Sample records for viable therapeutic strategy

  1. How Can We Prevent Violence Becoming a Viable Political Strategy?


    Patricia Justino


    A basic issue that conflict analysis investigates is how non-peaceful ways of living and governing become viable political strategies. Macro-level studies provide some important insights but micro-level analysis is vital to understand the mechanisms that make violence possible. This briefing outlines some preliminary findings in this respect from MICROCON, a major research programme analysing violent conflict at the micro level. It also discusses their implications for policies aimed at preve...

  2. Kinetoplastida: new therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Croft S.L.


    Full Text Available New formulations and therapeutic switching of the established drugs, amphotericin B and paromomycin, together with the discovery of miltefosine, have significantly improved the opportunities for treatment of visceral leishmaniasis (VL chemotherapy. However, for human African trypanosomiasis (HAT, Chagas disease and cutaneous leishmaniases there has been limited progress. For HAT, a novel diamidine, parfuramidine, is in phase III clinical trial for early-stage disease, but for the treatment of late-stage disease there are no new drugs and combinations of eflornithine with melarsoprol or nifurtimox have been the focus of clinical studies. For Chagas disease, different classes of compounds that have validated biochemical targets, sterol biosynthesis methylases and cysteine proteases, are in various stages of development. The genome sequences that are now available for the pathogens that cause the leishmaniases and trypanosomiases, and new methods for rapid validation of targets, are part of the solution to discover new drugs. The integration of medicinal chemistry, pharmacokinetics, project planning and interaction with the pharma/biotech sector are essential if progress is to be made. Although there are financial constraints, the appearance of new funding sources and not-for-profit product development partnerships offers hope for drug development.

  3. Enabling Strategy Formulation by ICT: A Viable Systems Approach

    NARCIS (Netherlands)

    Vriens, D.J.; Achterbergh, J.M.I.M.


    In this chapter the role of ICT for competitive intelligence is approached from the perspective of strategy formulation. The authors hold the view that competitive intelligence can be seen as knowledge necessary for the process of strategy formulation. To determine the role of ICT, it is proposed to

  4. Is Microcredit a Viable Strategy for Empowering Women?

    African Journals Online (AJOL)

    target women and provide accompanying education on health, nutrition, family planning, financial planning and budgeting and microenterprise development. The strategy for credit delivery differs from microcredit to microcredit. An important policy of credit schemes is the establishment of loan beneficiary selection criteria.

  5. Emerging therapeutic strategies for obesity. (United States)

    Foster-Schubert, Karen E; Cummings, David E


    The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss.

  6. Therapeutic strategies in pulmonary hypertension

    Directory of Open Access Journals (Sweden)

    Leonello eFuso


    Full Text Available Pulmonary hypertension (PH is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an ideal therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal-oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators.

  7. Early rheumatoid arthritis: therapeutic strategies. (United States)

    Emery, P


    The early stage of rheumatoid arthritis (RA) is a unique and critical phase of disease which is often characterized by profound inflammation, severe symptomatology and a high likelihood of radiological progression. Decisions on treatment strategies need to be taken before irreversible damage and functional deterioration occur. There is evidence that early intervention with disease-modifying drugs may reduce functional deterioration and improve long-term outcome. Stable genetic markers and rheumatoid factor are useful in predicting disease severity and thus in identifying those patients who require early aggressive therapy. The acute phase response (APR) is a valuable marker of disease activity and catabolism in RA, and suppression of the APR improves outcome. The use of early aggressive therapy to suppress disease efficiently in patients with a poor prognosis should improve the long-term morbidity and mortality associated with RA.

  8. ELISA microplate: a viable immunocapture platform over magnetic beads for immunoaffinity-LC-MS/MS quantitation of protein therapeutics? (United States)

    Yang, Wenchu; Kernstock, Robert; Simmons, Neal; Alak, Ala


    Evaluate the performance of ELISA microplates versus commonly used magnetic beads for biological sample cleanup and/or enrichment in immunoaffinity-LC-MS/MS to reduce tedious beads washing procedures and a relatively high assay cost. ELISA microplates were used as immunicapture platform and compared with magnetic beads for sample cleanup for LC-MS/MS quantitation of protein therapeutics. One unmodified and two surface-activated microplates provided comparable linear ranges and sensitivities for a therapeutic protein (mass 78 kDa) using a human serum sample of 100 µl with 1:1 dilution compared with Tosylactivated magnetic beads using 200 µl of human serum without sample dilution. The assays' precision and accuracy were all within acceptable ranges. No nonspecific binding or other selectivity issues were observed. The results suggested an ELISA microplate could be a viable immunocapture platform for immunoaffinity-LC-MS/MS quantitation of protein therapeutics.

  9. Survival Strategy of Erwinia amylovora against Copper: Induction of the Viable-but-Nonculturable State (United States)

    Ordax, Mónica; Marco-Noales, Ester; López, María M.; Biosca, Elena G.


    Copper compounds, widely used to control plant-pathogenic bacteria, have traditionally been employed against fire blight, caused by Erwinia amylovora. However, recent studies have shown that some phytopathogenic bacteria enter into the viable-but-nonculturable (VBNC) state in the presence of copper. To determine whether copper kills E. amylovora or induces the VBNC state, a mineral medium without copper or supplemented with 0.005, 0.01, or 0.05 mM Cu2+ was inoculated with 107 CFU/ml of this bacterium and monitored over 9 months. Total and viable cell counts were determined by epifluorescence microscopy using the LIVE/DEAD kit and by flow cytometry with 5-cyano-2,3-ditolyl tetrazolium chloride and SYTO 13. Culturable cells were counted on King's B nonselective solid medium. Changes in the bacterial morphology in the presence of copper were observed by scanning electron microscopy. E. amylovora entered into the VBNC state at all three copper concentrations assayed, much faster when the copper concentration increased. The addition of different agents which complex copper allowed the resuscitation (restoration of culturability) of copper-induced VBNC cells. Finally, copper-induced VBNC cells were virulent only for the first 5 days, while resuscitated cells always regained their pathogenicity on immature fruits over 9 months. These results have shown, for the first time, the induction of the VBNC state in E. amylovora as a survival strategy against copper. PMID:16672494

  10. [Therapeutic strategy for different types of epicanthus]. (United States)

    Gaofeng, Li; Jun, Tan; Zihan, Wu; Wei, Ding; Huawei, Ouyang; Fan, Zhang; Mingcan, Luo


    To explore the reasonable therapeutic strategy for different types of epicanthus. Patients with epicanthus were classificated according to the shape, extent and inner canthal distance and treated with different methods appropriately. Modified asymmetric Z plasty with two curve method was used in lower eyelid type epicanthus, inner canthus type epicanthus and severe upper eyelid type epicanthus. Moderate upper epicanthus underwent '-' shape method. Mild Upper epicanthus in two conditions which underwent nasal augumentation and double eyelid formation with normal inner canthal distance need no correction surgery. The other mild epicanthus underwent '-' shape method. A total of 66 cases underwent the classification and the appropriate treatment. All wounds healed well. During 3 to 12 months follow-up period, all epicanthus were corrected completely with natural contour and unconspicuous scars. All patients were satisfied with the results. Classification of epicanthus hosed on the shape, extent and inner canthal distance and correction with appropriate methods is a reasonable therapeutic strategy.

  11. [Classification and therapeutic strategy for chronic tonsillitis]. (United States)

    Pal'chun, V T


    The objective of the present study was to further develop and substantiate classification of chronic tonsillitis with due regard for etiology and pathogenesis of this disease. The author pays special attention to the fact that the toxico-allergic effect of focal infection of palatine tonsils (chronic tonsillitis, CT) is significantly more pronounced than that of focal infections of a different localization. The toxico-allergic manifestations of chronic tonsillitis are not infrequently realized through the associated non-specific infectious local and general complications and catalyze pathogenesis of the concomitant diseases. The classification developed taking into consideration etiology and pathogenesis of CT distinguishes two forms of chronic tonsillitis, viz. simple and toxico-allergic (TAF) CT, the latter being subdivided into two variants differing in the character of manifestations (TAF-1 and TAF-II). The clinical, morphological, and immunological characteristics of either form are described. It is emphasized that the most informative signs and symptoms of CT include the recurrence rate of tonsillitis in the medical history, purulent discharge from the tonsillar crypts apparent upon compression of their anterior surface with a spatula, and toxico-allergic reactions in combination with local signs and tonsillitis in the medical history. The therapeutic strategies for each forms of CT are specifies. The use of conservative therapy is recommended as the principal method for the treatment of the simple form, the strict compliance with the prescribed therapeutic modalities and repetition of the second therapeutic course within 3-4 months after the initial one being of primary importance. The treatment of TAF-1 should be started from conservative therapy the duration of which needs to be reduced in the absence of the marked desired effect bearing in mind the possibility of development of local and systemic complications. TAF-II requires urgent tonsillectomy because

  12. Therapeutic Strategies Targeting Cariogenic Biofilm Microenvironment. (United States)

    Liu, Y; Ren, Z; Hwang, G; Koo, H


    Cariogenic biofilms are highly structured microbial communities embedded in an extracellular matrix, a multifunctional scaffold that is essential for the existence of the biofilm lifestyle and full expression of virulence. The extracellular matrix provides the physical and biological properties that enhance biofilm adhesion and cohesion, as well as create a diffusion-modulating milieu, protecting the resident microbes and facilitating the formation of localized acidic pH niches. These biochemical properties pose significant challenges for the development of effective antibiofilm therapeutics to control dental caries. Conventional approaches focusing solely on antimicrobial activity or enhancing remineralization may not achieve maximal efficacy within the complex biofilm microenvironment. Recent approaches disrupting the biofilm microbial community and the microenvironment have emerged, including specific targeting of cariogenic pathogens, modulation of biofilm pH, and synergistic combination of bacterial killing and matrix degradation. Furthermore, new "smart" nanotechnologies that trigger drug release or activation in response to acidic pH are being developed that could enhance the efficacy of current and prospective chemical modalities. Therapeutic strategies that can locally disrupt the pathogenic niche by targeting the biofilm structure and its microenvironment to eliminate the embedded microorganism and facilitate the action of remineralizing agents may lead to enhanced and precise anticaries approaches.

  13. Proteasome inhibitors therapeutic strategies for cancer. (United States)

    D'Alessandro, Annamaria; Pieroni, Luisa; Ronci, Maurizio; D'Aguanno, Simona; Federici, Giorgio; Urbani, Andrea


    Aberrations in the Ubiquitin-Proteasome System (UPS) have been recently connected to the pathogenesis of several human protein degradation disorders (e.g., cancer and neurodegenerative diseases), so that proteasome is now considered an important target for drug discovery. Small molecules able to inhibit and modulate UPS have been, in fact, described as novel tools for a new approach in anti-cancer therapy. In particular Proteasome Inhibitors (PIs), blocking activation of nuclear factor-kappa B (NF-kB), trigger a decreased cellular proliferation and angiogenic cytokine production, induce cell death and inhibit tumor cell adhesion to stroma. Furthermore, several studies have demonstrated that PIs potentiate the activity of other anti-cancer treatment, in part by down-regulating chemoresistance pathways. Therefore pharmacologic, preclinical, and clinical data suggested the use of PIs in anticancer strategies, for their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases. This review focuses on recent advances in the development of PIs anticancer agents highlighting both novel patented compounds and novel therapeutic protocol of intervention.

  14. Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection. (United States)

    Madeira, Mila F M; Queiroz-Junior, Celso M; Montero-Melendez, Trinidad; Werneck, Silvia M C; Corrêa, Jôice D; Soriani, Frederico M; Garlet, Gustavo P; Souza, Daniele G; Teixeira, Mauro M; Silva, Tarcilia A; Perretti, Mauro


    Alveolar bone loss is a result of an aggressive form of periodontal disease (PD) associated with Aggregatibacter actinomycetemcomitans (Aa) infection. PD is often observed with other systemic inflammatory conditions, including arthritis. Melanocortin peptides activate specific receptors to exert antiarthritic properties, avoiding excessing inflammation and modulating macrophage function. Recent work has indicated that melanocortin can control osteoclast development and function, but whether such protection takes place in infection-induced alveolar bone loss has not been investigated. The purpose of this study was to evaluate the role of melanocortin in Aa-induced PD. Mice were orally infected with Aa and treated with the melanocortin analog DTrp8-γMSH or vehicle daily for 30 d. Then, periodontal tissue was collected and analyzed. Aa-infected mice treated with DTrp8-γMSH presented decreased alveolar bone loss and a lower degree of neutrophil infiltration in the periodontium than vehicle-treated animals; these actions were associated with reduced periodontal levels of TNF-α, IFN-γ, and IL-17A. In vitro experiments with cells differentiated into osteoclasts showed that osteoclast formation and resorptive activity were attenuated after treatment with DTrp8-γMSH. Thus, melanocortin agonism could represent an innovative way to tame overexuberant inflammation and, at the same time, preserve bone physiology, as seen after Aa infection.-Madeira, M. F. M., Queiroz-Junior, C. M., Montero-Melendez, T., Werneck, S. M. C., Corrêa, J. D., Soriani, F. M., Garlet, G. P., Souza, D. G., Teixeira, M. M., Silva, T. A., Perretti, M. Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection. © FASEB.

  15. [Type 2 diabetes: what therapeutic strategy?]. (United States)

    Grimaldi, A; Hartemann-Heurtier, A


    GOAL OF TREATMENT: Prevention of diabetic micro and macroangiopathy is the goal of treatment in type 2 diabetes mellitus. A well-controlled glucose level is the key to prevention of microangiopathy; there is no threshold level. Antihypertensive treatment, with the goal of blood pressure below 130/80 mmHg is also beneficial in preventing aggravation of microangiopathy. For macroangiopathy, prevention is based in priority on treatment of other risk factors for cardiovascular disease; the threshold level for drug treatment and the therapeutic objective are those defined for secondary prevention in non-diabetic patients, i.e. blood pressure below 140/80 mmHg and LDL cholesterol under 1.30 g/l. The beneficial effect of lower glucose levels on preventing macrovascular risk was not formally demonstrated by the UKPDS, probably because the difference between the control and the treatment group HbA1c levels was minimal, 0.9 points. REVISITING STRATEGY: It is thus time to revisit the preventive strategy for type 2 diabetes mellitus, i.e. step-by-step increments, as currently proposed for worsening glucose levels. Metformine should be prescribed if the HbA1c is above normal in order to achieve the demonstrated benefit in prevention of microangiopathy and in the hope, motivated by pathophysiology data, of preventing insulin failure. Slow-release insulin at bedtime should be added to the oral hypoglycemiants if fasting glucose exceeds 1.60 or 1.80 g/l, even if the HbA1c remains below 8%. NEW HYPOGLYCEMIANTS: The role of these new agents in this more "aggressive" strategy remains to be defined. Glinides will have to demonstrate their superiority over sulfamides (fewer episodes of hypoglycemia with comparable efficacy) to justify their high cost. Glitazones will have to demonstrate a beneficial effect in second intention combination with metformine on cardiovascular morbidity mortality in type 2 diabetes patients with a metabolic insulin-resistance syndrome and visceral obesity

  16. [Therapeutic strategies in the first psychotic episode]. (United States)

    Douki, S; Taktak, M J; Ben Zineb, S; Cheour, M


    A first psychotic episode includes a wide range of disorders with different outcomes: schizophrenia, bipolar disorder, schizophreniform disorder, schizoaffective disorder, drug-induced psychosis, brief reactive psychosis, organic psychoses and delusional disorder. The course and outcome of a first psychotic episode is greatly dependent on its initial management. Major clinical, etiopathogenic and therapeutic advances have been achieved in this field and have allowed specific management strategies to be adopted. The primary task of therapists involved in the management of patients who have experienced a first episode of psychosis is promotion of recovery and prevention of secondary morbidity, relapse and persistent disability. The main guidelines of an early psychosis management are:--to keep in mind that early psychosis is not early schizophrenia. Thus, clinicians and therapists should avoid an early diagnosis of schizophrenia. Diagnosis in early psychosis can be highly unstable. A diagnosis of schizophrenia, with its implications of pessimism, relapse and disability, does not contribute anything positive in terms of guiding treatment. On the contrary, such a diagnosis may damage the patient and family by stigmatizing them and affecting the way they are viewed and managed by healthcare professionals.--To integrate biological, psychological and social interventions: effective medications is useful in reducing the risk of relapse, but is not a guarantee against it. Psychological and social interventions can greatly help promote recovery.--To tailor the various strategies to met the needs of an individual: as an example, it is important to formulate appropriate strategies for the different stages of the illness (prodromal phase, acute phase, early recovery phase and late recovery phase) because patients have different therapeutic needs at each stage.--In the acute treatment, not to concentrate on short-term goals in indicating antipsychotic treatment: prescribing

  17. Therapeutic strategies in symptomatic portal biliopathy. (United States)

    Vibert, Eric; Azoulay, Daniel; Aloia, Thomas; Pascal, Gérard; Veilhan, Luc-Antoine; Adam, René; Samuel, Didier; Castaing, Denis


    Chronic portal obstruction can lead to formation of portal cavernoma (PC). Half of all patients with PC will develop cholestasis, termed portal biliopathy, and some will progress to symptomatic biliary obstruction. Because of the high hemorrhage risk associated with biliary surgery in patients with PC, the optimal therapeutic strategy is controversial. Retrospective review of a single hepatobiliary center experience, including 64 patients with PC identified 19 patients with concurrent symptomatic biliary obstruction. Ten patients underwent initial treatment with a retroperitoneal splenorenal anastomosis. For the remaining 9 patients, portal biliopathy was managed without portosystemic shunting (PSS). Outcomes, including symptom relief, the number of biliary interventions, and survivals, were studied in these 2 groups. Within 3 months of PSS, 7 of 10 patients (70%) experienced a reduction in biliary obstructive symptoms. Five of these 10 patients subsequently underwent uncomplicated biliary bypass, and none has recurred with biliary symptoms or required biliary intervention with a mean follow-up of 8.2 years. For patients without PSS, repeated percutaneous and endobiliary procedures were required to relieve biliary symptoms. Four of the 9 patients with persistent PC required surgical intrahepatic biliary bypass, which was technically more challenging. With a mean follow-up of 8 years, 1 of these 9 patients died of severe cholangitis, 1 remained jaundiced, and 7 were asymptomatic. This study, which represents the largest published experience with the surgical treatment of patients with symptomatic portal biliopathy, indicates that retroperitoneal splenorenal anastomosis improves outcomes and should be the initial treatment of choice.

