination with a delayed oral and eye drop application of cationic MP loaded with CpG-ODN or chIL-2 improved protection against challenge. The MP-IBDV-DNA-vaccinated chickens showed less pathological and histopathological bursal lesions, a reduced IBDV antigen load as well as T-cell influx into the bursa of Fabricius (BF) compared to the other groups (p<0.05). The addition of chIL-2 loaded MP improved challenge virus clearance from the BF as demonstrated by lower neutralizing antibody titers and reduced IL-4 and IFN-α mRNA expression in the bursa at 7 days postchallenge compared to the other challenged groups. Overall, the efficacy of the IBDV-DNA vaccine was improved by adsorption of the DNA vaccine onto cationic PLGA-MP, which also allowed mucosal application of the DNA vaccine.

  9. Potential therapeutic applications of aspirin and other cyclo-oxygenase inhibitors

    PubMed Central

    Farah, A. E.; Rosenberg, F.

    1980-01-01

    1 The ubiquitous actions of the cyclo-oxygenase inhibitors are described. 2 These include the inhibitory effect on prostaglandin synthesis and the direct effect of aspirin on lymphocytes and their ability to produce lymphokines. 3 Aspirin reduces some types of platelet aggregation possibly involving inhibition of the precursors of thromboxane A2 and prostacyclin. 4 The therapeutic implications in relation to transient ischaemic attacks, coronary artery disease and reno-allograft rejection are discussed. 5 The beneficial and adverse effects on the gastro-intestinal tract are described. 6 The effects of aspirin-like drugs on the genito-urinary tract are described with particular reference to their adverse effects on labour and their therapeutic effect on dysmenorrhoea. PMID:6776977

  10. The apelinergic system: the role played in human physiology and pathology and potential therapeutic applications.

    PubMed

    Ladeiras-Lopes, Ricardo; Ferreira-Martins, João; Leite-Moreira, Adelino F

    2008-05-01

    Apelin is a recently discovered peptide, identified as an endogenous ligand of receptor APJ. Apelin and receptor APJ are expressed in a wide variety of tissues including heart, brain, kidneys and lungs. Their interaction may have relevant pathophysiologic effects in those tissues. In fact, the last decade has been rich in illustrating the possible roles played by apelin in human physiology, namely as a regulating peptide of cardiovascular, hypothalamus-hypophysis, gastrointestinal, and immune systems. The possible involvement of apelin in the pathogenesis of high prevalence conditions and comorbidities - such as hypertension, heart failure, and Diabetes Mellitus Type 2 (T2DM) - rank it as a likely therapeutic target to be investigated in the future. The present paper is an overview of apelin physiologic effects and presents the possible role played by this peptide in the pathogenesis of a number of conditions as well as the therapeutic implications that might, therefore, be investigated.

  11. Optimization of ultrasound parameters of myocardial cavitation microlesions for therapeutic application.

    PubMed

    Miller, Douglas L; Dou, Chunyan; Owens, Gabe E; Kripfgans, Oliver D

    2014-06-01

    Intermittent high intensity ultrasound scanning with contrast microbubbles can induce scattered cavitation microlesions in the myocardium, which may be of value for tissue reduction therapy. Anesthetized rats were treated in a heated water bath with 1.5 MHz focused ultrasound pulses, guided by an 8 MHz imaging transducer. The relative efficacy with 2 or 4 MPa pulses, 1:4 or 1:8 trigger intervals and 5 or 10 cycle pulses was explored in six groups. Electrocardiogram premature complexes (PCs) induced by the triggered pulse bursts were counted, and Evans blue stained cardiomyocyte scores (SCSs) were obtained. The increase from 2 to 4 MPa produced significant increases in PCs and SCSs and eliminated an anticipated decline in the rate of PC induction with time, which might hinder therapeutic efficacy. Increased intervals and pulse durations did not yield significant increases in the effects. The results suggest that cavitation microlesion production can be refined and potentially lead to a clinically robust therapeutic method.

  12. Pathogenetic and therapeutic applications of microRNAs in major depressive disorder.

    PubMed

    Dwivedi, Yogesh

    2016-01-04

    As a class of noncoding RNAs, microRNAs (miRNAs) regulate gene expression by inhibiting translation of messenger RNAs. These miRNAs have been shown to play a critical role in higher brain functioning and actively participate in synaptic plasticity. Pre-clinical evidence demonstrates that expression of miRNAs is differentially altered during stress. On the other hand, depressed individuals show marked changes in miRNA expression in brain. MiRNAs are also target of antidepressants and electroconvulsive therapy. Moreover, these miRNAs are present in circulating blood and can be easily detected. Profiling of miRNAs in blood plasma/serum provides evidence that determination of miRNAs in blood can be used as possible diagnostic and therapeutic tool. In this review article, these aspects are critically reviewed and the role of miRNAs in possible etiopathogenesis and therapeutic implications in the context of major depressive disorder is discussed.

  13. Pathogenetic and therapeutic application of microRNAs in major depressive disorder

    PubMed Central

    Dwivedi, Yogesh

    2015-01-01

    As a class of noncoding RNAs, microRNAs (miRNAs) regulate gene expression by inhibiting translation of messenger RNAs. These miRNAs have been shown to play a critical role in higher brain functioning and actively participate in synaptic plasticity. Pre-clinical evidence demonstrates that expression of miRNAs is differentially altered during stress. On the other hand, depressed individuals show marked changes in miRNA expression in brain. MiRNAs are also target of antidepressants and electroconvulsive therapy. Moreover, these miRNAs are present in circulating blood and can be easily detected. Profiling of miRNAs in blood plasma/serum provide evidence that determination of miRNAs in blood can be used as possible diagnostic and therapeutic tool. In this review article, these aspects are critically reviewed and role of miRNAs in possible etiopathogenesis and therapeutic implications in the context of major depressive disorder is discussed. PMID:25689819

  14. The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease

    PubMed Central

    Recio, Carlota; Maione, Francesco; Iqbal, Asif J.; Mascolo, Nicola; De Feo, Vincenzo

    2017-01-01

    Cardiovascular disease (CVD) remains a leading cause of mortality and morbidity worldwide. Numerous therapies are currently under investigation to improve pathological cardiovascular complications, but yet, there have been very few new medications approved for intervention/treatment. Therefore, new approaches to treat CVD are urgently required. Attempts to prevent vascular complications usually involve amelioration of contributing risk factors and underlying processes such as inflammation, obesity, hyperglycaemia, or hypercholesterolemia. Historically, the development of peptides as therapeutic agents has been avoided by the Pharmaceutical industry due to their low stability, size, rate of degradation, and poor delivery. However, more recently, resurgence has taken place in developing peptides and their mimetics for therapeutic intervention. As a result, increased attention has been placed upon using peptides that mimic the function of mediators involved in pathologic processes during vascular damage. This review will provide an overview on novel targets and experimental therapeutic approaches based on peptidomimetics for modulation in CVD. We aim to specifically examine apolipoprotein A-I (apoA-I) and apoE mimetic peptides and their role in cholesterol transport during atherosclerosis, suppressors of cytokine signaling (SOCS)1-derived peptides and annexin-A1 as potent inhibitors of inflammation, incretin mimetics and their function in glucose-insulin tolerance, among others. With improvements in technology and synthesis platforms the future looks promising for the development of novel peptides and mimetics for therapeutic use. However, within the area of CVD much more work is required to identify and improve our understanding of peptide structure, interaction, and function in order to select the best targets to take forward for treatment. PMID:28111551

  15. The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease.

    PubMed

    Recio, Carlota; Maione, Francesco; Iqbal, Asif J; Mascolo, Nicola; De Feo, Vincenzo

    2016-01-01

    Cardiovascular disease (CVD) remains a leading cause of mortality and morbidity worldwide. Numerous therapies are currently under investigation to improve pathological cardiovascular complications, but yet, there have been very few new medications approved for intervention/treatment. Therefore, new approaches to treat CVD are urgently required. Attempts to prevent vascular complications usually involve amelioration of contributing risk factors and underlying processes such as inflammation, obesity, hyperglycaemia, or hypercholesterolemia. Historically, the development of peptides as therapeutic agents has been avoided by the Pharmaceutical industry due to their low stability, size, rate of degradation, and poor delivery. However, more recently, resurgence has taken place in developing peptides and their mimetics for therapeutic intervention. As a result, increased attention has been placed upon using peptides that mimic the function of mediators involved in pathologic processes during vascular damage. This review will provide an overview on novel targets and experimental therapeutic approaches based on peptidomimetics for modulation in CVD. We aim to specifically examine apolipoprotein A-I (apoA-I) and apoE mimetic peptides and their role in cholesterol transport during atherosclerosis, suppressors of cytokine signaling (SOCS)1-derived peptides and annexin-A1 as potent inhibitors of inflammation, incretin mimetics and their function in glucose-insulin tolerance, among others. With improvements in technology and synthesis platforms the future looks promising for the development of novel peptides and mimetics for therapeutic use. However, within the area of CVD much more work is required to identify and improve our understanding of peptide structure, interaction, and function in order to select the best targets to take forward for treatment.

  16. The Therapeutic Utility of Employment in Treating Drug Addiction: Science to Application.

    PubMed

    Silverman, Kenneth; Holtyn, August F; Morrison, Reed

    2016-06-01

    Research on a model Therapeutic Workplace has allowed for evaluation of the use of employment in the treatment of drug addiction. Under the Therapeutic Workplace intervention, adults with histories of drug addiction are hired and paid to work. To promote drug abstinence or adherence to addiction medications, participants are required to provide drug-free urine samples or take prescribed addiction medications, respectively, to gain access to the workplace and/or to maintain their maximum rate of pay. Research has shown that the Therapeutic Workplace intervention is effective in promoting and maintaining abstinence from heroin, cocaine and alcohol and in promoting adherence to naltrexone. Three models could be used to implement and maintain employment-based reinforcement in the treatment of drug addiction: A Social Business model, a Cooperative Employer model, and a Wage Supplement model. Under all models, participants initiate abstinence in a training and abstinence initiation phase (Phase 1). Under the Social Business model, Phase 1 graduates are hired as employees in a social business and required to maintain abstinence to maintain employment and/or maximum pay. Under the Cooperative Employer model, cooperating community employers hire graduates of Phase 1 and require them to maintain abstinence to maintain employment and/or maximum pay. Under the Wage Supplement Model, graduates of Phase 1 are offered abstinence-contingent wage supplements if they maintain competitive employment in a community job. Given the severity and persistence of the problem of drug addiction and the lack of treatments that can produce lasting effects, continued development of the Therapeutic Workplace is warranted.

  17. Future research and therapeutic applications of human stem cells: general, regulatory, and bioethical aspects

    PubMed Central

    2010-01-01

    There is much to be investigated about the specific characteristics of stem cells and about the efficacy and safety of the new drugs based on this type of cells, both embryonic as adult stem cells, for several therapeutic indications (cardiovascular and ischemic diseases, diabetes, hematopoietic diseases, liver diseases). Along with recent progress in transference of nuclei from human somatic cells, as well as iPSC technology, has allowed availability of lineages of all three germ layers genetically identical to those of the donor patient, which permits safe transplantation of organ-tissue-specific adult stem cells with no immune rejection. The main objective is the need for expansion of stem cell characteristics to maximize stem cell efficacy (i.e. the proper selection of a stem cell) and the efficacy (maximum effect) and safety of stem cell derived drugs. Other considerations to take into account in cell therapy will be the suitability of infrastructure and technical staff, biomaterials, production costs, biobanks, biosecurity, and the biotechnological industry. The general objectives in the area of stem cell research in the next few years, are related to identification of therapeutic targets and potential therapeutic tests, studies of cell differentiation and physiological mechanisms, culture conditions of pluripotent stem cells and efficacy and safety tests for stem cell-based drugs or procedures to be performed in both animal and human models in the corresponding clinical trials. A regulatory framework will be required to ensure patient accessibility to products and governmental assistance for their regulation and control. Bioethical aspects will be required related to the scientific and therapeutic relevance and cost of cryopreservation over time, but specially with respect to embryos which may ultimately be used for scientific uses of research as source of embryonic stem cells, in which case the bioethical conflict may be further aggravated. PMID:21143967

  18. Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

    PubMed

    Kou, Jinghong; Yang, Junling; Lim, Jeong-Eun; Pattanayak, Abhinandan; Song, Min; Planque, Stephanie; Paul, Sudhir; Fukuchi, Ken-Ichiro

    2015-02-01

    Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.

  19. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

    Lee, Stephen C.; Ruegsegger, Mark; Barnes, Philip D.; Smith, Bryan R.; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'etre of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multi-step work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  20. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  1. Insights into the Biology and Therapeutic Applications of Neural Stem Cells

    PubMed Central

    Harris, Lachlan; Zalucki, Oressia; Piper, Michael; Heng, Julian Ik-Tsen

    2016-01-01

    The cerebral cortex is essential for our higher cognitive functions and emotional reasoning. Arguably, this brain structure is the distinguishing feature of our species, and yet our remarkable cognitive capacity has seemingly come at a cost to the regenerative capacity of the human brain. Indeed, the capacity for regeneration and neurogenesis of the brains of vertebrates has declined over the course of evolution, from fish to rodents to primates. Nevertheless, recent evidence supporting the existence of neural stem cells (NSCs) in the adult human brain raises new questions about the biological significance of adult neurogenesis in relation to ageing and the possibility that such endogenous sources of NSCs might provide therapeutic options for the treatment of brain injury and disease. Here, we highlight recent insights and perspectives on NSCs within both the developing and adult cerebral cortex. Our review of NSCs during development focuses upon the diversity and therapeutic potential of these cells for use in cellular transplantation and in the modeling of neurodevelopmental disorders. Finally, we describe the cellular and molecular characteristics of NSCs within the adult brain and strategies to harness the therapeutic potential of these cell populations in the treatment of brain injury and disease. PMID:27069486

  2. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals.

    PubMed

    Hashimoto, Kenji; Ishiwata, Kiichi

    2006-01-01

    Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

  3. Potential applications of RNA interference-based therapeutics in the treatment of cardiovascular disease.

    PubMed

    Hassan, Ali

    2006-06-01

    RNA interference (RNAi) in eukaryotes is a recently identified phenomenon in which small double stranded RNA molecules called short interfering RNA (siRNA) interact with messenger RNA (mRNA) containing homologous sequences in a sequence-specific manner. Ultimately, this interaction results in degradation of the target mRNA. Because of the high sequence specificity of the RNAi process, and the apparently ubiquitous expression of the endogenous protein components necessary for RNAi, there appears to be little limitation to the genes that can be targeted for silencing by RNAi. Thus, RNAi has enormous potential, both as a research tool and as a mode of therapy. Several recent patents have described advances in RNAi technology that are likely to lead to new treatments for cardiovascular disease. These patents have described methods for increased delivery of siRNA to cardiovascular target tissues, chemical modifications of siRNA that improve their pharmacokinetic characteristics, and expression vectors capable of expressing RNAi effectors in situ. Though RNAi has only recently been demonstrated to occur in mammalian tissues, work has advanced rapidly in the development of RNAi-based therapeutics. Recently, therapeutic silencing of apoliporotein B, the ligand for the low density lipoprotein receptor, has been demonstrated in adult mice by systemic administration of chemically modified siRNA. This demonstrates the potential for RNAi-based therapeutics, and suggests that the future for RNAi in the treatment of cardiovascular disease is bright.

  4. Reverse genetics technology for Rift Valley fever virus: current and future applications for the development of therapeutics and vaccines.

    PubMed

    Bouloy, Michele; Flick, Ramon

    2009-11-01

    The advent of reverse genetics technology has revolutionized the study of RNA viruses, making it possible to manipulate their genomes and evaluate the effects of these changes on their biology and pathogenesis. The fundamental insights gleaned from reverse genetics-based studies over the last several years provide a new momentum for the development of designed therapies for the control and prevention of these viral pathogens. This review summarizes the successes and stumbling blocks in the development of reverse genetics technologies for Rift Valley fever virus and their application to the further dissection of its pathogenesis and the design of new therapeutics and safe and effective vaccines.

  5. Potential application of extracellular vesicles of human adipose tissue-derived mesenchymal stem cells in Alzheimer's disease therapeutics.

    PubMed

    Katsuda, Takeshi; Oki, Katsuyuki; Ochiya, Takahiro

    2015-01-01

    In the last 20 years, extracellular vesicles (EVs) have attracted attention as a versatile cell-cell communication mediator. The biological significance of EVs remains to be fully elucidated, but many reports have suggested that the functions of EVs mirror, at least in part, those of the cells from which they originate. Mesenchymal stem cells (MSCs) are a type of adult stem cell that can be isolated from connective tissue including bone marrow and adipose tissue and have emerged as an attractive candidate for cell therapy applications. Accordingly, an increasing number of reports have shown that EVs derived from MSCs have therapeutic potential in multiple diseases. We recently reported a novel therapeutic potential of EVs secreted from human adipose tissue-derived MSCs (hADSCs) (also known as adipose tissue-derived stem cells; ASCs) against Alzheimer's disease (AD). We found that hADSCs secrete exosomes carrying enzymatically active neprilysin, the most important β-amyloid peptide (Aβ)-degrading enzyme in the brain. In this chapter, we describe a method by which to evaluate the therapeutic potential of hADSC-derived EVs against AD from the point of view of their Aβ-degrading capacity.

  6. Towards Therapeutic Applications of Arthropod Venom K+-Channel Blockers in CNS Neurologic Diseases Involving Memory Acquisition and Storage

    PubMed Central

    Gati, Christiano D. C.; Mortari, Márcia R.; Schwartz, Elisabeth F.

    2012-01-01

    Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K+-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K+-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K+-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms. PMID:22701481

  7. [Sense of humour in schizophrenia--ability of humour reception and possibilities of its application in therapeutic interventions].

    PubMed

    Parnowska, Dorota; Braniecka, Anna; Radomska, Anna

    2013-01-01

    The existing research on sense of humour in schizophrenia is focused on two main areas, mainly, assessment of patients' abilities to understand and appreciate humour and denoting the possibilities of its application in therapeutic programs concentrating on the improvement of patients' functionality and preventing illness relapses. The vast majority of the conclusions from the above mentioned research corroborate the opinion on the usefulness of developing and reinforcing sense of humour in schizophrenia, emphasizing its beneficial effect on the patients' quality of life, above all, in terms of reducing aggression, anxiety and depression as well as improving general life satisfaction and social functioning. At the same time numerous research indicate low reception of humour in schizophrenia which can negatively influence its effective usage in therapeutic interventions. Further constraint with regard to the therapy can constitute an intensified fear for being laughed at, which has been confirmed in numerous empirical reports. Therefore, it seems that addressing humorous therapeutic interventions to the above mentioned group of patients requires especially careful planning taking into consideration its cognitive and affective limitations in the perception of humour and intensified fear for being laughed at.

  8. Moss-Produced, Glycosylation-Optimized Human Factor H for Therapeutic Application in Complement Disorders.

    PubMed

    Michelfelder, Stefan; Parsons, Juliana; Bohlender, Lennard L; Hoernstein, Sebastian N W; Niederkrüger, Holger; Busch, Andreas; Krieghoff, Nicola; Koch, Jonas; Fode, Benjamin; Schaaf, Andreas; Frischmuth, Thomas; Pohl, Martin; Zipfel, Peter F; Reski, Ralf; Decker, Eva L; Häffner, Karsten

    2016-12-08

    Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss (Physcomitrella patens). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant-specific sugar residues on protein N-glycans, yielding approximately 1 mg purified moss-derived human factor H per liter of initial P. patens culture after a multistep purification process. This glycosylation-optimized factor H showed full in vitro complement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS-induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss-derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation.

  9. Nanotechnology-Driven Therapeutic Interventions in Wound Healing: Potential Uses and Applications.

    PubMed

    Hamdan, Suzana; Pastar, Irena; Drakulich, Stefan; Dikici, Emre; Tomic-Canic, Marjana; Deo, Sapna; Daunert, Sylvia

    2017-03-22

    The chronic nature and associated complications of nonhealing wounds have led to the emergence of nanotechnology-based therapies that aim at facilitating the healing process and ultimately repairing the injured tissue. A number of engineered nanotechnologies have been proposed demonstrating unique properties and multiple functions that address specific problems associated with wound repair mechanisms. In this outlook, we highlight the most recently developed nanotechnology-based therapeutic agents and assess the viability and efficacy of each treatment, with emphasis on chronic cutaneous wounds. Herein we explore the unmet needs and future directions of current technologies, while discussing promising strategies that can advance the wound-healing field.

  10. Nanotechnology-Driven Therapeutic Interventions in Wound Healing: Potential Uses and Applications

    PubMed Central

    2017-01-01

    The chronic nature and associated complications of nonhealing wounds have led to the emergence of nanotechnology-based therapies that aim at facilitating the healing process and ultimately repairing the injured tissue. A number of engineered nanotechnologies have been proposed demonstrating unique properties and multiple functions that address specific problems associated with wound repair mechanisms. In this outlook, we highlight the most recently developed nanotechnology-based therapeutic agents and assess the viability and efficacy of each treatment, with emphasis on chronic cutaneous wounds. Herein we explore the unmet needs and future directions of current technologies, while discussing promising strategies that can advance the wound-healing field. PMID:28386594

  11. An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation.

    PubMed

    McDevitt, M R; Finn, R D; Sgouros, G; Ma, D; Scheinberg, D A

    1999-05-01

    A method for construction and operation of an 225Ac/213Bi generator capable of producing 25-100 mCi of 213Bi suitable for clinical antibody labeling is described. The generator has been designed to have an effective lifetime of several weeks, producing up to six therapeutic doses of radionuclide per day. To date, 57 clinical doses have been prepared and injected into patients using the described 213Bi generator. Factors such as radiation damage, radioprotection, iodide eluate chemistry, radiolabeling chemistry and radionuclide purity are addressed.

  12. Adjuvants: Classification, Modus Operandi, and Licensing

    PubMed Central

    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

  13. Cytokines: The Future of Intranasal Vaccine Adjuvants

    PubMed Central

    Thompson, Afton L.; Staats, Herman F.

    2011-01-01

    Due to its potential as an effective, needle-free route of immunization for use with subunit vaccines, nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental vaccine adjuvants, such as cholera toxin and E. coli heat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as nasal vaccine adjuvants. PMID:21826181

  14. Adjuvant analgesics in cancer pain: a review.

    PubMed

    Mitra, Raj; Jones, Stephanie

    2012-02-01

    Adjuvant analgesics (co-analgesics) are medications whose primary indication is the management of a medical condition with secondary effects of analgesia. Cancer pain is multifactorial and often involves inflammatory, nociceptive, and neuropathic pain subtypes. Adjuvant analgesics used in conjunction with opioids have been found to be beneficial in the management of many cancer pain syndromes; however, they are currently underutilized. Antidepressants, anticonvulsants, local anesthetics, topical agents, steroids, bisphosphonates, and calcitonin are all adjuvants which have been shown to be effective in the management of cancer pain syndromes. When utilizing analgesic adjuvants in the treatment of cancer pain, providers must take into account the particular side effect profile of the medication. Ideally, adjuvant analgesics will be initiated at lower dosages and escalated as tolerated until efficacy or adverse effects are encountered.

  15. Vaccine adjuvants: putting innate immunity to work.

    PubMed

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

    2010-10-29

    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.

  16. Optimization of Ultrasound Parameters of Myocardial Cavitation Microlesions for Therapeutic Application

    PubMed Central

    Miller, Douglas L.; Dou, Chunyan; Owens, Gabe E.; Kripfgans, Oliver D.

    2014-01-01

    Intermittent high intensity ultrasound scanning with contrast microbubbles can induce scattered cavitation microlesions in the myocardium, which may be of value for tissue reduction therapy. Anesthetized rats were treated in a heated water bath with 1.5 MHz focused ultrasound pulses, guided by an 8 MHz imaging transducer. The relative efficacy with 2 or 4 MPa pulses, 1:4 or 1:8 trigger intervals and 5 or 10 cycle pulses was explored in 6 groups. ECG premature complexes (PCs) induced by the triggered pulse bursts were counted, and Evans blue stained cardiomyocyte scores (SCSs) were obtained. The increase from 2 to 4 MPa produced significant increases in PCs and SCSs, and eliminated an anticipated decline in the rate of PC induction with time, which might hinder therapeutic efficacy. Increased intervals and pulse durations did not yield significant increases in the effects. The results suggest that cavitation microlesion production can be refined and potentially lead to a clinically robust therapeutic method. PMID:24613640

  17. Characterization and therapeutic application of canine adipose mesenchymal stem cells to treat elbow osteoarthritis.

    PubMed

    Kriston-Pál, Éva; Czibula, Ágnes; Gyuris, Zoltán; Balka, Gyula; Seregi, Antal; Sükösd, Farkas; Süth, Miklós; Kiss-Tóth, Endre; Haracska, Lajos; Uher, Ferenc; Monostori, Éva

    2017-01-01

    Visceral adipose tissue (AT) obtained from surgical waste during routine ovariectomies was used as a source for isolating canine mesenchymal stem cells (MSCs). As determined by cytofluorimetry, passage 2 cells expressed MSC markers CD44 and CD90 and were negative for lineage-specific markers CD34 and CD45. The cells differentiated toward osteogenic, adipogenic, and chondrogenic directions. With therapeutic aims, 30 dogs (39 joints) suffering from elbow dysplasia (ED) and osteoarthritis (OA) were intra-articularly transplanted with allogeneic MSCs suspended in 0.5% hyaluronic acid (HA). A highly significant improvement was achieved without any medication as demonstrated by the degree of lameness during the follow-up period of 1 y. Control arthroscopy of 1 transplanted dog indicated that the cartilage had regenerated. Histological analysis of the cartilage biopsy confirmed that the regenerated cartilage was of hyaline type. These results demonstrate that transplantation of allogeneic adipose tissue-derived mesenchymal stem cells (AT-MSCs) is a novel, noninvasive, and highly effective therapeutic tool in treating canine elbow dysplasia.

  18. A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins: part 2-model applications.

    PubMed

    Chen, X; Hickling, T P; Vicini, P

    2014-09-03

    A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins was built by recapitulating key underlying known biological processes for immunogenicity. The model is able to simulate immune responses based on protein-specific antigenic properties (e.g., number of T-epitopes and their major histocompatibility complex (MHC)-II binding affinities) and host-specific immunological/physiological characteristics (e.g., MHC-II allele genotype, drug clearance rate). Preliminary validation was performed using mouse studies with antigens such as ovalbumin (OVA) or OVA-derived peptide. Further, using adalimumab as an example therapeutic protein, the model is able to simulate immune responses against adalimumab in individual subjects and in a population, and also provides estimations of immunogenicity incidence and drug exposure reduction that can be validated experimentally. This is a first attempt at modeling immunogenicity of biologics, so the model simulations should be used to help understand the immunogenicity mechanisms and impacting factors, rather than making direct predictions. This prototype model needs to be subjected to extensive experimental validation and refinement before fulfilling its ultimate mission of predicting immunogenicity. Nevertheless, the current model could potentially set up the starting framework to integrate various in silico, in vitro, in vivo, and clinical immunogenicity assessment results to help meet the challenge of immunogenicity prediction.

  19. Therapeutic modulation of gut microbiota: current clinical applications and future perspectives.

    PubMed

    Ianiro, Gianluca; Bibbò, Stefano; Gasbarrini, Antonio; Cammarota, Giovanni

    2014-01-01

    Human beings and gut microbiota are in a symbiotic relationship, and the hypothesis of a "super organism" composed of the human organism and microbes has been recently proposed. The gut microbiota fulfills important metabolic and immunological tasks, and the impairment of its composition might alter homeostasis and lead to the development of microbiota-related diseases. The most common illnesses associated with alterations of the gut microbiota include inflammatory bowel disease, gastroenteric infections, irritable bowel syndrome and other gastrointestinal functional diseases, colorectal cancer, metabolic syndrome and obesity, liver diseases, allergic diseases, and neurological diseases such as autism. In theory, every disease associated with the impairment of intestinal microflora might benefit from the therapeutic modulation of the gut microbiota. A number of attempts to manipulate the microbiota have not produced identical results for every disease. Although antibiotics and probiotics have been available for a long time, the so-called fecal microbiota transplantation, which is a very old remedy, was only recently re-evaluated as a promising therapeutic approach for microbiota impairment. A comprehensive understanding of the gut microbiota composition, in states of both health and various diseases, is needed for the development of future approaches for microbiota modulation and for developing targeted therapies. In this review, we describe the role of the microbiota in several diseases and the related treatment options that are currently available.

  20. Mechanistic understanding and significance of small peptides interaction with MHC class II molecules for therapeutic applications.