  18. New Therapeutic Strategies for Primary Sclerosing Cholangitis. (United States)

    Williamson, Kate D; Chapman, Roger W


    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  19. Towards new therapeutic strategies in chondrosarcoma

    NARCIS (Netherlands)

    Schrage, Yvonne Maria


    This thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which

  20. Therapeutic Strategy for Chronic Headache in Children

    Directory of Open Access Journals (Sweden)

    H.O. Lezhenko


    Full Text Available The therapeutic efficacy of a combined homeopathic preparation Cefavora, which consists of alcoholic extracts of Ginkgo biloba, hawthorn (Crataegus and white mistletoe (Viscum album, has been studied in the treatment of chronic tension-type headache in children. It has been shown that alongside with elimination of headache manifestations, the use of homeopathic medicine has contributed to the normalization of adaptive mechanisms of autonomic regulation in children indicating its high therapeutic efficacy.

  1. Inflammatory bowel disease: potential therapeutic strategies

    DEFF Research Database (Denmark)

    Nielsen, O H; Vainer, B; Bregenholt, S


    This review deals with potential and possibly primary therapeutics that, through insight into the inflammatory cascade, result in more rational treatment principles replacing the classical therapy of inflammatory bowel disease (IBD), i.e. Crohn's disease (CD) and ulcerative colitis (UC). These ne...

  2. Towards new therapeutic strategies in chondrosarcoma


    Schrage, Yvonne Maria


    This thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which identified Src inhibitor dasatinib as a potential target in chondrosarcoma treatment. Subsequently, growth of the majority of chondrosarcoma cell cultures was inhibited by dasatinib. In addition to dasatini...

  3. Therapeutic Vaccine Strategies against Human Papillomavirus

    Directory of Open Access Journals (Sweden)

    Hadeel Khallouf


    Full Text Available High-risk types of human papillomavirus (HPV cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of cancer immunotherapy. This is reflected by the fact that a multitude of approaches has been utilized in therapeutic HPV vaccination design: protein and peptide vaccination, DNA vaccination, nanoparticle- and cell-based vaccines, and live viral and bacterial vectors. This review provides a comprehensive overview of completed and ongoing clinical trials in therapeutic HPV vaccination (summarized in tables, and also highlights selected promising preclinical studies. Special emphasis is given to adjuvant science and the potential impact of novel developments in vaccinology research, such as combination therapies to overcome tumor immune suppression, the use of novel materials and mouse models, as well as systems vaccinology and immunogenetics approaches.

  4. Therapeutic Vaccine Strategies against Human Papillomavirus (United States)

    Khallouf, Hadeel; Grabowska, Agnieszka K.; Riemer, Angelika B.


    High-risk types of human papillomavirus (HPV) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of cancer immunotherapy. This is reflected by the fact that a multitude of approaches has been utilized in therapeutic HPV vaccination design: protein and peptide vaccination, DNA vaccination, nanoparticle- and cell-based vaccines, and live viral and bacterial vectors. This review provides a comprehensive overview of completed and ongoing clinical trials in therapeutic HPV vaccination (summarized in tables), and also highlights selected promising preclinical studies. Special emphasis is given to adjuvant science and the potential impact of novel developments in vaccinology research, such as combination therapies to overcome tumor immune suppression, the use of novel materials and mouse models, as well as systems vaccinology and immunogenetics approaches. PMID:26344626

  5. [Therapeutic strategies in idiopatic inflammatory myopathies]. (United States)

    Chakour, Reza; Leimgruber, Annette; Bart, Pierre-Alexandre; Spertini, François


    Idiopathic inflammatory myopathies, such as polymyositis and dermatomyositis, share common clinical features such as progressive, symmetrical muscle weakness prevailing in the lower limbs, associated sometimes with muscle pains. High CK and typical biopsy insure the diagnosis. Possible causes for secondary myopathies and associated diseases should be actively investigated. The search for autoantibodies helps to better classify inflammatory myopathies and to better define the prognosis of the myopathy. Glucocorticoids are the cornerstone of the early phase therapy. Glucocorticoid-sparing agents, such as azathioprine and methotrexate, are second line agents but can be readily prescribed. In case of therapeutic resistance, a rescue treatment (ciclosporine, immunoglobulins, rituximab, cyclophosphamide) could be considered.

  6. Therapeutic Strategies for Hereditary Kidney Cancer. (United States)

    Sidana, Abhinav; Srinivasan, Ramaprasad


    The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers.

  7. Scenario Analysis to Identify Viable Conservation Strategies in Paraguay's Imperiled Atlantic Forest

    Directory of Open Access Journals (Sweden)

    Matthew J. Carlson


    Full Text Available A common challenge facing land use planning is assessment of the future performance of land use options. The challenge can be acute in developing regions where land use is expanding rapidly and funding and data needed for planning are scarce. To inform land use planning for a biosphere reserve located in Paraguay's Atlantic forest region, a scenario analysis explored the relative merits of conventional and conservation agricultural practices, sustained yield forestry, and protection. Simulations compared the long-term impacts on land cover, biotic carbon, and income of the area's residents. Ecological and economic decline were projected under conventional practices. Protection and forestry scenarios achieved only small relative improvements to ecological indicators at the cost of reduced economic performance. By addressing the underlying issue of land degradation, conservation agriculture including no-tillage was the most successful land use strategy both ecologically and economically. Identification of conservation agriculture as the most promising land use strategy prioritizes issues that must be addressed to achieve sustainability, most importantly the provision of education and funding to smallholder farmers. We conclude that scenario analysis offers a flexible strategy to integrate available data for the purpose of informing land use planning in data-limited regions such as Paraguay's Atlantic forest.

  8. [Therapeutic strategies in erosive digital polyarthrosis]. (United States)

    Sahinbegovic, E; Schett, G


    One of the most common forms of osteoarthritis is hand osteoarthritis. A subgroup, termed erosive hand osteoarthritis (EHOA), shows a highly destructive disease course with involvement of multiple joints, swelling as well as cartilage and bone destruction leading to progressive loss of hand function. EHOA is characterized by subchondral erosions of the finger joints as well as ankylosis. No disease modifying therapy is currently available for the treatment of EHOA and treatment options are confined to the control of symptoms. Acetaminophen and non-steroidal anti-inflammatory drugs are used to treat the signs and symptoms. So far cytokine blocking agents have not shown a convincing therapeutic effect and the effect size of chondroitin sulfate and bisphosphonates in EOHA is small.

  9. Current guidelines in defining therapeutic strategies. (United States)

    Ferrajoli, Alessandra; Keating, Michael J


    The past three decades have brought major changes in the approach toward chronic lymphocytic leukemia (CLL). This disease was considered a simple form of leukemia for which the only goal of treatment was control of the leukocytosis and of the symptoms related to disease expansion. Many biologic discoveries have increased our understanding of the disease process. New prognostic markers have been identified and are being incorporated into clinical practice. Now, CLL is considered a complex and challenging leukemia for which multiple treatment options are emerging, from chemotherapy to monoclonal antibodies, from vaccines to immunomodulatory strategies. The evaluation of treatment results also has been revolutionized: clones carrying genetic aberrations are monitored, and patients who have had a response are assessed for the presence of minimal residual disease.

  10. Is political behavior a viable coping strategy to perceived organizational politics? Unveiling the underlying resource dynamics. (United States)

    Sun, Shuhua; Chen, Huaizhong


    [Correction Notice: An Erratum for this article was reported in Vol 102(10) of Journal of Applied Psychology (see record 2017-34254-001). In the article, Table 1 contained a formatting error. Correlation coefficient values in the last four cells of column 6 were misplaced with correlation coefficient values in the last four cells of column 7. All versions of this article have been corrected.] We conduct a theory-driven empirical investigation on whether political behavior, as a coping strategy to perceived organizational politics, creates resource trade-offs in moderating the relationship between perceived organizational politics and task performance. Drawing on conservation of resources theory, we hypothesize that political behavior mitigates the adverse effect of perceived organizational politics on task performance via psychological empowerment, yet exacerbates its adverse effect on task performance via emotional exhaustion. Three-wave multisource data from a sample of 222 employees and their 75 supervisors were collected for hypothesis testing. Findings supported our hypotheses. Our study enhances understandings of the complex resource dynamics of using political behavior to cope with perceived organizational politics and highlights the need to move stress-coping research from a focus on the stress-buffering effect of coping on outcomes to a focus on the underlying competing resource dynamics. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  11. Allergen immunotherapy: Current and new therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Jennifer M. Rolland


    Full Text Available Allergen-specific immunotherapy (SIT involves the administration of gradually increasing amounts of an allergen extract to reduce clinical symptoms of allergy. Well-controlled clinical trials have demonstrated the efficacy of SIT in the treatment of allergic diseases, including rhinoconjunctivitis and asthma, and best practice protocols have been established. Nevertheless, application of this potentially curative treatment is restricted, largely due to the risk of serious adverse events, especially in asthmatics. Although efficacy is high for venom-induced allergy, success rates for the more common aeroallergen-induced disease range from 60 to 80% depending on the allergen. The practice of SIT is currently being refined following major advances in our knowledge of basic immune mechanisms. In particular, new T cell-targeted strategies are being explored with the awareness of the pivotal role allergen-specific T cells play in initiating and regulating the immune response to allergens. Current SIT induces decreased IgE class switching and eosinophil activation by downregulating production of the T helper (Th 2-type cytokines interleukin (IL-4 and IL-5. Therefore, allergen preparations that have ablated IgE binding while retaining T cell reactivity should still be clinically effective but have substantially improved safety. These approaches include the use of small peptides based on dominant T cell epitopes of allergens and chemically modified or recombinant allergen molecules. Both approaches have already been tested, with promising results, in animal models; peptide immunotherapy has been shown effective in clinical trials. Defined hypoallergenic molecules or peptides offer ease of standardization in addition to efficacy and safety and will result in more widespread use of SIT in clinical practice. Elucidation of mechanisms for downregulating Th2-predominant responses to allergen by SIT will enable the development of laboratory assays for

  12. Is radical prostatectomy a viable therapeutic option in clinically locally advanced (cT3) prostate cancer? (United States)

    Xylinas, Evanguelos; Daché, Arnaud; Rouprêt, Morgan


    According to the literature, the current preferred treatment for T3 prostate cancer is a combination of radiotherapy and extended hormone therapy. The preoperative staging based on digital rectal examination results alone now appears obsolete from the investigated series, in which 20% of T3 prostate cancer is over-staged during physical examination. Prostatic magnetic resonance imaging is becoming increasingly necessary to evaluate extraprostatic extension during the preoperative evaluation. European Association of Urology guidelines recommend the use of radical prostatectomy only in selected patients with cT3a who have a PSA cancer control obtained after the implementation of radical prostatectomy is variable from one series to another, with PSA-free survival rates at 5, 10 and 15 years ranging from 45 to 62%, 43 to 51% and 15 to 49%, respectively. The specific survival rates at 5, 10 and 15 years are between 84 and 98%, 84 and 91% and 76 and 84%, respectively. The surgical margins rate varies from 22% to 61% depending on the specific operative technique used and the surgeon's own experience level. Regarding urinary continence, functional outcomes are in line with those of prostatectomy for localized prostate cancer. Upon consideration of erectile dysfunction, the rates are linked with the type of surgery performed, which can at times be fairly extensive. There is no impact on the overall or specific survival rate of neoadjuvant treatments. One of the problems currently depends on the efficacy of early adjuvant treatment after prostatectomy, especially regarding the use of adjuvant external beam radiotherapy. Radical prostatectomy can be considered in selected cases as a viable alternative to the first-line treatment option. However, patients must be counselled that they may undergo complementary treatments during the postoperative course of the disease. © 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.

  13. Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers (United States)


    resistance to platinum, management of CCNE1-amplified ovarian cancers is challenging. In this research, we evaluate three novel strategies against...AWARD NUMBER: W81XWH-15-1-0564 TITLE: Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers PRINCIPAL INVESTIGATOR: Panagiotis A...Form Approved OMB No. 0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including

  14. Development of a therapeutic vaccination strategy against cervical neoplasia

    NARCIS (Netherlands)

    Riezebos-Brilman, Annelies


    The aim of the studies described in this thesis was to investigate the effi cacy of a therapeutic immunization strategy against cervical cancer and premalignant cervical disease. Cervical cancer is caused by persistent infection with high-risk human papillomavirus (HPV). Two of the early proteins of

  15. Therapeutic Listening as a health intervention strategy: an integrative review


    Ana Cláudia Mesquita; Emilia Campos de Carvalho


    Objective To investigate and evaluate the available evidence in the literature regarding the use of Therapeutic Listening as a health intervention strategy. Method Integrative review conducted on the following databases PubMed, CINAHL, The Cochrane Library, EMBASE, LILACS and APA PsycNET without restrictions of year or type of study. The keywords were combined in different ways to ensure extensive search of primary studies. ...

  16. Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells (United States)

    Oishi, Naoki; Wang, Xin Wei


    The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment. Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of

  17. Buffer-free therapeutic antibody preparations provide a viable alternative to conventionally buffered solutions: from protein buffer capacity prediction to bioprocess applications. (United States)

    Bahrenburg, Sven; Karow, Anne R; Garidel, Patrick


    Protein therapeutics, including monoclonal antibodies (mAbs), have significant buffering capacity, particularly at concentrations>50 mg/mL. This report addresses pH-related issues critical to adoption of self-buffered monoclonal antibody formulations. We evaluated solution conditions with protein concentrations ranging from 50 to 250 mg/mL. Samples were both buffer-free and conventionally buffered with citrate. Samples were non-isotonic or adjusted for isotonicity with NaCl or trehalose. Studies included accelerated temperature stability tests, shaking stability studies, and pH changes in infusion media as protein concentrate is added. We present averaged buffering slopes of capacity that can be applied to any mAb and present a general method for calculating buffering capacity of buffer-free, highly concentrated antibody liquid formulations. In temperature stability tests, neither buffer-free nor conventionally buffered solution conditions showed significant pH changes. Conventionally buffered solutions showed significantly higher opalescence than buffer-free ones. In general, buffer-free solution conditions showed less aggregation than conventionally buffered solutions. Shaking stability tests showed no differences between buffer-free and conventionally buffered solutions. "In-use" preparation experiments showed that pH in infusion bag medium can rapidly approximate that of self-buffered protein concentrate as concentrate is added. In summary, the buffer capacity of proteins can be predicted and buffer-free therapeutic antibody preparations provide a viable alternative to conventionally buffered solutions. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Chang Youn Lee


    Full Text Available Despite development of medicine, cardiovascular diseases (CVDs are still the leading cause of mortality and morbidity worldwide. Over the past 10 years, various stem cells have been utilized in therapeutic strategies for the treatment of CVDs. CVDs are characterized by a broad range of pathological reactions including inflammation, necrosis, hyperplasia, and hypertrophy. However, the causes of CVDs are still unclear. While there is a limit to the currently available target-dependent treatments, the therapeutic potential of stem cells is very attractive for the treatment of CVDs because of their paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. Various studies have recently reported increased therapeutic potential of transplantation of microRNA- (miRNA- overexpressing stem cells or small-molecule-treated cells. In addition to treatment with drugs or overexpressed miRNA in stem cells, stem cell-derived extracellular vesicles also have therapeutic potential because they can deliver the stem cell-specific RNA and protein into the host cell, thereby improving cell viability. Here, we reported the state of stem cell-based therapy for the treatment of CVDs and the potential for cell-free based therapy.

  19. Advances in pathogenesis and current therapeutic strategies for cardiorenal syndrome. (United States)

    Du, Yujun; Li, Xiujiang; Liu, Bin


    Cardiorenal syndrome (CRS) is characterized as a syndrome involving both the cardiovascular system and kidneys. Due to its complexity and high mortality, it has becoming a significant burden and a universal clinical challenge to society worldwide. The mechanisms underlying CRS are potentially multifactorial, including hemodynamic alterations, neurohormonal activation, inflammation, oxidative stress, iron disorders, anemia, and mineral metabolic derangements. Despite the understanding and awareness of CRS gaining attention, appropriate approaches to manage CRS remain deficient. Loop diuretic and thiazides, inhibition of the renin-angiotensin system, vitamin D receptor activation and dopamine and natriuretic peptides could potentially be helpful to improve the prognosis of CRS. Ultrafiltration might be an alternative therapeutic strategy for the loss of liquid. However, adenosine receptor antagonists do not appear to be superior to furosemide in CRS treatment. novel therapeutic approaches should be explored. © 2013.

  20. T cell avidity and tumor recognition: implications and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Roszkowski Jeffrey J


    Full Text Available Abstract In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

  1. Potential therapeutic strategy to treat substance abuse related disorders. (United States)

    Chang, Sulie L


    The "Potential Therapeutic Strategy to Treat Substance Abuse Related Disorders" session was chaired by Dr. Sulie Chang, director of NeuroImmune Phamacology at Seton University. The four presenters (and their topics) were: Dr. Wen-zhe Ho (Miniway to stop HIV/HCV), Dr. Ru-Band Lu (Low dose of memantine in the treatment of opioid dependence in human), Dr. Ping Zhang (Treatment of alcohol-related disorders-Learning from stem/progenitor cell), and Chia-Hsiang Chen (Treatment of methamphetamine abuse: an antibody-based immunotherapy approach).