    PubMed

    Afridi, Saifullah; Hoessli, Daniel C; Hameed, Muhammad Waqar

    2016-07-01

    Major histocompatibility complex (MHC) class II molecules are expressed by antigen-presenting cells and stimulate CD4(+) T cells, which initiate humoral immune responses. Over the past decade, interest has developed to therapeutically impact the peptides to be exposed to CD4(+) T cells. Structurally diverse small molecules have been discovered that act on the endogenous peptide exchanger HLA-DM by different mechanisms. Exogenously delivered peptides are highly susceptible to proteolytic cleavage in vivo; however, it is only when successfully incorporated into stable MHC II-peptide complexes that these peptides can induce an immune response. Many of the small molecules so far discovered have highlighted the molecular interactions mediating the formation of MHC II-peptide complexes. As potential drugs, these small molecules open new therapeutic approaches to modulate MHC II antigen presentation pathways and influence the quality and specificity of immune responses. This review briefly introduces how CD4(+) T cells recognize antigen when displayed by MHC class II molecules, as well as MHC class II-peptide-loading pathways, structural basis of peptide binding and stabilization of the peptide-MHC complexes. We discuss the concept of MHC-loading enhancers, how they could modulate immune responses and how these molecules have been identified. Finally, we suggest mechanisms whereby MHC-loading enhancers could act upon MHC class II molecules.

  1. Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics

    PubMed Central

    Lee, Gum Hwa; Kim, Sang Seong

    2016-01-01

    Chronic pain originating from neuronal damage remains an incurable symptom debilitating patients. Proposed molecular modalities in neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an important role in triggering surrounding immune cells. The multiple protein expressions complicate therapeutic development for neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for the incurable pain. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) facilitate the artificial manipulation of intracellular signaling through excitatory or inhibitory G protein subunits activated by biologically inert synthetic ligands. Expression of excitatory channelrhodopsins and inhibitory halorhodopsins on injured neurons or surrounding cells can attenuate neuropathic pain precisely controlled by light stimulation. To achieve the discrete treatment of injured neurons, we can exploit the transcriptome database obtained by RNA sequence analysis in specific neuropathies. This can recommend the suitable promoter information to target the injury sites circumventing intact neurons. Therefore, novel strategies benefiting from pharmacogenetics, optogenetics, and RNA sequencing might be promising for neuropathic pain treatment in future. PMID:26884648

  2. Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications.

    PubMed

    Shilo, Malka; Motiei, Menachem; Hana, Panet; Popovtzer, Rachela

    2014-02-21

    A critical problem in the treatment of neurodegenerative disorders and diseases, such as Alzheimer's and Parkinson's, is the incapability to overcome the restrictive mechanism of the blood-brain barrier (BBB) and to deliver important therapeutic agents to the brain. During the last decade, nanoparticles have gained attention as promising drug delivery agents that can transport across the BBB and increase the uptake of appropriate drugs in the brain. In this study we have developed insulin-targeted gold nanoparticles (INS-GNPs) and investigated quantitatively the amount of INS-GNPs that cross the BBB by the receptor-mediated endocytosis process. For this purpose, INS-GNPs and control GNPs were injected into the tail vein of male BALB/c mice. Major organs were then extracted and a blood sample was taken from the mice, and thereafter analyzed for gold content by flame atomic absorption spectroscopy. Results show that two hours post-intravenous injection, the amount of INS-GNPs found in mouse brains is over 5 times greater than that of the control, untargeted GNPs. Results of further experimentation on a rat model show that INS-GNPs can also serve as CT contrast agents to highlight specific brain regions in which they accumulate. Due to the fact that they can overcome the restrictive mechanism of the BBB, this approach could be a potentially valuable tool, helping to confront the great challenge of delivering important imaging and therapeutic agents to the brain for detection and treatment of neurodegenerative disorders and diseases.

  3. Delivery and therapeutic applications of gene editing technologies ZFNs, TALENs, and CRISPR/Cas9.

    PubMed

    LaFountaine, Justin S; Fathe, Kristin; Smyth, Hugh D C

    2015-10-15

    In recent years, several new genome editing technologies have been developed. Of these the zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas9 RNA-guided endonuclease system are the most widely described. Each of these technologies utilizes restriction enzymes to introduce a DNA double stranded break at a targeted location with the guide of homologous binding proteins or RNA. Such targeting is viewed as a significant advancement compared to current gene therapy methods that lack such specificity. Proof-of-concept studies have been performed to treat multiple disorders, including in vivo experiments in mammals and even early phase human trials. Careful consideration and investigation of delivery strategies will be required so that the therapeutic potential for gene editing is achieved. In this review, the mechanisms of each of these gene editing technologies and evidence of therapeutic potential will be briefly described and a comprehensive list of past studies will be provided. The pharmaceutical approaches of each of these technologies are discussed along with the current delivery obstacles. The topics and information reviewed herein provide an outline of the groundbreaking research that is being performed, but also highlights the potential for progress yet to be made using these gene editing technologies.

  4. Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications

    NASA Astrophysics Data System (ADS)

    Shilo, Malka; Motiei, Menachem; Hana, Panet; Popovtzer, Rachela

    2014-01-01

    A critical problem in the treatment of neurodegenerative disorders and diseases, such as Alzheimer's and Parkinson's, is the incapability to overcome the restrictive mechanism of the blood-brain barrier (BBB) and to deliver important therapeutic agents to the brain. During the last decade, nanoparticles have gained attention as promising drug delivery agents that can transport across the BBB and increase the uptake of appropriate drugs in the brain. In this study we have developed insulin-targeted gold nanoparticles (INS-GNPs) and investigated quantitatively the amount of INS-GNPs that cross the BBB by the receptor-mediated endocytosis process. For this purpose, INS-GNPs and control GNPs were injected into the tail vein of male BALB/c mice. Major organs were then extracted and a blood sample was taken from the mice, and thereafter analyzed for gold content by flame atomic absorption spectroscopy. Results show that two hours post-intravenous injection, the amount of INS-GNPs found in mouse brains is over 5 times greater than that of the control, untargeted GNPs. Results of further experimentation on a rat model show that INS-GNPs can also serve as CT contrast agents to highlight specific brain regions in which they accumulate. Due to the fact that they can overcome the restrictive mechanism of the BBB, this approach could be a potentially valuable tool, helping to confront the great challenge of delivering important imaging and therapeutic agents to the brain for detection and treatment of neurodegenerative disorders and diseases.

  5. Ocimum sanctum Linn. A reservoir plant for therapeutic applications: An overview

    PubMed Central

    Pattanayak, Priyabrata; Behera, Pritishova; Das, Debajyoti; Panda, Sangram K.

    2010-01-01

    The medicinal plants are widely used by the traditional medicinal practitioners for curing various diseases in their day to day practice. In traditional system of medicine, different parts (leaves, stem, flower, root, seeds and even whole plant) of Ocimum sanctum Linn. have been recommended for the treatment of bronchitis, malaria, diarrhea, dysentery, skin disease, arthritis, eye diseases, insect bites and so on. The O. sanctum L. has also been suggested to possess anti-fertility, anticancer, antidiabetic, antifungal, antimicrobial, cardioprotective, analgesic, antispasmodic and adaptogenic actions. Eugenol (1-hydroxy-2-methoxy-4-allylbenzene), the active constituents present in O. sanctum L. have been found to be largely responsible for the therapeutic potentials. The pharmacological studies reported in the present review confirm the therapeutic value of O. sanctum L. The results of the above studies support the use of this plant for human and animal disease therapy and reinforce the importance of the ethno-botanical approach as a potential source of bioactive substances. PMID:22228948

  6. Role of toll-like receptors and their adaptors in adjuvant immunotherapy for cancer.

    PubMed

    Seya, Tsukasa; Akazawa, Takashi; Uehori, Junji; Matsumoto, Misako; Azuma, Ichiro; Toyoshima, Kumao

    2003-01-01

    The potentiation of immune responses to tumor-associated antigen (Ag) is a pivotal issue in immunotherapy for cancer and thus requires the use of adjuvants, which are involved in efficient antibody (Ab) production and killer cell induction. The efficacy for tumor regression of a number of adjuvants that have been applied to immunotherapy in humans and tumor-bearing animal models has been tested without understanding of the function of adjuvants. Recent findings on the function of Toll-like receptors (TLRs) and their adaptors facilitated the elucidation of the molecular basis of adjuvant activity. TLR signaling was found to induce interferons (IFNs), chemokines and proinflammatory cytokines and mature dendritic cells (DCs) for enhanced efficiency in antigen presentation. The mediators then play a crucial role in the organization of acquired immunity and, together with matured DCs, activate cytotoxic T cells (CTL) and NK cells. These TLR outputs vary among adjuvants, which may depend on adjuvant-specific selection of appropriate sets of TLRs and their adaptors. Here we review how a variety of host immune responses are induced by an individual adjuvant to confer an adjuvant-specific anti-tumor immunity. We elaborate specifically on two adjuvants, BCG-cell wall skeleton and double-stranded RNA (dsRNA). The former activates TLR2/4 on DCs and induces tumor-specific CTL allowing general application to patients with surgically dissected cancer and improving prognosis, while the latter activates TLR3 on DCs to release type 1 IFN that induces tumor cell apoptosis and NK-mediated tumor cytotoxicity.

  7. Adjuvant aqueous ozone in the treatment of bisphosphonate induced necrosis of the jaws: report of two cases and long-term follow-up.

    PubMed

    Brozoski, M A; Lemos, C A; Da Graça Naclério-Homem, M; Deboni, M C Z

    2014-01-01

    Bisphosphonate induced necrosis of the jaws (BONJ) does not have a unique protocol of treatment and many therapeutic approaches have been arising in oral medicine with debatable results. A male and a female attended the University Oral Surgery Clinic presenting oral bone lesions induced by intravenous and oral bisphosphonates respectively as complications of dental extraction. Treatment included daily mouthwashes and weekly intra oral irrigations with 4 mg/L of aqueous-ozone, antibiotic therapy and sequential superficial debridment for sequestrectomies. Long-standing follow-ups showed complete mucosa covering of exposed bone area and resolution of purulent secretion. Antibacterial and antifungal properties of aqueous ozone may have played important roles in the treatment. The outcome measured intra oral examination and panoramic radiographs of the affected bone. The application of aqueous ozone daily mouthwashes and weekly professional irrigation were safe; free from adverse effects, easily of handling and worked as an important adjuvant therapeutic strategy for the treatment of BONJ.

  8. Toxicological Risks of Agrochemical Spray Adjuvants: Organosilicone Surfactants May Not Be Safe

    PubMed Central

    Mullin, Christopher A.; Fine, Julia D.; Reynolds, Ryan D.; Frazier, Maryann T.

    2016-01-01

    Agrochemical risk assessment that takes into account only pesticide active ingredients without the spray adjuvants commonly used in their application will miss important toxicity outcomes detrimental to non-target species, including humans. Lack of disclosure of adjuvant and formulation ingredients coupled with a lack of adequate analytical methods constrains the assessment of total chemical load on beneficial organisms and the environment. Adjuvants generally enhance the pesticidal efficacy and inadvertently the non-target effects of the active ingredient. Spray adjuvants are largely assumed to be biologically inert and are not registered by the USA EPA, leaving their regulation and monitoring to individual states. Organosilicone surfactants are the most potent adjuvants and super-penetrants available to growers. Based on the data for agrochemical applications to almonds from California Department of Pesticide Regulation, there has been increasing use of adjuvants, particularly organosilicone surfactants, during bloom when two-thirds of USA honey bee colonies are present. Increased tank mixing of these with ergosterol biosynthesis inhibitors and other fungicides and with insect growth regulator insecticides may be associated with recent USA honey bee declines. This database archives every application of a spray tank adjuvant with detail that is unprecedented globally. Organosilicone surfactants are good stand alone pesticides, toxic to bees, and are also present in drug and personal care products, particularly shampoos, and thus represent an important component of the chemical landscape to which pollinators and humans are exposed. This mini review is the first to possibly link spray adjuvant use with declining health of honey bee populations. PMID:27242985

  9. Poly(lactide)-containing multifunctional nanoparticles: Synthesis, domain-selective degradation and therapeutic applicability

    NASA Astrophysics Data System (ADS)

    Samarajeewa, Sandani

    Construction of nanoassemblies from degradable components is desired for packaging and controlled release of active therapeutics, and eventual biodegradability in vivo. In this study, shell crosslinked micelles composed of biodegradable poly(lactide) (PLA) core were prepared by the self-assembly of an amphiphilic diblock copolymer synthesized by a combination of ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Enzymatic degradation of the PLA cores of the nanoparticles was achieved upon the addition of proteinase K (PK). Kinetic analyses and comparison of the properties of the nanomaterials as a function of degradation extent will be discussed. Building upon our findings from selective-excavation of the PLA core, enzyme- and redox-responsive nanoparticles were constructed for the encapsulation and stimuli-responsive release of an antitumor drug. This potent chemotherapeutic, otherwise poorly soluble in water was dispersed into aqueous solution by the supramolecular co-assembly with an amphiphilic block copolymer, and the release from within the core of these nanoparticles were gated by crosslinking the hydrophilic shell region with a reduction-responsive crosslinker. Enzyme- and reduction-triggered release behavior of the antitumor drug was demonstrated along with their remarkably high in vitro efficacy. As cationic nanoparticles are a promising class of transfection agents for nucleic acid delivery, in the next part of the study, synthetic methodologies were developed for the conversion of the negatively-charged shell of the enzymatically-degradable shell crosslinked micelles to positively-charged cationic nanoparticles for the complexation of nucleic acids. These degradable cationic nanoparticles were found to efficiently deliver and transfect plasmid DNA in vitro. The hydrolysis of the PLA core and crosslinkers of the nanocarriers may provide a mechanism for their programmed disassembly within

  10. Recent advances in the biomedical applications of fumaric acid and its ester derivatives: The multifaceted alternative therapeutics.

    PubMed

    Das, Ratul Kumar; Brar, Satinder Kaur; Verma, Mausam

    2016-04-01

    Several lines of evidence have demonstrated the potential biomedical applications of fumaric acid (FA) and its ester derivatives against many human disease conditions. Fumaric acid esters (FAEs) have been licensed for the systemic treatment of the immune-mediated disease psoriasis. Biogen Idec Inc. announced about the safety and efficacy of the formulation FAE (BG-12) for treating RRMS (relapsing-remitting multiple sclerosis). Another FAE formulation DMF (dimethyl fumarate) was found to be capable of reduction in inflammatory cardiac conditions, such as autoimmune myocarditis and ischemia and reperfusion. DMF has also been reported to be effective as a potential neuroprotectant against the HIV-associated neurocognitive disorders (HAND). Many in vivo studies carried out on rat and mice models indicated inhibitory effects of fumaric acid on carcinogenesis of different origins. Moreover, FAEs has emerged as an important matrix ingredient in the fabrication of biodegradable scaffolds for tissue engineering applications. Drug delivery vehicles composed of FAEs have shown promising results in delivering some leading drug molecules. Apart from these specific applications and findings, many more studies on FAEs have revealed new therapeutic potentials with the scope of clinical applications. However, until now, this scattered vital information has not been written into a collective account and analyzed for minute details. The aim of this paper is to review the advancement made in the biomedical application of FA and FAEs and to focus on the clinical investigation and molecular interpretation of the beneficial effects of FA and FAEs.

  11. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures*

    PubMed Central

    Oh, Djin-Ye; Dowling, David J.; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T.; Sauld, John F.; Pettengill, Matthew; Kho, Alvin T.; Pollack, Henry J.; Steen, Hanno; Levy, Ofer

    2016-01-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  12. Lung cancer and β-glucans: review of potential therapeutic applications.

    PubMed

    Roudi, Raheleh; Mohammadi, Shahla Roudbar; Roudbary, Maryam; Mohsenzadegan, Monireh

    2017-03-16

    The potential of natural substances with immunotherapeutic properties has long been studied. β-glucans, a cell wall component of certain bacteria and fungi, potentiate the immune system against microbes and toxic substances. Moreover, β-glucans are known to exhibit direct anticancer effects and can suppress cancer proliferation through immunomodulatory pathways. Mortality of lung cancer has been alarmingly increasingly worldwide; therefore, treatment of lung cancer is an urgent necessity. Numerous researchers are now dedicated to using β-glucans as a therapy for lung cancer. In the present attempt, we have reviewed the studies addressing therapeutic effects of β-glucans in primary and metastatic lung cancer published in the time period of 1991-2016.

  13. Luminescent magnetic quantum dots for in vitro/in vivo imaging and applications in therapeutics.

    PubMed

    Acharya, Amitabha

    2013-06-01

    The quest for design of newer/advanced methods for medical diagnosis and targeted therapeutics are of utmost interest and challenging too, because of its importance in clinical diagnosis. Currently available diagnosis methodologies have their own disadvantages. These shortcomings can be overcome by using multimodal imaging systems where two or more imaging modalities may be coupled. Nanoparticles being widely studied for targeted drug delivery and as biological contrasting agents, might play a decisive role in such findings. This review is focused towards the ongoing research in the area of hybrid nanocomposites which can be used for both as MRI contrasting agent (magnetic nanoparticles) and molecular imaging studies (using fluorescent quantum dots) at in vitro and in vivo level. Though several reports are available in literature for such bimodal imaging systems, their clinical trials are very restricted, possibly because of the lack of communication between the in vitro and in vivo studies. This review is expected to bridge the gap between such studies.

  14. Prospects for the therapeutic application of lentivirus-based gene therapy to HIV-1 infection.

    PubMed

    Yamamoto, Takuya; Tsunetsugu-Yokota, Yasuko

    2008-02-01

    Highly active antiretroviral therapy is not sufficient to fully control HIV replication and problems of side effects and escape mutation have emerged. Current prophylactic and therapeutic vaccine strategies appear to be unable to confer full protection. However, given the rapid recent progress made in RNA interference and lentivirus technologies, it may soon be possible to develop effective gene therapies against HIV infection. We describe here the recent progress made in the lentivirus-based HIV-1-targeting RNAi system and the possibility that this system can be used to generate an anti-HIV-1 gene therapy. We speculate that this system would be most useful if it would be used in a coordinated manner with vaccines that can initiate and maintain potent anti-HIV immunity.

  15. Clinical application of infrared thermography in diagnosis and therapeutic assessment of vascular ischemic pain.

    PubMed

    Hsieh, J C; Chan, K H; Lui, P W; Lee, T Y

    1990-12-01

    Temperature is a very important and useful manifestation of various disease entities. The importance of body temperature as an indicator of disease has been known for centuries but in recent years attention has also been paid to how to conveniently and effectively make use of skin temperature as a diagnostic tool. Skin temperature can be measured with thermocouples, electronic thermistor-thermometers, electronic integrators, liquid crystal thermography, and infrared thermography. The temperature of extremities is largely dependent on the blood flow through peripheral vessels, and in the study of vascular diseases thermography has been, therefore, found to be useful. Blood flow can be assessed by many methods including washout techniques or laser Doppler flowmetry. Of these, infrared thermography has the advantages of being noninvasive, remote from the patient when in use, and capable of producing multiple recordings at short time intervals. Here we present a case of vascular ischemic pain which was diagnosed and therapeutically assessed by thermography.

  16. Eudragit EPO nanoparticles: application in improving therapeutic efficacy and reducing ulcerogenicity of meloxicam on oral administration.

    PubMed

    Khachane, Parag; Date, Abhijit A; Nagarsenker, Mangal S

    2011-08-01

    The objective of this investigation was to evaluate the potential of Eudragit EPO nanoparticles (EPO NP) in improving therapeutic efficacy of meloxicam (MLX). MLX loaded EPO NP were prepared by nanoprecipitation method and were characterized for particle size, encapsulation efficiency and for morphology. The in vitro dissolution profile of MLX loaded EPO NP and MLX suspension was evaluated. MLX loaded EPO NP had particle size of approximately 100 nm and the encapsulation efficiency of MLX was approximately 90%. The EPO NP significantly improved anti-inflammatory activity of MLX (P < 0.01) as compared to that of MLX suspension. The enhanced anti-inflammatory effect was maintained for a longer duration (6 h) in case of MLX loaded EPO NP Oral administration of MLX loaded EPO NP also resulted in lesser ulcerogenicity as compared to that of MLX suspension indicating that nanoparticles can also decrease the adverse effects associated with MLX treatment.

  17. [Experimental analysis of therapeutic properties of Rhodiola rosea L. and its possible application in medicine].

    PubMed

    Kucinskaite, Agne; Briedis, Vitalis; Savickas, Arūnas

    2004-01-01

    The paper presents a review of the scientific publications on Rhodiola rosea L. known for its adaptogenic characteristics. Biologically active substances salidroside, rosin, rosavin, rosarin and tyrosol, which are mainly found in plant rhizomes, demonstrate therapeutic effect. These active components effect the central nervous system by increasing the ability to concentrate, the mental and physical power; they are efficient in the asthenic states and improve general resistance of the cells and the organism against the harmful outer influence. They also prevent the heart system from stress and arrhythmias, and posses some antioxidant activity. Some data confirm that the Rhodiola rosea L. preparations stop the growth of the malignant tumors and metastases in the liver. Some preclinical and clinical data of the golden root preparations are discussed in the survey. The interaction of the herb with other medicines, its usage and effect, recommended doses, and its side effects are also reviewed in the paper.

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

    PubMed Central

    Zhang, Qi; Fujino, Masayuki; Xu, Jinhua; Li, Xiao-kang

    2015-01-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells. They have been identified as a cell population that may affect the activation of CD4+ and CD8+ T-cells to regulate the immune response negatively, which makes them attractive targets for the treatment of transplantation and autoimmune diseases. Several studies have suggested the potential suppressive effect of MDSCs on allo- and autoimmune responses. Conversely, MDSCs have also been found at various stages of differentiation, accumulating during pathological situations, not only during tumor development but also in a variety of inflammatory immune responses, bone marrow transplantation, and some autoimmune diseases. These findings appear to be contradictory. In this review, we summarize the roles of MDSCs in different transplantation and autoimmune diseases models as well as the potential to target these cells for therapeutic benefit. PMID:26078493

  19. Splicing factor gene mutations in the myelodysplastic syndromes: impact on disease phenotype and therapeutic applications.

    PubMed

    Pellagatti, Andrea; Boultwood, Jacqueline

    2017-01-01

    Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies.

  20. Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer's disease.

    PubMed

    Iturria-Medina, Yasser; Carbonell, Félix M; Sotero, Roberto C; Chouinard-Decorte, Francois; Evans, Alan C

    2017-02-28

    Generative models focused on multifactorial causal mechanisms in brain disorders are scarce and generally based on limited data. Despite the biological importance of the multiple interacting processes, their effects remain poorly characterized from an integrative analytic perspective. Here, we propose a spatiotemporal multifactorial causal model (MCM) of brain (dis)organization and therapeutic intervention that accounts for local causal interactions, effects propagation via physical brain networks, cognitive alterations, and identification of optimum therapeutic interventions. In this article, we focus on describing the model and applying it at the population-based level for studying late onset Alzheimer's disease (LOAD). By interrelating six different neuroimaging modalities and cognitive measurements, this model accurately predicts spatiotemporal alterations in brain amyloid-β (Aβ) burden, glucose metabolism, vascular flow, resting state functional activity, structural properties, and cognitive integrity. The results suggest that a vascular dysregulation may be the most-likely initial pathologic event leading to LOAD. Nevertheless, they also suggest that LOAD it is not caused by a unique dominant biological factor (e.g. vascular or Aβ) but by the complex interplay among multiple relevant direct interactions. Furthermore, using theoretical control analysis of the identified population-based multifactorial causal network, we show the crucial advantage of using combinatorial over single-target treatments, explain why one-target Aβ based therapies might fail to improve clinical outcomes, and propose an efficiency ranking of possible LOAD interventions. Although still requiring further validation at the individual level, this work presents the first analytic framework for dynamic multifactorial brain (dis)organization that may explain both the pathologic evolution of progressive neurological disorders and operationalize the influence of multiple interventional

  1. Kinetic modelling of GlmU reactions - prioritization of reaction for therapeutic application.

    PubMed

    Singh, Vivek K; Das, Kaveri; Seshadri, Kothandaraman

    2012-01-01

    Mycobacterium tuberculosis(Mtu), a successful pathogen, has developed resistance against the existing anti-tubercular drugs necessitating discovery of drugs with novel action. Enzymes involved in peptidoglycan biosynthesis are attractive targets for antibacterial drug discovery. The bifunctional enzyme mycobacterial GlmU (Glucosamine 1-phosphate N-acetyltransferase/ N-acetylglucosamine-1-phosphate uridyltransferase) has been a target enzyme for drug discovery. Its C- and N- terminal domains catalyze acetyltransferase (rxn-1) and uridyltransferase (rxn-2) activities respectively and the final product is involved in peptidoglycan synthesis. However, the bifunctional nature of GlmU poses difficulty in deciding which function to be intervened for therapeutic advantage. Genetic analysis showed this as an essential gene but it is still unclear whether any one or both of the activities are critical for cell survival. Often enzymatic activity with suitable high-throughput assay is chosen for random screening, which may not be the appropriate biological function inhibited for maximal effect. Prediction of rate-limiting function by dynamic network analysis of reactions could be an option to identify the appropriate function. With a view to provide insights into biochemical assays with appropriate activity for inhibitor screening, kinetic modelling studies on GlmU were undertaken. Kinetic model of Mtu GlmU-catalyzed reactions was built based on the available kinetic data on Mtu and deduction from Escherichia coli data. Several model variants were constructed including coupled/decoupled, varying metabolite concentrations and presence/absence of product inhibitions. This study demonstrates that in coupled model at low metabolite concentrations, inhibition of either of the GlmU reactions cause significant decrement in the overall GlmU rate. However at higher metabolite concentrations, rxn-2 showed higher decrement. Moreover, with available intracellular concentration of the

  2. Adjuvants for foot-and-mouth disease virus vaccines: recent progress.

    PubMed

    Cao, Yimei

    2014-11-01

    Foot-and-mouth disease (FMD) is a highly contagious and rapidly spreading disease of cloven-hoofed animals. In most countries, animals are immunized with inactivated whole virus vaccines to control the spread of foot-and-mouth disease virus (FMDV); however, there are safety and efficacy (especially, cell-mediated immunity) concerns. Many efforts are currently devoted to the development of effective vaccines by combining the application of protective antigens together with the search for specific and targeting adjuvants that maximizes the immunogenicity with a desired immune response. In this review, we outline previous studies performed with both traditional adjuvants as well as the most promising new generation adjuvants such as ligands for Toll-like receptors (TLRs) or different cytokines, focusing mostly on their efficacy when used with FMD vaccine, and somewhat on mechanisms by which adjuvants mediate their effects.

  3. Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

    PubMed Central

    den Brok, Martijn H.; Büll, Christian; Wassink, Melissa; de Graaf, Annemarie M.; Wagenaars, Jori A.; Minderman, Marthe; Thakur, Mayank; Amigorena, Sebastian; Rijke, Eric O.; Schrier, Carla C.; Adema, Gosse J.

    2016-01-01

    Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity. PMID:27819292

  4. From the discovery of monoclonal antibodies to their therapeutic application: an historical reappraisal.

    PubMed

    Ribatti, Domenico

    2014-09-01

    Vertebrate make billions of different antibodies, each with a binding site that recognizes a specific region of a macromolecule. The hybridoma technique allows monoclonal antibodies, highly specific antibodies produced in the laboratory by a variety of methods. In the last 35 years since the first process for creating monoclonal antibodies was introduced, their application have improved the growing biotechnology industry, but the most important application concerns the therapy of human malignancies.

  5. Safety of vaccine adjuvants: focus on autoimmunity.

    PubMed

    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.

  6. Anti-arthritic Effects of Total Flavonoids from Juniperus sabina on Complete Freund's Adjuvant Induced Arthritis in Rats

    PubMed Central

    Zhao, Jun; Liu, Tao; Xu, Fang; You, Shuping; Xu, Fang; Li, Chenyang; Gu, Zhengyi

    2016-01-01

    Context: Twigs and leaves of Juniperus sabina L. have been traditionally used as the medicinal herb in China for the treatment of many ailments including rheumatoid arthritis (RA). Aims: To confirm the therapeutic effect of total flavonoids from J. sabina (JSTF) on RA-induced by Complete Freund's Adjuvant (CFA) in rats. Settings and Design: Wistar rats (200 ± 20 g) were immunized by intradermal injection of 0.1 mL of CFA into the right hind metatarsal footpad. JSTF was administered orally at the dose of 125,250 and 500 mg/kg on 14 days after the induction of adjuvant arthritis. Tripterygium glycoside (20 mg/kg) was used as a positive control. Paw swelling, arthritic score, body weight loss, serum cytokines, inflammatory mediators, and histological change were measured. Results: We found that JSTF could ameliorate paw swelling of CFA rats, and significantly inhibit arthritic score (P < 0.05). The overproduction of tumor necrosis factor alpha and interleukin 1beta were remarkably suppressed in the serum of JSTF (125,500 mg/kg) treated rats (P < 0.05). Histopathological studies also showed a marked decrease of synovial inflammatory infiltration and synovial lining hyperplasia in the joints of JSTF-treated animals. Six flavonoids were isolated and from JSTF by various chromatographic methods and identified as follows: Catechin, quercitrin, isoquercitrin, isoscutellarein 7-O-β-D-xylopyranoside, isoscutellarein 7-O-β-D-xylopyranose-(1 → 3)-α-L-rhamnoside, and rutin. Conclusions: These results suggest the potential therapeutically effect of JSTF as an anti-arthritis agent toward CFA-induced arthritis in rats, and verified therapeutic applications of J. sabina on RA in folk medicine. SUMMARY Twigs and leaves of Juniperus sabina L. have been traditionally used as the medicinal herb in China for the treatment of rheumatoid arthritisJSTF could ameliorate paw swelling of CFA rats, and significantly inhibit arthritic scoreHistopathological studies showed a marked decrease

  7. Chemical Synthesis, Versatile Structures and Functions of Tailorable Adjuvants for Optimizing Oral Vaccination.

    PubMed

    Zhang, Lei; Hu, Chaohua; Yang, Wendi; Liu, Xiaolin; Wu, Yunkun

    2016-12-28

    Oral vaccines have become a recent focus because of their potential significance in disease prevention and therapy. In the development of oral vaccine-based therapeutics, synthetic materials with tailorable structures and versatile functions can act as antigen conveyers with adjuvant effects, reduce the time cost for vaccine optimization, and provide high security and enhanced immunity. This review presents an overview of the current status of tailoring synthetic adjuvants for oral vaccination, modification strategies for producing effectors with specific structures and functions, enhancement of immune-associated efficiencies, including the barrier-crossing capability to protect antigens in the gastrointestinal tract, coordination of the antigens penetrating mucosa and cell barriers, targeting of concentrated antigens to immune-associated cells, and direct stimulation of immune cells. Finally, we focus on prospective synthetic adjuvants that facilitate the use of oral vaccines via two approaches, namely, in vivo antigen expression and cancer immunotherapy.

  8. Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer.

    PubMed

    Morad, Samy A F; Davis, Traci S; MacDougall, Matthew R; Tan, Su-Fern; Feith, David J; Desai, Dhimant H; Amin, Shantu G; Kester, Mark; Loughran, Thomas P; Cabot, Myles C

    2017-02-09

    The anticancer properties of ceramide, a sphingolipid with potent tumor-suppressor properties, can be dampened via glycosylation, notably in multidrug resistance wherein ceramide glycosylation is characteristically elevated. Earlier works using the ceramide analog, C6-ceramide, demonstrated that the antiestrogen tamoxifen, a first generation P-glycoprotein (P-gp) inhibitor, blocked C6-ceramide glycosylation and magnified apoptotic responses. The present investigation was undertaken with the goal of discovering non-anti-estrogenic alternatives to tamoxifen that could be employed as adjuvants for improving the efficacy of ceramide-centric therapeutics in treatment of cancer. Herein we demonstrate that the tamoxifen metabolites, desmethyltamoxifen and didesmethyltamoxifen, and specific, high-affinity P-gp inhibitors, tariquidar and zosuquidar, synergistically enhanced C6-ceramide cytotoxicity in multidrug resistant HL-60/VCR acute myelogenous leukemia (AML) cells, whereas the selective estrogen receptor antagonist, fulvestrant, was ineffective. Active C6-ceramide-adjuvant combinations elicited mitochondrial ROS production and cytochrome c release, and induced apoptosis. Cytotoxicity was mitigated by introduction of antioxidant. Effective adjuvants markedly inhibited C6-ceramide glycosylation as well as conversion to sphingomyelin. Active regimens were also effective in KG-1a cells, a leukemia stem cell-like line, and in LoVo human colorectal cancer cells, a solid tumor model. In summary, our work details discovery of the link between P-gp inhibitors and the regulation and potentiation of ceramide metabolism in a pro-apoptotic direction in cancer cells. Given the active properties of these adjuvants in synergizing with C6-ceramide, independent of drug resistance status, stemness, or cancer type, our results suggest that the C6-ceramide-containing regimens could provide alternative, promising therapeutic direction, in addition to finding novel, off-label applications

  9. Metabolic glycoengineering bacteria for therapeutic, recombinant protein, and metabolite production applications.

    PubMed

    Saeui, Christopher T; Urias, Esteban; Liu, Lingshu; Mathew, Mohit P; Yarema, Kevin J

    2015-10-01

    Metabolic glycoengineering is a specialization of metabolic engineering that focuses on using small molecule metabolites to manipulate biosynthetic pathways responsible for oligosaccharide and glycoconjugate production. As outlined in this article, this technique has blossomed in mammalian systems over the past three decades but has made only modest progress in prokaryotes. Nevertheless, a sufficient foundation now exists to support several important applications of metabolic glycoengineering in bacteria based on methods to preferentially direct metabolic intermediates into pathways involved in lipopolysaccharide, peptidoglycan, teichoic acid, or capsule polysaccharide production. An overview of current applications and future prospects for this technology are provided in this report.

  10. The therapeutic applications of celery oil seed extract on the plasticizer di(2-ethylhexyl) phthalate toxicity.

    PubMed

    El-Shinnawy, Nashwa A

    2015-04-01

    The present study investigated the impact of two doses, 500 mg/kg and 1000 mg/kg, of di(2-ethylhexyl) phthalate (DEHP) and studied the possible therapeutic dose of celery oil seed extract for 6 weeks on some atheroscelerogenic, obesogenic, antioxidant and liver functions in rats. Both doses of DEHP caused over-expression of peroxisome proliferator-activated receptor alpha (PPARα) messenger RNA with significant increase in liver weights, relative liver weights, serum cholesterol (Chol), triglycerides, low-density lipoprotein Chol, liver total lipids, along with an increase in the activities of serum aspartate aminotransferase, alanine aminotransferase, serum endothelin 1 and liver tissue thiobarbituric acid reactive substances (TBARS). Additionally, DEHP administration to rats resulted in significant decrease in final body weights, serum total protein, albumin, liver total protein and serum total nitric oxide. Our study confirmed the role of oral combination of Apium graveolens (celery) oil seed extract at small cumulative doses (50 µl/kg for 6 weeks) with DEHP in ameliorating the toxicological effects of DEHP, which was revealed in reducing the expression of PPARα, lipid profile, with restoring liver functions, vascular oxidative stress and inhibition of TBARS activity.

  11. Inteins in pathogenic fungi: a phylogenetic tool and perspectives for therapeutic applications.

    PubMed

    Theodoro, Raquel Cordeiro; Bagagli, Eduardo

    2009-05-01

    Inteins or 'internal proteins' are coding sequences that are transcribed and translated with flanking sequences (exteins). After translation, the inteins are excised by an autocatalytic process and the host protein assumes its normal conformation and develops its expected function. These parasitic genetic elements have been found in important, conserved proteins in all three domains of life. Most of the eukaryotic inteins are present in the fungi kingdom and the PRP8 intein is one of the most widespread inteins, occurring in important pathogens such as Cryptococcus neoformans (varieties grubii and neoformans), Cryptococcus gattii, Histoplasma capsulatum and Paracoccidioides brasiliensis. The knowledge of conserved and non-conserved domains in inteins have opened up new opportunities for the study of population variability in pathogenic fungi, including their phylogenetic relationships and recognition or diagnoses of species. Furthermore, inteins in pathogenic fungi should also be considered a promising therapeutic drug target, since once the autocatalytic splicing is inhibited, the host protein, which is typically vital, will not be able to perform its normal function and the fungal cell will not survive or reproduce.

  12. Laser microporation of the skin: prospects for painless application of protective and therapeutic vaccines

    PubMed Central

    Scheiblhofer, Sandra; Thalhamer, Josef; Weiss, Richard

    2013-01-01

    Introduction: In contrast to muscle and subcutaneous tissue, the skin is easily accessible and provides unique immunological properties. Increasing knowledge about the complex interplay of skin-associated cell types in the development of cutaneous immune responses has fueled efforts to target the skin for vaccination as well as for immunotherapy. Areas covered: This review provides an overview on skin layers and their resident immunocompetent cell types. Advantages and shortcomings of standard methods and innovative technologies to circumvent the outermost skin barrier are addressed. Studies employing fractional skin ablation by infrared lasers for cutaneous delivery of drugs, as well as high molecular weight molecules such as protein antigens or antibodies, are reviewed, and laserporation is introduced as a versatile transcutaneous vaccination platform. Specific targeting of the epidermis or the dermis by different laser settings, the resulting kinetics of uptake and transport and the immune response types elicited are discussed, and the potential of this transcutaneous delivery platform for allergen-specific immunotherapy is demonstrated. Expert opinion: Needle-free and painless vaccination approaches have the potential to replace standard methods due to their improved safety and optimal patient compliance. The use of fractional laser devices for stepwise ablation of skin layers might be advantageous for both vaccination against microbial pathogens, as well as immunotherapeutic approaches, such as allergen-specific immunotherapy. Thorough investigation of the underlying immunological mechanisms will help to provide the knowledge for a rational design of transcutaneous protective/therapeutic vaccines. PMID:23425032

  13. Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases.

    PubMed

    Xitong, Dang; Xiaorong, Zeng

    2016-01-10

    Exosomes are 30-120 nm membrane bound vesicles secreted naturally by almost all cells and exist in all body fluids. Accumulating evidence has shown that exosomes contain proteins, lipids, DNA, mRNA, miRNA, and lncRNA that can be transferred from producer cells to recipient cells, facilitating cell-cell communication. As the natural carrier of these signal molecules, exosomes possess many other properties such as stability, biocompatibility, biological barrier permeability, low toxicity, and low immunogenicity, which make them an attractive vehicle for therapeutic delivery. How exosomes target recipient cells in vivo remains largely unknown, however, exosomes are selectively enriched in some transmembrane proteins that can be genetically engineered to display ligands/homing peptides on their surface, which confers exosome targeting capability to cells bearing cognate receptors. With the discovery of many peptides homing to diseased tissues or organs through phage display and in vivo biopanning technologies, there is ample opportunity to explore the potential use of exosome for targeted gene therapy. Here, we briefly review exosome biogenesis, mechanisms of exosome-mediated cell–cell communication, and exosome isolation and purification methods, and specifically focus on the emerging exosome targeting technologies.

  14. Biotechnological and biomedical applications of mesenchymal stem cells as a therapeutic system.

    PubMed

    Rahimzadeh, Amirbahman; Mirakabad, Fatemeh Sadat Tabatabaei; Movassaghpour, Aliakbar; Shamsasenjan, Karim; Kariminekoo, Saber; Talebi, Mehdi; Shekari, Abolfazl; Zeighamian, Vahideh; Ghalhar, Masoud Gandomkar; Akbarzadeh, Abolfazl

    2016-01-01

    Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells which reside in bone marrow (BM), support homing of hematopoietic stem cells (HSCs) and self-renewal in the BM. These cells have the potential to differentiate into tissues of mesenchymal origin, such as fibroblasts, adipocytes, cardiomyocytes, and stromal cells. MSCs can express surface molecules like CD13, CD29, CD44, CD73, CD90, CD166, CXCL12 and toll-like receptors (TLRs). Different factors, such as TGF-β, IL-10, IDO, PGE-2, sHLA-G5, HO, and Galectin-3, secreted by MSCs, induce interaction in cell to cell immunomodulatory effects on innate and adaptive cells of the immune system. Furthermore, these cells can stimulate and increase the TH2 and regulatory T-cells through inhibitory effects on the immune system. MSCs originate from the BM and other tissues including the brain, adipose tissue, peripheral blood, cornea, thymus, spleen, fallopian tube, placenta, Wharton's jelly and umbilical cord blood. Many studies have focused on two significant features of MSC therapy: (I) MSCs can modulate T-cell-mediated immunological responses, and (II) systemically administered MSCs home in to sites of ischemia or injury. In this review, we describe the known mechanisms of immunomodulation and homing of MSCs. As a result, this review emphasizes the functional role of MSCs in modulating immune responses, their capability in homing to injured tissue, and their clinical therapeutic potential.

  15. An analysis of the demarcation problem in science and its application to therapeutic touch theory.

    PubMed

    Newbold, David; Roberts, Julia

    2007-12-01

    This paper analyses the demarcation problem from the perspective of four philosophers: Popper, Kuhn, Lakatos and Feyerabend. To Popper, pseudoscience uses induction to generate theories, and only performs experiments to seek to verify them. To Popper, falsifiability is what determines the scientific status of a theory. Taking a historical approach, Kuhn observed that scientists did not follow Popper's rule, and might ignore falsifying data, unless overwhelming. To Kuhn, puzzle-solving within a paradigm is science. Lakatos attempted to resolve this debate, by suggesting history shows that science occurs in research programmes, competing according to how progressive they are. The leading idea of a programme could evolve, driven by its heuristic to make predictions that can be supported by evidence. Feyerabend claimed that Lakatos was selective in his examples, and the whole history of science shows there is no universal rule of scientific method, and imposing one on the scientific community impedes progress. These positions are used in turn, to examine the scientific status of therapeutic touch theory. The paper concludes that imposing a single rule of method can impede progress, in the face of multiple epistemologies, and the choice of scientific approach should be a pragmatic one based on the aims of the programme.

  16. [Gap junctional intercellular communication: a new mechanism in pathophysiology of migraine with aura. Therapeutic applications].

    PubMed

    Sarrouilhe, D; Dejean, C

    2012-12-01

    Migraine is a common, recurrent and disabling primary headache disorder, which affects up to 20% of the population. About a third of patients with migraine have attacks with aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms. Cortical spreading depression, a wave of electrical activity that moves across the cerebral cortex through neuronal-glial cell gap junctions, would be involved in the triggering of migraine aura. Moreover, cortical spreading depression activates perivascular trigeminal afferents in the neocortex, that through central and peripheral reflex, cause inflammatory reaction in the meninges to generate the headache. Tonabersat, a novel benzopyran compound, was selected for clinical trial on the basis of its inhibitory activity on cortical spreading depression and neurogenic inflammation in animal models of migraine. Moreover, tonabersat inhibited trigeminal ganglion neuronal-glial cell gap junctions, suggesting that this compound could prevent peripheral sensitization within the ganglion. In clinical trial, tonabersat showed a preventive effect on attacks of migraine with aura but had no efficacy on non-aura attacks and in the acute treatment of migraine. In conclusion, neuronal-glial cell gap junctional intercellular communication seems to be involved in the pathophysiology of migraine with aura and is emerging as a new promising therapeutic target for prophylactic treatment of patients with chronic attacks.

  17. The therapeutic application of CRISPR/Cas9 technologies for HIV

    PubMed Central

    Saayman, Sheena; Ali, Stuart A.; Morris, Kevin V.; Weinberg, Marc S.

    2015-01-01

    Introduction The use of antiretroviral therapy (ART) has led to a significant decrease in morbidity and mortality in HIV-infected individuals. Nevertheless gene-based therapies represent a promising therapeutic paradigm for HIV-1, as they have the potential for sustained viral inhibition and reduced treatment interventions. One new method amendable to a gene-based therapy is the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing system. Areas covered CRISPR/Cas9 can be engineered to successfully modulate an array of disease-causing genetic elements. We discuss the diverse roles that CRISPR/Cas9 may play in targeting HIV and eradicating infection. The Cas9 nuclease coupled with one or more small guide RNAs (sgRNAs) can target the provirus to mediate excision of the integrated viral genome. Moreover, a modified nuclease deficient Cas9 fused to transcription activating domains may induce targeted activation of proviral gene expression allowing for the purging of the latent reservoirs. These technologies can also be exploited to target host dependency factors such as the co-receptor CCR5, thus preventing cellular entry of the virus. Expert opinion The diversity of the CRISPR/Cas9 technologies hold great promise for targeting different stages of the viral life cycle, and have the capacity for mediating an effective and sustained genetic therapy against HIV. PMID:25865334

  18. Role of calcium, glutamate and NMDA in major depression and therapeutic application.

    PubMed

    Deutschenbaur, Lorenz; Beck, Johannes; Kiyhankhadiv, Anna; Mühlhauser, Markus; Borgwardt, Stefan; Walter, Marc; Hasler, Gregor; Sollberger, Daniel; Lang, Undine E

    2016-01-04

    Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.

  19. Application of Cerenkov radiation generated in plastic optical fibers for therapeutic photon beam dosimetry.

    PubMed

    Jang, Kyoung Won; Yagi, Takahiro; Pyeon, Cheol Ho; Yoo, Wook Jae; Shin, Sang Hun; Jeong, Chiyoung; Min, Byung Jun; Shin, Dongho; Misawa, Tsuyoshi; Lee, Bongsoo

    2013-02-01

    A Cerenkov fiber-optic dosimeter (CFOD) is fabricated using plastic optical fibers to measure Cerenkov radiation induced by a therapeutic photon beam. We measured the Cerenkov radiation generated in optical fibers in various irradiation conditions to evaluate the usability of Cerenkov radiation for a photon beam therapy dosimetry. As a results, the spectral peak of Cerenkov radiation was measured at a wavelength of 515 nm, and the intensity of Cerenkov radiation increased linearly with increasing irradiated length of the optical fiber. Also, the intensity peak of Cerenkov radiation was measured in the irradiation angle range of 30 to 40 deg. In the results of Monte Carlo N-particle transport code simulations, the relationship between fluxes of electrons over Cerenkov threshold energy and energy deposition of a 6 MV photon beam had a nearly linear trend. Finally, percentage depth doses for the 6 MV photon beam could be obtained using the CFOD and the results were compared with those of an ionization chamber. Here, the mean dose difference was about 0.6%. It is anticipated that the novel and simple CFOD can be effectively used for measuring depth doses in radiotherapy dosimetry.

  20. Mimics of Host Defense Proteins; Strategies for Translation to Therapeutic Applications.

    PubMed

    Scott, Richard W; Tew, Gregory N

    2017-01-01

    New infection treatments are urgently needed to combat the rising threat of multi-drug resistant bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins (HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at multiple targets and their repertoire includes disruptive membrane and intracellular activities against numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these novel activities are associated with a low potential for emergence of resistance and little crossresistance with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candidates for new antibiotics; however, their development has been plagued by the many therapeutic limitations associated with natural peptidic agents. This review focuses on HDP mimetic approaches aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early efforts with β-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but demonstrated that antimicrobial activity was modulated by more, complex structural properties. Several approaches have used lipidation to increase the hydrophobicity and membrane activity. One lead compound, LTX-109, has entered clinical study as a topical agent to treat impetigo and nasal decolonization. In a more significant departure from the amino acid like peptidomimetics, considerable effort has been directed at developing amphiphilic compounds that recapitulate the structural and biological properties of HDPs on small abiotic scaffolds. The lead compound from this approach, brilacidin, has completed two phase 2 studies as an intravenous agent for skin infections.

  1. Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole.

    PubMed

    Carlson, Robert W; Henderson, I Craig

    2003-01-01

    downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.

  2. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review.

    PubMed

    Ma, Ke; Zhang, Hongxiu; Baloch, Zulqarnain

    2016-05-14

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

  3. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review

    PubMed Central

    Ma, Ke; Zhang, Hongxiu; Baloch, Zulqarnain

    2016-01-01

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies. PMID:27187381

  4. [What to think of "adjuvant" or "neoadjuvant" thermotherapy in the treatment of uveal melanomas?].

    PubMed

    Grange, J D

    2001-02-01

    Before 810Nm laser thermotherapy has been usd for uveal melanoma, several authors especially in Essen (Germany) were asking themselves about the possibilities of xenon arc or argon laser effects on uveal melanomas. High rates of recurrences due to the non penetration of therapeutic light till the sclera had led to the conception of using adjuvant thermotherapy associated with radiotherapy, through microwaves, ultrasounds or ferromagnetic seeds. In Leyden (Netherlands) was proposed the use of 810Nm laser diode initially as an adjuvant to radiotherapy and later on as primary isolated treatment ("neo adjuvant" TTT), especially for small tumours located in the posterior pole (juxta-papillary tumours). TTT used alone should not be proposed for tumours of inital height of more than 3,5 to 4mm. "Neo adjuvant" thermotherapy finds some other indications like decompensated naevi responsible for macular detachment. Bigger peripheral tumours stabilized by protonbeam therapy but associated with persistent detachment after the 12(th) month could be treated with "adjuvant" TTT. Finally the importance of the quality of the tumour edges treatment should be emphasized.

  5. Quillaja Saponin Variants with Central Glycosidic Linkage Modifications Exhibit Distinct Conformations and Adjuvant Activities

    PubMed Central

    Walkowicz, William E.; Fernández-Tejada, Alberto; George, Constantine; Corzana, Francisco; Jiménez-Barbero, Jesús; Gin, David Y.

    2016-01-01

    Immunological adjuvants such as the saponin natural product QS-21 help stimulate the immune response to co-administered antigens and have become increasingly important in the development of prophylactic and therapeutic vaccines. However, clinical use of QS21 is encumbered by chemical instability, dose-limiting toxicity, and low-yielding purification from the natural source. Previous studies of structure–activity relationships in the four structural domains of QS-21 have led to simplified, chemically stable variants that retain potent adjuvant activity and low toxicity in mouse vaccination models. However, modification of the central glycosyl ester linkage has not yet been explored. Herein, we describe the design, synthesis, immunologic evaluation, and molecular dynamics analysis of a series of novel QS-21 variants with different linker lengths, stereochemistry, and flexibility to investigate the role of this linkage in saponin adjuvant activity and conformation. Despite relatively conservative structural modifications, these variants exhibit striking differences in in vivo adjuvant activity that correlate with specific conformational preferences. These results highlight the junction of the triterpene and linear oligosaccharide domains as playing a critical role in the immunoadjuvant activity of the Quillaja saponins and also suggest a mechanism of action involving interaction with a discrete macromolecular target, in contrast to the non-specific mechanisms of emulsion-based adjuvants. PMID:27014435

  6. Therapeutic applications of radioactive 131iodine: Procedures and incidents with capsules

    PubMed Central

    Al Aamri, Marwa; Ravichandran, Ramamoorthy; Binukumar, John Pichy; Al Balushi, Naima

    2016-01-01

    Background: Treatments for thyrotoxicosis and carcinoma thyroid are carried out by oral administration of radioactive iodine (131I) in the form of liquid or capsules. The liquid form of 131I has higher risk factors such as vapourization, spillage and need for management of higher activity wastes. Use of 131I in capsule form simplify procedures of handling compared to liquid form of 131I. The guidelines of safe handling and quality assurance aspects for therapeutic use 131I are well outlined by International Atomic Energy Agency (IAEA) reports. Aim: A few unusual incidents with I-131 capsules encountered in the past need to be highlighted from health physics point of view. Materials and Methods: In Royal Hospital, Oman, I-131 is imported in capsules, and the total activity handled/year steadily increased over 10 years. Discrete activities range from 185 MBq (5 mCi) up to 7.4 GBq (200 mCi). In four incidents deviations in standard operational procedures were recorded. Results: Nature of incidents is described as follows: (1) After assay of activity, the capsule was directly put in the lead container with missing of inner cap. (2) Patient poured water in the Perspex tube, when the capsule was handed over to her, making an emergency situation. (3) In 3 high activity capsules (2 nos 2.96 GBq, 1 no. 4.26 GBq), observed sticky behavior in capsule holder on the 2nd day post receipt, which were in order on the 1st day. (4) A capsule could not be swallowed by a patient, which was taken back from the mouth. Monitoring of patient later did not show residual ingested activity. Conclusions: The report documents some of the unusual incidents for information to other centers engaged in such radioactive administrations. PMID:27385885

  7. Maghemite/poly( d,l-lactide- co-glycolyde) composite nanoplatform for therapeutic applications

    NASA Astrophysics Data System (ADS)

    Pérez-Artacho, Beatriz; Gallardo, Visitación; Ruiz, M. Adolfina; Arias, José L.

    2012-03-01

    A reproducible methodology is described for the synthesis, by following the double emulsion/solvent evaporation technique, of magnetic nanocomposites (average diameter ≈ 135 nm) consisting of maghemite nuclei and a biodegradable poly( d, l-lactide- co-glycolide) matrix. The heterogeneous structure of the nanoparticles can confer them the responsiveness to magnetic gradients, giving both the possibility of their use as a drug delivery system and adequate heating characteristics for a hyperthermia effect. The physical chemistry of the nanocomposites was extensively characterized, this establishing that their surface properties were similar to that of pure poly( d, l-lactide- co-glycolide). From an electrokinetic point of view, zeta potential determinations (as a function of the ionic strength, and pH) pointed out that the nanocomposites were almost indistinguishable from the copolymer. The surface thermodynamic analysis agreed with the electrophoretic one in suggesting that the coverage of the magnetic nuclei was complete, since the hydrophilic nature of maghemite was modified and the nanoparticles turned into hydrophobic, just like the copolymer, when they were embedded into poly( d, l-lactide- co-glycolide). The magnetic behaviours of the composite nanoparticles were also checked. Their heating properties were studied in vitro in a high-frequency alternating gradient of magnetic field: a stable maximum temperature of 47 °C was satisfactorily achieved within 45 min. Blood compatibility of the nanocomposites was also defined in vitro. To our knowledge, this is the first time that such kind of magnetic-sensitive nanoformulation with very promising characteristics (e.g. blood compatibility, magnetic drug targeting capabilities, and hyperthermia) has been developed for therapeutic purposes.

  8. Therapeutic application of natural inhibitors against snake venom phospholipase A2

    PubMed Central

    Perumal Samy, Ramar; Gopalakrishnakone, Ponnampalam; Chow, Vincent TK

    2012-01-01

    Natural inhibitors occupy an important place in the potential to neutralize the toxic effects caused by snake venom proteins and enzymes. It has been well recognized for several years that animal sera, some of the plant and marine extracts are the most potent in neutralizing snake venom phospholipase A2 (svPLA2). The implication of this review to update the latest research work which has been accomplished with svPLA2 inhibitors from various natural sources like animal, marine organisms presents a compilation of research in this field over the past decade and revisiting the previous research report including those found in plants. In addition to that the bioactive compounds/inhibitor molecules from diverse sources like aristolochic alkaloid, flavonoids and neoflavonoids from plants, hydrocarbones ­2, 4 dimethyl hexane, 2 methylnonane, and 2, 6 dimethyl heptane obtained from traditional medicinal plants Tragia involucrata (Euphorbiaceae) member of natural products involved for the inhibitory potential of phospholipase A2 (PLA2) enzymes in vitro and also decrease both oedema induced by snake venom as well as human synovial fluid PLA2. Besides marine natural products that inhibit PLA2 are manoalide and its derivatives such as scalaradial and related compounds, pseudopterosins and vidalols, tetracylne from synthetic chemicals etc. There is an overview of the role of PLA2 in inflammation that provides a rationale for seeking inhibitors of PLA2 as anti-inflammatory agents. However, more studies should be considered to evaluate antivenom efficiency of sera and other agents against a variety of snake venoms found in various parts of the world. The implications of these new groups of svPLA2 toxin inhibitors in the context of our current understanding of snake biology as well as in the development of new novel antivenoms therapeutics agents in the efficient treatment of snake envenomations are discussed. PMID:22359435

  9. Newcastle Disease Virus: Potential Therapeutic Application for Human and Canine Lymphoma.

    PubMed

    Sánchez, Diana; Pelayo, Rosana; Medina, Luis Alberto; Vadillo, Eduardo; Sánchez, Rogelio; Núñez, Luis; Cesarman-Maus, Gabriela; Sarmiento-Silva, Rosa Elena

    2015-12-23

    Research on oncolytic viruses has mostly been directed towards the treatment of solid tumors, which has yielded limited information regarding their activity in hematological cancer. It has also been directed towards the treatment of humans, yet veterinary medicine may also benefit. Several strains of the Newcastle disease virus (NDV) have been used as oncolytics in vitro and in a number of in vivo experiments. We studied the cytolytic effect of NDV-MLS, a low virulence attenuated lentogenic strain, on a human large B-cell lymphoma cell line (SU-DHL-4), as well as on primary canine-derived B-cell lymphoma cells, and compared them to healthy peripheral blood mononuclear cells (PBMC) from both humans and dogs. NDV-MLS reduced cell survival in both human (42% ± 5%) and dog (34% ± 12%) lymphoma cells as compared to untreated controls. No significant effect on PBMC was seen. Cell death involved apoptosis as documented by flow-cytometry. NDV-MLS infections of malignant lymphoma tumors in vivo in dogs were confirmed by electron microscopy. Early (24 h) biodistribution of intravenous injection of 1 × 10(12) TCID50 (tissue culture infective dose) in a dog with T-cell lymphoma showed viral localization only in the kidney, the salivary gland, the lung and the stomach by immunohistochemistry and/or endpoint PCR. We conclude that NDV-MLS may be a promising agent for the treatment of lymphomas. Future research is needed to elucidate the optimal therapeutic regimen and establish appropriate biosafety measures.