  2. Therapeutic strategies of urinary disorders in MS. Practice and algorithms. (United States)

    Denys, P; Phe, V; Even, A; Chartier-Kastler, E


    Review the literature on therapeutic strategies and guidelines for the treatment of neurogenic bladder in multiple sclerosis. A search on available articles on consensus, recommendations guidelines and algorithm of treatment of urinary tract dysfunction in multiple sclerosis. Five national consensus guidelines were recently published and proposed guidelines for the first and second line treatments. Multiple sclerosis patients suffering from lower urinary tract disorders must benefit from an early diagnosis and simple first line evaluation and treatment. More complex and invasive evaluation in the neuro-urology unit is appropriate for patients who failed to first line treatment or in case of complications. Copyright © 2014. Published by Elsevier Masson SAS.

  3. TNF biology, pathogenic mechanisms and emerging therapeutic strategies (United States)

    Kalliolias, George D.; Ivashkiv, Lionel B.


    TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of ‘short-term transcriptional memory’. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases. PMID:26656660

  4. Are Biofuels an Effective and Viable Energy Strategy for Industrialized Societies? A Reasoned Overview of Potentials and Limits


    Gomiero, Tiziano


    In this paper, I analyze the constraints that limit biomass from becoming an alternative, sustainable and efficient energy source, at least in relation to the current metabolism of developed countries. In order to be termed sustainable, the use of an energy source should be technically feasible, economically affordable and environmentally and socially viable, considering society as a whole. Above all, it should meet society’s “metabolic needs,” a fundamental issue that is overlooked in the ma...

  5. Extracellular matrix administration as a potential therapeutic strategy for periodontal ligament regeneration. (United States)

    Saito, Masahiro; Tsuji, Takashi


    The current strategies employed for the treatment of connective tissue disease include the application of stem cells, the use of functional molecules that can reorganize tissue integrity and cellular activities to recover connective tissue function. Approaches to the regeneration of periodontal tissue, which is the tooth-supporting connective tissue, have made some progress recently and provide a useful experimental model for the evaluation of future strategies to treat connective tissue diseases such as periodontal disease. The ultimate goal of periodontal tissue regeneration is to reconstruct the ligament structure that will sustain the required mechanical force to connect with mineralized tissues such as cementum and alveolar bone. In this review, we discuss the proposed use of extracellular matrix (ECM) administration therapy as an additional therapeutic strategy to stem cell transplantation and cytokine administration in the current field of periodontal tissue regeneration therapy. Although various available tissue engineering technologies can now achieve periodontal tissue regeneration, ECM administration therapy is likely to play an essential future role in the development and regeneration of periodontal tissue and attenuate the signaling events that mediate tissue degradation. Hence, ECM administration could serve as a novel technology in periodontal tissue regeneration and also as a viable approach to alleviating connective tissue disorders such as Marfan's syndrome.

  6. Controlling mutation: intervening in evolution as a therapeutic strategy. (United States)

    Cirz, Ryan T; Romesberg, Floyd E


    Mutation is the driving force behind many processes linked to human disease, including cancer, aging, and the evolution of drug resistance. Mutations have traditionally been considered the inevitable consequence of replicating large genomes with polymerases of finite fidelity. Observations over the past several decades, however, have led to a new perspective on the process of mutagenesis. It has become clear that, under some circumstances, mutagenesis is a regulated process that requires the induction of pro-mutagenic enzymes and that, at least in bacteria, this induction may facilitate evolution. Herein, we review what is known about induced mutagenesis in bacteria as well as evidence that it contributes to the evolution of antibiotic resistance. Finally, we discuss the possibility that components of induced mutation pathways might be targeted for inhibition as a novel therapeutic strategy to prevent the evolution of antibiotic resistance.

  7. Current and Potential Therapeutic Strategies for Hemodynamic Cardiorenal Syndrome. (United States)

    Obi, Yoshitsugu; Kim, Taehee; Kovesdy, Csaba P; Amin, Alpesh N; Kalantar-Zadeh, Kamyar


    Cardiorenal syndrome (CRS) encompasses conditions in which cardiac and renal disorders co-exist and are pathophysiologically related. The newest classification of CRS into seven etiologically and clinically distinct types for direct patient management purposes includes hemodynamic, uremic, vascular, neurohumoral, anemia- and/or iron metabolism-related, mineral metabolism-related and protein-energy wasting-related CRS. This classification also emphasizes the pathophysiologic pathways. The leading CRS category remains hemodynamic CRS, which is the most commonly encountered type in patient care settings and in which acute or chronic heart failure leads to renal impairment. This review focuses on selected therapeutic strategies for the clinical management of hemodynamic CRS. This is often characterized by an exceptionally high ratio of serum urea to creatinine concentrations. Loop diuretics, positive inotropic agents including dopamine and dobutamine, vasopressin antagonists including vasopressin receptor antagonists such as tolvaptan, nesiritide and angiotensin-neprilysin inhibitors are among the pharmacologic agents used. Additional therapies include ultrafiltration (UF) via hemofiltration or dialysis. The beneficial versus unfavorable effects of these therapies on cardiac decongestion versus renal blood flow may act in opposite directions. Some of the most interesting options for the outpatient setting that deserve revisiting include portable continuous dobutamine infusion, peritoneal dialysis and outpatient UF via hemodialysis or hemofiltration. The new clinically oriented CRS classification system is helpful in identifying therapeutic targets and offers a systematic approach to an optimal management algorithm with better understanding of etiologies. Most interventions including UF have not shown a favorable impact on outcomes. Outpatient portable dobutamine infusion is underutilized and not well studied. Revisiting traditional and novel strategies for outpatient

  8. Music as a Therapeutic Assistant: Strategy to Reduce Work Stress

    Directory of Open Access Journals (Sweden)

    Dereck Sena de Lima


    Full Text Available Objective: to understand the influence of music as a therapeutic assistant in reducing work stress of nursing professionals in a basic health unit. Method: it is an exploratory and descriptive research with a quantitative approach, developed with 9 nursing professionals from UBS Integrated Nova Esperança in João Pessoa, Paraíba. Data collection began after approval of the Research Ethics Committee of the Health Sciences Center of the Federal University of Paraíba, nº. 0508/16, CAAE: 58741916.6.0000.5188. Results: we identified that 33.3% of nursing professionals presented signs of stress, of the 33.3% who presented stress, 100% demonstrated to be in the resistance phase, 100% of the nursing professionals evaluated the musical strategy in a positive way. Conclusion: the musical strategy received extremely positive evaluations by the participants of the research, about 100% of professionals said that listening to music can reduce work stress.

  9. Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications (United States)


    Abstract Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686–729. PMID:25546574

  10. Therapeutic strategies for spinal muscular atrophy: SMN and beyond

    Directory of Open Access Journals (Sweden)

    Melissa Bowerman


    Full Text Available Spinal muscular atrophy (SMA is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.

  11. Tackling Ebola: new insights into prophylactic and therapeutic intervention strategies. (United States)

    de Wit, Emmie; Feldmann, Heinz; Munster, Vincent J


    Since its discovery in 1976, Ebolavirus has caused periodic outbreaks of viral hemorrhagic fever associated with severe and often fatal disease. Ebolavirus is endemic in Central Africa and the Philippines. Although there is currently no approved treatment available, the past 10 years has seen remarkable progress in our understanding of the pathogenicity of Ebolavirus and the development of prophylactic and post-exposure therapies against it. In vitro and in vivo experiments have shown that Ebolavirus pathogenicity is multifactorial, including viral and host determinants. Besides their function in the virus replication cycle, the viral glycoprotein, nucleoprotein, minor matrix protein and polymerase cofactor are viral determinants of pathogenicity, with evasion of the host innate and adaptive immune responses as the main mechanism. Although no licensed Ebolavirus vaccines are currently available, vaccine research in non-human primates, the 'gold standard' animal model for Ebolavirus, has produced several promising candidates. A combination of DNA vaccination and a recombinant adenovirus serotype 5 boost resulted in cross-protective immunity in non-human primates. A recombinant vesicular stomatitis vaccine vector protected non-human primates in pre- and post-exposure challenge studies. Several antiviral therapies are currently under investigation, but only a few of these have been tested in non-human primate models. Antisense therapies, in which oligonucleotides inhibit viral replication, have shown promising results in non-human primates following post-exposure treatment. In light of the severity of Ebolavirus disease and the observed increase in Ebolavirus outbreaks over the past decade, the expedited translation of potential candidate therapeutics and vaccines from bench to bedside is currently the most challenging task for the field. Here, we review the current state of Ebolavirus research, with emphasis on prophylactic and therapeutic intervention strategies.

  12. Are Biofuels an Effective and Viable Energy Strategy for Industrialized Societies? A Reasoned Overview of Potentials and Limits

    Directory of Open Access Journals (Sweden)

    Tiziano Gomiero


    Full Text Available In this paper, I analyze the constraints that limit biomass from becoming an alternative, sustainable and efficient energy source, at least in relation to the current metabolism of developed countries. In order to be termed sustainable, the use of an energy source should be technically feasible, economically affordable and environmentally and socially viable, considering society as a whole. Above all, it should meet society’s “metabolic needs,” a fundamental issue that is overlooked in the mainstream biofuels narrative. The EROI (Energy Return on Investment of biofuels reaches a few units, while the EROI of fossil fuels is 20–30 or higher and has a power density (W/m2 thousands of times higher than the best biofuels, such as sugarcane in Brazil. When metabolic approaches are used it becomes clear that biomass cannot represent an energy carrier able to meet the metabolism of industrialized societies. For our industrial society to rely on “sustainable biofuels” for an important fraction of its energy, most of the agricultural and non-agricultural land would need to be used for crops, and at the same time a radical cut to our pattern of energy consumption would need to be implemented, whilst also achieving a significant population reduction.

  13. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies (United States)

    Distrutti, Eleonora; Monaldi, Lorenzo; Ricci, Patrizia; Fiorucci, Stefano


    In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome (IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial (Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful (Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required. PMID:26900286

  14. Cell-based therapeutic strategies for multiple sclerosis. (United States)

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A


    The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  15. Therapeutic strategies for secondary hyperparathyroidism in dialysis patients. (United States)

    Ogata, Hiroaki; Koiwa, Fumihiko; Ito, Hidetoshi; Kinugasa, Eriko


    Secondary hyperparathyroidism (SHPT) leads not only to bone disorders, but also to cardiovascular complications in long-term dialysis patients. Conventional treatment with calcium (Ca) supplement, phosphate (P) binders and active vitamin D analogs lead in part to amelioration of SHPT, but are simultaneously associated with unacceptable side-effects, including hypercalcemia, hyperphosphatemia, and increased Ca x P products, which are the risk factors for cardiovascular disease in dialysis patients. Conventional treatment has been unable to facilitate the attainment of optimal management of SHPT proposed in the K/DOQI guidelines. Cinacalcet HCl (cinacalcet), a novel calcimimetic compound, restores the sensitivity of the Ca-sensing receptor in parathyroid cells, and decreases serum parathyroid hormone (PTH) without introducing hypercalcemia or hyperphosphatemia. Cinacalcet treatment enables a significant number of patients to achieve the K/DOQI guideline. Based on experimental data, calcimimetics could ameliorate cardiovascular calcification and remodeling in uremic rats with SHPT. Clinical trials have shown that cinacalcet significantly reduced the risks of parathyroidectomy, fracture and cardiovascular hospitalization among long-term dialysis patients with SHPT. Parathyroid intervention therapy (parathyroidectomy and percutaneous direct injection) is also a useful alternative. In the present article, we review novel therapeutic strategies for SHPT.

  16. Immune modulation as a therapeutic strategy in bone regeneration. (United States)

    Schlundt, Claudia; Schell, Hanna; Goodman, Stuart B; Vunjak-Novakovic, Gordana; Duda, Georg N; Schmidt-Bleek, Katharina


    We summarize research approaches and findings on bone healing and regeneration that were presented at a workshop at the 60th annual meeting of the Orthopedic Research Society (ORS) in New Orleans in 2014. The workshop was designed to discuss the role of inflammation in bone regeneration in the context of fundamental biology, and to develop therapeutic strategies that involve immune modulation. Delayed or non-healing of bone is a major clinical problem, with around 10% of fracture patients suffering from unsatisfying healing outcomes. Inflammation is traditionally seen as a defense mechanism, but was recently found essential in supporting and modulating regenerative cascades. In bone healing, macrophages and T- and B-cells interact with progenitor cells, bone forming osteoblasts and remodeling osteoclasts. Among the cells of the innate immunity, macrophages are promising candidates for targets in immune-modulatory interventions that would overcome complications in bone healing and bone-related diseases. Among the cells of the adaptive immune system, CD8+ T cells have been shown to have a negative impact on bone fracture healing outcome, whereas regulatory T cells could be promising candidates that have a positive, modulating effect on bone fracture healing. This workshop addressed recent advances and key challenges in this exciting interdisciplinary research field.

  17. Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy. (United States)

    Ingram, N; Porter, C D


    Deregulated tumour growth and neovascularization result in an inadequate tumour blood supply, leading to areas of chronic hypoxia and necrosis. Irregular vascular structure and abnormal tumour physiology also cause erratic blood flow in tumour vessels. We reasoned that tumour stroma, including vascular endothelial cells, would consequently experience transient hypoxia that may allow transcriptional targeting as part of an antivascular gene therapy approach to cancer. To exploit hypoxia for transcriptional regulation, retroviral vectors were generated with modified LTRs: a 6-mer of hypoxia response elements in place of the viral enhancer produced near wild-type levels of expression in hypoxia but was functionally inert in normoxia. In a tumour xenograft model, expression was mainly around areas of necrosis, which were shown to be hypoxic; no expression was detected in tumour stroma. Time-course experiments in vitro demonstrated that expression was transient in response to a hypoxic episode, such that a reporter gene would be insensitive to acute hypoxia in vivo. In contrast, a significant therapeutic effect was seen upon ganciclovir administration with a vector expressing thymidine kinase (TK) in the tumour stroma. Expression of TK was more effective when targeted to acute hypoxia in the stroma compared to chronic hypoxia in the poorly vascularized regions of the tumour cell compartment. The data presented here are evidence that hypoxia in the stromal compartment does occur and that transient hypoxia constitutes a valid therapeutic target.

  18. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes

    National Research Council Canada - National Science Library

    Abdi, Reza; Fiorina, Paolo; Adra, Chaker N; Atkinson, Mark; Sayegh, Mohamed H


    ... of certain hematopoietic molecules. Because of their developmental plasticity, the notion of MSC-based therapeutic intervention has become an emerging strategy for the replacement of injured tissues...

  19. Enteric microbiota leads to new therapeutic strategies for ulcerative colitis. (United States)

    Chen, Wei-Xu; Ren, Li-Hua; Shi, Rui-Hua


    Ulcerative colitis (UC) is a leading form of inflammatory bowel disease that involves chronic relapsing or progressive inflammation. As a significant proportion of UC patients treated with conventional therapies do not achieve remission, there is a pressing need for the development of more effective therapies. The human gut contains a large, diverse, and dynamic population of microorganisms, collectively referred to as the enteric microbiota. There is a symbiotic relationship between the human host and the enteric microbiota, which provides nutrition, protection against pathogenic organisms, and promotes immune homeostasis. An imbalance of the normal enteric microbiota composition (termed dysbiosis) underlies the pathogenesis of UC. A reduction of enteric microbiota diversity has been observed in UC patients, mainly affecting the butyrate-producing bacteria, such as Faecalibacterium prausnitzii, which can repress pro-inflammatory cytokines. Many studies have shown that enteric microbiota plays an important role in anti-inflammatory and immunoregulatory activities, which can benefit UC patients. Therefore, manipulation of the dysbiosis is an attractive approach for UC therapy. Various therapies targeting a restoration of the enteric microbiota have shown efficacy in treating patients with active and chronic forms of UC. Such therapies include fecal microbiota transplantation, probiotics, prebiotics, antibiotics, helminth therapy, and dietary polyphenols, all of which can alter the abundance and composition of the enteric microbiota. Although there have been many large, randomized controlled clinical trials assessing these treatments, the effectiveness and safety of these bacteria-driven therapies need further evaluation. This review focuses on the important role that the enteric microbiota plays in maintaining intestinal homeostasis and discusses new therapeutic strategies targeting the enteric microbiota for UC.

  20. Creating a viable financial structure for electricity generation projects in Quebec : latest techniques and strategies; Creer une structure financiere viable pour les projets de production d'electricite au Quebec : dernieres techniques et strategies

    Energy Technology Data Exchange (ETDEWEB)

    Dorion, M. [McCarthy Tetrault, Quebec City, PQ (Canada)


    Several factors, such as the rapid rise in electricity demand, the increase in electricity prices, technological progress, and environmental concerns have prompted the Quebec government to develop strategies and measures to restructure its electricity industry. Independent electricity producers in Quebec rely primarily on water, natural gas, biomass, and wind power to generate electricity. Calls for tender were made by Hydro-Quebec Production and Hydro-Quebec Distribution in order to meet the expected increased electricity demand in the province in the next few years. Financial markets in Quebec are also following developments in the electricity market. Financing for electric power generation projects is available from a variety of sources including debt financing, conventional corporate financing, leasing, security, equity investment, strategic partners, and institutional investors. The author discussed risk management associated with a private production project, with reference to general risks, specific risks, and financial risks. The basic principles in terms of risk allocation were examined along with the specific risks related to the source of energy production (hydroelectricity, combined cycle natural gas and cogeneration, biomass, and wind power) and the possible management solutions.

  1. Advances toward regenerative medicine in the central nervous system: challenges in making stem cell therapy a viable clinical strategy. (United States)

    Stoll, Elizabeth A


    Over recent years, there has been a great deal of interest in the prospects of stem cell-based therapies for the treatment of nervous system disorders. The eagerness of scientists, clinicians, and spin-out companies to develop new therapies led to premature clinical trials in human patients, and now the initial excitement has largely turned to skepticism. Rather than embracing a defeatist attitude or pressing blindly ahead, I argue it is time to evaluate the challenges encountered by regenerative medicine in the central nervous system and the progress that is being made to solve these problems. In the twenty years since the adult brain was discovered to have an endogenous regenerative capacity, much basic research has been done to elucidate mechanisms controlling proliferation and cellular identity; how stem cells may be directed into neuronal lineages; genetic, pharmacological, and behavioral interventions that modulate neurogenic activity; and the exact nature of limitations to regeneration in the adult, aged, diseased and injured CNS. These findings should prove valuable in designing realistic clinical strategies to improve the prospects of stem cell-based therapies. In this review, I discuss how basic research continues to play a critical role in identifying both barriers and potential routes to regenerative therapy in the CNS.