  10. Newcastle Disease Virus: Potential Therapeutic Application for Human and Canine Lymphoma

    PubMed Central

    Sánchez, Diana; Pelayo, Rosana; Medina, Luis Alberto; Vadillo, Eduardo; Sánchez, Rogelio; Núñez, Luis; Cesarman-Maus, Gabriela; Sarmiento-Silva, Rosa Elena

    2015-01-01

    Research on oncolytic viruses has mostly been directed towards the treatment of solid tumors, which has yielded limited information regarding their activity in hematological cancer. It has also been directed towards the treatment of humans, yet veterinary medicine may also benefit. Several strains of the Newcastle disease virus (NDV) have been used as oncolytics in vitro and in a number of in vivo experiments. We studied the cytolytic effect of NDV-MLS, a low virulence attenuated lentogenic strain, on a human large B-cell lymphoma cell line (SU-DHL-4), as well as on primary canine-derived B-cell lymphoma cells, and compared them to healthy peripheral blood mononuclear cells (PBMC) from both humans and dogs. NDV-MLS reduced cell survival in both human (42% ± 5%) and dog (34% ± 12%) lymphoma cells as compared to untreated controls. No significant effect on PBMC was seen. Cell death involved apoptosis as documented by flow-cytometry. NDV-MLS infections of malignant lymphoma tumors in vivo in dogs were confirmed by electron microscopy. Early (24 h) biodistribution of intravenous injection of 1 × 1012 TCID50 (tissue culture infective dose) in a dog with T-cell lymphoma showed viral localization only in the kidney, the salivary gland, the lung and the stomach by immunohistochemistry and/or endpoint PCR. We conclude that NDV-MLS may be a promising agent for the treatment of lymphomas. Future research is needed to elucidate the optimal therapeutic regimen and establish appropriate biosafety measures. PMID:26703717

  11. Uveal melanoma and macular degeneration: molecular biology and potential therapeutic applications.

    PubMed

    Economou, Mario-Alexander

    2008-12-01

    Uveal melanoma is the most common primary intraocular malignant tumor in adults with 30% to 50% of patients that ultimately succumb to metastatic disease, mainly to the liver. (Shields et al. 1991) Although new diagnostic and therapeutic tools have been developed during the most recent years, only the eye conservation rate has been achieved, while the survival rate remains poor. The reason for this liver-homing is largely unknown, but it is conceivable that hepatic environmental factors may be implicated in the growth, dissemination, and progression of this malignancy. The insulin-like growth factor (IGF-1) that binds to the IGF-1 receptor (IGF-1R) is mainly produced in the liver. It has been shown to be crucial for tumor transformation, maintenance of malignant phenotype, promotion of cell growth, and prevention of apoptosis. (Baserga 1995) The hepatocyte growth factor/scatter factor (HGF/SF) is another growth factor produced in the liver and exerts its biological effects through binding to the plasma membrane receptor c-Met. The activation of this receptor by HGF/SF ligand can induce proliferation, motility, adhesion, and invasion of tumor cells. (Cruz et al. 2003) Metastasis is a process involving many components, including tumor cell adhesion, migration, extracellular matrix (ECM) proteolysis, and invasion. The tumor cells undergo intravasation, disperse via the vascular and the lymphatic systems, and finally extravasate to invade the secondary sites. In all these steps, proteolytic enzyme systems are involved, including the matrix metalloproteinase (MMP) system and the plasminogen activation system. The migration of a malignant cell through the ECM and the basement membrane requires proteolytic activities. (Stetler-Stevenson et al. 1993). Efforts to target the IGF-I system has been made with different types of cancer but not with uveal melanoma.

  12. [Adjuvant dermato-cosmetic acne therapy].

    PubMed

    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.

  13. Non-Specific Immunotherapies and Adjuvants

    MedlinePlus

    ... and Side Effects Treatment Types Immunotherapy Non-specific cancer immunotherapies and adjuvants Non-specific immunotherapies don’t target ... This makes BCG useful as a form of cancer immunotherapy. BCG was one of the earliest immunotherapies used ...

  14. Extended Adjuvant Therapy for Breast Cancer

    Cancer.gov

    An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

  15. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Cancer.gov

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  16. Therapeutic application of mesenchymal stem cells in bone and joint diseases.

    PubMed

    Liu, Yi; Wu, Jianmei; Zhu, Youming; Han, Jinxiang

    2014-02-01

    Mesenchymal stem cells (MSCs), the non-hematopoietic progenitor cells, are multi-potent stem cells from a variety of tissues with the capability of self-renewal, proliferation, differentiation into multi-lineage cell types, as well as anti-inflammatory and immunomodulatory. These properties make MSCs an ideal source of cell therapy in bone and joint diseases. This review describes the advances of animal study and preliminary clinical application in the past few years, related to MSC-based cell therapy in the common bone and joint diseases, including osteoarthritis, rheumatoid arthritis, osteoporosis, osteonecrosis of the femoral head and osteogenesis imperfecta. It highlights the promising prospect of MSC in clinical application of bone and joint diseases.

  17. Diagnostic and therapeutic applications of diode lasers and solid state lasers in medicine

    NASA Astrophysics Data System (ADS)

    Jacques, S. L.; Welch, A. J.; Motamedi, M.; Rastegar, S.

    1992-05-01

    The Texas Medical Center in Houston and the nearby UT Medical Branch at Galveston together constitute a major center of medical research activities. Laser applications in medicine are under development with the engineering assistance of the colloborating engineering centers at Rice University, UT-Austin, and Texas A&M Univ. In addition, this collective is collaborating with the Naval Research Laboratory, where new developments in laser design are underway, in order to transfer promising new laser technology rapidly into the medical environment.

  18. Diagnostic and therapeutic applications of diode lasers and solid state lasers in medicine. Progress report

    SciTech Connect

    Jacques, S.L.; Welch, A.J.; Motamedi, M.; Rastegar, S.; Tittel, F.; Esterowitz, L.

    1992-05-01

    The Texas Medical Center in Houston and the nearby UT Medical Branch at Galveston together constitute a major center of medical research activities. Laser applications in medicine are under development with the engineering assistance of the colloborating engineering centers at Rice University, UT-Austin, and Texas A&M Univ. In addition, this collective is collaborating with the Naval Research Laboratory, where new developments in laser design are underway, in order to transfer promising new laser technology rapidly into the medical environment.

  19. Diagnostic and therapeutic applications of diode lasers and solid state lasers in medicine

    SciTech Connect

    Jacques, S.L. . Cancer Center); Welch, A.J. ); Motamedi, M. . Medical Branch); Rastegar, S. ); Tittel, F. ); Esterowitz, L. )

    1992-05-01

    The Texas Medical Center in Houston and the nearby UT Medical Branch at Galveston together constitute a major center of medical research activities. Laser applications in medicine are under development with the engineering assistance of the colloborating engineering centers at Rice University, UT-Austin, and Texas A M Univ. In addition, this collective is collaborating with the Naval Research Laboratory, where new developments in laser design are underway, in order to transfer promising new laser technology rapidly into the medical environment.

  20. Diagnostic and therapeutic applications of diode lasers and solid state lasers in medicine. Progress report

    SciTech Connect

    Jacques, S.L.; Welch, A.J.; Motamedi, M.; Rastegar, S.; Tittel, F.; Esterowitz, L.

    1993-05-01

    The Texas Medical Center in Houston and the nearby UT Medical Branch at Galveston together constitute a major center of medical research activities. Laser applications in medicine are under development with the engineering assistance of the collaborating engineering enters at Rice University, UT-Austin, Texas A&M Univ. In addition, this collective is collaborating with the naval Research Laboratory, where new developments in laser design are underway, in order to transfer promising new laser technology rapidly into the medical environment.

  1. Toll-Like Receptors Expression and Signaling in Glia Cells in Neuro-Amyloidogenic Diseases: Towards Future Therapeutic Application

    PubMed Central

    Trudler, Dorit; Farfara, Dorit; Frenkel, Dan

    2010-01-01

    Toll-like receptors (TLRs) are known to be expressed by innate immune response cells and to play a critical role in their activation against foreign pathogens. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system (CNS). TLR signaling was reported to be associated with a yin-yang effect in the CNS. While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases. This paper will focus on TLR signaling in glial cells in neurodegenerative diseases such as Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis, and Parkinson's disease. Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application. PMID:20706642

  2. Beyond phage display: non-traditional applications of the filamentous bacteriophage as a vaccine carrier, therapeutic biologic, and bioconjugation scaffold

    PubMed Central

    Henry, Kevin A.; Arbabi-Ghahroudi, Mehdi; Scott, Jamie K.

    2015-01-01

    For the past 25 years, phage display technology has been an invaluable tool for studies of protein–protein interactions. However, the inherent biological, biochemical, and biophysical properties of filamentous bacteriophage, as well as the ease of its genetic manipulation, also make it an attractive platform outside the traditional phage display canon. This review will focus on the unique properties of the filamentous bacteriophage and highlight its diverse applications in current research. Particular emphases are placed on: (i) the advantages of the phage as a vaccine carrier, including its high immunogenicity, relative antigenic simplicity and ability to activate a range of immune responses, (ii) the phage’s potential as a prophylactic and therapeutic agent for infectious and chronic diseases, (iii) the regularity of the virion major coat protein lattice, which enables a variety of bioconjugation and surface chemistry applications, particularly in nanomaterials, and (iv) the phage’s large population sizes and fast generation times, which make it an excellent model system for directed protein evolution. Despite their ubiquity in the biosphere, metagenomics work is just beginning to explore the ecology of filamentous and non-filamentous phage, and their role in the evolution of bacterial populations. Thus, the filamentous phage represents a robust, inexpensive, and versatile microorganism whose bioengineering applications continue to expand in new directions, although its limitations in some spheres impose obstacles to its widespread adoption and use. PMID:26300850

  3. Structure of Freund's complete and incomplete adjuvants

    PubMed Central

    Dvorak, Ann M.; Dvorak, H. F.

    1974-01-01

    Emulsions of complete (CFA) and incomplete (IFA) Freund's adjuvants were examined in the light and electron microscopes, and the resulting morphological findings were correlated with the effectiveness of the emulsions as immunological adjuvants. Thick (viscous) emulsions of both IFA and CFA consisted of highly stable, three-dimensional meshworks composed of interconnecting strands of antigen-containing water droplets interspersed in oil phase. Included mycobacteria were confined to this meshwork and were coated with an adherent surface layer of water droplets. Thin Freund's adjuvants were less stable, relatively coarse emulsions, but even in such preparations mycobacteria showed a striking affinity for the surface of water droplets when these contained low concentrations of antigens such as human serum albumin (HSA). The characteristic adjuvant effect of CFA was observed only when associations between mycobacteria and water droplets took place. Thus, no adjuvant effect occurred with oil-in-water (o/w) emulsions, nor when antigen and mycobacteria-in-oil were injected into separate foot pads. Further, a good adjuvant effect was observed even with thin emulsions when mycobacteria-water droplet associations were abundant. These morphological and immunological data suggest that CFA is a device for bringing extrinsic, water-soluble antigens into intimate, stable contact with myco-bacteria, thereby conferring on them the ability to elicit an immunological response qualitatively similar to that induced by mycobacteria-in-oil to the intrinsic antigen, tuberculin. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5 PMID:4605156

  4. Modulation of HIV-1 immunity by adjuvants

    PubMed Central

    Moody, M. Anthony

    2014-01-01

    Purpose of review To summarize the role of adjuvants in eliciting desirable antibody responses against HIV-1 with particular emphasis on both historical context and recent developments. Recent findings Increased understanding of the role of pattern recognition receptors such as Toll-like receptors in recruiting and directing the immune system has increased the variety of adjuvant formulations being tested in animal models and humans. Across all vaccine platforms, adjuvant formulations have been shown to enhance desirable immune responses such as higher antibody titers and increased functional activity. Although no vaccine formulation has yet succeeded in eliciting broad neutralizing antibodies against HIV-1, the ability of adjuvants to direct the immune response to immunogens suggests they will be critically important in any successful HIV-1 vaccine. Summary The parallel development of adjuvants along with better HIV-1 immunogens will be needed for a successful AIDS vaccine. Additional comparative testing will be required to determine the optimal adjuvant and immunogen regimen that can elicit antibody responses capable of blocking HIV-1 transmission. PMID:24670321

  5. Adjuvant therapy after surgical stone management.

    PubMed

    Ferrandino, Michael N; Monga, Manoj; Preminger, Glenn M

    2009-01-01

    The aim of this article was to review the most widely researched adjuvant medical therapies for the surgical management of urolithiasis. Articles were identified and reviewed from PubMed and Medline databases with MeSH headings focusing on the various surgical treatments of urolithiasis and adjuvant therapy. Additional articles were retrieved from references and conference proceedings. Surgical treatments reviewed included shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy. Adjuvant therapy was considered medical or complementary therapy as an adjunct to these surgical interventions. Adjuvant therapy for the surgical management of urolithiasis has been documented to increase stone-free rates, reduce stone remission rates, prevent renal damage, and decrease postoperative morbidity. A variety of agents have been studied, ranging from antioxidants to alpha-blockers and to alkalinizing agents. Additionally, there is increasing interest in complementary adjuvant therapy (ie, acupuncture). Adjuvant therapy is a fertile area for research in the surgical management of urolithiasis. The optimal agents have yet to be determined and therefore further investigation is warranted and necessary.

  6. Derive and conquer: sourcing and differentiating stem cells for therapeutic applications.

    PubMed

    Klimanskaya, Irina; Rosenthal, Nadia; Lanza, Robert

    2008-02-01

    Although great progress has been made in the isolation and culture of stem cells, the future of stem-cell-based therapies and their productive use in drug discovery and regenerative medicine depends on two key factors: finding reliable sources of multipotent and pluripotent cells and the ability to control their differentiation to generate desired derivatives. It is essential for clinical applications to establish reliable sources of pathogen-free human embryonic stem cells (ESCs) and develop suitable differentiation techniques. Here, we address some of the problems associated with the sourcing of human ESCs and discuss the current status of stem-cell differentiation technology.

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

    PubMed

    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.

  8. The preparation and characterization of superparamagnetic nanoparticles for biomedical imaging and therapeutic application

    NASA Astrophysics Data System (ADS)

    Gunn, Jonathan W.

    Effective clinical diagnosis and treatment of cancer is reliant upon the positive identification of damaged tissue before and after surgical or radiation treatment. The promise of next generation contrast agents is the sensitive and selective recognition of cancerous tissue using highly specific targeting ligands. Multimodal nanoparticles may fill this role as cell-targeted agents capable of exhibiting contrast enhancement in both magnetic resonance (MR) and optical imaging. Specifically, iron oxide nanoparticles coated with biocompatible polymers serve as both a biodegradable MR imaging agent as well as a platform for small molecule, protein and fluorophore modification. In the work presented here, iron oxide nanoparticles have been coated with either poly(ethylene glycol) (PEG) or a graft copolymer chitosan-PEG for prolonged stability, and functionalized with: (1) peptide-major histocompatibility complexes for T-cell trafficking during immunotherapy, (2) annexin V for apoptosis detection during post-therapy evaluation, or (3) biotin for fusion protein pretreatment imaging (e.g. for use in non-Hodgekin's lymphoma). Each nanoparticle system has been characterized for proper surface modification, physical profile, targeting functionality and bioactivity. Additionally, two novel nuclear magnetic resonance (NMR) techniques have been developed for sensitive iron oxide nanoparticle quantification, and direct PEG coating quantification of nanoparticles. These techniques may be applicable to multiple nanoparticle formulations using NMR systems ubiquitous in academic and professional laboratories. The development of new nanoparticle systems for a variety of clinical applications, as well as novel characterization techniques will offer new possibilities for both clinicians and researchers alike.

  9. Plant-Mediated Synthesis of Silver Nanoparticles: Their Characteristic Properties and Therapeutic Applications

    NASA Astrophysics Data System (ADS)

    Chung, Ill-Min; Park, Inmyoung; Seung-Hyun, Kim; Thiruvengadam, Muthu; Rajakumar, Govindasamy

    2016-01-01

    Interest in "green nanotechnology" in nanoparticle biosynthesis is growing among researchers. Nanotechnologies, due to their physicochemical and biological properties, have applications in diverse fields, including drug delivery, sensors, optoelectronics, and magnetic devices. This review focuses on the green synthesis of silver nanoparticles (AgNPs) using plant sources. Green synthesis of nanoparticles is an eco-friendly approach, which should be further explored for the potential of different plants to synthesize nanoparticles. The sizes of AgNPs are in the range of 1 to 100 nm. Characterization of synthesized nanoparticles is accomplished through UV spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, and scanning electron microscopy. AgNPs have great potential to act as antimicrobial agents. The green synthesis of AgNPs can be efficiently applied for future engineering and medical concerns. Different types of cancers can be treated and/or controlled by phytonanotechnology. The present review provides a comprehensive survey of plant-mediated synthesis of AgNPs with specific focus on their applications, e.g., antimicrobial, antioxidant, and anticancer activities.

  10. Atomization from agricultural spray nozzles: Effects of air shear and tank mix adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Spray adjuvants can have a substantial impact on spray atomization from agricultural nozzles; however, this process is also affected by the nozzle type, operating pressure and, for aerial application, the airspeed of application. Different types of ground spray nozzle can dramatically affect the im...

  11. Therapeutic application of extracellular vesicles in acute and chronic renal injury.

    PubMed

    Rovira, Jordi; Diekmann, Fritz; Campistol, Josep M; Ramírez-Bajo, María José

    2016-07-23

    A new cell-to-cell communication system was discovered in the 1990s, which involves the release of vesicles into the extracellular space. These vesicles shuttle bioactive particles, including proteins, mRNA, miRNA, metabolites, etc. This particular communication has been conserved throughout evolution, which explains why most cell types are capable of producing vesicles. Extracellular vesicles (EVs) are involved in the regulation of different physiological processes, as well as in the development and progression of several diseases. EVs have been widely studied over recent years, especially those produced by embryonic and adult stem cells, blood cells, immune system and nervous system cells, as well as tumour cells. EV analysis from bodily fluids has been used as a diagnostic tool for cancer and recently for different renal diseases. However, this review analyses the importance of EVs generated by stem cells, their function and possible clinical application in renal diseases and kidney transplantation.

  12. A background to nuclear transfer and its applications in agriculture and human therapeutic medicine*

    PubMed Central

    Campbell, Keith HS

    2002-01-01

    The development of a single celled fertilized zygote to an animal capable of reproduction involves not only cell division but the differentiation or specialization to numerous cell types forming each tissue and organ of the adult animal. The technique of nuclear transfer allows the reconstruction of an embryo by the transfer of genetic material from a single donor cell, to an unfertilized egg from which the genetic material has been removed. Successful development of live offspring from such embryos demonstrates that the differentiated state of the donor nucleus is not fixed and can be reprogrammed by the egg cytoplasm to control embryo and fetal development. Nuclear transfer has many applications in agriculture and human medicine. This article will review some of the factors associated with the success of embryo development following nuclear transfer and outline the potential uses of the technology. PMID:12033731

  13. Inflammatory therapeutic targets in coronary atherosclerosis—from molecular biology to clinical application

    PubMed Central

    Linden, Fabian; Domschke, Gabriele; Erbel, Christian; Akhavanpoor, Mohammadreza; Katus, Hugo A.; Gleissner, Christian A.

    2014-01-01

    Atherosclerosis is the leading cause of death worldwide. Over the past two decades, it has been clearly recognized that atherosclerosis is an inflammatory disease of the arterial wall. Accumulating data from animal experiments have supported this hypothesis, however, clinical applications making use of this knowledge remain scarce. In spite of optimal interventional and medical therapy, the risk for recurrent myocardial infarction remains by about 20% over 3 years after acute coronary syndromes, novel therapies to prevent atherogenesis or treat atherosclerosis are urgently needed. This review summarizes selected potential molecular inflammatory targets that may be of clinical relevance. We also review recent and ongoing clinical trails that target inflammatory processes aiming at preventing adverse cardiovascular events. Overall, it seems surprising that translation of basic science into clinical practice has not been a great success. In conclusion, we propose to focus on specific efforts that promote translational science in order to improve outcome and prognosis of patients suffering from atherosclerosis. PMID:25484870

  14. Therapeutic Potential of Tolerogenic Dendritic Cells in IBD: From Animal Models to Clinical Application

    PubMed Central

    Cabezón, Raquel; Benítez-Ribas, Daniel

    2013-01-01

    The gut mucosa undergoes continuous antigenic exposure from food antigens, commensal flora derived ligands, and pathogens. This constant stimulation results in controlled inflammatory responses that are effectively suppressed by multiple factors. This tight regulation, necessary to maintain intestinal homeostasis, is affected during inflammatory bowel diseases (IBD) resulting in altered immune responses to harmless microorganisms. Dendritic cells (DCs) are sentinels of immunity, located in peripheral and lymphoid tissues, which are essential for homeostasis of T cell-dependent immune responses. The expression of a particular set of pathogen recognition receptors allows DCs to initiate immune responses. However, in the absence of danger signals, different DC subsets can induce active tolerance by inducing regulatory T cells (Treg), inhibiting inflammatory T helper cell responses, or both. Interestingly, several protocols to generate clinical grade tolerogenic DC (tol-DCs) in vitro have been described, opening the possibility to restore the intestinal homeostasis to bacterial flora by cellular therapy. In this review, we discuss different DC subsets and their role in IBD. Additionally, we will review preclinical studies performed in animal models while describing recent characterization of tol-DCs from Crohn's disease patients for clinical application. PMID:24319468

  15. Temperature-Responsive Smart Nanocarriers for Delivery Of Therapeutic Agents: Applications and Recent Advances.

    PubMed

    Karimi, Mahdi; Sahandi Zangabad, Parham; Ghasemi, Alireza; Amiri, Mohammad; Bahrami, Mohsen; Malekzad, Hedieh; Ghahramanzadeh Asl, Hadi; Mahdieh, Zahra; Bozorgomid, Mahnaz; Ghasemi, Amir; Rahmani Taji Boyuk, Mohammad Reza; Hamblin, Michael R

    2016-08-24

    Smart drug delivery systems (DDSs) have attracted the attention of many scientists, as carriers that can be stimulated by changes in environmental parameters such as temperature, pH, light, electromagnetic fields, mechanical forces, etc. These smart nanocarriers can release their cargo on demand when their target is reached and the stimulus is applied. Using the techniques of nanotechnology, these nanocarriers can be tailored to be target-specific, and exhibit delayed or controlled release of drugs. Temperature-responsive nanocarriers are one of most important groups of smart nanoparticles (NPs) that have been investigated during the past decades. Temperature can either act as an external stimulus when heat is applied from the outside, or can be internal when pathological lesions have a naturally elevated termperature. A low critical solution temperature (LCST) is a special feature of some polymeric materials, and most of the temperature-responsive nanocarriers have been designed based on this feature. In this review, we attempt to summarize recent efforts to prepare innovative temperature-responsive nanocarriers and discuss their novel applications.

  16. Gene Editing and Genetic Lung Disease. Basic Research Meets Therapeutic Application.

    PubMed

    Alapati, Deepthi; Morrisey, Edward E

    2017-03-01

    Although our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin deficiency is extensive, treatment options are lacking. Because the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intratracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene-editing technology is a promising approach to repairing or inactivating disease-causing mutations. Recent reports have provided proof of concept by using CRISPR/Cas9 to successfully repair or inactivate mutations in animal models of monogenic human diseases. Potential pulmonary applications of CRISPR/Cas9 gene editing include gene correction of monogenic diseases in pre- or postnatal lungs and ex vivo gene editing of patient-specific airway stem cells followed by autologous cell transplant. Strategies to enhance gene-editing efficiency and eliminate off-target effects by targeting pulmonary stem/progenitor cells and the assessment of short-term and long-term effects of gene editing are important considerations as the field advances. If methods continue to advance rapidly, CRISPR/Cas9-mediated gene editing may provide a novel opportunity to correct monogenic diseases of the respiratory system.

  17. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications.

    PubMed

    Ryter, Stefan W; Alam, Jawed; Choi, Augustine M K

    2006-04-01

    The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

  18. Antimicrobial Peptides and Innate Lung Defenses: Role in Infectious and Noninfectious Lung Diseases and Therapeutic Applications.

    PubMed

    Hiemstra, Pieter S; Amatngalim, Gimano D; van der Does, Anne M; Taube, Christian

    2016-02-01

    Respiratory infections are a major clinical problem, and treatment is increasingly complicated by the emergence of microbial antibiotic resistance. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed. Antimicrobial peptides, central effector molecules of the immune system, are being considered as alternatives to conventional antibiotics. These peptides display a range of activities, including not only direct antimicrobial activity, but also immunomodulation and wound repair. In the lung, airway epithelial cells and neutrophils in particular contribute to their synthesis. The relevance of antimicrobial peptides for host defense against infection has been demonstrated in animal models and is supported by observations in patient studies, showing altered expression and/or unfavorable circumstances for their action in a variety of lung diseases. Importantly, antimicrobial peptides are active against microorganisms that are resistant against conventional antibiotics, including multidrug-resistant bacteria. Several strategies have been proposed to use these peptides in the treatment of infections, including direct administration of antimicrobial peptides, enhancement of their local production, and creation of more favorable circumstances for their action. In this review, recent developments in antimicrobial peptides research in the lung and clinical applications for novel therapies of lung diseases are discussed.

  19. From contraception to cancer: a review of the therapeutic applications of LHRH analogues as antitumor agents.

    PubMed Central

    Corbin, A.

    1982-01-01

    LHRH and its analogues produce profound antireproductive effects in both sexes of a variety of animal species. Although the LHRH agonists induce gonadotropin release, gonadal steroid secretion, ovulation, and spermatogenesis as an expression of their traditional profertility pharmacologic profile, they paradoxically and characteristically cause predominant antifertility effects which have been extensively evaluated for potential contraceptive purposes. These agonists produce their antireproductive effects in both males and females by common mechanisms, ultimately resulting in disruption of pituitary-gonadal function, depression of steroidogenesis, and inhibition of target organs dependent on such gonadal support. Similar antireproductive effects have been observed with the LHRH antagonists which competitively inhibit LHRH-induced gonadotropin secretion resulting in reduced blood gonadal steroid levels. Use of the inhibitory properties has been extended to cancer therapy based on the ability of the LHRH analogues (particularly the agonists) to inhibit the growth of steroid-dependent (responsive) tumors (e.g., mammary, prostate) similar to that produced by gonadectomy and antisteroid treatments. The use of these peptides for selected hormone-sensitive tumors presents a novel pharmacotherapeutic application for this class of drug. PMID:6810559

  20. Application of the Barcelona Clinic Liver Cancer therapeutic strategy and impact on survival

    PubMed Central

    Hernández-Camba, Alejandro; Turnes, Juan; Ramos, Luis Martin; Arranz, Laura; Mera, José; Crespo, Javier; Quintero, Enrique

    2015-01-01

    Background The Barcelona Clinic Liver Cancer (BCLC) classification of hepatocellular carcinoma (HCC) has proved useful in the management of HCC patients. However, BCLC-recommended first-line treatment is not always applicable in clinical practice. Objective We performed a multicentre retrospective analysis of reasons for deviation from first-line treatment in 2008–2012. Methods One to three-year survival data were analysed using Kaplan-Meier method. Results A total of 407 consecutive HCC patients (66.6 ± 3 years, 83% male) with cirrhosis were included. Tumours were detected during surveillance in 53% of patients, grouped as Child-Pugh A (67%), B (25%) and C (8%); and BCLC A (including stage 0, 44%), B (26%), C (15%) and D (15%). In 31% of patients, first-line treatment was not feasible (51% in early stages) due to: technical reasons (74%); patient non-conformity (20%); medical decision (3%); and disease progression (3%). One to three-year survival of patients not receiving the recommended first-line treatment was similar to that of patients treated according to BCLC recommendations (log-rank, p = 0.229). Conclusion In real-life practice one-third of HCC patients could not receive first-line BCLC treatment. In our cohort of patients, similar short and medium-term survival was observed. Long-term prospective studies are required to determine the best alternative treatment option when BCLC first-line treatment is not feasible. PMID:26279838

  1. The "ouzo effect", recent developments and application to therapeutic drug carrying

    NASA Astrophysics Data System (ADS)

    Botet, Robert

    2012-03-01

    This short review is about the spontaneous emulsification effect, aka the "ouzo effect". Under certain conditions, pouring a mixture ol a totally water-miscible solvent and a hydrophobic oil into water, generates spontaneously nanometric droplets which are stable, even without surfactant. A basic example is anise-flavored aperitif, which is known from ages in South Europe and North Africa. Then, it is an amazingly old topic, potentially important in a number of applications - such as food additives, paints, cosmetic products or pharmaceutic drugs -, though the main mechanisms are yet essentially unexplained. This phenomenon is presently under intensive investigation using both microfluidic experiments and large-scale numerical simulations, through a CNRS project grouping four laboratories in France. This presentation will give an overview of the history, context and development of the ouzo effect, as well as recent advancements and ideas in the field. This unique effect is now related to two major streams of the scientific research, namely: nano-technology and bio-technology. Consequences in the latter domain is outlined.

  2. Functional and structural characterization of four mouse monoclonal antibodies to complement C3 with potential therapeutic and diagnostic applications.

    PubMed

    Subías Hidalgo, Marta; Yébenes, Hugo; Rodríguez-Gallego, César; Martín-Ambrosio, Adrián; Domínguez, Mercedes; Tortajada, Agustin; Rodríguez de Córdoba, Santiago; Llorca, Oscar

    2017-03-01

    C3 is the central component of the complement system. Upon activation, C3 sequentially generates various proteolytic fragments, C3a, C3b, iC3b, C3dg, each of them exposing novel surfaces, which are sites of interaction with other proteins. C3 and its fragments are therapeutic targets and markers of complement activation. We report the structural and functional characterization of four monoclonal antibodies (mAbs) generated by immunizing C3-deficient mice with a mixture of human C3b, iC3b and C3dg fragments, and discuss their potential applications. This collection includes three mAbs interacting with native C3 and inhibiting AP complement activation; two of them by blocking the cleavage of C3 by the AP C3-converase and one by impeding formation of the AP C3-convertase. The interaction sites of these mAbs in the target molecules were determined by resolving the structures of Fab fragments bound to C3b and/or iC3b using electron microscopy. A fourth mAb specifically recognizes the iC3b, C3dg, and C3d fragments. It binds to an evolutionary-conserved neoepitope generated after C3b cleavage by FI, detecting iC3b/C3dg deposition over opsonized surfaces by flow cytometry and immunohistochemistry in human and other species. Because well-characterized anti-complement mAbs are uncommon, the mAbs reported here may offer interesting therapeutic and diagnostic opportunities.

  3. Engineering a Cysteine-Free Form of Human Fibroblast Growth Factor-1 for “Second Generation” Therapeutic Application

    SciTech Connect

    Xia, Xue; Kumru, Ozan S.; Blaber, Sachiko I.; Middaugh, C. Russell; Li, Ling; Ornitz, David M.; Sutherland, Mason A.; Tenorio, Connie A.; Blaber, Michael

    2016-07-06

    Human fibroblast growth factor-1 (FGF-1) has broad therapeutic potential in regenerative medicine but has undesirable biophysical properties of low thermostability and 3 buried cysteine (Cys) residues (at positions 16, 83, and 117) that interact to promote irreversible protein unfolding under oxidizing conditions. Mutational substitution of such Cys residues eliminates reactive buried thiols but cannot be accomplished simultaneously at all 3 positions without also introducing further substantial instability. The mutational introduction of a novel Cys residue (Ala66Cys) that forms a stabilizing disulfide bond (i.e., cystine) with one of the extant Cys residues (Cys83) effectively eliminates one Cys while increasing overall stability. This increase in stability offsets the associated instability of remaining Cys substitution mutations and permits production of a Cys-free form of FGF-1 (Cys16Ser/Ala66Cys/Cys117Ala) with only minor overall instability. The addition of a further stabilizing mutation (Pro134Ala) creates a Cys-free FGF-1 mutant with essentially wild-type biophysical properties. The elimination of buried free thiols in FGF-1 can substantially increase the protein half-life in cell culture. Here, we show that the effective cell survival/mitogenic functional activity of a fully Cys-free form is also substantially increased and is equivalent to wild-type FGF-1 formulated in the presence of heparin sulfate as a stabilizing agent. The results identify this Cys-free FGF-1 mutant as an advantageous “second generation” form of FGF-1 for therapeutic application.

  4. Phenotype and functional evaluation of ex vivo generated antigen-specific immune effector cells with potential for therapeutic applications.

    PubMed

    Han, Shuhong; Huang, Yuju; Liang, Yin; Ho, Yuchin; Wang, Yichen; Chang, Lung-Ji

    2009-08-06

    Ex vivo activation and expansion of lymphocytes for adoptive cell therapy has demonstrated great success. To improve safety and therapeutic efficacy, increased antigen specificity and reduced non-specific response of the ex vivo generated immune cells are necessary. Here, using a complete protein-spanning pool of pentadecapeptides of the latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV), a weak viral antigen which is associated with EBV lymphoproliferative diseases, we investigated the phenotype and function of immune effector cells generated based on IFN-gamma or CD137 activation marker selection and dendritic cell (DC) activation. These ex vivo prepared immune cells exhibited a donor- and antigen-dependent T cell response; the IFN-gamma-selected immune cells displayed a donor-related CD4- or CD8-dominant T cell phenotype; however, the CD137-enriched cells showed an increased ratio of CD4 T cells. Importantly, the pentadecapeptide antigens accessed both class II and class I MHC antigen processing machineries and effectively activated EBV-specific CD4 and CD8 T cells. Phenotype and kinetic analyses revealed that the IFN-gamma and the CD137 selections enriched more central memory T (Tcm) cells than did the DC-activation approach, and after expansion, the IFN-gamma-selected effector cells showed the highest level of antigen-specificity and effector activities. While all three approaches generated immune cells with comparable antigen-specific activities, the IFN-gamma selection followed by ex vivo expansion produced high quality and quantity of antigen-specific effector cells. Our studies presented the optimal approach for generating therapeutic immune cells with potential for emergency and routine clinical applications.

  5. Evaluation of a 2-aminoimidazole variant as adjuvant treatment for dermal bacterial infections.

    PubMed

    Draughn, G Logan; Allen, C Leigh; Routh, Patricia A; Stone, Maria R; Kirker, Kelly R; Boegli, Laura; Schuchman, Ryan M; Linder, Keith E; Baynes, Ronald E; James, Garth; Melander, Christian; Pollard, Angela; Cavanagh, John

    2017-01-01

    2-Aminoimidazole (2-AI)-based compounds have been shown to efficiently disrupt biofilm formation, disperse existing biofilms, and resensitize numerous multidrug-resistant bacteria to antibiotics. Using Pseudomonas aeruginosa and Staphylococcus aureus, we provide initial pharmacological studies regarding the application of a 2-AI as a topical adjuvant for persistent dermal infections. In vitro assays indicated that the 2-AI H10 is nonbactericidal, resensitizes bacteria to antibiotics, does not harm the integument, and promotes wound healing. Furthermore, in vivo application of H10 on swine skin caused no gross abnormalities or immune reactions. Taken together, these results indicate that H10 represents a promising lead dermal adjuvant compound.

  6. Evaluation of a 2-aminoimidazole variant as adjuvant treatment for dermal bacterial infections

    PubMed Central

    Draughn, G Logan; Allen, C Leigh; Routh, Patricia A; Stone, Maria R; Kirker, Kelly R; Boegli, Laura; Schuchman, Ryan M; Linder, Keith E; Baynes, Ronald E; James, Garth; Melander, Christian; Pollard, Angela; Cavanagh, John

    2017-01-01

    2-Aminoimidazole (2-AI)-based compounds have been shown to efficiently disrupt biofilm formation, disperse existing biofilms, and resensitize numerous multidrug-resistant bacteria to antibiotics. Using Pseudomonas aeruginosa and Staphylococcus aureus, we provide initial pharmacological studies regarding the application of a 2-AI as a topical adjuvant for persistent dermal infections. In vitro assays indicated that the 2-AI H10 is nonbactericidal, resensitizes bacteria to antibiotics, does not harm the integument, and promotes wound healing. Furthermore, in vivo application of H10 on swine skin caused no gross abnormalities or immune reactions. Taken together, these results indicate that H10 represents a promising lead dermal adjuvant compound. PMID:28138218

  7. Adjuvant effects of saponins on animal immune responses*

    PubMed Central

    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. PMID:17323426

  8. Potential therapeutic application of intravenous autologous bone marrow infusion in patients with alcoholic liver cirrhosis.

    PubMed

    Saito, Takafumi; Okumoto, Kazuo; Haga, Hiroaki; Nishise, Yuko; Ishii, Rika; Sato, Chikako; Watanabe, Hisayoshi; Okada, Akio; Ikeda, Motoki; Togashi, Hitoshi; Ishikawa, Tsuyoshi; Terai, Shuji; Sakaida, Isao; Kawata, Sumio

    2011-09-01

    The present study was conducted to evaluate the application and efficacy of autologous bone marrow infusion (ABMi) for improvement of liver function in patients with alcoholic liver cirrhosis (ALC). Five subjects and 5 control patients with ALC who had abstained from alcohol intake for 24 weeks before the study were enrolled. Autologous bone marrow cells were washed and injected intravenously, and the changes in serum liver function parameters, and the level of the type IV collagen 7S domain as a marker of fibrosis, were monitored for 24 weeks. The distribution of activated bone marrow was assessed by indium-111-chloride bone marrow scintigraphy. The number of cells infused was 8.0±7.3×10(9) (mean±standard error). The serum levels of albumin and total protein and the prothrombin time were significantly higher during the follow-up period after ABMi than during the observation period in treated patients, whereas no such changes were observed in the controls. In the patients who received ABMi, the Child-Pugh score decreased in all 3 who were classified as class B; the serum levels of type IV collagen 7S domain improved in 4 of the 5 patients; and bone marrow scintigraphy demonstrated an increase of indium-111-chloride uptake in 3 of the 4 patients tested. ABMi for patients with ALC helps improve liver function parameters in comparison with observation during abstinence and ameliorates the degree of fibrosis in terms of serum markers and bone marrow activation in most cases.

  9. Therapeutic effect of topical application of linoleic acid and lincomycin in combination with betamethasone valerate in melasma patients.

    PubMed Central

    Lee, Mu-Hyoung; Kim, Hyun-Jin; Ha, Dong-Ju; Paik, Jong-Hyun; Kim, Hong-Yong

    2002-01-01

    Melasma is an acquired symmetric hypermelanosis characterized by irregular light-to gray-brown macules and patches on sun-exposed areas. Many therapeutic agents are available but are unsatisfactory. Recently, it has been demonstrated that lincomycin (LM) and linoleic acid (LA) can inhibit melanogenesis in vitro. Our purpose was to investigate the clinical efficacy of topical application of LM and LA in combination with betamethasone valerate (BV) in melasma patients. Forty-seven Korean female adults with clinically diagnosed melasma were enrolled in a 6-week, double-blind, randomized clinical trial. Patients were treated with one application of the vehicle (group A), 2% LM mixed with 0.05% BV (group B), or 2% LM mixed with 0.05% BV and 2% LA (group C) on the face every night. Determination of efficacy was based on the Melasma Area and Severity Index (MASI) score and objective assessment (no effect, mild, moderate, or excellent) at intervals of 2 weeks until the end of the study at 6 weeks. After 6 weeks, in comparison with the pre-treatment MASI score, the average MASI score of group C decreased to 68.9%, compared with 98% in group A (p<0.05) and 85.4% in group B. There was no statistically significant difference between group A and group B. Seven patients (43.7%) in group C revealed more than moderate improvement in objective assessment, compared with none in group A and two patients (12.5%) in group B. There were no significant side effects. Topical application of linoleic acid is considered to be effective in the treatment of melasma patients. PMID:12172049

  10. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    NASA Astrophysics Data System (ADS)

    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. Beyond antigens and adjuvants: formulating future vaccines.

    PubMed

    Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J

    2016-03-01

    The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines.

  12. (Neo)adjuvant systemic therapy for melanoma.

    PubMed

    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.

  13. Hypofractionated adjuvant whole breast radiotherapy: progress and prospects.

    PubMed

    Yarnold, John; Haviland, Joanne

    2010-11-01

    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. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept.

    PubMed

    Cruz-Tapias, Paola; Agmon-Levin, Nancy; Israeli, Eitan; Anaya, Juan-Manuel; Shoenfeld, Yehuda

    2013-01-01

    ASIA syndrome, "Autoimmune (Auto-inflammatory) Syndromes Induced by Adjuvants" includes at least four conditions which share a similar complex of signs and symptoms and have been defined by hyperactive immune responses: siliconosis, macrophagic myofasciitis syndrome, Gulf war syndrome and post-vaccination phenomena. Exposure to adjuvants has been documented in these four medical conditions, suggesting that the common denominator to these syndromes is a trigger entailing adjuvant activity. An important role of animal models in proving the ASIA concept has been established. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely used to understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development of new diagnostic, predictive and therapeutic methods. In the current review we wish to unveil the variety of ASIA animal models associated with systemic and organ specific autoimmune diseases induced by adjuvants. We included in this review animal models for rheumatoid arthritis-like disease, for systemic lupus erythematosus-like disease, autoimmune thyroid disease-like disease, antiphospholipid syndrome, myocarditis and others. All these models support the concept of ASIA, as the Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants.

  15. The Position of His-Tag in Recombinant OspC and Application of Various Adjuvants Affects the Intensity and Quality of Specific Antibody Response after Immunization of Experimental Mice.

    PubMed

    Krupka, Michal; Masek, Josef; Barkocziova, Lucia; Turanek Knotigova, Pavlina; Kulich, Pavel; Plockova, Jana; Lukac, Robert; Bartheldyova, Eliska; Koudelka, Stepan; Chaloupkova, Radka; Sebela, Marek; Zyka, Daniel; Droz, Ladislav; Effenberg, Roman; Ledvina, Miroslav; Miller, Andrew D; Turanek, Jaroslav; Raska, Milan

    2016-01-01

    Lyme disease, Borrelia burgdorferi-caused infection, if not recognized and appropriately treated by antibiotics, may lead to chronic complications, thus stressing the need for protective vaccine development. The immune protection is mediated by phagocytic cells and by Borrelia-specific complement-activating antibodies, associated with the Th1 immune response. Surface antigen OspC is involved in Borrelia spreading through the host body. Previously we reported that recombinant histidine tagged (His-tag) OspC (rOspC) could be attached onto liposome surfaces by metallochelation. Here we report that levels of OspC-specific antibodies vary substantially depending upon whether rOspC possesses an N' or C' terminal His-tag. This is the case in mice immunized: (a) with rOspC proteoliposomes containing adjuvants MPLA or non-pyrogenic MDP analogue MT06; (b) with free rOspC and Montanide PET GEL A; (c) with free rOspC and alum; or (d) with adjuvant-free rOspC. Stronger responses are noted with all N'-terminal His-tag rOspC formulations. OspC-specific Th1-type antibodies predominate post-immunization with rOspC proteoliposomes formulated with MPLA or MT06 adjuvants. Further analyses confirmed that the structural features of soluble N' and C' terminal His-tag rOspC and respective rOspC proteoliposomes are similar including their thermal stabilities at physiological temperatures. On the other hand, a change in the position of the rOspC His-tag from N' to C' terminal appears to affect substantially the immunogenicity of rOspC arguably due to steric hindrance of OspC epitopes by the C' terminal His-tag itself and not due to differences in overall conformations induced by changes in the His-tag position in rOspC variants.

  16. The Position of His-Tag in Recombinant OspC and Application of Various Adjuvants Affects the Intensity and Quality of Specific Antibody Response after Immunization of Experimental Mice

    PubMed Central

    Krupka, Michal; Masek, Josef; Barkocziova, Lucia; Turanek Knotigova, Pavlina; Kulich, Pavel; Plockova, Jana; Lukac, Robert; Bartheldyova, Eliska; Koudelka, Stepan; Chaloupkova, Radka; Sebela, Marek; Zyka, Daniel; Droz, Ladislav; Effenberg, Roman; Ledvina, Miroslav; Miller, Andrew D.; Turanek, Jaroslav; Raska, Milan

    2016-01-01

    Lyme disease, Borrelia burgdorferi-caused infection, if not recognized and appropriately treated by antibiotics, may lead to chronic complications, thus stressing the need for protective vaccine development. The immune protection is mediated by phagocytic cells and by Borrelia-specific complement-activating antibodies, associated with the Th1 immune response. Surface antigen OspC is involved in Borrelia spreading through the host body. Previously we reported that recombinant histidine tagged (His-tag) OspC (rOspC) could be attached onto liposome surfaces by metallochelation. Here we report that levels of OspC-specific antibodies vary substantially depending upon whether rOspC possesses an N' or C' terminal His-tag. This is the case in mice immunized: (a) with rOspC proteoliposomes containing adjuvants MPLA or non-pyrogenic MDP analogue MT06; (b) with free rOspC and Montanide PET GEL A; (c) with free rOspC and alum; or (d) with adjuvant-free rOspC. Stronger responses are noted with all N'-terminal His-tag rOspC formulations. OspC-specific Th1-type antibodies predominate post-immunization with rOspC proteoliposomes formulated with MPLA or MT06 adjuvants. Further analyses confirmed that the structural features of soluble N' and C' terminal His-tag rOspC and respective rOspC proteoliposomes are similar including their thermal stabilities at physiological temperatures. On the other hand, a change in the position of the rOspC His-tag from N' to C' terminal appears to affect substantially the immunogenicity of rOspC arguably due to steric hindrance of OspC epitopes by the C' terminal His-tag itself and not due to differences in overall conformations induced by changes in the His-tag position in rOspC variants. PMID:26848589

  17. Chemical adjuvants for plasmid DNA vaccines.

    PubMed

    Greenland, John R; Letvin, Norman L

    2007-05-10

    Plasmid DNA vaccines are a promising modality for immunization against a variety of human pathogens. Immunization via multiple routes with plasmid DNA can elicit potent cellular immune responses, and these immunogens can be administered repeatedly without inducing anti-vector immunity. Nonetheless, the immunogenicity of plasmid DNA vaccines has been limited by problems associated with delivery. A number of adjuvants have been designed to improve plasmid DNA immunogenicity, either by directly stimulating the immune system or by enhancing plasmid DNA expression. Chemical adjuvants for enhancing plasmid DNA expression include liposomes, polymers, and microparticles, all of which have shown promise for enhancing the expression and immunogenicity of plasmid DNA vaccines in animal models. Micro- and nanoparticles have not been shown to enhance immune responses to plasmid DNA vaccines. However, formulation of plasmid DNA with some non-particulate polymeric adjuvants has led to a statistically significant enhancement of immune responses. Further development of these technologies will significantly improve the utility of plasmid DNA vaccination.

  18. Systemic immunotoxicity reactions induced by adjuvanted vaccines.

    PubMed

    Batista-Duharte, Alexander; Portuondo, Deivys; Pérez, O; Carlos, Iracilda Zeppone

    2014-05-01

    Vaccine safety is a topic of concern for the treated individual, the family, the health care personnel, and the others involved in vaccination programs as recipients or providers. Adjuvants are necessary components to warrant the efficacy of vaccines, however the overstimulation of the immune system is also associated with adverse effects. Local reactions are the most frequent manifestation of toxicity induced by adjuvanted vaccines and, with the exception of the acute phase response (APR), much less is known about the systemic reactions that follow vaccination. Their low frequency or subclinical expression meant that this matter has been neglected. In this review, various systemic reactions associated with immune stimulation will be addressed, including: APR, hypersensitivity, induction or worsening of autoimmune diseases, modification of hepatic metabolism and vascular leak syndrome (VLS), with an emphasis on the mechanism involved. Finally, the authors analyze the current focus of discussion about vaccine safety and opportunities to improve the design of new adjuvanted vaccines in the future.

  19. Peptide assemblies: from cell scaffolds to immune adjuvants

    NASA Astrophysics Data System (ADS)

    Collier, Joel

    2011-03-01

    This talk will discuss two interrelated aspects of peptide self-assemblies in biological applications: their use as matrices for regenerative medicine, and their use as chemically defined adjuvants for directing immune responses against engineered antigens. In the first half of the presentation, the design of peptide self-assemblies as analogues for the extracellular matrix will be described, with a focus on self-assemblies displaying multiple different cell-binding peptides. We conducted multi-factorial investigations of peptide co-assemblies containing several different ligand-bearing peptides using statistical ``design of experiments'' (DoE). Using the DoE techniques of factorial experimentation and response surface modeling, we systematically explored how precise combinations of ligand-bearing peptides modulated endothelial cell growth, in the process finding interactions between ligands not previously appreciated. By investigating immune responses against the materials intended for tissue engineering applications, we discovered that the basic self-assembling peptides were minimally immunogenic or non-immunogenic, even when delivered in strong adjuvants. -But when they were appended to an appropriately restricted epitope peptide, these materials raised strong and persistent antibody responses. These responses were dependent on covalent conjugation between the epitope and self-assembling domains of the peptides, were mediated by T cells, and could be directed towards both peptide epitopes and conjugated protein antigens. In addition to their demonstrated utility as scaffolds for regenerative medicine, peptide self-assemblies may also be useful as chemically defined adjuvants for vaccines and immunotherapies. This work was funded by NIH/NIDCR (1 R21 DE017703-03), NIH/NIBIB (1 R01 EB009701-01), and NSF (CHE-0802286).

  20. Human adipose tissue stem cells: relevance in the pathophysiology of obesity and metabolic diseases and therapeutic applications.

    PubMed

    Cignarelli, Angelo; Perrini, Sebastio; Ficarella, Romina; Peschechera, Alessandro; Nigro, Pasquale; Giorgino, Francesco

    2012-12-10

    Stem cells are unique cells exhibiting self-renewing properties and the potential to differentiate into multiple specialised cell types. Totipotent or pluripotent stem cells are generally abundant in embryonic or fetal tissues, but the use of discarded embryos as sources of these cells raises challenging ethical problems. Adult stem cells can also differentiate into a wide variety of cell types. In particular, adult adipose tissue contains a pool of abundant and accessible multipotent stem cells, designated as adipose-derived stem cells (ASCs), that are able to replicate as undifferentiated cells, to develop as mature adipocytes and to differentiate into multiple other cell types along the mesenchymal lineage, including chondrocytes, myocytes and osteocytes, and also into cells of endodermal and neuroectodermal origin, including beta-cells and neurons, respectively. An impairment in the differentiation potential and biological functions of ASCs may contribute to the development of obesity and related comorbidities. In this review, we summarise different aspects of the ASCs with special reference to the isolation and characterisation of these cell populations, their relation to the biochemical features of the adipose tissue depot of origin and to the metabolic characteristics of the donor subject and discuss some prospective therapeutic applications.

  1. The Potential of Minipigs in the Development of Anticancer Therapeutics: Species Comparison and Examples of Special Applications.

    PubMed

    Mahl, Andreas; Dincer, Zuhal; Heining, Peter

    2016-04-01

    Minipigs are increasingly being used as an alternative to dog or monkey in nonclinical safety testing of pharmaceuticals since they share similar anatomical and physiological characteristics to humans. Integrative assessment of pharmacodynamic and pharmacokinetic data sets of drug candidates fromin silico,in vitro, andin vivoinvestigations form the basis for selecting the most relevant nonrodent species for toxicology studies. Developing anticancer therapeutics represents a special challenge for species selection due to their effects on multiple organ systems. The toxicological profile of anticancer drugs can be associated with steep dose-response curves, especially due to dose-limiting toxicity on the alimentary, hematopoietic, and immune systems. Selection of an appropriate species for toxicology studies is of importance to avoid an inappropriately low (without benefit for the late-stage cancer patient) or high clinical starting dose (with a risk of unexpected adverse reactions). Although the minipig has been the preferred species to develop drugs applied topically, it is only rarely used in anticancer drug development compared to dog and monkey. In this context, we discuss the potential of minipigs in anticancer drug development with examples of programs for oral and dermal administration, intravascular application in drug-eluting stents, and local chemotherapy (chemoembolization).

  2. From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

    PubMed Central

    Tian, Na; Li, Jialiang; Shi, Jinming; Sui, Guangchao

    2017-01-01

    Alternative pre-mRNA splicing is a crucial process that allows the generation of diversified RNA and protein products from a multi-exon gene. In tumor cells, this mechanism can facilitate cancer development and progression through both creating oncogenic isoforms and reducing the expression of normal or controllable protein species. We recently demonstrated that an alternative cyclin D-binding myb-like transcription factor 1 (DMTF1) pre-mRNA splicing isoform, DMTF1β, is increasingly expressed in breast cancer and promotes mammary tumorigenesis in a transgenic mouse model. Aberrant pre-mRNA splicing is a typical event occurring for many cancer-related functional proteins. In this review, we introduce general aberrant pre-mRNA splicing in cancers and discuss its therapeutic application using our recent discovery of the oncogenic DMTF1 isoform as an example. We also summarize new insights in designing novel targeting strategies of cancer therapies based on the understanding of deregulated pre-mRNA splicing mechanisms. PMID:28257090

  3. Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

    PubMed Central

    Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

    2010-01-01

    Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

  4. Microbiota Influences Vaccine and Mucosal Adjuvant Efficacy

    PubMed Central

    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

  5. Microbiota Influences Vaccine and Mucosal Adjuvant Efficacy.

    PubMed

    Kim, Yun-Gi

    2017-02-01

    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.

  6. Adjuvants and vector systems for allergy vaccines.

    PubMed

    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.

  7. Multifunctional, chitosan-based nano therapeutics: design and application for two- and three-dimensional cell culture systems

    NASA Astrophysics Data System (ADS)

    Suarato, Giulia

    There is a constant demand for sensitive and effective anti-cancer drug delivery systems, capable of detecting early-stage pathological conditions and increasing patient survival. Recently, chitosan-based drug delivery nanocomplexes have shown to smartly respond to the distinctive features of the tumor microenvironment, a complex network of extracellular molecules, stromal and endothelial cells, which supports the tumor formation and its metastatic invasion. Due to biocompatibility, easy chemical tailorability, and pH-responsiveness, chitosan has emerged as a promising candidate for the formulation of supramolecular multifunctional materials. The present study focuses on the design, fabrication and characterization of fluorescently labelled, hydrophobically modified glycol chitosan nano-micelles (HGC NPs), suitably tailored for the delivery of anti-neoplastic compounds to various tumor models. Doxorubicin-loaded HGC NPs have been delivered to a bone cancer model, both in monolayer and in 3D spheroid configuration, to assess for differences in the delivery profiles and in the therapeutic efficacy. Compared to the free drug, nanocomplexes showed rapid uptake and a more homogeneous distribution in 3D spheroids, a powerful cellular tool which recapitulates some of the in vivo tumor microenvironment features. In a second part of this thesis work, with the purpose of designing an active targeting tumor-homing nano-therapeutic system, HGC NPs have been linked, via avidin-biotin interaction, with a IVS4 peptide, a small molecule with inhibitory activity on MMP-14-mediated functions. An extensive study conducted on triple negative breast cancer cells in monolayer revealed the MMP-14-IVS4-HGC association at the cancer cell membrane, the preferential uptake, and the consequent impairment of protease-associated migratory ability. As an additional application of our engineered construct, HGC micelles have been decorated with a liver kinase B1 (LKB1), a critical kinase involved

  8. A novel adjuvant-free H fusion system for the production of recombinant immunogens in Escherichia coli: Its application to a 12 kDa antigen from Cryptosporidium parvum.

    PubMed

    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.

  9. Evolving concepts regarding the use of radiotherapy in the adjuvant management of periampullary pancreatic adenocarcinoma.

    PubMed

    Abrams, Ross Allen

    2012-01-01

    Presently, many oncologists feel that radiotherapy should not be part of curative intent, adjuvant management for pancreatic adenocarcinoma ("pancreatic cancer"). Historically, among oncologists who provided adjuvant therapy in this context, radiotherapy was included. This review examines the historical development of this controversy as well as (a) the history and principles of systemic and regional adjuvant therapy, (b) relevant nonsurgical studies using combined radiotherapy and chemotherapy for curative intent management of locally unresectable pancreatic cancer, (c) relevant results from surgical adjuvant studies using combined radiotherapy and chemotherapy for curative intent management of resected pancreatic cancer, and (d) results from phase III cooperative group studies of the adjuvant management of pancreatic cancer. Whether we conclude that adjuvant management should be used in a given clinical context depends on the disease and stage-specific results with surgery alone, risk of local and/or systemic failure, efficacy of chemotherapy and radiotherapy for addressing subclinical disease in this context, and the quality of data and studies available for making these assessments. In some settings where locoregional and systemic failure are codominant, both radiotherapy and chemotherapy are required for optimal results. For the adjuvant management of pancreatic cancer, many relevant studies with chemoradiotherapy have had serious limitations because they were nonrandomized, otherwise flawed in design and/or execution, inadequately stratified for currently known prognostic factors, or did not adequately consider radiotherapy technical details and quality assurance. As demonstrated in a secondary analysis of Radiation Therapy Oncology Group trial 9704, these factors are sufficiently powerful, when inadequately recognized and considered, to have obscured the potential therapeutic benefit of radiotherapy. Progress in pancreatic cancer has been hard to achieve

  10. Thermo-therapeutic applications of chitosan- and PEG-coated NiFe2O4 nanoparticles

    NASA Astrophysics Data System (ADS)

    Manjura Hoque, S.; Tariq, Mehrin; Liba, S. I.; Salehin, F.; Mahmood, Z. H.; Khan, M. N. I.; Chattopadhayay, K.; Islam, Rafiqul; Akhter, S.