  2. Therapeutic strategies in an animal model of neurodegeneration

    NARCIS (Netherlands)

    Borre, Y.E.


    Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads

  3. Ecological carbon sequestration via wood harvest and storage (WHS): Can it be a viable climate and energy strategy? (United States)

    Zeng, N.; Zaitchik, B. F.; King, A. W.; Wullschleger, S. D.


    A carbon sequestration strategy is proposed in which forests are sustainably managed to optimal carbon productivity, and a fraction of the wood is selectively harvested and stored to prevent decomposition under anaerobic, dry or cold conditions. Because a large flux of CO2 is constantly assimilated into the world's forests via photosynthesis, cutting off its return pathway to the atmosphere forms an effective carbon sink. The live trees serve as a `carbon scrubber' or `carbon remover' that provides continuous sequestration (negative emissions). The stored wood is a semi-permanent carbon sink, but also serves as a `biomass/bioenergy reserve' that could be utilized in the future.Based on forest coarse wood production rate, land availability, bioconservation and other practical constraints, we estimate a carbon sequestration potential for wood harvest and storage (WHS) 1-3 GtC y-1. The implementation of such a scheme at our estimated lower value of 1 GtC y-1 would imply a doubling of the current world wood harvest rate. This can be achieved by harvesting wood at a modest harvesting intensity of 1.2 tC ha-1 y-1, over a forest area of 8 Mkm2 (800 Mha). To achieve the higher value of 3 GtC y-1, forests need to be managed this way on half of the world's forested land, or on a smaller area but with higher harvest intensity. However, the actual implementation may face challenges that vary regionally. We propose `carbon sequestration and biomass farms' in the tropical deforestation frontiers with mixed land use for carbon, energy, agriculture, as well as conservation. In another example, the forests damaged by insect infestation could be thinned to reduce fire and harvested for carbon sequestration.We estimate a cost of $10-50/tCO2 for harvest and storage around the landing site. The technique is low tech, distributed and reversible. We compare the potential of WHS with a number of other carbon sequestration methods. We will also show its impact on future land carbon sink

  4. "Is political behavior a viable coping strategy to perceived organizational politics? Unveiling the underlying resource dynamics": Correction to Sun and Chen (2017). (United States)


    Reports an error in "Is Political Behavior a Viable Coping Strategy to Perceived Organizational Politics? Unveiling the Underlying Resource Dynamics" by Shuhua Sun and Huaizhong Chen (Journal of Applied Psychology, Advanced Online Publication, May 22, 2017, np). In the article, Table 1 contained a formatting error. Correlation coefficient values in the last four cells of column 6 were misplaced with correlation coefficient values in the last four cells of column 7. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2017-22542-001.) We conduct a theory-driven empirical investigation on whether political behavior, as a coping strategy to perceived organizational politics, creates resource trade-offs in moderating the relationship between perceived organizational politics and task performance. Drawing on conservation of resources theory, we hypothesize that political behavior mitigates the adverse effect of perceived organizational politics on task performance via psychological empowerment, yet exacerbates its adverse effect on task performance via emotional exhaustion. Three-wave multisource data from a sample of 222 employees and their 75 supervisors were collected for hypothesis testing. Findings supported our hypotheses. Our study enhances understandings of the complex resource dynamics of using political behavior to cope with perceived organizational politics and highlights the need to move stress-coping research from a focus on the stress-buffering effect of coping on outcomes to a focus on the underlying competing resource dynamics. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  5. Extracellular vesicles: A new therapeutic strategy for joint conditions. (United States)

    Tofiño-Vian, Miguel; Guillén, Maria Isabel; Alcaraz, Maria José


    Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Clinical Appearance of Oral Candida Infection and Therapeutic Strategies


    Patil, Shankargouda; Rao, Roopa S.; Majumdar, Barnali; Anil, Sukumaran


    Candida species present both as commensals and opportunistic pathogens of the oral cavity. For decades, it has enthralled the clinicians to investigate its pathogenicity and to improvise newer therapeutic regimens based on the updated molecular research. Candida is readily isolated from the oral cavity, but simple carriage does not predictably result in development of an infection. Whether it remains as a commensal, or transmutes into a pathogen, is usually determined by pre-existing or assoc...

  7. Factors associated with therapeutic strategies in patients with splanchnic vein thrombosis: Results of an international registry

    NARCIS (Netherlands)

    Riva, N.; Ageno, W.; Schulman, S.; Bang, S.M.; Sartori, M.T.; Grandone, E.; Beyer, J.; Barillari, G.; Di Minno, D.; Duce, R.; Malato, A.; Santoro, R.; Poli, D.; Verhamme, P.; Martinelli, I.; Kamphuisen, P.; Alatri, A.; Becattini, C.; Bucherini, E.; Piana, A.; De Stefano, V.; Dentali, F.


    Background Treatment of splanchnic vein thrombosis (SVT) is challenging due to the heterogeneous clinical presentation and the increased bleeding risk. We aimed to describe current treatment strategies and factors associated with therapeutic decisions. Materials and Methods Between May 2008 and

  8. Therapeutic Strategies for Sleep Apnea in Hypertension and Heart Failure

    Directory of Open Access Journals (Sweden)

    Akiko Noda


    Full Text Available Sleep-disordered breathing (SDB causes hypoxemia, negative intrathoracic pressure, and frequent arousal, contributing to increased cardiovascular disease mortality and morbidity. Obstructive sleep apnea syndrome (OSAS is linked to hypertension, ischemic heart disease, and cardiac arrhythmias. Successful continuous positive airway pressure (CPAP treatment has a beneficial effect on hypertension and improves the survival rate of patients with cardiovascular disease. Thus, long-term compliance with CPAP treatment may result in substantial blood pressure reduction in patients with resistant hypertension suffering from OSAS. Central sleep apnea and Cheyne-Stokes respiration occur in 30–50% of patients with heart failure (HF. Intermittent hypoxemia, nocturnal surges in sympathetic activity, and increased left ventricular preload and afterload due to negative intrathoracic pressure all lead to impaired cardiac function and poor life prognosis. SDB-related HF has been considered the potential therapeutic target. CPAP, nocturnal O2 therapy, and adaptive servoventilation minimize the effects of sleep apnea, thereby improving cardiac function, prognosis, and quality of life. Early diagnosis and treatment of SDB will yield better therapeutic outcomes for hypertension and HF.

  9. Potential Therapeutic Benefits of Strategies Directed to Mitochondria (United States)

    Lesnefsky, Edward J.; Stowe, David F.


    Abstract The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279–347. PMID:20001744

  10. Therapeutic strategies for targeting the ovarian tumor stroma. (United States)

    Ko, Song Yi; Naora, Honami


    Epithelial ovarian cancer is the most lethal type of gynecologic malignancy. Sixty percent of women who are diagnosed with ovarian cancer present with advanced-stage disease that involves the peritoneal cavity and these patients have a 5-year survival rate of less than 30%. For more than two decades, tumor-debulking surgery followed by platinum-taxane combination chemotherapy has remained the conventional first-line treatment of ovarian cancer. Although the initial response rate is 70%-80%, most patients with advanced-stage ovarian cancer eventually relapse and succumb to recurrent chemoresistant disease. A number of molecular aberrations that drive tumor progression have been identified in ovarian cancer cells and intensive efforts have focused on developing therapeutic agents that target these aberrations. However, increasing evidence indicates that reciprocal interactions between tumor cells and various types of stromal cells also play important roles in driving ovarian tumor progression and that these stromal cells represent attractive therapeutic targets. Unlike tumor cells, stromal cells within the tumor microenvironment are in general genetically stable and are therefore less likely to become resistant to therapy. This concise review discusses the biological significance of the cross-talk between ovarian cancer cells and three major types of stromal cells (endothelial cells, fibroblasts, macrophages) and the development of new-generation therapies that target the ovarian tumor microenvironment.

  11. New Prophylactic and Therapeutic Strategies for Spinal Cord Injury. (United States)

    Park, Sookyoung; Park, Kanghui; Lee, Youngjeon; Chang, Kyu-Tae; Hong, Yonggeun


    Melatonin production by the pineal gland in the vertebrate brain has attracted much scientific attention. Pineal melatonin is regulated by photoperiodicity, whereas circadian secretion of melatonin produced in the gastrointestinal tract is regulated by food intake. Thus, the circadian rhythm of pineal melatonin depends upon whether a species is diurnal or nocturnal. Spinal cord injury (SCI) involves damage to the spinal cord caused by trauma or disease that results in compromise or loss of body function. Melatonin is the most efficient and commonly used pharmacological antioxidant treatment for SCI. Melatonin is an indolamine secreted by the pineal gland during the dark phase of the circadian cycle. Neurorehabilitation is a complex medical process that focuses on improving function and repairing damaged connections in the brain and nervous system following injury. Physical activity associated with an active lifestyle reduces the risk of obesity, cardiovascular disease, type 2 diabetes, osteoporosis, and depression and protects against neurological conditions, including Parkinson's disease, Alzheimer's disease, and ischemic stroke. Physical activity has been shown to increase the gene expression of several brain neurotrophins (brain-derived neurotrophic factor [BDNF], nerve growth factor, and galanin) and the production of mitochondrial uncoupling protein 2, which promotes neuronal survival, differentiation, and growth. In summary, melatonin is a neural protectant, and when combined with therapeutic exercise, the hormone prevents the progression of secondary neuronal degeneration in SCI. The present review briefly describes the pathophysiological mechanisms underlying SCI, focusing on therapeutic targets and combined melatonin and exercise therapy, which can attenuate secondary injury mechanisms with minimal side effects.

  12. Current Diagnostic and Therapeutic Strategies in Microvascular Angina


    Mumma, Bryn; Flacke, Nathalie


    Microvascular angina is common among patients with signs and symptoms of acute coronary syndrome and is associated with an increased risk of cardiovascular and cerebrovascular events. Unfortunately, microvascular is often under-recognized in clinical settings. The diagnosis of microvascular angina relies on assessment of the functional status of the coronary microvasculature. Invasive strategies include acetylcholine provocation, intracoronary Doppler ultrasound, and intracoronary thermodilut...

  13. Current Diagnostic and Therapeutic Strategies in Microvascular Angina (United States)

    Mumma, Bryn; Flacke, Nathalie


    Microvascular angina is common among patients with signs and symptoms of acute coronary syndrome and is associated with an increased risk of cardiovascular and cerebrovascular events. Unfortunately, microvascular is often under-recognized in clinical settings. The diagnosis of microvascular angina relies on assessment of the functional status of the coronary microvasculature. Invasive strategies include acetylcholine provocation, intracoronary Doppler ultrasound, and intracoronary thermodilution; noninvasive strategies include cardiac positron emission tomography (PET), cardiac magnetic resonance, and Doppler echocardiography. Once the diagnosis of microvascular angina is established, treatment is focused on improving symptoms and reducing future risk of cardiovascular and cerebrovascular events. Pharmacologic options and lifestyle modifications for patients with microvascular angina are similar to those for patients with coronary artery disease. PMID:25685641

  14. Optochiasmatic arachnoiditis and neurotuberculosis: prognostic indicators and therapeutic strategies. (United States)

    Gourie-Devi, M


    Tuberculous meningitis (TBM) is a serious meningitic infection commonly found to occur in the developing countries endemic to tuberculosis. Based on the clinical features alone, the diagnosis of TBM can neither be made nor excluded with certainty. Unfortunately there is still no single diagnostic method that is both sufficiently rapid and sensitive. Most factors found to correlate with poor outcome can be directly traced to the stage of the disease at the time of diagnosis. The only way to reduce the mortality and morbidity is by early diagnosis and timely recognition of complications and institution of the appropriate treatment strategies.

  15. The multifaceted mitochondrion: An attractive candidate for therapeutic strategies. (United States)

    Strappazzon, Flavie; Cecconi, Francesco


    Mitochondria are considered the powerhouse of the cell and disturbances in mitochondrial functions are involved in several disorders such as neurodegeneration and mitochondrial diseases. This review summarizes pharmacological strategies that aim at modifying the number of mitochondria, their dynamics or the mitochondrial quality-control mechanisms, in several pathological instances in which any of these mechanisms are impaired or abnormal. The interplay between different cellular pathways that involve mitochondria in order to respond to stress is highlighted. Such a high mitochondrial plasticity could be exploited for new treatments. Copyright © 2015. Published by Elsevier Ltd.

  16. Therapeutic strategies based on glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F


    excursions. Furthermore, via its ability to enhance satiety, GLP-1 reduces food intake, thereby limiting weight gain, and may even cause weight loss. Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency...... of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation...

  17. Clinical appearance of oral candida infection and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Shankargouda ePatil


    Full Text Available Candida species present both as commensals and opportunistic pathogens of the oral cavity. For decades, it has enthralled the clinicians to investigate its pathogenicity and to improvise newer therapeutic regimens based on the updated molecular research. Candida is readily isolated from the oral cavity, but simple carriage does not predictably result in development of an infection. Whether it remains as a commensal, or transmutes into a pathogen, is usually determined by pre-existing or associated variations in the host immune system. The candida infections may range from non-life threatening superficial mucocutaneous disorders to invasive disseminated disease involving multiple organs. In fact, with the increase in number of AIDS cases, there is a resurgence of less common forms of oral candida infections. The treatment after confirmation of the diagnosis should include recognizing and eliminating the underlying causes such as ill-fitting oral appliances, history of medications (antibiotics, corticosteroids, etc., immunological and endocrine disorders, nutritional deficiency states and prolonged hospitalization. Treatment with appropriate topical antifungal agents such as amphotericin, nystatin or miconazole usually resolves the symptoms of superficial infection. Occasionally, administration of systemic antifungal agents may be necessary in immunocompromised patients, the selection of which should be based upon history of recent azole exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data.

  18. Plasma cells in immunopathology: concepts and therapeutic strategies. (United States)

    Tiburzy, Benjamin; Kulkarni, Upasana; Hauser, Anja Erika; Abram, Melanie; Manz, Rudolf Armin


    Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells.

  19. A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine (United States)

    Tada, Yuji; Shimada, Hideaki; Hiroshima, Kenzo; Tagawa, Masatoshi


    Malignant mesothelioma, closely linked with occupational asbestos exposure, is relatively rare in the frequency, but the patient numbers are going to increase in the next few decades all over the world. The current treatment modalities are not effective in terms of the overall survival and the quality of life. Mesothelioma mainly develops in the thoracic cavity and infrequently metastasizes to extrapleural organs. A local treatment can thereby be beneficial to the patients, and gene therapy with an intrapleural administration of vectors is one of the potential therapeutics. Preclinical studies demonstrated the efficacy of gene medicine for mesothelioma, and clinical trials with adenovirus vectors showed the safety of an intrapleural injection and a possible involvement of antitumor immune responses. Nevertheless, low transduction efficiency remains the main hurdle that hinders further clinical applications. Moreover, rapid generation of antivector antibody also inhibits transgene expressions. In this paper, we review the current status of preclinical and clinical gene therapy for malignant mesothelioma and discuss potential clinical directions of gene medicine in terms of a combinatory use with anticancer agents and with immunotherapy. PMID:23484132

  20. Focus on Therapeutic Strategies of Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Marilena Durazzo


    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most common chronic liver disease in the Western world (it affects 30% of the general adult population. The NAFLD encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH, defined by steatosis, hepatocellular damage, and lobular inflammation in individuals without significant alcohol consumption and negative viral, congenital, and autoimmune liver disease markers. Currently, NAFLD is considered an emerging epidemic in light of the dramatic increase in obesity rates. With the progressive nature of NASH and its rising prevalence there is a significant need for a specific and targeted treatments since to date there has not been any validated therapies for NAFLD other than weight loss, which is well known to have a poor long-term success rate. In recent years, visceral adipose tissue has taken an important role in NAFLD pathogenesis, and current therapeutic approaches aim at reducing visceral obesity and free fatty acid overflow to the liver. This paper is focused on the treatments used for NAFLD and the potential new therapy.

  1. [Therapeutic strategies to increase the effectiveness of cough]. (United States)

    Torres-Castro, Rodrigo; Monge, Gonzalo; Vera, Roberto; Puppo, Homero; Céspedes, Juan; Vilaró, Jordi


    Cough is a natural reflex that protects respiratory airways against infections or mucus retention. Cough maintains an adequate cleaning of the airways and is a mainstay of respiratory therapy. It can be triggered voluntarily by the patient or by a specific cough device. Peak cough flow (PCF) is used to assess the effectiveness of the cough. When this value is below 160 L/min, cough is considered inefficient and becomes a risk factor for respiratory problems. Patients with weak cough, especially those with neuromuscular disease, have in common a low tidal volume and a decreased maximum insufflation capacity. Both factors directly affect the inspiratory phase previous to cough, which is considered vital to obtain the optimum flow for a productive cough. Different therapeutic measures may help to increase cough efficiency among patients with cough weakness. These interventions may be performed using manual techniques or by mechanical devices. The aim of this review is to analyze the different techniques available for cough assistance, set a hierarchy of use and establish a scientific basis for their application in clinical practice.