    2016-07-01

    The paper reports the thermo-therapeutic applications of chitosan- and PEG-coated nickel ferrite (NiFe2O4) nanoparticles. In this study NiFe2O4 nanoparticles were synthesized by the co-precipitation method, tuning the particle size through heat treatment in the temperature range from 200-800 °C for 3 h. XRD and TEM analysis revealed that the the ultrafine nanoparticles were of size 2-58 nm. Crystallinity of the NiFe2O4 nanoparticles in the as-dried condition with the particle size ˜2-3 nm was confirmed from the presence of a lattice fringe in the HRTEM image. VSM measurements showed that a superparamagnetic/ferromagnetic transition occurs with increasing particle size, which was further confirmed by Mössbauer spectroscopy. The nickel ferrite nanoparticles with optimum particle size of 10 nm were then coated with materials commonly used for biomedical applications, i.e. chitosan and PEG, to form homogeneous suspensions. The hydrodynamic diameter and the polydispersity index (PDI) were analyzed by dynamic light scattering at the physiological temperature of 37 °C and found to be 187 nm and 0.21 for chitosan-coated nanoparticles and 285 nm and 0.32 for PEG-coated ones. The specific loss power of rf induction heating by the set-up for hyperthermia and r 2 relaxivity by the nuclear magnetic resonance were determined. The results of induction heating measurements showed that the temperature attained by the nanoparticles of size 10 nm and concentration of about 20 mg ml-1 was >70 °C (for chitosan) and >64 °C (for PEG). It has been demonstrated that the required temperature for hyperthermia heating could be tuned by tuning the particle size, shape and magnetization and the concentration of solution. For other potential biomedical applications of the NiFe2O4 nanoparticle solution, e.g. magnetic resonance imaging, the NMR studies yielded the T 1 and T 2 relaxivities as 0.348 and 89 mM-1 s-1 respectively. The fact that the T 2 relaxivity is orders of magnitude higher

  11. Adjuvant chemotherapy in soft tissue sarcomas…Conflicts, consensus, and controversies.

    PubMed

    Bajpai, Jyoti; Susan, Deepa

    2016-01-01

    Soft tissue sarcomas (STSs) are an uncommon and diverse group of more than 50 mesenchymal malignancies. Each of these histologic subtypes represents a unique disease with distinct biologic behavior and varying sensitivity to chemotherapy. The judicious use of adjuvant/neoadjuvant chemotherapy along with surgery and radiation in the treatment of localized STS has a role in improving patient outcomes by decreasing local and distant recurrences. There is evidence that the use of adjuvant chemotherapy to a mixed cohort of chemo sensitive and insensitive sarcoma subtypes results in limited benefit. Therefore, it is of paramount importance to identify the subpopulation with high metastatic potential and to identify effective histology-specific treatment options to these patients. Present perspective, will focus on the rationale for adjuvant chemotherapy in sarcoma, with emphasis on the histology driven chemotherapy. It will outline key therapeutic opportunities and hurdles in adjuvant medical treatment of sarcoma, focusing on specific subtypes that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations.

  12. In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

    PubMed Central

    Chisholm, Carly Fleagle; Nguyen, Bao Han; Soucie, Kaitlin R.; Torres, Raul M.; Carpenter, John F.; Randolph, Theodore W.

    2015-01-01

    Subvisible particles in a therapeutic protein product may act as adjuvants to promote unwanted immune responses against the protein. Silicone oil is used as a lubricant in prefilled syringes, and microdroplets of silicone oil are often detected in protein formulations expelled from prefilled syringes. In order to test the adjuvant potency of silicone oil microdroplets, antibody responses in mice to subcutaneous injections of formulations of ovalbumin (OVA) that contained silicone oil microdroplets were measured. These responses were compared against responses to oil-free OVA formulations and to OVA formulations that contained microparticulate aluminum hydroxide (“alum”), the common vaccine adjuvant. When administered with high concentrations of silicone oil microdroplets, OVA formulations elicited strong anti-OVA IgG1 and IgG2a antibody responses. These responses were equivalent to those observed when alum microparticles were added to OVA formulations, suggesting that silicone oil can act as a potent adjuvant. However, when OVA formulations were prepared with lower levels of silicone oil that had been obtained directly from commercial siliconized syringes, the anti-OVA antibody response was not enhanced significantly compared to responses against OVA alone. PMID:26190624

  13. Neurotoxicity Questions Regarding Common Peripheral Nerve Block Adjuvants in Combination with Local Anesthetics

    PubMed Central

    Knight, Joshua B.; Schott, Nicholas J.; Kentor, Michael L.; Williams, Brian A.

    2015-01-01

    Purpose of Review Outline the analgesic role of perineural adjuvants for local anesthetic nerve block injections, and evaluate current knowledge regarding whether adjuvants modulate the neurocytologic properties of local anesthetics. Recent Findings Perineural adjuvant medications such as dexmedetomidine, clonidine, buprenorphine, dexamethasone, and midazolam play unique analgesic roles. The dosing of these medications to prevent neurotoxicity is characterized in various cellular and in vivo models. Much of this mitigation may be via reducing the dose of local anesthetic used while achieving equal or superior analgesia. Dose-concentration animal models have shown no evidence of deleterious effects. Clinical observations regarding blocks with combined bupivacaine-clonidine-buprenorphine-dexamethasone have shown beneficial effects on block duration and rebound pain without long-term evidence of neurotoxicity. In vitro and in vivo studies of perineural clonidine and dexmedetomidine show attenuation of perineural inflammatory responses generated by local anesthetics. Summary Dexmedetomidine added as a peripheral nerve blockade adjuvant improves block duration without neurotoxic properties. The combined adjuvants clonidine, buprenorphine, and dexamethasone do not appear to alter local anesthetic neurotoxicity. Midazolam significantly increases local anesthetic neurotoxicity in vitro, but when combined with clonidine-buprenorphine-dexamethasone (sans local anesthetic) produces no in vitro or in vivo neurotoxicity. Further larger-species animal testing and human trials will be required to reinforce the clinical applicability of these findings. PMID:26207854

  14. Formulation, High Throughput In Vitro Screening and In Vivo Functional Characterization of Nanoemulsion-Based Intranasal Vaccine Adjuvants

    PubMed Central

    Wong, Pamela T.; Leroueil, Pascale R.; Smith, Douglas M.; Ciotti, Susan; Bielinska, Anna U.; Janczak, Katarzyna W.; Mullen, Catherine H.; Groom, Jeffrey V.; Taylor, Erin M.; Passmore, Crystal; Makidon, Paul E.; O’Konek, Jessica J.; Myc, Andrzej; Hamouda, Tarek; Baker, James R.

    2015-01-01

    Vaccine adjuvants have been reported to induce both mucosal and systemic immunity when applied to mucosal surfaces and this dual response appears important for protection against certain pathogens. Despite the potential advantages, however, no mucosal adjuvants are currently approved for human use. Evaluating compounds as mucosal adjuvants is a slow and costly process due to the need for lengthy animal immunogenicity studies. We have constructed a library of 112 intranasal adjuvant candidate formulations consisting of oil-in-water nanoemulsions that contain various cationic and nonionic surfactants. To facilitate adjuvant development we first evaluated this library in a series of high-throughput, in vitro assays for activities associated with innate and adaptive immune activation in vivo. These in vitro assays screened for the ability of the adjuvant to bind to mucin, induce cytotoxicity, facilitate antigen uptake in epithelial and dendritic cells, and activate cellular pathways. We then sought to determine how these parameters related to adjuvant activity in vivo. While the in vitro assays alone were not enough to predict the in vivo adjuvant activity completely, several interesting relationships were found with immune responses in mice. Furthermore, by varying the physicochemical properties of the surfactant components (charge, surfactant polar head size and hydrophobicity) and the surfactant blend ratio of the formulations, the strength and type of the immune response generated (TH1, TH2, TH17) could be modulated. These findings suggest the possibility of using high-throughput screens to aid in the design of custom adjuvants with unique immunological profiles to match specific mucosal vaccine applications. PMID:25962136

  15. Induction of lupus autoantibodies by adjuvants

    USGS Publications Warehouse

    Satoh, M.; Kuroda, Y.; Yoshida, H.; Behney, K.M.; Mizutani, A.; Akaogi, J.; Nacionales, D.C.; Lorenson, T.D.; Rosenbauer, R.J.; Reeves, W.H.

    2003-01-01

    Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNF?? production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines. ?? 2003 Elsevier Ltd. All rights reserved.

  16. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-08-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  17. Are there negative CNS impacts of aluminum adjuvants used in vaccines and immunotherapy?

    PubMed

    Shaw, Christopher A; Li, Dan; Tomljenovic, Lucija

    2014-01-01

    In spite of a common view that aluminum (Al) salts are inert and therefore harmless as vaccine adjuvants or in immunotherapy, the reality is quite different. In the following article we briefly review the literature on Al neurotoxicity and the use of Al salts as vaccine adjuvants and consider not only direct toxic actions on the nervous system, but also the potential impact for triggering autoimmunity. Autoimmune and inflammatory responses affecting the CNS appear to underlie some forms of neurological disease, including developmental disorders. Al has been demonstrated to impact the CNS at every level, including by changing gene expression. These outcomes should raise concerns about the increasing use of Al salts as vaccine adjuvants and for the application as more general immune stimulants.

  18. Neuroprotection of cerebrolysin in tissue culture models of brain ischemia: post lesion application indicates a wide therapeutic window.

    PubMed

    Schauer, E; Wronski, R; Patockova, J; Moessler, H; Doppler, E; Hutter-Paier, B; Windisch, M

    2006-07-01

    All attempts to reduce neuronal damage after acute brain ischemia by the use of neuroprotective compounds have failed to prove efficacy in clinical trials so far. One of the main reasons might be the relatively narrow time window for intervention. In this study 2 different tissue culture models of ischemia, excitotoxic lesion by the use of glutamate and oxygen-glucose deprivation (OGD), were used to investigate the effects of delayed application of Cerebrolysin (Cere) on neuronal survival. This drug consists of low molecular weight peptides with neuroprotective and neurotrophic properties similar to naturally occurring growth factors. After both types of lesion, acute as well as delayed treatment with Cere resulted in a dose dependent and significant rescue of neurons. In the model of excitotoxic cell death significant drug effects were found even when the treatment started with a delay of 96 hours after addition of glutamate. In the OGD model pronounced effects were found after 48 hours delay of treatment, and even after 72 hours a small but significant rescue of neurons was detected. The neuroprotective effects of a single addition of Cerebrolysin to the culture medium resulted in significant protection until end of the experiments which was up to 2 weeks after the initial lesion. A shift of the efficacious dosages from low to high concentrations indicates that most likely active compounds are used up, indicating that multiple dosing might even increase the effect size. In conclusion the results indicate that Cere displays a relatively wide therapeutic time window which might be explained by a combination of acute neuroprotective properties and neurotrophic efficacy.

  19. Immunotherapy applications of carbon nanotubes: from design to safe applications.

    PubMed

    Fadel, Tarek R; Fahmy, Tarek M

    2014-04-01

    Carbon nanotubes (CNTs) have the potential to overcome significant challenges related to vaccine development and immunotherapy. Central to these applications is an improved understanding of CNT interactions with the immune system. Unique properties such as high aspect ratio, flexible surface chemistry, and control over structure and morphology may allow for enhanced target specificity and transport of antigens across cell membranes. Although recent work has demonstrated the potential of CNTs to amplify the immune response as adjuvants, other results have also linked their proinflammatory properties to harmful health effects. Here, we review the recent advances of CNT-based immunological research, focusing on current understandings of therapeutic efficacy and mechanisms of immunotoxicology.

  20. Mucinous adenocarcinoma of perianal region: an uncommon disease treated with neo-adjuvant chemo-radiation.

    PubMed

    Purkayastha, Abhishek; Sharma, Neelam; Dutta, Vibha; Bisht, Niharika; Pandya, Tejas

    2016-01-01

    Mucinous adenocarcinoma of the perianal region is an oncologic rarity posing a diagnostic and therapeutic dilemma for treating oncologists due to very few reported cases without definite therapeutic guidelines. It accounts for 2% to 3% of all gastrointestinal malignancies and are historically known to arise from chronic anal fistulas and ischiorectal or perianal abscesses. We hereby report a sporadic and interesting case of perianal mucinous adenocarcinoma in a 56-year-old male initially treated with alternative medicines and local surgery for recurrent fistula in ano of 2 years duration. He presented with complaints of discharging growth in perianal region, painful defecation associated with occasional blood mixed stools of 6 months duration. Incisional biopsy from the ulcer revealed mucinous adenocarcinoma. Contrast enhanced computed tomography (CT) scan and whole body positron emission tomography (PET) scan showed a localized perianal growth which was further confirmed with colonoscopy. With no pre-set treatment protocol for this rare entity, he was managed with neo-adjuvant concurrent chemo-radiation (CCRT) followed by abdominoperineal resection (APR) and adjuvant chemotherapy. Presently he is on 3 monthly follow-up since last 1 year post APR and adjuvant chemotherapy without any evidence of recurrence or distant metastasis. To the best of knowledge, our report may be one of the rarest cases of this disease entity where the duration of anal fistula was merely 2 years in contrast to the established criteria that the fistula precedes carcinoma by at least 10 years.

  1. Mucinous adenocarcinoma of perianal region: an uncommon disease treated with neo-adjuvant chemo-radiation

    PubMed Central

    Sharma, Neelam; Dutta, Vibha; Bisht, Niharika; Pandya, Tejas

    2016-01-01

    Mucinous adenocarcinoma of the perianal region is an oncologic rarity posing a diagnostic and therapeutic dilemma for treating oncologists due to very few reported cases without definite therapeutic guidelines. It accounts for 2% to 3% of all gastrointestinal malignancies and are historically known to arise from chronic anal fistulas and ischiorectal or perianal abscesses. We hereby report a sporadic and interesting case of perianal mucinous adenocarcinoma in a 56-year-old male initially treated with alternative medicines and local surgery for recurrent fistula in ano of 2 years duration. He presented with complaints of discharging growth in perianal region, painful defecation associated with occasional blood mixed stools of 6 months duration. Incisional biopsy from the ulcer revealed mucinous adenocarcinoma. Contrast enhanced computed tomography (CT) scan and whole body positron emission tomography (PET) scan showed a localized perianal growth which was further confirmed with colonoscopy. With no pre-set treatment protocol for this rare entity, he was managed with neo-adjuvant concurrent chemo-radiation (CCRT) followed by abdominoperineal resection (APR) and adjuvant chemotherapy. Presently he is on 3 monthly follow-up since last 1 year post APR and adjuvant chemotherapy without any evidence of recurrence or distant metastasis. To the best of knowledge, our report may be one of the rarest cases of this disease entity where the duration of anal fistula was merely 2 years in contrast to the established criteria that the fistula precedes carcinoma by at least 10 years. PMID:28138619

  2. Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

    PubMed Central

    Sundahl, Nora; Clarisse, Dorien; Bracke, Marc; Offner, Fritz; Berghe, Wim Vanden; Beck, Ilse M.

    2016-01-01

    Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting. PMID:27713909

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

    PubMed

    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.

  4. Immune Responses in Pigs Vaccinated with Adjuvanted and Non-Adjuvanted A(H1N1)pdm/09 Influenza Vaccines Used in Human Immunization Programmes

    PubMed Central

    Lefevre, Eric A.; Carr, B. Veronica; Inman, Charlotte F.; Prentice, Helen; Brown, Ian H.; Brookes, Sharon M.; Garcon, Fanny; Hill, Michelle L.; Iqbal, Munir; Elderfield, Ruth A.; Barclay, Wendy S.; Gubbins, Simon; Bailey, Mick; Charleston, Bryan

    2012-01-01

    Following the emergence and global spread of a novel H1N1 influenza virus in 2009, two A(H1N1)pdm/09 influenza vaccines produced from the A/California/07/09 H1N1 strain were selected and used for the national immunisation programme in the United Kingdom: an adjuvanted split virion vaccine and a non-adjuvanted whole virion vaccine. In this study, we assessed the immune responses generated in inbred large white pigs (Babraham line) following vaccination with these vaccines and after challenge with A(H1N1)pdm/09 virus three months post-vaccination. Both vaccines elicited strong antibody responses, which included high levels of influenza-specific IgG1 and haemagglutination inhibition titres to H1 virus. Immunisation with the adjuvanted split vaccine induced significantly higher interferon gamma production, increased frequency of interferon gamma-producing cells and proliferation of CD4−CD8+ (cytotoxic) and CD4+CD8+ (helper) T cells, after in vitro re-stimulation. Despite significant differences in the magnitude and breadth of immune responses in the two vaccinated and mock treated groups, similar quantities of viral RNA were detected from the nasal cavity in all pigs after live virus challenge. The present study provides support for the use of the pig as a valid experimental model for influenza infections in humans, including the assessment of protective efficacy of therapeutic interventions. PMID:22427834

  5. Natural zeolite clinoptilolite: new adjuvant in anticancer therapy.

    PubMed

    Pavelić, K; Hadzija, M; Bedrica, L; Pavelić, J; Dikić, I; Katić, M; Kralj, M; Bosnar, M H; Kapitanović, S; Poljak-Blazi, M; Krizanac, S; Stojković, R; Jurin, M; Subotić, B; Colić, M

    2001-01-01

    Natural silicate materials, including zeolite clinoptilolite, have been shown to exhibit diverse biological activities and have been used successfully as a vaccine adjuvant and for the treatment of diarrhea. We report a novel use of finely ground clinoptilolite as a potential adjuvant in anticancer therapy. Clinoptilolite treatment of mice and dogs suffering from a variety of tumor types led to improvement in the overall health status, prolongation of life-span, and decrease in tumors size. Local application of clinoptilolite to skin cancers of dogs effectively reduced tumor formation and growth. In addition, toxicology studies on mice and rats demonstrated that the treatment does not have negative effects. In vitro tissue culture studies showed that finely ground clinoptilolite inhibits protein kinase B (c-Akt), induces expression of p21WAF1/CIP1 and p27KIP1 tumor suppressor proteins, and blocks cell growth in several cancer cell lines. These data indicate that clinoptilolite treatment might affect cancer growth by attenuating survival signals and inducing tumor suppressor genes in treated cells.

  6. Treatment of early uterine sarcomas: disentangling adjuvant modalities

    PubMed Central

    Zagouri, Flora; Dimopoulos, Athanasios-Meletios; Fotiou, Stelios; Kouloulias, Vassilios; Papadimitriou, Christos A

    2009-01-01

    Uterine sarcomas are a rare group of neoplasms with aggressive clinical course and poor prognosis. They are classified into four main histological subtypes in order of decreasing incidence: carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas and "other" sarcomas. The pathological subtype demands a tailored approach. Surgical resection is regarded as the mainstay of treatment. Total abdominal hysterectomy and bilateral salpingo-oophorectomy represents the standard treatment of uterine sarcomas. Pelvic and para-aortic lymph node dissection in carcinosarcomas is recommended, given their high incidence of lymph node metastases, and may have a role in endometrial stromal sarcomas. Adjuvant radiation therapy has historically been of little survival value, but it appears to improve local control and may delay recurrence. Regarding adjuvant chemotherapy, there is little evidence in the literature supporting its use except for carcinosarcomas. However, more trials are needed to address these issues, especially, their sequential application. Patients with uterine sarcomas should be referred to large academic centers for participation in clinical trials. PMID:19356236

  7. Synergistic effect of programmed cell death protein 1 blockade and secondary lymphoid tissue chemokine in the induction of anti-tumor immunity by a therapeutic cancer vaccine.

    PubMed

    Moeini, Soheila; Saeidi, Mohsen; Fotouhi, Fatemeh; Mondanizadeh, Mahdieh; Shirian, Sadegh; Mohebi, Alireza; Gorji, Ali; Ghaemi, Amir

    2017-02-01

    The use of DNA vaccines has become an attractive approach for generating antigen-specific cytotoxic CD8(+) T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be improved by using an adjuvant injected together with checkpoint antibodies. In the current study, we evaluated whether the therapeutic effects of a DNA vaccine encoding human papilloma virus type 16 (HPV-16) E7 can be enhanced by combined application of an immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway and secondary lymphoid tissue chemokine (SLC) also known as CCL21 adjuvant, in a mouse cervical cancer model. The therapeutic effects of the DNA vaccine in combination with CCL21 adjuvant plus PD-1 blockade was evaluated using a tumor growth curve. To further investigate the mechanism underlying the antitumor response, cytolytic and lymphocyte proliferation responses in splenocytes were measured using non-radioactive cytotoxicity and MTT assays, respectively. Vascular endothelial growth factor (VEGF) and IL-10 expression in the tumor and the levels of IFN-γ and IL-4 in supernatants of spleno-lymphocyte cultures were measured using ELISA. The immune efficacy was evaluated by in vivo tumor regression assay. The results showed that vaccination with a DNA vaccine in combination with the CCL21 adjuvant plus PD-1 blockade greatly enhanced cytotoxic T lymphocyte production and lymphocyte proliferation rates and greatly inhibited tumor progression. Moreover, the vaccine in combination with adjuvant and blockade significantly reduced intratumoral VEGF, IL-10 and splenic IL-4 but induced the expression of splenic IFN-γ. This formulation could be an effective candidate for a vaccine against cervical cancers and merits further investigation.

  8. Adjuvant and salvage therapy with leflunomide for recalcitrant cytomegalovirus infections in hematopoietic cell transplantation recipients: A case series.

    PubMed

    El Chaer, Firas; Mori, Nobuyoshi; Shah, Dimpy; Oliver, Nora; Wang, Emily; Jan, Anna; Doan, Vi; Tverdek, Frank; Tayar, Jean; Ariza-Heredia, Ella; Chemaly, Roy F

    2016-11-01

    Cytomegalovirus (CMV) reactivation is a clinically significant complication in hematopoietic stem cell transplant (HCT) recipients. Alternative therapy for multidrug-resistant CMV is limited and often fails. Leflunomide has been used to treat resistant CMV infections, however, data on efficacy, safety, and guidance for therapeutic drug level monitoring are lacking. In this report, we describe 3 HCT recipients with multi-drug resistant CMV infections who received leflunomide as adjuvant and salvage therapy. The therapeutic effect of leflunomide as an anti-CMV agent based on virologic responses and therapeutic drug monitoring were evaluated.

  9. [Adjuvant therapy of breast cancer with trastuzumab].

    PubMed

    Beneder, Christine; Marth, Christian

    2008-01-01

    With the approval of trastuzumab (Herceptin) in 1998, a new era of breast cancer treatment has been heralded. This antibody is directed at the intracellular domain of a member of the epidermal growth factor receptor family, the so-called HER2 receptor. About 25-30% of all breast cancers overexpress this factor, which is associated with a more unfavorable prognosis. Trastuzumab is indicated for patients whose tumor overexpresses HER2. All previous studies on the adjuvant therapy with trastuzumab show very consistent results and provide evidence that the risk of recurrence can be reduced by half by the antibody. Nevertheless, there are still numerous open and controversially discussed questions concerning the use of trastuzumab in adjuvant therapy.

  10. Therapeutic Recreation

    ERIC Educational Resources Information Center

    Parks and Recreation, 1971

    1971-01-01

    Graphic profiles of (1) the professional membership of the National Therapeutic Recreation Society, (2) state-level employment opportunities in the field, and (3) educational opportunities at U.S. colleges and universities. (MB)

  11. DNA Vaccine Electroporation and Molecular Adjuvants

    DTIC Science & Technology

    2016-03-16

    Suschak and Schmaljohn DNA Vaccine Electroporation and Molecular Adjuvants 1 Abstract To date, there is no protective vaccine for Ebola virus...infection. Safety concerns have prevented the use of live-attenuated vaccines , and forced researchers to examine new vaccine formulations. DNA... vaccination is an attractive method for inducing protective immunity to a variety of pathogens, but the low immunogenicity seen in larger animals and

  12. Adjuvant treatment strategies for early colon cancer.

    PubMed

    Waterston, Ashita M; Cassidy, Jim

    2005-01-01

    Colon cancer remains a major cause of death; however, in the last 3 years a number of trials have been published that have led to changes in the treatment of patients with this disease. Initially, the adjuvant treatment of patients following curative resection was based on their Dukes staging; this is now being refined by consideration of other pathological factors, as well as the investigation of newer prognostic markers such as p53, Ki67 and a number of genes on chromosome 18. Tumours generally develop from the progressive accumulation of genetic events, although some develop through mutation or inactivation of DNA mismatch repair proteins leading to microsatellite instability; this is particularly important in Lynch's syndrome. The loss of gene expression can occur by deletion or mutation of genes or by aberrant methylation of CpG islands. In patients with Dukes C colon cancer the standard of care for adjuvant chemotherapy was previously based on bolus fluorouracil (5-fluorouracil) and folinic acid (leucovorin) administered 5 days per month or weekly for 6 months. Recent studies with a combination of infusional fluorouracil, folinic acid and oxaliplatin have been found to be superior. A further study replacing fluorouracil with oral capecitabine has also demonstrated equivalent disease-free survival. Although some debate remains regarding the benefit of adjuvant treatment for patients with Dukes B colon cancer, the emerging consensus is that, for those patients who are younger and have high-risk features, chemotherapy should be discussed. A number of large vaccine trials have also been conducted in the adjuvant setting and, overall, these have been disappointing. This is a rapidly advancing area of therapy and the results of new trials are awaited to determine whether additional benefits can be achieved with biological therapies such as anti-vascular endothelial growth factor and anti-epithelial growth factor receptor monoclonal antibodies, which have already

  13. Dose-dense and sequential strategies in adjuvant breast cancer therapy.

    PubMed

    Untch, M; Von Koch, F; Crohns, C; Sobotta, K; Kahlert, S; Konecny, G; Hepp, H

    2001-05-01

    Several attempts have been made to improve the survival rates of breast cancer patients. The benefit of adjuvant chemotherapy was clearly shown, but the absolute difference of 2% to 11% in overall survival, depending on the patient group, is disappointingly small. In particular, high-risk patients, such as those with > or = 10 involved lymph nodes, extracapsular spread, or vascular invasion, still have an excessive risk of recurrence even after standard adjuvant chemotherapy. To increase the survival rates after adjuvant therapy, new chemotherapeutic agents and new strategies of application are currently being evaluated in clinical trials. Chemotherapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF) seems to be safe and effective in patients with breast cancer. In addition, in metastatic patients, dose-intensified chemotherapy is being investigated. The introduction of epirubicin (Ellence), an agent less cardiotoxic and equally active compared to doxorubicin, enabled the escalation of anthracyclines in adjuvant therapy without serious cardiotoxic effects. The combination of dose-intensified chemotherapy and sequential application in the treatment of breast cancer is reviewed.

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

    PubMed

    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.

  15. Adjuvant and neoadjuvant treatment in pancreatic cancer.

    PubMed

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

    2012-04-14

    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.

  16. Differential enzyme-linked immunosorbent assay and ligand-binding mass spectrometry for analysis of biotransformation of protein therapeutics: application to various FGF21 modalities.

    PubMed

    Hager, Todd; Spahr, Chris; Xu, Jing; Salimi-Moosavi, Hossein; Hall, Michael

    2013-03-05

    Novel protein therapeutics have become increasingly important modalities for treating diseases. Such therapeutics include recombinant fusions of pharmacoactive polypeptides to half-life extenders such as monoclonal antibodies, fragments of antibodies, and albumin. Half-life extension can also be achieved via chemical attachment to polymers such as polyethylene glycol. Any of these therapeutics may be susceptible to biotransformation, most notably in vivo proteolytic truncation, and it is vital to understand this phenomenon during early drug development to ensure correct pharmacokinetic profiling and optimize the in vivo stability through re-engineering. In this paper, we describe an integrated approach that combines differential enzyme-linked immunosorbent assay (ELISA) with ligand-binding-mass spectrometry (LB-MS) to provide a thorough understanding of the biotransformation of novel protein therapeutics. Differential ELISA allows for a fast, high-throughput means to reveal gross in vivo proteolytic liabilities. Ensuing LB-MS analysis provides higher resolution details such as specific vulnerable loci to allow design refinement of the molecule. In this work, the power of the approach is elucidated by application to the optimization of a promising drug candidate, FGF21.

  17. Effective treatment of rat adjuvant-induced arthritis by celastrol

    PubMed Central

    Cascão, R.; Vidal, B.; Raquel, H.; Neves-Costa, A.; Figueiredo, N.; Gupta, V.; Fonseca, J.E.; Moita, L.F.

    2012-01-01

    We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4 days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol. PMID:22415021

  18. Salvage interstitial brachytherapy based on computed tomography for recurrent cervical cancer after radical hysterectomy and adjuvant radiation therapy: case presentations and introduction of the technique

    PubMed Central

    Liu, Zhong-Shan; Guo, Jie; Zhao, Yang-Zhi; Lin, Xia; Chen, Bin; Zhang, Ming; Li, Jiang-Ming; Ren, Xiao-Jun; Zhang, Bing-Ya

    2016-01-01

    Purpose Locally recurring cervical cancer after surgery and adjuvant radiotherapy remains a major therapeutic challenge. This paper presents a new therapeutic technique for such patients: interstitial brachytherapy (BT) guided by real-time three-dimensional (3D) computed tomography (CT). Material and methods Sixteen patients with recurrent cervical cancer after radical surgery and adjuvant external-beam radiotherapy (EBRT) were included in this study. These patients underwent high-dose-rate (HDR) interstitial BT with free-hand placement of metal needles guided by real-time 3D-CT. Six Gy in 6 fractions were prescribed for the high-risk clinical target volume (HR-CTV). D90 and D100 for HR-CTV of BT, and the cumulative D2cc for the bladder, rectum, and sigmoid, including previous EBRT and present BT were analyzed. Treatment-related complications and 3-month tumor-response rates were investigated. Results The mean D90 value for HR-CTV was 52.5 ± 3.3 Gy. The cumulative D2cc for the bladder, rectum, and sigmoid were 85.6 ± 5.8, 71.6 ± 6.4, and 69.6 ± 5.9 Gy, respectively. The mean number of needles was 6.1 ± 1.5, with an average depth of 3.5 ± 0.9 cm for each application. Interstitial BT was associated with minor complications and passable tumor-response rate. Conclusions Interstitial BT guided by real-time 3D-CT for recurrent cervical cancer results in good dose-volume histogram (DVH) parameters. The current technique may be clinically feasible. However, long-term clinical outcomes should be further investigated. PMID:27895683

  19. A comprehensive linear programming tool to optimize formulations of ready-to-use therapeutic foods: An application to Ethiopia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ready-to-use therapeutic food (RUTF) is the standard of care for children suffering from noncomplicated severe acute malnutrition (SAM). The objective was to develop a comprehensive linear programming (LP) tool to create novel RUTF formulations for Ethiopia. A systematic approach that surveyed inter...

  20. Biologic adjuvants for fracture healing

    PubMed Central

    2012-01-01

    Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. PMID:23198865

  1. Novel therapeutic approaches for haemophilia.

    PubMed

    Shetty, S; Ghosh, K

    2015-03-01

    The major therapy for haemophilia is plasma derived or recombinant clotting factors which are evolving steadily to increase potency, stability and half-life. Research in the area of haemophilia therapeutics, however, is not restricted only to modifications in the recombinant products, but alternate therapeutic strategies are being developed which are in different phases of experimental and clinical trials. This chapter reviews the diverse molecular innovations which are being developed for alternate therapeutic approaches in haemophilia. The data is mainly extracted from the literature and the Conference abstracts. Some of the novel therapeutic approaches include inhibition of anticoagulant pathway factors (activated protein C, antithrombin, tissue factor pathway inhibitor) by monoclonal antibodies, peptide inhibitors, DNA or RNA aptamers, use of variant coagulation factors (factor Xa, factor Va) which are more resistant to inactivation or enzymatically more active and antibody-mediated therapy including a humanized anti-factor IXa/X bispecific antibody mimicking factor VIII. Other approaches include nonsense mutation suppression, induction of prothrombotic microparticles by P-selectin-immunoglobulin chimeras, suppression of fibrinolytic potential either by antifibrinolytics or by the use of mutant molecules of fibrinolytic inhibitors. Few products are proposed as 'stand alone' treatment for haemophilia, while a few can be used as adjuvant therapies to recombinant factors with an aim to reduce the amount of factor intake. All efforts are underway to produce an alternate, novel drug for haemophilia which will have an increased half-life, subcutaneously injectable, non-immunogenic and effective both in the presence and absence of inhibitors.

  2. Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents.

    PubMed

    Conlon, J Michael; Mechkarska, Milena; Lukic, Miodrag L; Flatt, Peter R

    2014-07-01

    Frog skin constitutes a rich source of peptides with a wide range of biological properties. These include host-defense peptides with cytotoxic activities against bacteria, fungi, protozoa, viruses, and mammalian cells. Several hundred such peptides from diverse species have been described. Although attention has been focused mainly on antimicrobial activity, the therapeutic potential of frog skin peptides as anti-infective agents remains to be realized and no compound based upon their structures has yet been adopted in clinical practice. Consequently, alternative applications are being explored. Certain naturally occurring frog skin peptides, and analogs with improved therapeutic properties, show selective cytotoxicity against tumor cells and viruses and so have potential for development into anti-cancer and anti-viral agents. Some peptides display complex cytokine-mediated immunomodulatory properties. Effects on the production of both pro-inflammatory and anti-inflammatory cytokines by peritoneal macrophages and peripheral blood mononuclear cells have been observed so that clinical applications as anti-inflammatory, immunosuppressive, and immunostimulatory agents are possible. Several frog skin peptides, first identified on the basis of antimicrobial activity, have been shown to stimulate insulin release both in vitro and in vivo and so show potential as incretin-based therapies for treatment of patients with Type 2 diabetes mellitus. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Ascaphidae, Alytidae, Pipidae, Dicroglossidae, Leptodactylidae, Hylidae, and Ranidae families that complement their potential role as anti-infectives for use against multidrug-resistant microorganisms.

  3. Surface engineering tumor cells with adjuvant-loaded particles for use as cancer vaccines.

    PubMed

    Ahmed, Kawther K; Geary, Sean M; Salem, Aliasger K

    2017-02-28

    Cell surface engineering is an expanding field and whilst extensive research has been performed decorating cell surfaces with biomolecules, the engineering of cell surfaces with particles has been a largely unexploited area. This study reports on the assembly of cell-particle hybrids where irradiated tumor cells were surface engineered with adjuvant-loaded, biodegradable, biocompatible, polymeric particles, with the aim of generating a construct capable of functioning as a therapeutic cancer vaccine. Successfully assembled cell-particle hybrids presented here comprised either melanoma cells or prostate cancer cells stably adorned with Toll-like receptor-9 ligand-loaded particles using streptavidin-biotin cross-linking. Both cell-particle assemblies were tested in vivo for their potential as therapeutic cancer vaccines yielding promising therapeutic results for the prostate cancer model. The ramifications of results obtained for both tumor models are openly discussed.

  4. From discovery to licensure, the Adjuvant System story

    PubMed Central

    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

  5. Biotherapy in the Adjuvant Treatment of Colorectal Cancer

    PubMed Central

    Tazi, El Mehdi; Essadi, Ismail; Boutayeb, Saber; M’rabti, Hind; Errihani, Hassan

    2011-01-01

    The use of adjuvant chemotherapy has improved survival in early-stage colon cancer. Ongoing adjuvant clinical trials are evaluating the addition of targeted therapies to standard chemotherapy regimen. Preliminary results with bevacizumab were disappointing. Also, cetuximab added to chemotherapy does not seem to be better than chemotherapy alone, even in selected wild-type KRAS populations. A better understanding of mechanisms of action of drugs, tumor biology, and predictive biomarkers are needed to design future adjuvant trials. PMID:27942334

  6. MACROMOLECULAR THERAPEUTICS

    PubMed Central

    Yang, Jiyuan; Kopeček, Jindřich

    2014-01-01

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

  7. Macromolecular therapeutics.

    PubMed

    Yang, Jiyuan; Kopeček, Jindřich

    2014-09-28

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated.

  8. Coca (Erythroxylum coca) Control is Affected by Glyphosate Formulations and Adjuvants.

    PubMed

    Marshall, E J P; Solomon, Keith R; Carrasquilla, Gabriel

    2009-01-01

    The aerial spray program for the eradication of coca in Colombia uses Glyphos, a local formulation of glyphosate tank-mixed with an adjuvant product, Cosmo-Flux. There are some potential risks to amphibians from direct overspraying of shallow waters. In order to evaluate potential alternative mixtures, a field experiment was conducted at the Center of National Training of Police Operations in Tolima province, Colombia. Plants of coca were established with irrigation and grown to 75 cm tall. A randomized split-plot design experiment was laid out and sprayed with a range of glyphosate formulations and different adjuvants using an experimental ground sprayer. Assessments were made of plant vigor, height, and above-ground standing crop (fresh weight) 3 wk after application. Resprouting of plants was assessed at 9 wk after treatment. Unformulated glyphosate applied as the product Rodeo gave poorer control of coca than two formulated products, Roundup Biactive (from Europe) and Colombian Glyphos. In general, these products performed well without added adjuvants, giving control similar to that of the eradication mixture with Cosmo-Flux. There was some evidence that addition of the adjuvant Silwet L-77 and to a lesser extent Mixture B (from the United Kingdom) gave more rapid herbicide symptoms. There were also indications that glyphosate rates of less than 3.69 kg acid equivalents (a.e.)/ha could give control in the range of 95%. Depending on the environmental risk requirements, the experiment indicates that, should other spray mixtures be required, there are potential alternatives. These would require extensive field testing to cover different environmental conditions, different coca varieties, and particularly aerial application, prior to a recommendation. Should the glyphosate product require changing, Roundup Biactive may be considered. Should the adjuvant require changing, then on the basis of this research, Silwet L-77 and Mixture B would be good candidates for

  9. DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies.

    PubMed

    Le Pogam, Carole; Patel, Satyananda; Gorombei, Petra; Guerenne, Laura; Krief, Patricia; Omidvar, Nader; Tekin, Nilgun; Bernasconi, Elena; Sicre, Flore; Schlageter, Marie-Helene; Chopin, Martine; Noguera, Maria-Elena; West, Robert; Abu, Ansu; Mathews, Vikram; Pla, Marika; Fenaux, Pierre; Chomienne, Christine; Padua, Rose Ann

    2015-10-20

    We have previously shown that a specific promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) DNA vaccine combined with all-trans retinoic acid (ATRA) increases the number of long term survivors with enhanced immune responses in a mouse model of acute promyelocytic leukemia (APL). This study reports the efficacy of a non-specific DNA vaccine, pVAX14Flipper (pVAX14), in both APL and high risk myelodysplastic syndrome (HR-MDS) models. PVAX14 is comprised of novel immunogenic DNA sequences inserted into the pVAX1 therapeutic plasmid. APL mice treated with pVAX14 combined with ATRA had increased survival comparable to that obtained with a specific PML-RARA vaccine. Moreover, the survival advantage correlated with decreased PML-RARA transcript levels and increase in anti-RARA antibody production. In HR-MDS mice, pVAX14 significantly improved survival and reduced biomarkers of leukemic transformation such as phosphorylated mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1. In both preclinical models, pVAX14 vaccine significantly increased interferon gamma (IFNγ) production, memory T-cells (memT), reduced the number of colony forming units (CFU) and increased expression of the adapter molecule signalling to NF-κB, MyD88. These results demonstrate the adjuvant properties of pVAX14 providing thus new approaches to improve clinical outcome in two different models of myeloid malignancies, which may have potential for a broader applicability in other cancers.

  10. [Value of adjuvant basic therapy in chronic recurrent skin diseases. Neurodermatitis atopica/psoriasis vulgaris].

    PubMed

    Schöpf, E; Mueller, J M; Ostermann, T

    1995-07-01

    Atopic dermatitis and psoriasis vulgaris belong to the most common diseases in dermatology. Since these chronical diseases progress over years and decades, they may lead to restrictions in private and professional life as well as to psychological stress of concerned patients. Therefore, a lasting, stabilising, stage-adjusted topical treatment is necessary. Main component of this treatment in a complete therapeutical concept consists in an adjuvant basic therapy with oil baths and with emollients containing urea or no drug additives at all. Thus the vehicle itself is therapeutically effective. Altered structure and function of the skin measured by increased transepidermal water loss, dysfunction of skin lipid barrier, augmented skin permeability and skin roughness can be improved. Due to this treatment clinical symptoms can be diminished and relapses can be avoided. Corticosteroids and other specific medications can be reduced by using basic therapeutics with little side effects. This means economical benefit as well. So far adjuvant basic treatment is an essential part in the therapy of chronic inflammatory skin diseases.

  11. Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis.

    PubMed

    Rovenská, E; Svík, K; Stancíková, M; Rovenský, J

    1999-01-01

    Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism of drug effects have enabled the use of new drugs and drug combinations in rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme therapy and combined therapy with cyclosporin in rats with adjuvant arthritis. Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5 or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for a period of 40 days from the adjuvant application. Levels of serum albumin, changes in hind paw swelling and bone erosions were measured in rats as variables of inflammation and arthritis-associated destructive changes. Treatment with 5 mg of cyclosporin A, as well as with the combination therapy with cyclosporin A plus PHL, significantly inhibited both the inflammation and destructive arthritis-associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited these disease markers, although to a lesser extent and at a later stage of arthritis development. The results show the inhibitory effect of enzyme therapy on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A given in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.

  12. Degradable emulsion as vaccine adjuvant reshapes antigen-specific immunity and thereby ameliorates vaccine efficacy

    PubMed Central

    Huang, Chung-Hsiung; Huang, Chiung-Yi; Cheng, Chih-Ping; Dai, Shih-Hsiung; Chen, Hsin-Wei; Leng, Chih-Hsiang; Chong, Pele; Liu, Shih-Jen; Huang, Ming-Hsi

    2016-01-01

    This study describes the feasibility and adjuvant mechanism of a degradable emulsion for tuning adaptive immune responses to a vaccine antigen. We featured a mouse model with ovalbumin (OVA) as the antigen to deepen our understanding of the properties of a degradable emulsion-based adjuvant, dubbed PELC, interacting with immune cells and to elucidate their roles in vaccine immunogenicity in vivo. First, we demonstrated that the emulsion, which is stabilized by an amphiphilic bioresorbable polymer, shows degradation in mimic human body conditions and considerable tolerance in vivo. Then, we confirmed the model protein could be loaded into the emulsion and released from the matrix in a sustained manner, subsequently driving the production of antigen-specific antibodies. We also comprehended that PELC not only recruits antigen-presenting cells (APCs) to the injection site but also induces the activation of the recruited APCs and migration to the draining lymph nodes. As an adjuvant for cancer immunotherapy, PELC-formulated OVA could strongly enhance antigen-specific T-cell responses as well as anti-tumor ability with respected to non-formulated OVA, using OVA protein/EG7 cells as a tumor antigen/tumor cell model. Accordingly, our data paved the way for the clinical application of degradable emulsions based on amphiphilic bioresorbable polymers as vaccine adjuvants. PMID:27827451

  13. Overview of adjuvant systemic therapy in early stage breast cancer.

    PubMed

    Newman, Lisa A; Singletary, S Eva

    2007-04-01

    The benefits of adjuvant systemic therapy in reducing risk of distant relapse from breast cancer have been recognized for several decades. The intent of adjuvant therapy is to eliminate the occult micrometastatic breast cancer burden before it progresses into clinically apparent disease. Successful delivery of effective adjuvant systemic therapy as a complement to surgical management of breast cancer has contributed to the steady declines in breast cancer mortality observed internationally over the past 2 decades. Ongoing clinical and translational research in breast cancer seeks to improve the efficacy of systemic agents for use in the conventional postoperative (adjuvant) setting.

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

    PubMed

    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.

  15. [Is there alternative to FOLFOX adjuvant chemotherapy for stage III colorectal cancer patients?].

    PubMed

    Esch, Anouk; Coriat, Romain; Perkins, Géraldine; Brezault, Catherine; Chaussade, Stanislas

    2012-01-01

    Being the second cancer for men and the third cancer for women in France, colorectal cancer represents a serious public health issue. Its incidence has increased these last years and despite new therapeutics being developed, it still has a bad prognostic. Thanks in part to Hemoccult national mass screening program, its diagnosis is made possible at an earlier stage, which makes a surgical curative resection and the carrying out of adjuvant chemotherapy possible. For stage III colic cancer that has been surgically removed, adjuvant chemotherapy by FOLFOX 4 has to be offered. Nevertheless, because of its toxicities, the patient's high age, important comorbidities or post-surgical complications, this chemotherapy occasionally cannot be done. What are the colorectal cancer prognostic factors which would guide the chemotherapy? TNM classification, number of examined lymph nodes, MSI status, and presence or not of a perforation or a perinervous, lymphatic or venous invasion is recognized prognostic factors. Also, what are the alternatives of FOLFOX 4 regimen as colorectal cancer adjuvant treatment?

  16. Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

    PubMed

    Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

    2016-01-01

    Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.

  17. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients.

    PubMed

    Dienstmann, Rodrigo; Salazar, Ramon; Tabernero, Josep

    2015-06-01

    For more than three decades, postoperative chemotherapy-initially fluoropyrimidines and more recently combinations with oxaliplatin-has reduced the risk of tumor recurrence and improved survival for patients with resected colon cancer. Although universally recommended for patients with stage III disease, there is no consensus about the survival benefit of postoperative chemotherapy in stage II colon cancer. The most recent adjuvant clinical trials have not shown any value for adding targeted agents, namely bevacizumab and cetuximab, to standard chemotherapies in stage III disease, despite improved outcomes in the metastatic setting. However, biomarker analyses of multiple studies strongly support the feasibility of refining risk stratification in colon cancer by factoring in molecular characteristics with pathologic tumor staging. In stage II disease, for example, microsatellite instability supports observation after surgery. Furthermore, the value of BRAF or KRAS mutations as additional risk factors in stage III disease is greater when microsatellite status and tumor location are taken into account. Validated predictive markers of adjuvant chemotherapy benefit for stage II or III colon cancer are lacking, but intensive research is ongoing. Recent advances in understanding the biologic hallmarks and drivers of early-stage disease as well as the micrometastatic environment are expected to translate into therapeutic strategies tailored to select patients. This review focuses on the pathologic, molecular, and gene expression characterizations of early-stage colon cancer; new insights into prognostication; and emerging predictive biomarkers that could ultimately help define the optimal adjuvant treatments for patients in routine clinical practice.

  18. Adjuvant Cancer Biotherapy by Viscum Album Extract Isorel: Overview of Evidence Based Medicine Findings.

    PubMed

    Sunjic, Suzana Borovic; Gasparovic, Ana Cipak; Vukovic, Tea; Weiss, Thomas; Weiss, Elisabeth Sussman; Soldo, Ivo; Djakovic, Nikola; Zarkovic, Tomislav; Zarkovic, Neven

    2015-09-01

    Within the integrative medicine one of the most frequently used adjuvant cancer biotherapies is based on aqueous mistletoe (Viscum album) extracts. Tumor growth inhibition, stimulation of host immune response and improvement of the quality of life are the positive effects of mistletoe therapy described in several preclinical and clinical studies. However, cumulative results of the evidence based medicine findings on such treatments are rarely given. Therefore, this paper evaluates the evidence based findings describing effects of the Viscum album extract Isorel in cancer therapy with respect to the type of therapy, stage and type of illness. This study presents cumulated data for 74 patients with different types and stages of cancer treated by Viscum album extract as adjuvant treatment to different conventional therapies, mostly combined surgery and radiotherapy. The biotherapy effectiveness was evaluated according to the outcome as (1) no major therapeutic improvement (15% of patients), (2) prevention of tumor recurrence (47% of patients) and (3) regression of cancer (38% of patients). Notably, there was no obvious health worsening during the follow up period at all. Thus, the results obtained for conventional anticancer therapies combined with adjuvant biotherapy based on Viscum album extract seem to be beneficial for the majority of cancer patients (85%) without serious side effects.

  19. Therapeutic proteins.

    PubMed

    Dimitrov, Dimiter S

    2012-01-01

    Protein-based therapeutics are highly successful in clinic and currently enjoy unprecedented recognition of their potential. More than 100 genuine and similar number of modified therapeutic proteins are approved for clinical use in the European Union and the USA with 2010 sales of US$108 bln; monoclonal antibodies (mAbs) accounted for almost half (48%) of the sales. Based on their pharmacological activity, they can be divided into five groups: (a) replacing a protein that is deficient or abnormal; (b) augmenting an existing pathway; (c) providing a novel function or activity; (d) interfering with a molecule or organism; and (e) delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins. Therapeutic proteins can also be grouped based on their molecular types that include antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytics. They can also be classified based on their molecular mechanism of activity as (a) binding non-covalently to target, e.g., mAbs; (b) affecting covalent bonds, e.g., enzymes; and (c) exerting activity without specific interactions, e.g., serum albumin. Most protein therapeutics currently on the market are recombinant and hundreds of them are in clinical trials for therapy of cancers, immune disorders, infections, and other diseases. New engineered proteins, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs, and proteins with optimized pharmacokinetics, are currently under development. However, in the last several decades, there are no conceptually new methodological developments comparable, e.g., to genetic engineering leading to the development of recombinant therapeutic proteins. It appears that a paradigm change in methodologies and understanding of mechanisms is needed to overcome major

  20. Adjuvant therapy of resectable rectal cancer.

    PubMed

    Minsky, Bruce D

    2002-08-01

    The two conventional treatments for clinically resectable rectal cancer are surgery followed by postoperative combined modality therapy and preoperative combined modality therapy followed by surgery and postoperative chemotherapy. Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhanced sphincter preservation. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy are in progress.

  1. Pushing the limits of hypofractionation for adjuvant whole breast radiotherapy.

    PubMed

    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.

  2. Defensins as anti-inflammatory compounds and mucosal adjuvants

    PubMed Central

    Kohlgraf, Karl G; Pingel, Lindsey C; Dietrich, Deborah E; Brogden, Kim A

    2010-01-01

    Human neutrophil peptide α-defensins and human β-defensins are small, well-characterized peptides with broad antimicrobial activities. In mixtures with microbial antigens, defensins attenuate proinflammatory cytokine responses by dendritic cells in culture, attenuate proinflammatory cytokine responses in the nasal fluids of exposed mice and enhance antibody responses in the serum of vaccinated mice. Although the exact mechanisms are unknown, defensins first start by binding to microbial antigens and adhesins, often attenuating toxic or inflammatory-inducing capacities. Binding is not generic; it appears to be both defensin-specific and antigen-specific with high affinities. Binding of defensins to antigens may, in turn, alter the interaction of antigens with epithelial cells and antigen-presenting cells attenuating the production of proinflammatory cytokines. The binding of defensins to antigens may also facilitate the delivery of bound antigen to antigen-presenting cells in some cases via specific receptors. These interactions enhance the immunogenicity of the bound antigen in an adjuvant-like fashion. Future research will determine the extent to which defensins can suppress early events in inflammation and enhance systemic antibody responses, a very recent and exciting concept that could be exploited to develop therapeutics to prevent or treat a variety of oral mucosal infections, particularly where inflammation plays a role in the pathogenesis of disease and its long-term sequelae. PMID:20020832

  3. Aflibercept and Ang1 supplementation improve neoadjuvant or adjuvant chemotherapy in a preclinical model of resectable breast cancer

    PubMed Central

    Wu, Florence T. H.; Paez-Ribes, Marta; Xu, Ping; Man, Shan; Bogdanovic, Elena; Thurston, Gavin; Kerbel, Robert S.

    2016-01-01

    Phase III clinical trials evaluating bevacizumab (an antibody to the angiogenic ligand, VEGF-A) in breast cancer have found improved responses in the presurgical neoadjuvant setting but no benefits in the postsurgical adjuvant setting. The objective of this study was to evaluate alternative antiangiogenic therapies, which target multiple VEGF family members or differentially modulate the Angiopoietin/Tie2 pathway, in a mouse model of resectable triple-negative breast cancer (TNBC). Neoadjuvant therapy experiments involved treating established orthotopic xenografts of an aggressive metastatic variant of the MDA-MB-231 human TNBC cell line, LM2-4. Adjuvant therapies were given after primary tumor resections to treat postsurgical regrowths and distant metastases. Aflibercept (‘VEGF Trap’, which neutralizes VEGF-A, VEGF-B and PlGF) showed greater efficacy than nesvacumab (an anti-Ang2 antibody) as an add-on to neoadjuvant/adjuvant chemotherapy. Concurrent inhibition of Ang1 and Ang2 signaling (through an antagonistic anti-Tie2 antibody) was not more efficacious than selective Ang2 inhibition. In contrast, short-term perioperative BowAng1 (a recombinant Ang1 variant) improved the efficacy of adjuvant chemotherapy. In conclusion, concurrent VEGF pathway inhibition is more likely than Ang/Tie2 pathway inhibition (e.g., anti-Ang2, anti-Ang2/Ang1, anti-Tie2) to improve neoadjuvant/adjuvant chemotherapies for TNBC. Short-term perioperative Ang1 supplementation may also have therapeutic potential in conjunction with adjuvant chemotherapy for TNBC. PMID:27841282

  4. [Nuclear transfer and therapeutic cloning].

    PubMed

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

    2005-03-01

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

  5. Proteases as therapeutics

    PubMed Central

    Craik, Charles S.; Page, Michael J.; Madison, Edwin L.

    2015-01-01

    Proteases are an expanding class of drugs that hold great promise. The U.S. FDA (Food and Drug Administration) has approved 12 protease therapies, and a number of next generation or completely new proteases are in clinical development. Although they are a well-recognized class of targets for inhibitors, proteases themselves have not typically been considered as a drug class despite their application in the clinic over the last several decades; initially as plasma fractions and later as purified products. Although the predominant use of proteases has been in treating cardiovascular disease, they are also emerging as useful agents in the treatment of sepsis, digestive disorders, inflammation, cystic fibrosis, retinal disorders, psoriasis and other diseases. In the present review, we outline the history of proteases as therapeutics, provide an overview of their current clinical application, and describe several approaches to improve and expand their clinical application. Undoubtedly, our ability to harness proteolysis for disease treatment will increase with our understanding of protease biology and the molecular mechanisms responsible. New technologies for rationally engineering proteases, as well as improved delivery options, will expand greatly the potential applications of these enzymes. The recognition that proteases are, in fact, an established class of safe and efficacious drugs will stimulate investigation of additional therapeutic applications for these enzymes. Proteases therefore have a bright future as a distinct therapeutic class with diverse clinical applications. PMID:21406063

  6. Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: to use or not to use?

    PubMed

    Strioga, Marius M; Darinskas, Adas; Pasukoniene, Vita; Mlynska, Agata; Ostapenko, Valerijus; Schijns, Virgil

    2014-07-07

    Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens.

  7. Application of Fluorescent Protein Expressing Strains to Evaluation of Anti-Tuberculosis Therapeutic Efficacy In Vitro and In Vivo

    PubMed Central

    Kong, Ying; Yang, Dong; Cirillo, Suat L. G.; Li, Shaoji; Akin, Ali; Francis, Kevin P.; Maloney, Taylor; Cirillo, Jeffrey D.