  2. [Mantle cell lymphoma: Towards a personalized therapeutic strategy?]. (United States)

    Navarro Matilla, Belén; García-Marco, José A


    Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  3. [Complications and postoperative therapeutic strategies in cross-linking]. (United States)

    Kohlhaas, M


    The reduced corneal mechanical stability in keratoconus and similar collagen diseases can lead to a progressive and irregular corneal shape and decrease of visual acuity. A progression of keratectatic diseases can be shown with corneal topography. Keratoconus can be treated by photo-oxidative cross-linking of the corneal collagen. In order to achieve a high absorption of irradiation energy in the cornea, riboflavin at a concentration of 0.1% and UVA light at a wavelength of 370 nm corresponding to the relative maximum absorption of riboflavin (vitamin B2) are used. Evidence for corneal cross-linking are the increase of biomechanical stiffness, the increased resistance against enzymatic degradation, a higher shrinkage temperature, a lower swelling rate and an increased diameter of collagen fibers. The currently available data demonstrate that the therapeutic cross-linking procedure is safe when respecting the important theoretical and clinical parameters and that a progression of the keratoconus can be avoided. In 80% of cases an average levelling of the curvature of approximately 2 dpt can be achieved, which leads not only to stabilization but also to an increase in visual acuity of approximately 1.2 lines. In a Cochrane review from 2015 publications about complications and results were reviewed. Complication rates ranged from 1-10% depending on the initial situation, comorbidities and stage of the keratoconus. The most important complications are early epithelial wound healing problems as well as extremely rare perforations. Corneal cross-linking is a well-established and safe procedure but is not free of complications.

  4. Quality of life, coping strategies and support needs of women seeking Traditional Chinese Medicine for infertility and viable pregnancy in Australia: a mixed methods approach. (United States)

    Ried, Karin; Alfred, Ann


    Infertility affects about 15% of couples in Western-societies with most progressing to fertility clinics for treatment. Despite being common, infertility is often experienced as a lonely road for affected couples. In this paper we expand on our previously published findings of women's experiences with infertility or difficulty of viable pregnancy who had sought Traditional Chinese Medicine (TCM) therapy in Australia, and focus on women's quality of life, coping strategies, and support needs. We applied mixed methods using the Tuebingen Quality of Life and the COPE questionnaires and in-depth interviews with 25 women with primary or secondary infertility, recurrent miscarriages or unexplained stillbirth, and who had consulted a TCM practitioner. We used a thematic approach to analyse the interviews, and descriptive statistics to evaluate questionnaire responses. Women reported through both questionnaires and interviews compromised quality of life due to the high level of distress, guilt, grief, and frustration caused by infertility. However, our women represented a highly motivated sample, actively seeking alternative support. While the TCM approach to infertility management increased women's sense of personal agency and control through education and continuity of care, the need for greater understanding and support on a societal level remains. In infertility, ongoing emotional and instrumental support is pivotal to the wellbeing and quality of life of the affected. Traditional Chinese Medicine addresses some support needs in infertility not routinely available in the Western model of care. More peer-led and professional-led support groups are greatly needed for women experiencing infertility to help break isolation and raise awareness of integrative approaches to fertility management.

  5. Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

    Directory of Open Access Journals (Sweden)

    Jaume Folch


    Full Text Available Alzheimer’s disease (AD currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC. PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5. Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

  6. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

    Directory of Open Access Journals (Sweden)

    Hiroshi Katoh


    Full Text Available Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs. Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

  7. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy. (United States)

    Guiraud, Simon; Chen, Huijia; Burns, David T; Davies, Kay E


    What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X-linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene-replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re-establish muscle function. © 2015 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

  8. Therapeutic strategies for the patient with treatment-resistant anxiety. (United States)

    Coplan, J D; Tiffon, L; Gorman, J M


    Outcome of anxiety disorder treatment with psychotherapy and medication is generally as good as or better than that of other psychiatric illnesses. Nevertheless, refractory cases occur. The first step in approaching the treatment-resistant patient with an anxiety disorder is to be certain that the treatment has been adequate. Failure to provide an adequate dose of medication for adequate periods of time may be the most common cause of "treatment resistance." The second step is to reconsider the diagnosis and/or determine if new diagnoses have emerged since the original consultation. Depression and substance abuse are especially likely to complicate anxiety disorders. Several studies have shown that concomitant personality disorders (axis II) increase the occurrence of resistance to standard treatment and must be addressed through psychotherapy. Last, a variety of possible underlying medical conditions, including thyroid disorder, arrhythmia, and complex partial seizure, should be considered. Then, the clinician should consider a variety of pharmacologic approaches that are specific to each anxiety disorder. Panic disorder patients who are refractory to imipramine frequently respond to high-potency benzodiazepines, monoamine oxidase (MAO) inhibitors, serotonin reuptake inhibitors, or various combinations. Generalized anxiety disorder, if unresponsive to benzodiazepines, may respond to buspirone or a tricyclic antidepressant. Patients with obsessive compulsive disorder who have failed to respond to clomipramine or fluoxetine and other serotonin reuptake blockers may benefit from augmentation strategies using combination therapies including buspirone, fenfluramine, and neuroleptics. Social phobia refractory to beta-blockers and MAO inhibitors may benefit from buspirone, fenfluramine, and neuroleptics. Social phobia refractory to beta-blockers and MAO inhibitors may benefit from buspirone, fluoxetine, or alprazolam.

  9. Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies (United States)

    Yu-Wai-Man, Patrick; Griffiths, Philip G.; Chinnery, Patrick F.


    paraplegia, and multiple sclerosis, where mitochondrial dysfunction is also thought to be an important pathophysiological player. A number of vertebrate and invertebrate disease models has recently been established to circumvent the lack of human tissues, and these have already provided considerable insight by allowing direct RGC experimentation. The ultimate goal is to translate these research advances into clinical practice and new treatment strategies are currently being investigated to improve the visual prognosis for patients with mitochondrial optic neuropathies. PMID:21112411

  10. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Directory of Open Access Journals (Sweden)

    Zhong SHI


    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

  11. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin (United States)


    and therapeutic effects of metformin . Science 310:1642–1646. 17. Hallows KR, Kobinger GP, Wilson JM, Witters LA , Foskett JK (2003) Physiological...Disease; Metformin A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin Michael J. Caplan...proliferative components of cyst expansion. Metformin , a drug in wide clinical use for both non-insulin dependent diabetes mellitus and Polycystic Ovary

  12. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management (United States)

    Fedorenko, Inna V.; Gibney, Geoffrey T.; Smalley, Keiran S. M.


    The recent years have seen a significant shift in the expectations for the therapeutic management of disseminated melanoma. The clinical success of BRAF targeted therapy suggest that long-term disease control may one day be a reality for genetically defined sub-groups of melanoma patients. Despite this progress, few advances have been made in developing targeted therapeutic strategies for the 50% of patients whose melanomas are BRAF wild-type. The most significant sub-group of BRAF wild-type tumors is the 15–20% of all melanomas that harbor activating NRAS mutations. Emerging preclinical and clinical evidence suggests that NRAS mutant melanomas have patterns of signal transduction and biological behavior that is distinct from BRAF mutant melanomas. This overview will discuss the unique clinical and prognostic behavior of NRAS mutant melanoma and will summarize the emerging data on how NRAS-driven signaling networks can be translated into novel therapeutic strategies. PMID:23069660

  13. Therapeutic immunization strategies against cervical cancer : induction of cell-mediated immunity in murine models

    NARCIS (Netherlands)

    Bungener, Laura Barbara


    The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high

  14. [Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus]. (United States)

    Ciotta, L; Pagano, I; Stracquadanio, M; Di Leo, S; Andò, A; Formuso, C


    The premenstrual dysphoric disorder (PMDD) is one of the main problems of the premenstrual phase. It consists of symptoms that sometimes invalidate the scope of employment, social and psycho-affective of patients, requiring thus a diagnostic and therapeutic approach as detailed and accurate as possible. The therapeutic strategies available for this disease are many, but recently the emphasis has been on Vitex agnus castus (VAC), considered by many as evidence drug of choice for both PMS and for the PMDD, being with satisfactory therapeutic properties and small side effects. Our study evaluated a group of patients suffering from PMDD and the clinical efficacy of treatment with VAC (and compared the effectiveness of the results of a more homogeneous group of patients treated with fluoxetine). This study confirms the data reported in the literature regarding the effectiveness of VAC therapy with no side effects.

  15. Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer. (United States)

    Harada, Koji; Ferdous, Tarannum; Ueyama, Yoshiya


    Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo-radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations.

  16. Minimal intervention dentistry: part 1. From 'compulsive' restorative dentistry to rational therapeutic strategies. (United States)

    Featherstone, J D B; Doméjean, S


    The concept of minimal intervention dentistry is based on all the factors that affect the onset and progression of disease and therefore integrates concepts of prevention, control and treatment. The field of minimal intervention dentistry is wide, including the detection of lesions as early as possible, the identification of risk factors (risk assessment) and the implementation of preventive strategies and health education for the patient. When the effects of the disease are present, in the form of a carious lesion, other therapeutic strategies are required, but in this case the least invasive solutions should be chosen, for example remineralisation, therapeutic sealants and restorative care aimed at conserving the maximum amount of sound tissue. This article aims to enlighten dental practitioners as to the foundations of minimal intervention dentistry in order to help them in the implementation of modern concepts into everyday clinical practice.

  17. Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies. (United States)

    Wang, S Z; Rui, Y F; Lu, J; Wang, C


    Intervertebral disc degeneration (IDD) is a chronic, complex process associated with low back pain; mechanisms of its occurrence have not yet been fully elucidated. Its process is not only accompanied by morphological changes, but also by systematic changes in its histological and biochemical properties. Many cellular and molecular mechanisms have been reported to be related with IDD and to reverse degenerative trends, abnormal conditions of the living cells and altered cell phenotypes would need to be restored. Promising biological therapeutic strategies still rely on injection of active substances, gene therapy and cell transplantation. With advanced study of tissue engineering protocols based on cell therapy, combined use of seeding cells, bio-active substances and bio-compatible materials, are promising for IDD regeneration. Recently reported progenitor cells within discs themselves also hold prospects for future IDD studies. This article describes the background of IDD, current understanding and implications of potential therapeutic strategies. © 2014 John Wiley & Sons Ltd.

  18. [Work-related musculoskeletal disorders in dentistry professionals. 2. Prevention, ergonomic strategies and therapeutic programs]. (United States)

    Sartorio, F; Franchignoni, F; Ferriero, G; Vercelli, S; Odescalchi, L; Augusti, D; Migliario, M


    In dental professionals the risk of developing work-related musculoskeletal disorders (WMSD) can be minimized through a combination of prevention, ergonomic strategies, and specific therapeutic programs. Prevention includes early identification of symptoms, analysis of working posture and activity, and the evaluation of equipment (such as dental instruments, position of the dental unit, patient and operator chairs, and lighting). The ergonomic strategies are based on identifying the best daily timetable (including periodic pauses) and most efficient team organization, as well as establishing the correct position that should be held at the patient chair. Finally specific therapeutic programs are very important in preventing or treating WMSD. In fact, fitness exercises such as mobilization, stretching or muscular and cardiovascular training are recognized as fundamental for dental professionals, and when WMSD occurs physiatric care and physical therapy are recommended.

  19. Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Hun Soon Jung


    Full Text Available Human papillomaviruses (HPVs are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings.

  20. Crosstalk between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

    Directory of Open Access Journals (Sweden)

    Abdelouahid El-Khattouti


    Full Text Available Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches.

  1. Novel therapeutic strategies for patients with triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Zhang J


    Full Text Available Jun-Fei Zhang,1 Jia Liu,1,2 Yu Wang,1,2 Bin Zhang1,2 1Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, People’s Republic of China; 2Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, People’s Republic of China Abstract: Triple-negative breast cancer (TNBC represents a very heterogeneous group of breast diseases. Currently, the backbone of therapy for TNBC is mainly chemotherapy as there are no effective specific targeted agents approved to treat TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. Therefore, new targeted strategies are, accordingly, urgently needed. This article discusses the recent developments in targeted agents explored for TNBC, aiming to offer novel therapeutic strategies that can potentially assist in designing personalized therapeutics in the future as well as provide the basis for further research in an attempt to target TNBC. Keywords: therapeutic strategies, TNBC, targeted agents

  2. Managing Viable Knowledge

    NARCIS (Netherlands)

    Achterbergh, J.M.I.M.; Vriens, D.J.


    In this paper, Beer's Viable System Model (VSM) is applied to knowledge management. Based on the VSM, domains of knowledge are identified that an organization should possess to maintain its viability. The logic of the VSM is also used to support the diagnosis, design and implementation of the

  3. New insights into therapeutic strategies for gut microbiota modulation in inflammatory diseases (United States)

    Vieira, Angélica Thomaz; Fukumori, Claudio; Ferreira, Caroline Marcantonio


    The interaction between the gut microbiota and the host immune system is very important for balancing and resolving inflammation. The human microbiota begins to form during childbirth; the complex interaction between bacteria and host cells becomes critical for the formation of a healthy or a disease-promoting microbiota. C-section delivery, formula feeding, a high-sugar diet, a high-fat diet and excess hygiene negatively affect the health of the microbiota. Considering that the majority of the global population has experienced at least one of these factors that can lead to inflammatory disease, it is important to understand strategies to modulate the gut microbiota. In this review, we will discuss new insights into gut microbiota modulation as potential strategies to prevent and treat inflammatory diseases. Owing to the great advances in tools for microbial analysis, therapeutic strategies such as prebiotic, probiotic and postbiotic treatment and fecal microbiota transplantation have gained popularity. PMID:27757227

  4. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury. (United States)

    Pachori, Alok S; Melo, Luis G; Hart, Melanie L; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D; Stahl, Gregory L; Pratt, Richard E; Dzau, Victor J


    Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

  5. Therapeutic Strategies for Mitochondrial Dysfunction and Oxidative Stress in Age-Related Metabolic Disorders. (United States)

    Bhatti, J S; Kumar, S; Vijayan, M; Bhatti, G K; Reddy, P H


    Mitochondria are complex, intercellular organelles present in the cells and are involved in multiple roles including ATP formation, free radicals generation and scavenging, calcium homeostasis, cellular differentiation, and cell death. Many studies depicted the involvement of mitochondrial dysfunction and oxidative damage in aging and pathogenesis of age-related metabolic disorders and neurodegenerative diseases. Remarkable advancements have been made in understanding the structure, function, and physiology of mitochondria in metabolic disorders such as diabetes, obesity, cardiovascular diseases, and stroke. Further, much progress has been done in the improvement of therapeutic strategies, including lifestyle interventions, pharmacological, and mitochondria-targeted therapeutic approaches. These strategies were mainly focused to reduce the mitochondrial dysfunction caused by oxidative stress and to retain the mitochondrial health in various diseases. In this chapter, we have highlighted the involvement of mitochondrial dysfunction in the pathophysiology of various disorders and recent progress in the development of mitochondria-targeted molecules as therapeutic measures for metabolic disorders. © 2017 Elsevier Inc. All rights reserved.

  6. CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges. (United States)

    Yi, Lang; Li, Jinming


    Cancer is characterized by multiple genetic and epigenetic alterations that drive malignant cell proliferation and confer chemoresistance. The ability to correct or ablate such mutations holds immense promise for combating cancer. Recently, because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has been widely used in cancer therapeutic explorations. Several studies used CRISPR-Cas9 to directly target cancer cell genomic DNA in cellular and animal cancer models which have shown therapeutic potential in expanding our anticancer protocols. Moreover, CRISPR-Cas9 can also be employed to fight oncogenic infections, explore anticancer drugs, and engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. Here, we summarize these preclinical CRISPR-Cas9-based therapeutic strategies against cancer, and discuss the challenges and improvements in translating therapeutic CRISPR-Cas9 into clinical use, which will facilitate better application of this technique in cancer research. Further, we propose potential directions of the CRISPR-Cas9 system in cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies. (United States)

    Beretta, Simone; Versace, Alessandro; Carone, Davide; Riva, Matteo; Dell'Era, Valentina; Cuccione, Elisa; Cai, Ruiyao; Monza, Laura; Pirovano, Silvia; Padovano, Giada; Stiro, Fabio; Presotto, Luca; Paternò, Giovanni; Rossi, Emanuela; Giussani, Carlo; Sganzerla, Erik P; Ferrarese, Carlo


    Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm3 absolute mean difference; p therapy.

  8. Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. (United States)

    Deng, Yan; Wang, Chi Chiu; Choy, Kwong Wai; Du, Quan; Chen, Jiao; Wang, Qin; Li, Lu; Chung, Tony Kwok Hung; Tang, Tao


    During recent decades there have been remarkable advances in biology, in which one of the most important discoveries is RNA interference (RNAi). RNAi is a specific post-transcriptional regulatory pathway that can result in silencing gene functions. Efforts have been done to translate this new discovery into clinical applications for disease treatment. However, technical difficulties restrict the development of RNAi, including stability, off-target effects, immunostimulation and delivery problems. Researchers have attempted to surmount these barriers and improve the bioavailability and safety of RNAi-based therapeutics by optimizing the chemistry and structure of these molecules. This paper aimed to describe the principles of RNA interference, review the therapeutic potential in various diseases and discuss the new strategies for in vivo delivery of RNAi to overcome the challenges. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies. (United States)

    Singla, Heena; Ludhiadch, Abhilash; Kaur, Raman Preet; Chander, Harish; Kumar, Vinod; Munshi, Anjana


    HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis (United States)

    Di Rocco, Giuliana; Baldari, Silvia


    Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs. PMID:27994623

  11. Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Seung Taek Ji


    Full Text Available The primary cause of death among chronic diseases worldwide is ischemic cardiovascular diseases, such as stroke and myocardial infarction. Recent evidence indicates that adult stem cell therapies involving cardiovascular regeneration represent promising strategies to treat cardiovascular diseases. Owing to their immunomodulatory properties and vascular repair capabilities, mesenchymal stem cells (MSCs are strong candidate therapeutic stem cells for use in cardiovascular regeneration. However, major limitations must be overcome, including their very low survival rate in ischemic lesion. Various attempts have been made to improve the poor survival and longevity of engrafted MSCs. In order to develop novel therapeutic strategies, it is necessary to first identify stem cell modulators for intracellular signal triggering or niche activation. One promising therapeutic strategy is the priming of therapeutic MSCs with stem cell modulators before transplantation. Another is a tissue engineering-based therapeutic strategy involving a cell scaffold, a cell-protein-scaffold architecture made of biomaterials such as ECM or hydrogel, and cell patch- and 3D printing-based tissue engineering. This review focuses on the current clinical applications of MSCs for treating cardiovascular diseases and highlights several therapeutic strategies for promoting the therapeutic efficacy of MSCs in vitro or in vivo from cell priming to tissue engineering strategies, for use in cardiovascular regeneration.

  12. Therapeutic strategies in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). (United States)

    Nakamura, Tatsufumi; Nishiura, Yoshihiro; Eguchi, Katsumi


    Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic progressive myelopathy characterized by bilateral pyramidal tracts involvement with sphincteric disturbances. HTLV-I infects approximately 10-20 million people worldwide. There are large endemic areas in southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa. Since the primary neuropathological feature of HAM/TSP is chronic inflammation caused by HTLV-I infection in the spinal cord, various treatments focusing on immunomodulatory or anti-viral effects were performed for HAM/TSP patients until now. However, there are still many of problems, such as insufficient effects, side effects and expensive costs in long-term treatments, etc., in these treatments. Therefore, an ideal therapeutic strategy against HAM/TSP is still not established yet. Although only a small proportion of HTLV-I-infected individuals develops HAM/TSP, neurological symptoms are certainly progressive once myelopathy develops, leading to deterioration of the quality of life. Therefore, we now need the therapeutic regimens to protect the development, or be able to commence the treatments as soon as possible after the development safely and inexpensively even in long-term course or lifelong course of treatment. As HTLV-I-infected CD4(+) T cells are the first responders in the immunopathogenesis of HAM/TSP, the ideal treatment is the elimination of HTLV-I-infected cells from the peripheral blood. In this article, we will review the therapeutic strategies against HAM/TSP up to now and will introduce our new therapeutic approach focusing on the targeting of HTLV-I-infected cells in HAM/TSP patients.

  13. Understanding HIV infection for the design of a therapeutic vaccine. Part II: Vaccination strategies for HIV. (United States)

    de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A


    HIV infection leads to a gradual loss CD4(+) T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive lifelong adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore, there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. Copyright © 2014. Published by Elsevier Masson SAS.

  14. Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies. (United States)

    Agnihotri, Sameer; Burrell, Kelly E; Wolf, Amparo; Jalali, Sharzhad; Hawkins, Cynthia; Rutka, James T; Zadeh, Gelareh


    Glioblastoma (GBM) is the most common and lethal primary brain tumor. Over the past few years tremendous genomic and proteomic characterization along with robust animal models of GBM have provided invaluable data that show that "GBM", although histologically indistinguishable from one another, are comprised of molecularly heterogenous diseases. In addition, robust pre-clinical models and a better understanding of the core pathways disrupted in GBM are providing a renewed optimism for novel strategies targeting these devastating tumors. Here, we summarize a brief history of the disease, our current molecular knowledge, lessons from animal models and emerging concepts of angiogenesis, invasion, and metabolism in GBM that may lend themselves to therapeutic targeting.

  15. Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics. (United States)

    Rosini, Michela; Simoni, Elena; Caporaso, Roberta; Minarini, Anna


    Alzheimer's disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimer's disease molecular mechanisms.

  16. The porphyrias: clinic, diagnostics, novel investigative tools and evolving molecular therapeutic strategies. (United States)

    van Serooskerken, A-M van Tuyll; Poblete-Gutiérrez, P; Frank, J


    The porphyrias are clinically and genetically heterogeneous metabolic disorders resulting from a predominantly hereditary dysfunction of specific enzymes involved in heme biosynthesis. Today, the clinical, biochemical, and genetic characteristics of this fascinating group of diseases are well established. Recently, different in vitro and animal models have facilitated the investigation of etiopathologic mechanisms in the different types of porphyria and the development of causal treatment strategies such as pathway interference, enzyme replacement, and gene therapy. The continuous progress in basic science has made an invaluable contribution to the rapid translation of discoveries made in the laboratory into new diagnostics and therapeutics in the near future. 2010 S. Karger AG, Basel.

  17. Therapeutic strategies in Sickle Cell Anemia: The past present and future. (United States)

    Fernandes, Queenie


    Sickle Cell Anemia (SCA) was one of the first hemoglobinopathies to be discovered. It is distinguished by the mutation-induced expression of a sickle cell variant of hemoglobin (HbS) that triggers erythrocytes to take a characteristic sickled conformation. The complex physiopathology of the disease and its associated clinical complications has initiated multi-disciplinary research within its field. This review attempts to lay emphasis on the evolution, current standpoint and future scope of therapeutic strategies in SCA. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The Assessment of the Colo-rectal Polyps in Order to the New Diagnostic and Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Raluca Diac Andreea


    Full Text Available Objective. Assessment of the histological and endoscopic features of the colo-rectal polyps is requered for the application of the new diagnostic and therapeutical strategies in the managment of the diminutive polyps.

  19. HIV-1 latency: an update of molecular mechanisms and therapeutic strategies. (United States)

    Battistini, Angela; Sgarbanti, Marco


    The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host's genome but it does not actively replicate, becoming invisible to the host immune system and unaffected by existing antiviral drugs. Rebound of viremia and recovery of systemic infection that follows interruption of therapy, necessitates life-long treatments with problems of compliance, toxicity, and untenable costs, especially in developing countries where the infection hits worst. Extensive research efforts have led to the proposal and preliminary testing of several anti-latency compounds, however, overall, eradication strategies have had, so far, limited clinical success while posing several risks for patients. This review will briefly summarize the more recent advances in the elucidation of mechanisms that regulates the establishment/maintenance of latency and therapeutic strategies currently under evaluation in order to eradicate HIV persistence.

  20. The Conceptual Oligometastatic Non-small Cell Lung Cancer and Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Xiaozheng KANG


    Full Text Available Non-small cell lung cancer (NSCLC ranks among the most prevalent malignancies and is the major cause of cancer-related deaths worldwide. Nearly 20%-50% will accompany by metastatic disease and the most common extrapulmonary sites of distant metastases are the brain, bone, liver and adrenal gland. The oligometastatic state is a biologically mild tumor stage and a intermediate state in which spread may be limited to specific organs and metastases might be present in limited numbers. Oligometastases are thought to arise from micrometastases, which have been dormant for a period of time. Local control may be an crucial component of a curative therapeutic strategy in the following four clinical schemes: to prohibit metastases; to cure occult metastatic disease; to remedy oligometastases; and to deracinate any residual lesion after systemic therapy. This review aims to outline the concept of the oligometastatic NSCLC and its strategies of treatment.

  1. Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies. (United States)

    Tyrrell, Jean; Callaghan, Máire


    Iron acquisition is vital to microbial survival and is implicated in the virulence of many of the pathogens that reside in the cystic fibrosis (CF) lung. The multifaceted nature of iron acquisition by both bacterial and fungal pathogens encompasses a range of conserved and species-specific mechanisms, including secretion of iron-binding siderophores, utilization of siderophores from other species, release of iron from host iron-binding proteins and haemoproteins, and ferrous iron uptake. Pathogens adapt and deploy specific systems depending on iron availability, bioavailability of the iron pool, stage of infection and presence of competing pathogens. Understanding the dynamics of pathogen iron acquisition has the potential to unveil new avenues for therapeutic intervention to treat both acute and chronic CF infections. Here, we examine the range of strategies utilized by the primary CF pathogens to acquire iron and discuss the different approaches to targeting iron acquisition systems as an antimicrobial strategy.

  2. Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond (United States)

    Gross, Christina; Berry-Kravis, Elizabeth M; Bassell, Gary J


    Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS. PMID:21796106

  3. Goethe's anxieties, depressive episodes and (self-)therapeutic strategies: a contribution to method integration in psychotherapy. (United States)

    Holm-Hadulla, Rainer M


    In psychiatry and psychotherapy, abstract scientific principles need to be exemplified by narrative case reports to gain practical precision. Goethe was one of the most creative writers, productive scientists, and effective statesmen that ever lived. His descriptions of feelings, emotions, and mental states related to anxieties, depressive episodes, dysthymia, and creativity are unique in their phenomenological precision and richness. His life and work can thus serve as an excellent example enhancing our understanding of the relationship between anxiety, depression and creativity. Furthermore, he described (self-)therapeutic strategies that reinforce and refine modern views. Goethe's self-assessments in his works and letters, and the descriptions by others are analyzed under the perspective of current psychiatric classification. His therapeutic techniques and recommendations are compared with cognitive-behavioral, psychodynamic, and existential psychotherapy to amplify modern concepts of psychotherapy. From a scientific perspective, several distinctive depressive episodes can be diagnosed in Goethe's life. They were characterized by extended depressive moods, lack of drive, and loss of interest and self-esteem combined with social retreat. Goethe displayed diffuse and phobic anxieties as well as dysthymia. His (self-)therapeutic strategies were: (a) the systematic use of helping alliances, (b) behavioral techniques, (c) cognitive reflection on meanings and beliefs, (d) psychodynamic and psychoanalytic remembering, repeating, and working through, and (e) existential striving for self-actualization, social commitment, meaning, and creativity. In Goethe's life, creative incubation, illumination, and elaboration appear to have been associated with psychic instability and dysthymia, sometimes with depressive episodes in a clinical sense. On the one hand, his creative work was triggered by anxieties, dysthymia, and depressive moods. On the other hand, his creativity

  4. Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives

    Directory of Open Access Journals (Sweden)

    Sumit Sarkar


    Full Text Available Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway and depositions of cytoplasmic fibrillary inclusions (Lewy bodies which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia, poor balance, and difficulty in walking (Parkinsonian gait. In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology.

  5. Arterial stiffness and stroke: de-stiffening strategy, a therapeutic target for stroke (United States)

    Chen, Yajing; Shen, Fanxia; Liu, Jianrong; Yang, Guo-Yuan


    Stroke is the second leading cause of mortality and morbidity worldwide. Early intervention is of great importance in reducing disease burden. Since the conventional risk factors cannot fully account for the pathogenesis of stroke, it is extremely important to detect useful biomarkers of the vascular disorder for appropriate intervention. Arterial stiffness, a newly recognised reliable feature of arterial structure and function, is demonstrated to be associated with stroke onset and serve as an independent predictor of stroke incidence and poststroke functional outcomes. In this review article, different measurements of arterial stiffness, especially pressure wave velocity, were discussed. We explained the association between arterial stiffness and stroke occurrence by discussing the secondary haemodynamic changes. We reviewed clinical data that support the prediction role of arterial stiffness on stroke. Despite the lack of long-term randomised double-blind controlled therapeutic trials, it is high potential to reduce stroke prevalence through a significant reduction of arterial stiffness (which is called de-stiffening therapy). Pharmacological interventions or lifestyle modification that can influence blood pressure, arterial function or structure in either the short or long term are promising de-stiffening therapies. Here, we summarised different de-stiffening strategies including antihypertension drugs, antihyperlipidaemic agents, chemicals that target arterial remodelling and exercise training. Large and well-designed clinical trials on de-stiffening strategy are needed to testify the prevention effect for stroke. Novel techniques such as modern microscopic imaging and reliable animal models would facilitate the mechanistic analyses in pathophysiology, pharmacology and therapeutics. PMID:28959494

  6. Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer. (United States)

    Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin


    One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Image-guided local delivery strategies enhance therapeutic nanoparticle uptake in solid tumors. (United States)

    Mouli, Samdeep K; Tyler, Patrick; McDevitt, Joseph L; Eifler, Aaron C; Guo, Yang; Nicolai, Jodi; Lewandowski, Robert J; Li, Weiguo; Procissi, Daniel; Ryu, Robert K; Wang, Y Andrew; Salem, Riad; Larson, Andrew C; Omary, Reed A


    Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nanoablation and nanoembolization. Nanoablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in a rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nanoembolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin-functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intratumoral DOX-SPIO uptake, with limited off-target delivery in tumor-bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.

  8. Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies (United States)

    Mileo, Anna Maria; Miccadei, Stefania


    Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data. PMID:26649142

  9. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. (United States)

    Yoshida, Go J


    The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing

  10. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment

    Directory of Open Access Journals (Sweden)

    Go J. Yoshida


    strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

  11. An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases

    Directory of Open Access Journals (Sweden)

    Fiszer Agnieszka


    Full Text Available Abstract Background RNA interference (RNAi and antisense strategies provide experimental therapeutic agents for numerous diseases, including polyglutamine (polyQ disorders caused by CAG repeat expansion. We compared the potential of different oligonucleotide-based strategies for silencing the genes responsible for several polyQ diseases, including Huntington's disease and two spinocerebellar ataxias, type 1 and type 3. The strategies included nonallele-selective gene silencing, gene replacement, allele-selective SNP targeting and CAG repeat targeting. Results Using the patient-derived cell culture models of polyQ diseases, we tested various siRNAs, and antisense reagents and assessed their silencing efficiency and allele selectivity. We showed considerable allele discrimination by several SNP targeting siRNAs based on a weak G-G or G-U pairing with normal allele and strong G-C pairing with mutant allele at the site of RISC-induced cleavage. Among the CAG repeat targeting reagents the strongest allele discrimination is achieved by miRNA-like functioning reagents that bind to their targets and inhibit their translation without substantial target cleavage. Also, morpholino analog performs well in mutant and normal allele discrimination but its efficient delivery to cells at low effective concentration still remains a challenge. Conclusions Using three cellular models of polyQ diseases and the same experimental setup we directly compared the performance of different oligonucleotide-based treatment strategies that are currently under development. Based on the results obtained by us and others we discussed the advantages and drawbacks of these strategies considering them from several different perspectives. The strategy aimed at nonallele-selective inhibiting of causative gene expression by targeting specific sequence of the implicated gene is the easiest to implement but relevant benefits are still uncertain. The gene replacement strategy that

  12. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Alana M. Horowitz


    Full Text Available Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

  13. Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

    Directory of Open Access Journals (Sweden)

    Claudia P. Miller


    Full Text Available Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies.

  14. Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation

    Directory of Open Access Journals (Sweden)

    Shyi-Jou Chen


    Full Text Available The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA, immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy.

  15. A novel therapeutic strategy for experimental stroke using docosahexaenoic acid complexed to human albumin

    Directory of Open Access Journals (Sweden)

    Belayev Ludmila


    Full Text Available Despite tremendous efforts in ischemic stroke research and significant improvements in patient care within the last decade, therapy is still insufficient. There is a compelling, urgent need for safe and effective neuroprotective strategies to limit brain injury, facilitate brain repair, and improve functional outcome. Recently, we reported that docosahexaenoic acid (DHA; 22:6, n-3 complexed to human albumin (DHA-Alb is highly neuroprotective after temporary middle cerebral artery occlusion (MCAo in young rats. This review highlights the potency of DHA-Alb therapy in permanent MCAo and aged rats and whether protection persists with chronic survival. We discovered that a novel therapy with DHA-Alb improved behavioral outcomes accompanied by attenuation of lesion volumes even when animals were allowed to survive three weeks after experimental stroke. This treatment might provide the basis for future therapeutics for patients suffering from ischemic stroke.

  16. Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Caroline Perronnet


    Full Text Available Two decades of molecular, cellular, and functional studies considerably increased our understanding of dystrophins function and unveiled the complex etiology of the cognitive deficits in Duchenne muscular dystrophy (DMD, which involves altered expression of several dystrophin-gene products in brain. Dystrophins are normally part of critical cytoskeleton-associated membrane-bound molecular scaffolds involved in the clustering of receptors, ion channels, and signaling proteins that contribute to synapse physiology and blood-brain barrier function. The utrophin gene also drives brain expression of several paralogs proteins, which cellular expression and biological roles remain to be elucidated. Here we review the structural and functional properties of dystrophins and utrophins in brain, the consequences of dystrophins loss-of-function as revealed by numerous studies in mouse models of DMD, and we discuss future challenges and putative therapeutic strategies that may compensate for the cognitive impairment in DMD based on experimental manipulation of dystrophins and/or utrophins brain expression.

  17. Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases (United States)

    Skeate, Joseph G.; Woodham, Andrew W.; Einstein, Mark H.; Da Silva, Diane M.; Kast, W. Martin


    ABSTRACT Carcinomas of the anogenital tract, in particular cervical cancer, remains one of the most common cancers in women, and represent the most frequent gynecological malignancies and the fourth leading cause of cancer death in women worldwide. Human papillomavirus (HPV)-induced lesions are immunologically distinct in that they express viral antigens, which are necessary to maintain the cancerous phenotype. The causal relationship between HPV infection and anogenital cancer has prompted substantial interest in the development of therapeutic vaccines against high-risk HPV types targeting the viral oncoproteins E6 and E7. This review will focus on the most recent clinical trials for immunotherapies for mucosal HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced diseases. Progress in peptide- and protein-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune checkpoint inhibition, immune response modifiers, and adoptive cell therapy for HPV will be discussed. PMID:26835746

  18. Oncogenic Human Papillomavirus: Application of CRISPR/Cas9 Therapeutic Strategies for Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Shuai Zhen


    Full Text Available Oncogenic human papillomaviruses (HPVs cause different types of cancer especially cervical cancer. HPV-associated carcinogenesis provides a classical model system for clustered regularly interspaced short palindromic repeats (CRISPR/Cas9 based cancer therapies since the viral oncogenes E6 and E7 are exclusively expressed in cancerous cells. Sequence-specific gene knockdown/knockout using CRISPR/Cas9 shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, CRISPR/Cas9-based targeting therapy requires further validation of its efficacy in vitro and in vivo to eliminate the potential off-target effects, necessitates verification of the delivery vehicles and the combinatory use of conventional therapies with CRISPR/Cas9 to ensure the feasibility and safety. In this review we discuss the potential of combining CRISPR/Cas9 with other treatment options as therapies for oncogenic HPVs-associated carcinogenesis. and present our assessment of the promising path to the development of CRISPR/Cas9 therapeutic strategies for clinical settings.