    2016-01-01

    The slow growth of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), hinders development of new diagnostics, therapeutics and vaccines. Using non-invasive real-time imaging technologies to monitor the disease process in live animals would facilitate TB research in all areas. We developed fluorescent protein (FP) expressing Mycobacterium bovis BCG strains for in vivo imaging, which can be used to track bacterial location, and to quantify bacterial load in live animals. We selected an optimal FP for in vivo imaging, by first cloning six FPs: tdTomato, mCherry, mPlum, mKate, Katushka and mKeima, into mycobacteria under either a mycobacterial Hsp60 or L5 promoter, and compared their fluorescent signals in vitro and in vivo. Fluorescence from each FP-expressing strain was measured with a multimode reader using the optimal excitation and emission wavelengths for the FP. After normalizing bacterial numbers with optical density, the strain expressing L5-tdTomato displayed the highest fluorescence. We used the tdTomato-labeled M. bovis BCG to obtain real-time images of pulmonary infections in living mice and rapidly determined the number of bacteria present. Further comparison between L5-tdTomato and Hsp60-tdTomato revealed that L5-tdTomato carried four-fold more tdTomato gene copies than Hsp60-tdTomato, which eventually led to higher protein expression of tdTomato. Evaluating anti-TB efficacy of rifampicin and isoniazid therapy in vitro and in vivo using the L5-tdTomato strain demonstrated that this strain can be used to identify anti-TB therapeutic efficacy as quickly as 24 h post-treatment. These M. bovis BCG reporter strains represent a valuable new tool for evaluation of therapeutics, vaccines and virulence. PMID:26934495

  8. Adjuvant chemotherapy in elderly patients with pancreatic cancer

    PubMed Central

    Nagrial, A M; Chang, D K; Nguyen, N Q; Johns, A L; Chantrill, L A; Humphris, J L; Chin, V T; Samra, J S; Gill, A J; Pajic, M; Pinese, M; Colvin, E K; Scarlett, C J; Chou, A; Kench, J G; Sutherland, R L; Horvath, L G; Biankin, A V

    2014-01-01

    Background: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer. Methods: We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative. Results: The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ⩾70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8% P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27–2.78, P=0.002). Conclusion: Patients aged ⩾70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer. PMID:24263063

  9. The effect of immediate breast reconstruction on the timing of adjuvant chemotherapy: a systematic review.

    PubMed

    Xavier Harmeling, J; Kouwenberg, Casimir A E; Bijlard, Eveline; Burger, Koert N J; Jager, Agnes; Mureau, Marc A M

    2015-09-01

    Adjuvant 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 current systematic review aims to investigate this effect. During October 2014, a systematic search for clinical studies was performed in six databases with keywords related to breast reconstruction and chemotherapy. Eligible studies met the following inclusion criteria: (1) research population consisted of women receiving therapeutic mastectomy, (2) comparison of IBR with mastectomy only groups, (3) TTC was clearly presented and mentioned as outcome measure, and (4) original studies only (e.g., cohort study, randomized controlled trial, case-control). Fourteen studies were included, representing 5270 patients who had received adjuvant chemotherapy, of whom 1942 had undergone IBR and 3328 mastectomy only. One study found a significantly shorter mean TTC of 12.6 days after IBR, four studies found a significant delay after IBR averaging 6.6-16.8 days, seven studies found no significant difference in TTC between IBR and mastectomy only, and two studies did not perform statistical analyses for comparison. In studies that measured TTC from surgery, mean TTC varied from 29 to 61 days for IBR and from 21 to 60 days for mastectomy only. This systematic review of the current literature showed that IBR does not necessarily delay the start of adjuvant chemotherapy to a clinically relevant extent, suggesting that in general IBR is a valid option for non-metastatic breast cancer patients.

  10. Mucosal adjuvants to improve wildlife rabies vaccination.

    PubMed

    Fry, Tricia; Van Dalen, Kaci; Hurley, Jerome; Nash, Paul

    2012-10-01

    RABORAL V-RG(®)a is a recombinant vaccine used in oral rabies vaccination (ORV) programs for wildlife in the United States. Vaccination rates for raccoons are substantially lower than vaccination rates for gray foxes and coyotes. Research suggests that the low viscosity of the oral vaccine may preclude animals from receiving an effective dose when biting into the vaccine bait delivery system. We evaluated the possibility of using two benign compounds, chitosan and N,N,N-trimethylated chitosan (TMC), to increase the viscosity of the vaccine and potentially act as adjuvants to improve the immune response in raccoons (Procyon lotor). Forty mildly sedated raccoons were orally vaccinated via needleless syringe with either RABORAL V-RG (n = 12), chitosan+RABORAL V-RG (n = 12), TMC+ RABORAL V-RG (n = 12), or no vaccine (n = 4), on day 0 and again on day 90. We collected sera every 2-4 wk for 4 mo and evaluated rabies virus-neutralizing antibodies (rVNA). Raccoons were considered responders if rVNA titers were ≥ 0.1 IU/mL. Eleven of 12 raccoons vaccinated with TMC+RABORAL V-RG responded after one dose of vaccine, as did eight of 12 vaccinated with RABORAL V-RG, and three of 12 vaccinated with chitosan+ RABORAL V-RG. Our results suggest that the inclusion of an adjuvant, such as TMC, could increase vaccine efficacy to aid in controlling rabies virus spread in wildlife reservoirs.

  11. Safety assessment of adjuvanted vaccines: Methodological considerations

    PubMed Central

    Da Silva, Fernanda Tavares; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID:26029975

  12. [Development of agonists/antagonists for protease-activated receptors (PARs) and the possible therapeutic application to gastrointestinal diseases].

    PubMed

    Sekiguchi, Fumiko

    2005-06-01

    Protease-activated receptors (PARs), a family of G-protein-coupled seven-transmembrane-domain receptors, are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand by certain serine proteases. Among four PAR family members cloned to date, PAR-1, PAR-2, and PAR-4 can also be activated through a non-enzymatic mechanism, which is achieved by direct binding of exogenously applied synthetic peptides based on the tethered ligand sequence, known as PARs-activating peptides, to the body of the receptor. Various peptide mimetics have been synthesized as agonists for PARs with improved potency, selectivity, and stability. Some peptide mimetics and/or nonpeptide compounds have also been developed as antagonists for PAR-1 and PAR-4. PARs are widely distributed in the mammalian body, especially throughout the alimentary systems, and play various roles in physiological/pathophysiological conditions, i.e., modulation of salivary, gastric, or pancreatic glandular exocrine secretion, gastrointestinal smooth muscle motility, gastric mucosal cytoprotection, suppression/facilitation of visceral pain and inflammation, etc. Thus PARs are now considered novel therapeutic targets, and development of selective agonists and/or antagonists for PARs might provide a novel strategy for the treatment of various diseases that are resistant to current therapeutics.

  13. Therapeutic applications of the TAT-mediated protein transduction system for complex I deficiency and other mitochondrial diseases.

    PubMed

    Lin, Bo-Yu; Kao, Mou-Chieh

    2015-09-01

    Among the five enzyme complexes in the oxidative phosphorylation system, NADH-coenzyme Q oxidoreductase (also called complex I) is the largest, most intricate, and least understood. This enzyme complex spans the inner mitochondrial membrane and catalyzes the first step of electron transfer by the oxidation of NADH, and thereby provides two electrons for the reduction of quinone to quinol. Complex I deficiency is associated with many severe mitochondrial diseases, including Leber hereditary optic neuropathy and Leigh syndrome. However, to date, conventional treatments for the majority of genetic mitochondrial diseases are only palliative. Developing a reliable and convenient therapeutic approach is therefore considered to be an urgent need. Targeted proteins fused with the protein transduction domain of human immunodeficiency virus 1 transactivator of transcription (TAT) have been shown to enter cells by crossing plasma membranes while retaining their biological activities. Recent developments show that, in fusion with mitochondrial targeting sequences (MTSs), TAT-MTS-bound cargo can be correctly transported into mitochondria and restore the missing function of the cargo protein in patients' cells. The available evidence suggests that the TAT-mediated protein transduction system holds great promise as a potential therapeutic approach to treat complex I deficiency, as well as other mitochondrial diseases.

  14. Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

    PubMed Central

    Ishima, Yu; Kragh-Hansen, Ulrich; Maruyama, Toru; Otagiri, Masaki

    2013-01-01

    Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent. PMID:24490156

  15. Therapeutic advantages of medicinal herbs fermented with Lactobacillus plantarum, in topical application and its activities on atopic dermatitis.

    PubMed

    Joo, Seong Soo; Won, Tae Joon; Nam, Sang Yoon; Kim, Yun-Bae; Lee, Young Chul; Park, So-Yong; Park, Hee Yong; Hwang, Kwang Woo; Lee, Do Ik

    2009-07-01

    The use of herbal medicines in the therapeutic treatment of atopic dermatitis (AD) has been suggested recently. The present study examined whether selected herbal extracts fermented in Lactobacillus plantarum (FHE) possessed anti-AD properties. In addition, the study assessed the increased bioavailability of these herbal extracts both in vitro and in vivo. The data from these experiments revealed that FHE inhibited the proliferation of splenic T and B cells in a dose-dependent manner, when activated with their mitogens. Moreover, the expression of Th1/Th2 mRNA cytokines (IL-2, IL-4, IL-5, IL-13) from mouse splenocytes was inhibited severely as was cyclosporine A. Furthermore, the release of beta-hexosaminidase in RBL-2H3 mast cells was suppressed significantly. FHE also reduced the plasma level of IgE in dust mite extract-induced AD-like NC/Nga mice. More dramatic results were found in the histological changes, which were observed by hematoxylin-eosin and toluidine blue staining, as well as in the macroscopic features on dorsal lesions of AD-like NC/Nga mice. In conclusion, the results presented in this study suggest that FHE may have therapeutic advantages for the treatment of AD due to its increased immune-suppressive and increased absorptive effects, which were fortified by L. plantarum fermentation.

  16. The potential therapeutic applications and prognostic significance of metastasis-associated in colon cancer-1 (MACC1) in cancers

    PubMed Central

    2016-01-01

    The metastasis-associated in colon cancer-1 (MACC1) gene was identified in 2009. Expression of MACC1 was found to be significantly upregulated in primary and metastatic colon carcinomas compared to normal tissues or adenomas. The induction of MACC1 occurs at the crucial step of transition from a benign to a malignant phenotype. The aim of this review was to summarise current results of non-clinical and clinical studies on the role of MACC1 in the carcinogenesis and progression of cancer, as well its potential therapeutic and prognostic significance. The gene encoding the HGF receptor MET is a transcriptional target of MACC1. In addition to promoting the proliferation, invasion, and migration of colon cancer cells in cell culture and tumour growth and metastasis in mouse models, MACC1 also contributes to carcinogenesis and progression of colorectal cancer through the β-catenin signalling pathway and mesenchymal-epithelial transition. MACC1 knockdown with si/sh RNA was investigated in cell lines of different types of cancer. MACC1 is a promising therapeutic target for antitumour and antimetastatic intervention strategies for cancers. Here, it is presented as a potential independent prognostic indicator of reduced overall survival as well as of the occurrence of distant metastasis in patients with different types of cancer. PMID:27688722

  17. Therapeutic Antioxidant Medical Gas

    PubMed Central

    Nakao, Atsunori; Sugimoto, Ryujiro; Billiar, Timothy R; McCurry, Kenneth R

    2009-01-01

    Medical gases are pharmaceutical gaseous molecules which offer solutions to medical needs and include traditional gases, such as oxygen and nitrous oxide, as well as gases with recently discovered roles as biological messenger molecules, such as carbon monoxide, nitric oxide and hydrogen sulphide. Medical gas therapy is a relatively unexplored field of medicine; however, a recent increasing in the number of publications on medical gas therapies clearly indicate that there are significant opportunities for use of gases as therapeutic tools for a variety of disease conditions. In this article, we review the recent advances in research on medical gases with antioxidant properties and discuss their clinical applications and therapeutic properties. PMID:19177183

  18. Adjuvant chemotherapy for endometrial cancer after hysterectomy

    PubMed Central

    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

  19. Vaccine Adjuvants: from 1920 to 2015 and Beyond

    PubMed Central

    Di Pasquale, Alberta; Preiss, Scott; Tavares Da Silva, Fernanda; Garçon, Nathalie

    2015-01-01

    The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines. PMID:26343190

  20. Chrysin Increases the Therapeutic Efficacy of Docetaxel and Mitigates Docetaxel-Induced Edema.

    PubMed

    Lim, Hyun-Kyung; Kim, Kyoung Mee; Jeong, Seong-Yun; Choi, Eun Kyung; Jung, Joohee

    2016-05-05

    Docetaxel (DTX) is an effective commercial anticancer agent for chemotherapy in non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, and prostate cancer, but its adverse effects including edema, neurotoxicity, and hair loss limit its application. To improve the chemotherapeutic efficacy of DTX and reduce adverse effects, combination therapy is one of the alternative methods. So chrysin, which has various biological activities including anticancer effects, was considered. In vitro, the combination of chrysin and DTX was investigated in A549 cells. Increased cytotoxicity, suppressed cellular proliferation, and induced apoptosis were observed with posttreatment of chrysin following DTX treatment. In vivo, chrysin enhanced the tumor growth delay of DTX and increased DTX-induced apoptosis in the A549-derived xenograft model. Furthermore, chrysin prevented DTX-induced edema in ICR mouse. These results indicated that chrysin strengthened the therapeutic efficacy of DTX and diminished the adverse effect of DTX, suggesting chrysin could be exploited as an adjuvant therapy for NSCLC.

  1. No benefit of therapeutic vaccination in clinically healthy cats persistently infected with feline leukemia virus.

    PubMed

    Helfer-Hungerbuehler, A Katrin; Spiri, Andrea M; Riond, Barbara; Grest, Paula; Boretti, Felicitas S; Hofmann-Lehmann, Regina

    2015-03-24

    Therapeutic vaccinations have a potential application in infections where no curative treatment is available. In contrast to HIV, efficacious vaccines for a cat retrovirus, feline leukemia virus (FeLV), are commercially available. However, the infection is still prevalent, and no effective treatment of the infection is known. By vaccinating persistently FeLV-infected cats and presenting FeLV antigens to the immune system of the host, e.g., in the form of recombinant and/or adjuvanted antigens, we intended to shift the balance toward an advantage of the host so that persistent infection could be overcome by the infected cat. Two commercially available FeLV vaccines efficacious in protecting naïve cats from FeLV infection were tested in six experimentally and persistently FeLV-infected cats: first, a canarypox-vectored vaccine, and second, an adjuvanted, recombinant envelope vaccine was repeatedly administered with the aim to stimulate the immune system. No beneficial effects on p27 antigen and plasma viral RNA loads, anti-FeLV antibodies, or life expectancy of the cats were detected. The cats were unable to overcome or decrease viremia. Some cats developed antibodies to FeLV antigens although not protective. Thus, we cannot recommend vaccinating persistently FeLV-infected cats as a means of improving their FeLV status, quality of life or life expectancy. We suggest testing of all cats for FeLV infection prior to FeLV vaccination.

  2. Adjuvant therapy for colon cancer in the new millenium.

    PubMed

    Rao, S; Cunningham, D

    2003-01-01

    A significant proportion of patients with colon cancer who undergo curative surgical resection develop metastatic disease. Over the last 20 years large prospective randomised studies have demonstrated a clear survival benefit for patients with stage III colon cancer who are treated with adjuvant 5FU based chemotherapy. At the present time 6 months of 5FU and leucovorin is generally considered the standard adjuvant therapy. For stage II disease the routine use of adjuvant treatment remains controversial. Newer drugs such as oxaliplatin, irinotecan, and the oral fluoropyrimidines have proven active in advanced colorectal cancer and are currently being evaluated in the adjuvant setting. Molecular markers for this disease are being identified and may help define those patients who would benefit from therapy. The integration of adjuvant immunotherapy with conventional chemotherapy offers the potential to improve the long-term outcome for surgically resected colon cancer.

  3. Predictive markers of safety and immunogenicity of adjuvanted vaccines.

    PubMed

    Mastelic, Beatris; Garçon, Nathalie; Del Giudice, Giuseppe; Golding, Hana; Gruber, Marion; Neels, Pieter; Fritzell, Bernard

    2013-11-01

    Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.

  4. Emerging Roles of the Host Defense Peptide LL-37 in Human Cancer and its Potential Therapeutic Applications

    PubMed Central

    Wu, William K.K.; Wang, Guangshun; Coffelt, Seth B.; Betancourt, Aline M.; Lee, Chung W.; Fan, Daiming; Wu, Kaichun; Yu, Jun; Sung, Joseph J.Y.; Cho, Chi H.

    2010-01-01

    Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does it eliminate pathogenic microbes directly, LL-37 also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. While overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide. PMID:20521250

  5. Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications.

    PubMed

    Wu, William K K; Wang, Guangshun; Coffelt, Seth B; Betancourt, Aline M; Lee, Chung W; Fan, Daiming; Wu, Kaichun; Yu, Jun; Sung, Joseph J Y; Cho, Chi H

    2010-10-15

    Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does LL-37 eliminate pathogenic microbes directly but also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. Although overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide.

  6. [Regulation of inflammatory responses by endothelial cells--understanding the molecular mechanism(s) and its therapeutic application to sepsis].

    PubMed

    Okajima, Kenji

    2008-03-01

    Endothelial cells are activated by shear-stress and inflammatory mediators that are capable of activating sensory neurons. Activated endothelial cells increase the production of nitric oxide and prostaglandins, thereby regulating inflammatory responses induced by various insults. Dysfunction of sensory neurons and excess inflammatory mediators released from activated neutrophils damage endothelial cells, thereby increasing inflammatory responses such as an increase in tumor necrosis factor production. Pulmonary endothelial dysfunction plays a critical role in the development of acute lung injury and shock, leading to multi-organ failure. Determination of soluble E-selectin in serum samples of patients with sepsis predicts the future development of acute lung injury. Therapeutic agents that are capable of stimulating sensory neurons or inhibiting leukocyte activation might be useful in the treatment of severe sepsis especially when these agents are administered in the early stage of severe sepsis.

  7. Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma.

    PubMed

    Wolterink, Silke; Moldenhauer, Gerhard; Fogel, Mina; Kiefel, Helena; Pfeifer, Marco; Lüttgau, Sandra; Gouveia, Ricardo; Costa, Julia; Endell, Jan; Moebius, Ulrich; Altevogt, Peter

    2010-03-15

    Recent work has identified L1CAM (CD171) as a novel marker for human carcinoma progression. Functionally, L1CAM promotes tumor cell invasion and motility, augments tumor growth in nude mice, and facilitates experimental tumor metastasis. These functional features qualify L1 as an interesting target molecule for tumor therapy. Here, we generated a series of novel monoclonal antibodies (mAb) to the L1CAM ectodomain that were characterized by biochemical and functional means. All novel mAbs reacted specifically with L1CAM and not with the closely related molecule CHL1, whereas antibodies to the COOH terminal part of L1CAM (mAb2C2, mAb745H7, pcytL1) showed cross-reactivity. Among the novel mAbs, L1-9.3 was selected and its therapeutic potential was analyzed in various isotype variants in a model of SKOV3ip cells growing i.p. in CD1 nude mice. Only therapy with the IgG2a variant efficiently prolonged survival and reduced tumor burden. This was accompanied by an increased infiltration of F4/80-positive monocytic cells. Clodronate pretreatment of tumor-bearing animals led to the depletion of monocytes and abolished the therapeutic effect of L1-9.3/IgG2a. Expression profiling of tumor-derived mRNA revealed that L1-9.3/IgG2a therapy induced altered expression of cellular genes associated with apoptosis and tumor growth. Our results establish that anti-L1 mAb therapy acts via immunologic and nonimmunologic effector mechanism to block tumor growth. The novel antibodies to L1CAM could become helpful tools for the therapy of L1-positive human carcinomas.

  8. Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer's Disease Biology: Characterization of Putative Cognates for Therapeutic Applications.

    PubMed

    Jha, Niraj Kumar; Jha, Saurabh Kumar; Kumar, Dhiraj; Kejriwal, Noopur; Sharma, Renu; Ambasta, Rashmi K; Kumar, Pravir

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative process primarily characterized by amyloid-β (Aβ) agglomeration, neuroinflammation, and cognitive dysfunction. The prominent cause for dementia is the deposition of Aβ plaques and tau-neurofibrillary tangles that hamper the neuronal organization and function. Aβ pathology further affects numerous signaling cascades that disturb the neuronal homeostasis. For instance, Aβ deposition is responsible for altered expression of insulin encoding genes that lead to insulin resistance, and thereby affecting insulin signaling pathway and glucose metabolism in the brain. As a result, the common pathology of insulin resistance between Type-2 diabetes mellitus and AD has led AD to be proposed as a form of diabetes and termed 'Type-3 diabetes'. Since accumulation of Aβ is the prominent cause of neuronal toxicity in AD, its clearance is the prime requisite for therapeutic prospects. This purpose is expertly fulfilled by the potential role of Aβ degrading enzymes such as insulin degrading enzyme (IDE) and Neprilysin (NEP). Therefore, their molecular study is important to uncover the proteolytic and regulatory mechanism of Aβ degradation. Herein, (i) In silico sequential and structural analysis of IDE and NEP has been performed to identify the molecular entities for proteolytic degradation of Aβ in the AD brain, (ii) to analyze their catalytic site to demonstrate the enzymatic action played by IDE and NEP, (iii) to identify their structural homologues that could behave as putative partners of IDE and NEP with similar catalytic action and (iv) to illustrate various IDE- and NEP-mediated therapeutic approaches and factors for clearing Aβ in AD.

  9. Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

    PubMed Central

    HogenEsch, Harm

    2013-01-01

    Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines. PMID:23335921

  10. Bisphosphonates in the adjuvant treatment of young women with breast cancer: the estrogen rich is a poor candidate!

    PubMed

    Azim, Hamdy A; Kamal, Nermine S; Malak, Rafaat A

    2013-06-01

    During the last 2 decades the role of bisphosphonates (BPs) to reduce skeletal-related events from bone metastases in breast cancer has been well defined. Several preclinical studies have strongly suggested that BPs may also provide an anti-cancer effect in early breast cancer. Indeed, the use of adjuvant BPs represents a unique approach that attempts at eradicating occult tumor micro-metastases residing in the bone marrow via targeting the bone microenvironment to render it less favorable for cancer cell growth. Although, this concept has been tested clinically for more than 15 years, no final consensus has been reached as for the routine use of BPs in the adjuvant phase of breast cancer, owing to conflicting results of randomized studies. Nevertheless, accumulating evidence from recent trials has indicated a therapeutic benefit of adjuvant BPs-particularly zoledronic acid-in women with established menopause, with no or perhaps detrimental effects in premenopausal women. Indeed, this hypothesis has opened a new chapter on the role of estrogen-poor microenvironment as a potential pre-requisite for the anti-tumor effects of BPs in the adjuvant phase of breast cancer. In this review, we will emphasize the biological rational of using BPs to target bone microenvironment in patients with early breast cancer and we will explore mechanistic differences; related to bisphosphonates effects in premenopausal versus postmenopausal women and how the endocrine environment would influence the anticancer potential of these compounds.

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

    PubMed

    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.

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

    PubMed

    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.

  13. Boron Neutron Capture Therapty (BNCT) in an Oral Precancer Model: Therapeutic Benefits and Potential Toxicity of a Double Application of BNCT with a Six-Week Interval

    SciTech Connect

    Andrea Monti Hughes; Emiliano C.C. Pozzi; Elisa M. Heber; Silvia Thorp; Marcelo Miller; Maria E. Itoiz; Romina F. Aromando; Ana J. Molinari; Marcela A. Garabalino; David W. Nigg; Veronica A. Trivillin; Amanda E. Schwint

    2011-11-01

    Given the clinical relevance of locoregional recurrences in head and neck cancer, we developed a novel experimental model of premalignant tissue in the hamster cheek pouch for long-term studies and demonstrated the partial inhibitory effect of a single application of Boron Neutron Capture Therapy (BNCT) on tumor development from premalignant tissue. The aim of the present study was to evaluate the effect of a double application of BNCT with a 6 week interval in terms of inhibitory effect on tumor development, toxicity and DNA synthesis. We performed a double application, 6 weeks apart, of (1) BNCT mediated by boronophenylalanine (BPA-BNCT); (2) BNCT mediated by the combined application of decahydrodecaborate (GB-10) and BPA [(GB-10 + BPA)-BNCT] or (3) beam-only, at RA-3 nuclear reactor and followed the animals for 8 months. The control group was cancerized and sham-irradiated. BPA-BNCT, (GB- 10 + BPA)-BNCT and beam-only induced a reduction in tumor development from premalignant tissue that persisted until 8, 3, and 2 months respectively. An early maximum inhibition of 100% was observed for all 3 protocols. No normal tissue radiotoxicity was detected. Reversible mucositis was observed in premalignant tissue, peaking at 1 week and resolving by the third week after each irradiation. Mucositis after the second application was not exacerbated by the first application. DNA synthesis was significantly reduced in premalignant tissue 8 months post-BNCT. A double application of BPA-BNCT and (GB-10 + BPA)-BNCT, 6 weeks apart, could be used therapeutically at no additional cost in terms of radiotoxicity in normal and dose-limiting tissues.

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

    PubMed

    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.

  15. [Recurrent micro-satellite stable colonic cancer: prolonged survival of 16 years without adjuvant therapy].

    PubMed

    Grothe, D; Kasperk, R

    2004-10-01

    Long-term survival in malignant disease is often linked to intensified therapeutic interventions. We report the case of a colonic cancer in a 78 years old female patient, who underwent her first operation in 1987 for a symptomatic T4 carcinoma. Since then, the patient has always denied any form of follow-up examination and adjuvant therapy. Recently, she has undergone her fourth operation, which for the first time demonstrated peritoneal carcinosis, and is still in very good health.Clinical experience shows that in some cases standard therapies may unexpectedly produce extremely long survival times. This has to be kept in mind when the value of prognostic markers is discussed and limits the validity of survival data in the context of small scale studies dealing with especially extended therapeutic protocols.

  16. Practical Synthesis of Prostratin, DPP, and Their Analogs, Adjuvant Leads Against Latent HIV

    PubMed Central

    Wender, Paul A.; Kee, Jung-Min; Warrington, Jeffrey M.

    2009-01-01

    Although antiretroviral therapies have been effective in decreasing active viral loads in AIDS patients, the persistence of latent viral reservoirs prevents eradication of the virus. Prostratin and DPP (12-deoxyphorbol-13-phenylacetate) activate the latent virus and thus represent promising adjuvants for antiviral therapy. Their limited supply and the challenges of accessing related structures have, however, impeded therapeutic development and the search for clinically superior analogs. Here we report a practical synthesis of prostratin and DPP starting from phorbol or crotophorbolone, agents readily available from renewable sources, including a biodiesel candidate. This synthesis reliably supplies gram quantities of the therapeutically promising natural products, hitherto available only in low and variable amounts from natural sources, and opens access to a variety of new analogs. PMID:18451298

  17. Liposomes as immune adjuvants: T cell dependence.

    PubMed

    Beatty, J D; Beatty, B G; Paraskevas, F; Froese, E

    1984-08-01

    The T cell dependence of the immune adjuvant action of liposomes containing the soluble antigens bovine serum albumin (BSA) and chicken immunoglobulin (CIgG) was studied with use of a quantitative enzyme-linked immunosorbent assay to measure serum antibody levels. Normal BALB/c mice, adult thymectomized mice, and congenitally athymic (nu+/nu+) mice were intravenously inoculated with liposomes containing BSA (Lip-BSA). The high levels of serum anti-BSA antibody that were seen in the normal group were decreased in the adult thymectomized group and were almost completely abrogated in the nu+/nu+ group. Reconstitution of nu+/nu+ mice with normal thymocytes and cortisone-resistant thymocytes led to a partial restoration of the anti-BSA antibody production after Lip-BSA immunization. Examination of the class of immunoglobulin produced in normal mice, immunized with Lip-BSA, showed an early low IgM response and a sustained higher IgG response that was primarily due to the IgG1 subclass. Trypsin removal of BSA exposed on the liposome surface decreased the resulting serum anti-BSA antibody level by 30% to 50%. Animals could be primed equally with a very low dose (0.2 micrograms) of Lip-BSA or with peritoneal macrophages that had phagocytosed the same dose of Lip-BSA. The adjuvant effect of liposomes containing CIgG on the number and type of specific anti-CIgG antibody-producing cells in the spleen was an early increase in IgM-producing cells followed by a substantially higher increase in IgG-producing cells. These observations suggest that liposome encapsulation of a soluble T-dependent antigen stimulates the helper T cell, not the suppressor T cell population, and that this stimulation involves uptake by macrophages.

  18. Targeting Human Poly(ADP-Ribose) Polymerase-1 with Natural Medicines and Its Potential Applications in Ovarian Cancer Therapeutics.

    PubMed

    Song, Min; Li, Jun-Lan; Li, Xiao-Ping; Kan, Shi-Feng

    2015-09-07

    Targeting poly(ADP-ribose) polymerase-1 (PARP-1) has been established as an efficient therapeutics for advanced ovarian cancer. In this study, we describe an integrated procedure that combines virtual computer screening and an experimental enzyme assay to discover novel potent PARP-1 inhibitors from more than 130000 commercially available natural products. The protocol employed a stepwise strategy to fast exclude typical PARP-1 non-binders and then performing rigorous prediction to identify promising candidates with high potency against PARP-1. Consequently, eight natural products were hit and tested to determine their inhibitory activities against the PARP-1 catalytic domain. From these, four compounds, i.e., puerarin, phloretin, chlorogenic acid, and biochanin A, were found to have high or moderate potencies with inhibitory IC50 values of 6, 470, 25, and 86 nM, respectively. The values are comparable to that (IC50  = 1.94 nM) of the FDA-approved agent olaparib. Structural and energetic analyses of the modeled structures of the PARP-1 catalytic domain complexed with the newly identified inhibitors revealed a common binding mode in the complexes: the active site of PARP-1 is composed of a thin polar helix and a flat non-polar pocket; the inhibitors can form a number of hydrogen bonds and electrostatic forces with the helix, while tightly packing against the pocket to define chemical interactions.

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

    PubMed

    Gerdts, Volker

    2015-01-01

    Adj