  19. RNA Interference as a Therapeutic Strategy for the Treatment of Liver Diseases. (United States)

    Gonzalez-Rodriguez, Agueda; Valverde, Angela M


    RNA interference has emerged as an innovative technology for gene silencing that degrades mRNAs complementary to the antisense strands of double-stranded, short interfering RNAs (siRNAs). Its therapeutic application has important advantages over small-molecule drugs since offers the possibility of targeting virtually all genes and allows selective silencing of one or several genes. So far, a relative small proportion of cellular proteins can bind and respond to chemical drugs. Based on that, RNA interference-mediated gene silencing is widely considered as a crucial breakthrough in molecular biology with a direct translation to medicine. The liver has been widely chosen as a model system for the development of RNA interference therapy due to the convenience and availability of effective delivery into this tissue. Numerous preclinical models have revealed promising results, but the safety of this technology remains the primary challenge in developing siRNA based treatments. Liver diseases comprise a broad spectrum of genetic and non-genetic pathologies including acute fulminant liver injury that demands urgent medical care, or chronic pathologies such as nonalcoholic fatty liver (NAFLD), alcoholic liver disease, liver cirrhosis, viral hepatitis and hepatocellular carcinoma (HCC). In some cases restoration of liver function is not possible and alternatives to liver transplantation offering novel and efficient therapeutic approaches are urgently needed. In this review, we describe recent insights on the advantages of using RNA interference in preclinical settings as a targeted strategy with potential to markedly improve the treatment of liver diseases.

  20. Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications. (United States)

    Liu, Chang; Zhang, Li; Liu, Hao; Cheng, Kun


    The CRISPR-Cas9 genome-editing system is a part of the adaptive immune system in archaea and bacteria to defend against invasive nucleic acids from phages and plasmids. The single guide RNA (sgRNA) of the system recognizes its target sequence in the genome, and the Cas9 nuclease of the system acts as a pair of scissors to cleave the double strands of DNA. Since its discovery, CRISPR-Cas9 has become the most robust platform for genome engineering in eukaryotic cells. Recently, the CRISPR-Cas9 system has triggered enormous interest in therapeutic applications. CRISPR-Cas9 can be applied to correct disease-causing gene mutations or engineer T cells for cancer immunotherapy. The first clinical trial using the CRISPR-Cas9 technology was conducted in 2016. Despite the great promise of the CRISPR-Cas9 technology, several challenges remain to be tackled before its successful applications for human patients. The greatest challenge is the safe and efficient delivery of the CRISPR-Cas9 genome-editing system to target cells in human body. In this review, we will introduce the molecular mechanism and different strategies to edit genes using the CRISPR-Cas9 system. We will then highlight the current systems that have been developed to deliver CRISPR-Cas9 in vitro and in vivo for various therapeutic purposes. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. (United States)

    Schinke, Carolina; Giricz, Orsolya; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Barreryo, Laura; Bhagat, Tushar; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit


    Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. © 2015 by The American Society of Hematology.

  2. TU-EF-210-00: Therapeutic Strategies and Image Guidance

    Energy Technology Data Exchange (ETDEWEB)



    The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imaging Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.

  3. [Proposal of new trace elements classification to be used in nutrition, oligotherapy and other therapeutics strategies]. (United States)

    Ramírez Hernández, Javier; Bonete Pérez, María José; Martínez Espinosa, Rosa María


    1) to propose a new classification of the trace elements based on a study of the recently reported research; 2) to offer detailed and actualized information about trace elements. the analysis of the research results recently reported reveals that the advances of the molecular analysis techniques point out the importance of certain trace elements in human health. A detailed analysis of the catalytic function related to several elements not considered essential o probably essentials up to now is also offered. To perform the integral analysis of the enzymes containing trace elements informatics tools have been used. Actualized information about physiological role, kinetics, metabolism, dietetic sources and factors promoting trace elements scarcity or toxicity is also presented. Oligotherapy uses catalytic active trace elements with therapeutic proposals. The new trace element classification here presented will be of high interest for different professional sectors: doctors and other professions related to medicine; nutritionist, pharmaceutics, etc. Using this new classification and approaches, new therapeutic strategies could be designed to mitigate symptomatology related to several pathologies, particularly carential and metabolic diseases. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  4. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases. (United States)

    Brennan, Frank R; Cauvin, Annick; Tibbitts, Jay; Wolfreys, Alison


    An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and

  5. Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers. (United States)

    Fuse, Miho J; Okada, Koutaroh; Oh-Hara, Tomoko; Ogura, Hayato; Fujita, Naoya; Katayama, Ryohei


    Neurotrophic receptor tyrosine kinase 1 ( NTRK1 ) gene rearrangement leads to constitutive activation of NTRK1, which induces high-transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKI), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecule inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or larotrectinib (LOXO-101). Furthermore, cabozantinib with an IGF1R inhibitor such as OSI-906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Mol Cancer Ther; 16(10); 2130-43. ©2017 AACR . ©2017 American Association for Cancer Research.

  6. Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies. (United States)

    Sundaram, Gayathri; Brew, Bruce J; Jones, Simon P; Adams, Seray; Lim, Chai K; Guillemin, Gilles J


    The excitotoxin quinolinic acid, a by-product of the kynurenine pathway, is known to be involved in several neurological diseases including multiple sclerosis (MS). Quinolinic acid levels are elevated in experimental autoimmune encephalomyelitis rodents, the widely used animal model of MS. Our group has also found pathophysiological concentrations of quinolinic acid in MS patients. This led us to investigate the effect of quinolinic acid on oligodendrocytes; the main cell type targeted by the autoimmune response in MS. We have examined the kynurenine pathway (KP) profile of two oligodendrocyte cell lines and show that these cells have a limited threshold to catabolize exogenous quinolinic acid. We further propose and demonstrate two strategies to limit quinolinic acid gliotoxicity: 1) by neutralizing quinolinic acid's effects with anti-quinolinic acid monoclonal antibodies and 2) directly inhibiting quinolinic acid production from activated monocytic cells using specific KP enzyme inhibitors. The outcome of this study provides a new insight into therapeutic strategies for limiting quinolinic acid-induced neurodegeneration, especially in neurological disorders that target oligodendrocytes, such as MS.

  7. Chained lightning: part III--Emerging technology, novel therapeutic strategies, and new energy modalities for radiosurgery. (United States)

    Hoh, Daniel J; Liu, Charles Y; Chen, Joseph C T; Pagnini, Paul G; Yu, Cheng; Wang, Michael Y; Apuzzo, Michael L J


    Radiosurgery is fundamentally the harnessing of energy and delivering it to a focal target for a therapeutic effect. The evolution of radiosurgical technology and practice has served toward refining methodologies for better conformal energy delivery. In the past, this has resulted in developing strategies for improved beam generation and delivery. Ultimately, however, our current instrumentation and treatment modalities may be approaching a practical limit with regard to further optimizing energy containment. In looking forward, several strategies are emerging to circumvent these limitations and improve conformal radiosurgery. Refinement of imaging techniques through functional imaging and nanoprobes for cancer detection may benefit lesion localization and targeting. Methods for enhancing the biological effect while reducing radiation-induced changes are being examined through dose fractionation schedules. Radiosensitizers and photosensitizers are being investigated as agents for modulating the biological response of tissues to radiation and alternative energy forms. Discovery of new energy modalities is being pursued through development of microplanar beams, free electron lasers, and high-intensity focused ultrasound. The exploration of these future possibilities will provide the tools for radiosurgical treatment of a broader spectrum of diseases for the next generation.

  8. Protection of the Blood-Brain Barrier as a Therapeutic Strategy for Brain Damage. (United States)

    Michinaga, Shotaro; Koyama, Yutaka


    Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.

  9. Challenges in the development of novel therapeutic strategies for treatment of endometriosis. (United States)

    Vanhie, Arne; Tomassetti, Carla; Peeraer, Karen; Meuleman, Christel; D'Hooghe, Thomas


    Endometriosis is an estrogen-dependent disease that results in pelvic pain and infertility. Its treatment is often frustrating due to limited medical treatment options, complex surgical treatment and high recurrence rates. Despite the advances in our understanding of the pathogenesis over the last decades and the consequent novel therapeutic strategies, no new drugs have been introduced in daily clinical practice. In the first part we present an overview of the pathogenesis of endometriosis. In the second part we discuss how new insights have led to the development of novel nonhormonal strategies for the treatment of endometriosis, focusing on anti-inflammatory and anti-angiogenic agents. In the third part we describe the problems encountered in the translation from experimental drugs to routine medicine for the treatment of endometriosis. Despite the multitude of agents that have been tested in preclinical trials, only few drugs have passed to the stage of clinical testing and none have been introduced into clinical practice. It is our opinion that the major challenges in the translation from novel agents for endometriosis is due to the use of inadequate rodent models and a lack of standardization in the design and reporting of preclinical endometriosis models.

  10. Therapeutic strategy for granulomatous lobular mastitis: a clinicopathological study of 12 patients. (United States)

    Akahane, Kazuhisa; Tsunoda, Nobuyuki; Kato, Masamichi; Noda, Sumiyo; Shimoyama, Yoshie; Ishigakis, Satoko; Satake, Hiroko; Nakamura, Shigeo; Nagino, Masato


    Granulomatous lobular mastitis (GLM) is a rare inflammatory pseudotumor. No therapeutic modality for this disease has been established because of its rarity. The purpose of this study is to evaluate the treatment strategies of GLM. Twelve women who met the histological criteria for GLM were retrospectively studied. The clinical data and the presentation, histopathology, and management of the disease were analyzed by reviewing the patients' medical records. The diagnosis of GLM was confirmed histologically by core needle biopsy in 9 cases, by vacuum-assisted biopsy in 2 cases, and by excisional biopsy in 1 case. Ten patients received corticosteroid treatment and another two patients were treated with local excision or incision and drainage. The median initial dosage of corticosteroid (Prednisolone) was 30 mg/day (range: 15-60 mg/day), and the dosages were tapered according to improvement. The median duration of corticosteroid treatment was 5 months (range: 1-12 months). The median follow-up period was 22 months (range: 6-104 months), and no patient treated with corticosteroid demonstrated recurrence. However, patients treated with excision or incision and drainage had recurrences. These results suggest that steroid treatment may be the first choice in treatment strategies for GLM.

  11. Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

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    Van Lint Carine


    Full Text Available Abstract The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway.

  12. Therapeutic Strategies for Oxidative Stress-Related Cardiovascular Diseases: Removal of Excess Reactive Oxygen Species in Adult Stem Cells

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    Hyunyun Kim


    Full Text Available Accumulating evidence indicates that acute and chronic uncontrolled overproduction of oxidative stress-related factors including reactive oxygen species (ROS causes cardiovascular diseases (CVDs, atherosclerosis, and diabetes. Moreover ROS mediate various signaling pathways underlying vascular inflammation in ischemic tissues. With respect to stem cell-based therapy, several studies clearly indicate that modulating antioxidant production at cellular levels enhances stem/progenitor cell functionalities, including proliferation, long-term survival in ischemic tissues, and complete differentiation of transplanted cells into mature vascular cells. Recently emerging therapeutic strategies involving adult stem cells, including endothelial progenitor cells (EPCs, for treating ischemic CVDs have highlighted the need to control intracellular ROS production, because it critically affects the replicative senescence of ex vivo expanded therapeutic cells. Better understanding of the complexity of cellular ROS in stem cell biology might improve cell survival in ischemic tissues and enhance the regenerative potentials of transplanted stem/progenitor cells. In this review, we will discuss the nature and sources of ROS, drug-based therapeutic strategies for scavenging ROS, and EPC based therapeutic strategies for treating oxidative stress-related CVDs. Furthermore, we will discuss whether primed EPCs pretreated with natural ROS-scavenging compounds are crucial and promising therapeutic strategies for vascular repair.

  13. New Strategies for the Next Generation of Matrix-Metalloproteinase Inhibitors: Selectively Targeting Membrane-Anchored MMPs with Therapeutic Antibodies

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    Laetitia Devy


    Full Text Available MMP intervention strategies have met with limited clinical success due to severe toxicities. In particular, treatment with broad-spectrum MMP-inhibitors (MMPIs caused musculoskeletal pain and inflammation. Selectivity may be essential for realizing the clinical potential of MMPIs. Here we review discoveries pinpointing membrane-bound MMPs as mediators of mechanisms underlying cancer and inflammation and as possible therapeutic targets for prevention/treatment of these diseases. We discuss strategies to target these therapeutic proteases using highly selective inhibitory agents (i.e., human blocking antibodies against individual membrane-bound MMPs.

  14. Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance. (United States)

    Hegazy, Ahmed M; Yamada, Daisuke; Kobayashi, Masahiko; Kohno, Susumu; Ueno, Masaya; Ali, Mohamed A E; Ohta, Kumiko; Tadokoro, Yuko; Ino, Yasushi; Todo, Tomoki; Soga, Tomoyoshi; Takahashi, Chiaki; Hirao, Atsushi


    Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients. © 2016 by The American

  15. Quercetin as an Emerging Anti-Melanoma Agent: A four-focus area therapeutic development strategy

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    Zoey Harris


    Full Text Available Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase -- a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes a feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated anti-proliferative and pro-apoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anti-cancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review we explore the potential of Quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a four-focus area strategy to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to i modulate cellular bioreduction potential and associated signaling cascades, ii affect transcription of relevant genes, iii regulate epigenetic processes, and iv develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.

  16. Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy. (United States)

    Pisano, Annalinda; Preziuso, Carmela; Iommarini, Luisa; Perli, Elena; Grazioli, Paola; Campese, Antonio F; Maresca, Alessandra; Montopoli, Monica; Masuelli, Laura; Sadun, Alfredo A; d'Amati, Giulia; Carelli, Valerio; Ghelli, Anna; Giordano, Carla


    Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease characterized by degeneration of retinal ganglion cells (RGCs) and consequent optic nerve atrophy. Peculiar features of LHON are incomplete penetrance and gender bias, with a marked male prevalence. Based on the different hormonal metabolism between genders, we proposed that estrogens play a protective role in females and showed that these hormones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs). We also showed that ERβ localize to the mitochondria of RGCs. Thus, targeting ERβ may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onset of disease in mutation carriers. Here, we tested the effects of ERβ targeting on LHON mitochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with a combination of natural estrogen-like compounds that bind ERβ with high selectivity. We demonstrated that these molecules improve cell viability by reducing apoptosis, inducing mitochondrial biogenesis and strongly reducing the levels of reactive oxygen species in LHON cells. These effects were abolished in cells with ERβ knockdown by silencing receptor expression or by using specific receptor antagonists. Our observations support the hypothesis that estrogen-like molecules may be useful in LHON prophylactic therapy. This is particularly important for lifelong disease prevention in unaffected LHON mutation carriers. Current strategies attempting to combat degeneration of RGCs during the acute phase of LHON have not been very effective. Implementing a different and preemptive approach with a low risk profile may be very helpful. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:

  17. New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape. (United States)

    Patel, Ami B; Vellore, Nadeem A; Deininger, Michael W


    The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Although these clonal disorders share certain clinical and genetic features, MF in particular is distinct for its complex mutational landscape, severe disease phenotype, and poor prognosis. The genetic complexity inherent to MF has made this disease extremely challenging to treat. Pharmacologic JAK inhibition has proven to be a transformative therapy in MPNs, alleviating symptom burden and improving survival, but has been hampered by off-target toxicities and, as monotherapy, has shown limited effects on mutant allele burden. In this review, we discuss the genetic heterogeneity contributing to the pathogenesis of MPNs, focusing on novel driver and epigenetic mutations and how they relate to combination therapeutic strategies. We discuss results from ongoing studies of new JAK inhibitors and report on new drugs and drug combinations that have demonstrated success in early preclinical and clinical trials, including type II JAK inhibitors, antifibrotic agents, and telomerase inhibitors. ©2016 American Association for Cancer Research.

  18. Management of treatment-resistant obsessive-compulsive disorder: An update on therapeutic strategies

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    Mishra Biswaranjan


    Full Text Available Background: Obsessive-compulsive disorder (OCD is a chronic psychiatric disorder characterized by recurrent, persistent thoughts and/or repetitive compulsive behaviors that cause anxiety or distress, are time-consuming, and cause significant socio-occupational dysfunction. Although OCD can be alleviated with pharmacological and behavioral treatments, up to 40-60% of patients do not have a satisfactory outcome. This paper aims to review the operational definitions and management of treatment-resistant OCD. Materials and Methods: A computerized search on Pubmed carried from 1980 to April 2006 led to the summarization of the results. Results: There are several strategies to manage treatment-resistant OCD. To start with, it is necessary to define it and differentiate it from other comorbid psychiatric disorders. Adequate trials of selective serotonin reuptake inhibitors (SSRIs, including clomipramine, at the maximum recommended dosages for at least 12 weeks needs to be tried, along with cognitive behavioral therapy (CBT, before trying out other modalities of treatment, which include ECT, rTMS, and neurosurgery. Conclusion: OCD has various clinical and therapeutic implications as it has a chronic course. Unless diagnosed and treated in an effective manner, it carries the risk of becoming resistant to treatment. This paper attempts to present an algorithm of management that can be followed in treatment-resistant OCD. It also emphasizes the need to maximize the effect of each course of treatment before moving on to the next step of management.

  19. 3D bioprinting: A new insight into the therapeutic strategy of neural tissue regeneration. (United States)

    Hsieh, Fu-Yu; Hsu, Shan-hui


    Acute traumatic injuries and chronic degenerative diseases represent the world's largest unmet medical need. There are over 50 million people worldwide suffering from neurodegenerative diseases. However, there are only a few treatment options available for acute traumatic injuries and neurodegenerative diseases. Recently, 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. In this commentary, the newly developed 3D bioprinting technique involving neural stem cells (NSCs) embedded in the thermoresponsive biodegradable polyurethane (PU) bioink is reviewed. The thermoresponsive and biodegradable PU dispersion can form gel near 37 °C without any crosslinker. NSCs embedded within the water-based PU hydrogel with appropriate stiffness showed comparable viability and differentiation after printing. Moreover, in the zebrafish embryo neural deficit model, injection of the NSC-laden PU hydrogels promoted the repair of damaged CNS. In addition, the function of adult zebrafish with traumatic brain injury was rescued after implantation of the 3D-printed NSC-laden constructs. Therefore, the newly developed 3D bioprinting technique may offer new possibilities for future therapeutic strategy of neural tissue regeneration.

  20. Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

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    Mingyi Zhao


    Full Text Available Hypoxic-ischemic encephalopathy (HIE is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches.

  1. Essential Oils Loaded in Nanosystems: A Developing Strategy for a Successful Therapeutic Approach

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    Anna Rita Bilia


    Full Text Available Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils.

  2. Reliability of preoperative duplex scanning in designing a therapeutic strategy for chronic lower limb ischemia. (United States)

    Fontcuberta, Juan; Flores, Angel; Orgaz, Antonio; Doblas, Manuel; Gil, Jose; Leal, Ignacio; Rodriguez, Ruben; Benito, Jose Maria; Bermúdez, Maria Dolores


    The objective of this study was to compare the treatment plan designed on the basis of preoperative duplex scanning evaluation of the critical limb ischemia with the treatment plan finally carried out, after assessing the findings obtained during surgical or endovascular treatment. Over a period of 51 months a preoperative duplex scanning study was carried out in 335 consecutive patients with chronic critical ischemia, to design the best therapeutic strategy. Agreement between both plans were as follows: 80%, 82,7% and 59% in the examinations of the iliac arteries, femoropopliteal or tibial arteries respectively. The operation plan was more frequently modified due to a duplex scanning failure in procedures involving the the distal vessels(10 of 44 [22.7%], p < 0.01). In conclusion, duplex scanning evaluation of patients with occlusive arterial disease of the lower limbs permits the design of both a medical and a surgical or endovascular treatment plan with a high level of agreement with the findings obtained during the revascularization procedure.

  3. HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.

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    Michal Mielcarek


    Full Text Available Histone deacetylase (HDAC 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD, a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.

  4. Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

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    Anja Geiselhart


    Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.

  5. Current therapeutic strategies of anti-HER2 treatment in advanced breast cancer patients

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    Joanna Huszno


    Full Text Available The HER2/neu ( ERBB2 oncogene is amplified and/or overexpressed in approximately 20% of breast cancers, and is a strong prognostic factor for relapse and poor overall survival, particularly in node-positive patients. It is also an important predictor for response to trastuzumab, which has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. Treatment with the anti-HER2 humanized monoclonal antibody – trastuzumab significantly improves progression-free and overall survival among patients with HER2-positive breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses occurred, what cause the need for new targeted therapies for advanced disease. In clinical trials, there are tested new drugs to improve the results of treatment for this group of patients. This paper presents new drugs introduced into clinical practice for treatment of advanced breast cancer, whose molecular target are receptors of the HER2 family. In addition, new therapeutic strategies and drugs that are currently in clinical researches are discussed.

  6. 3D bioprinting: A new insight into the therapeutic strategy of neural tissue regeneration (United States)

    Hsieh, Fu-Yu; Hsu, Shan-hui


    ABSTRACT Acute traumatic injuries and chronic degenerative diseases represent the world’s largest unmet medical need. There are over 50 million people worldwide suffering from neurodegenerative diseases. However, there are only a few treatment options available for acute traumatic injuries and neurodegenerative diseases. Recently, 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. In this commentary, the newly developed 3D bioprinting technique involving neural stem cells (NSCs) embedded in the thermoresponsive biodegradable polyurethane (PU) bioink is reviewed. The thermoresponsive and biodegradable PU dispersion can form gel near 37°C without any crosslinker. NSCs embedded within the water-based PU hydrogel with appropriate stiffness showed comparable viability and differentiation after printing. Moreover, in the zebrafish embryo neural deficit model, injection of the NSC-laden PU hydrogels promoted the repair of damaged CNS. In addition, the function of adult zebrafish with traumatic brain injury was rescued after implantation of the 3D-printed NSC-laden constructs. Therefore, the newly developed 3D bioprinting technique may offer new possibilities for future therapeutic strategy of neural tissue regeneration. PMID:26709633

  7. NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies. (United States)

    Balistreri, Carmela R; Candore, Giuseppina; Accardi, Giulia; Colonna-Romano, Giuseppina; Lio, Domenico


    Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.

  8. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets (United States)

    Safi, Sher Zaman; Kumar, Selva; Ismail, Ikram Shah Bin


    The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

  9. Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma

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    Gregory A. Watson


    Full Text Available The hepatocyte growth factor (HGF receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA, yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressiog EA cell lines (Seg-1, Bic-1, Flo-1 were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752 on cell viability, apoptosis, motility, invasion, downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition.

  10. Farletuzumab for NSCLC: exploiting a well-known metabolic pathway for a new therapeutic strategy. (United States)

    Bronte, Giuseppe; Lo Vullo, Francesca; Pernice, Gianfranco; Galvano, Antonio; Fiorentino, Eugenio; Cicero, Giuseppe; Bazan, Viviana; Rolfo, Christian; Russo, Antonio


    Introduction: The therapeutic options for NSCLC are limited barring targeted drugs, such as EGFR tyrosine-kinase inhibitors and anaplastic lymphoma kinase inhibitors, for patients bearing oncogenic mutations. Platinum-based chemotherapy remains the best strategy for most patients. New targeted drugs, including mAbs and small molecules, are currently under clinical investigation for treating NSCLC patients. Areas covered: The authors of this article focus on farletuzumab , a mAb targeting folate receptor, which has been studied in ovarian cancer and various other malignancies. In this review, the authors review its potential as therapy for NSCLC, because of the biological rationale provided by the expression of folate receptor α in most of lung adenocarcinoma. The authors provide details of farletuzumab's mechanism of action and discuss the results from completed Phase I and Phase II clinical trials. They also highlight ongoing trials. Expert opinion: There are an increasing number of treatment options for NSCLC and it is hoped that farletuzumab could be added to them. That being said, further evidence for its use with NSCLC patients is still needed. It could have a synergic effect with pemetrexed, because these two drugs have a similar target, namely the folate pathway. This combined action could provide an improved efficacy, although there are some concerns about increased toxicity. However, the authors do note that the combination of farletuzumab with other cytotoxic drugs has not been shown to increase toxicity alone.

  11. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease

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    Ito K


    Full Text Available Kazuhiro Ito, Thomas Colley, Nicolas MercadoAirways Disease Section, National Heart and Lung Institute, Imperial College London, London, United KingdomAbstract: Chronic obstructive pulmonary disease (COPD progresses very slowly and the majority of patients are therefore elderly. COPD is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli and there are increasing evidences for a close relationship between premature aging and chronic inflammatory diseases. Thus, COPD is considered to be a disease of an accelerating aging. In this review, we collected the evidence for roles of aging on pathogenesis of COPD and considered future therapeutic strategy for COPD based on this senescence hypothesis. Since calorie restriction has been proved to extend lifespan, many efforts were made to clarify the molecular mechanism of aging. Aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death due to impaired DNA repair after damage by oxidative stress or telomere shortening as a result of repeated cell division. During aging, pulmonary function progressively deteriorates; innate immunity is impaired and pulmonary inflammation increases, accompanied by structural changes, such as an enlargement of airspaces. Noxious environmental gases, such as cigarette smoke, may worsen these aging-related events in the lung or accelerate aging of the lung due to reduction in anti-aging molecules and/or stimulation of aging molecules. Aging signaling are complex but conserved in divert species, such as worm, fruit fry, rodent and humans. Especially the insulin like growth factor (IGF-1 signaling was well documented. Geroprotectors are therapeutics that affect the root cause of aging and age-related diseases, and thus prolong the life-span of animals. Most of geroprotectors such as melatonin, metformin, rapamycin and

  12. Aplasia cutis congenita: review of 29 cases and proposal of a therapeutic strategy. (United States)

    Maillet-Declerck, Marie; Vinchon, Matthieu; Guerreschi, Pierre; Pasquesoone, Louise; Dhellemmes, Patrick; Duquennoy-Martinot, Véronique; Pellerin, Philippe


    Aplasia cutis congenita (ACC) is a rare congenital disorder, which most commonly involves the scalp, and can affect the galea, the pericranium, the bone, and the dura mater. ACC thus is at risk of infection and hemorrhage. There is no consensus over the ideal management and the role for plastic surgery. We reviewed retrospectively our experience with 29 patients treated between 1976 and 2011. The patients were 17 male and 12 female, 25 being referred immediately at birth. The size of the defect ranged from 1 to 192 cm2. Thirteen patients had bone aplasia. Initial conservative treatment was decided in five cases; 15 patients underwent excision-sutures with or without local plasty, 8 underwent pedicled scalp flap, and 1 had skin graft followed by further reconstruction by a free flap. Four patients died in neonatal period because of infection or associated ailments. All others patients achieved complete healing. The mortality rate of ACC remains high and increases with the size of bone defect. We propose a therapeutic strategy based on the size of the skin defect and the nature of underlying exposed structures. Cranioplasty is exceptionally necessary because of good spontaneous bone regeneration within few months or years. Cosmetic appearance can be improved later by skin expansion. Aplasia cutis congenita is a rare malformation with sometimes a rapid fatal issue. A precise evaluation of surface and depth of the lesion is essential to decide if and how to operate, in order to provide rapid and efficient coverage. Georg Thieme Verlag KG Stuttgart · New York.

  13. Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies. (United States)

    Braida, D; Guerini, F R; Ponzoni, L; Corradini, I; De Astis, S; Pattini, L; Bolognesi, E; Benfante, R; Fornasari, D; Chiappedi, M; Ghezzo, A; Clerici, M; Matteoli, M; Sala, M


    Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25(+/-) adolescent mice (SNAP-25(+/+)) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies.

  14. Computationally derived points of fragility of a human cascade are consistent with current therapeutic strategies.

    Directory of Open Access Journals (Sweden)

    Deyan Luan


    Full Text Available The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein-protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of

  15. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. (United States)

    Sardi, S Pablo; Clarke, Jennifer; Viel, Catherine; Chan, Monyrath; Tamsett, Thomas J; Treleaven, Christopher M; Bu, Jie; Sweet, Lindsay; Passini, Marco A; Dodge, James C; Yu, W Haung; Sidman, Richard L; Cheng, Seng H; Shihabuddin, Lamya S


    Mutations of GBA1, the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. Previously, we have shown that early treatment with glucocerebrosidase can modulate α-synuclein aggregation in a presymptomatic mouse model of Gaucher-related synucleinopathy (Gba1(D409V/D409V)) and ameliorate the associated cognitive deficit. To probe this link further, we have now evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of symptomatic Gba1(D409V/D409V) mice and in a transgenic mouse model overexpressing A53T α-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNS of symptomatic Gba1(D409V/D409V) mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin, tau, and proteinase K-resistant α-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1(D409V/D409V) mice (starting at 4 or 12 mo of age) also reversed their cognitive impairment when examined using a novel object recognition test. Correspondingly, overexpression of glucocerebrosidase in the CNS of A53T α-synuclein mice reduced the levels of soluble α-synuclein, suggesting that increasing the glycosidase activity can modulate α-synuclein processing and may modulate the progression of α-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1-related and non-GBA1-associated synucleinopathies, including PD.

  16. A pharmacodynamic comparison of a personalized strategy for anti-platelet therapy versus ticagrelor in achieving a therapeutic window. (United States)

    Malhotra, Nikita; Abunassar, Joseph; Wells, George A; McPherson, Ruth; Fu, Angel; Hibbert, Benjamin; Labinaz, Marino; Le May, Michel; Dick, Alexander; Glover, Chris; Froeschl, Michael; Marquis, Jean-François; Tran, Luan; Bernick, Jordan; Chong, Aun-Yeong; So, Derek Y F


    A therapeutic window in antiplatelet treatment has been associated with concurrent lowering of bleeding and ischemic risks. Prasugrel and ticagrelor provide potent platelet inhibition, but may increase bleeding. No study has evaluated a personalized therapy with selective use of novel P2Y12 inhibitory agents compared to empiric ticagrelor use. The objective of this study was to compare a personalized anti-platelet therapy strategy to empiric ticagrelor in achieving a therapeutic window. Using the CAPITAL registry, we performed a retrospective analysis to evaluate a personalized anti-platelet therapy (PAT) strategy, using a pharmacogenetic approach, and compared it to empiric ticagrelor. In the PAT group, carriers of CYP2C19*2 received prasugrel and non-carriers received clopidogrel. The primary outcome was the proportion of patients within a validated therapeutic window, after a steady state treatment (≥48h) of antiplatelet therapy, as measured by a P2Y12 reaction unit (PRU) >85 and strategy of ticagrelor. Future prospective evaluation of novel PAT strategies will be required to prove clinical utility. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding. (United States)

    Chen, Haojun; Wang, Guohao; Lang, Lixin; Jacobson, Orit; Kiesewetter, Dale O; Liu, Yi; Ma, Ying; Zhang, Xianzhong; Wu, Hua; Zhu, Lei; Niu, Gang; Chen, Xiaoyuan


    The efficacy of therapeutic drugs is highly dependent on their optimal in vivo pharmacokinetics. Albumin conjugation is considered to be one of the most effective means of protracting the short lifespan of peptides and proteins. In this study, we proposed a novel platform for developing long lasting therapeutics by conjugating a small molecular albumin binding moiety, truncated Evans blue, to either peptides or proteins. Using the anti-diabetic peptide drug Exendin-4 as a model peptide, we synthesized a new long-acting Exendin-4 derivative (denoted as Abextide). Through complexation with albumin in situ, the biological half-life of Abextide was significantly extended. The hypoglycemic effect of Abextide was also improved remarkably over Exendin-4. Thus, Abextide has considerable potential to treat type 2 diabetes. This strategy as a general technology platform can be applied to other small molecules and biologics for the development of long-acting therapeutic drugs.

  18. Small-Nucleic-Acid-Based Therapeutic Strategy Targeting the Transcription Factors Regulating the Vascular Inflammation, Remodeling and Fibrosis in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sung Won Youn


    Full Text Available Atherosclerosis arises when injury to the arterial wall induces an inflammatory cascade that is sustained by a complex network of cytokines, together with accumulation of lipids and fibrous material. Inflammatory cascades involve leukocyte adherence and chemotaxis, which are coordinated by the local secretion of adhesion molecules, chemotactic factors, and cytokines. Transcription factors are critical to the integration of the various steps of the cascade response to mediators of vascular injury, and are induced in a stimulus-dependent and cell-type-specific manner. Several small-nucleic-acid-based therapeutic strategies have recently been developed to target transcription factors: antisense oligodeoxynucleotides, RNA interference, microRNA, and decoy oligodeoxynucleotides. The aim of this review was to provide an overview of these particular targeted therapeutic strategies, toward regulation of the vascular inflammation, remodeling and fibrosis associated with atherosclerosis.

  19. Macromolecular therapeutics: emerging strategies for drug discovery in the postgenome era. (United States)

    Juliano, R L; Astriab-Fisher, A; Falke, D


    The postgenome era offers a plethora of potential therapeutic targets. Many of these targets will be addressable using small organic molecules as drug candidates. However, certain aspects of cell function, particularly those that rely on protein-protein or protein-nucleic acid interactions, will be difficult to influence using small molecules. Thus, the possibility of using highly specific macromolecules as potential therapeutic agents is an intriguing concept. Recent developments in several areas of research have brought this possibility closer to fruition. Peptide and nucleic acid combinatorial libraries allow the generation of novel molecules having exquisite selectivity. Structural information and molecular modeling also contribute to the design of new macromolecules with therapeutic potential. Perhaps most importantly, approaches for delivering macromolecules into the cell interior have been developed and applied with considerable success. Thus, the therapeutic use of macromolecules, including oligonucleotides, peptides, and proteins, may be an idea whose time has come.

  20. Human organ-on-a-chip BioMEMS devices for testing new diagnostic and therapeutic strategies (United States)

    Leary, James F.; Key, Jaehong; Vidi, Pierre-Alexandre; Cooper, Christy L.; Kole, Ayeeshik; Reece, Lisa M.; Lelièvre, Sophie A.


    MEMS human "organs-on-a-chip" can be used to create model human organ systems for developing new diagnostic and therapeutic strategies. They represent a promising new strategy for rapid testing of new diagnostic and therapeutic approaches without the need for involving risks to human subjects. We are developing multicomponent, superparamagnetic and fluorescent nanoparticles as X-ray and MRI contrast agents for noninvasive multimodal imaging and for antibody- or peptide-targeted drug delivery to tumor and precancerous cells inside these artificial organ MEMS devices. Magnetic fields can be used to move the nanoparticles "upstream" to find their target cells in an organs-on-achip model of human ductal breast cancer. Theoretically, unbound nanoparticles can then be removed by reversing the magnetic field to give a greatly enhanced image of tumor cells within these artificial organ structures. Using branched PDMS microchannels and 3D tissue engineering of normal and malignant human breast cancer cells inside those MEMS channels, we can mimic the early stages of human ductal breast cancer with the goal to improve the sensitivity and resolution of mammography and MRI of very small tumors and test new strategies for treatments. Nanomedical systems can easily be imaged by multicolor confocal microscopy inside the artificial organs to test targeting and therapeutic responses including the differential viability of normal and tumor cells during treatments. Currently we are using 2-dimensional MEMS structures, but these studies can be extended to more complex 3D structures using new 3D printing technologies.

  1. Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases. (United States)

    Oh, Doo-Byoung


    Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy.

  2. Exergaming as a viable therapeutic tool to improve static and dynamic balance among older adults and people with idiopathic Parkinson’s disease: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Dale Michael Harris


    Full Text Available The use of virtual reality games (known as ‘exergaming’ as a neurorehabilitation tool is gaining interest. Therefore, we aim to collate evidence for the effects of exergaming on the balance and postural control of older adults and people with idiopathic Parkinson’s disease (IPD. Six electronic databases were searched, from inception to April 2015, to identify relevant studies. Standardised mean differences (SMD and 95% confidence intervals (CI were used to calculate effect sizes between experimental and control groups. I2 statistics were used to determine levels of heterogeneity. 309 older adults and 74 people with IPD were assessed across eleven studies. The results showed that exergaming improved static balance (SMD 1.069, 95% CI 0.563 to 1.576, postural control (SMD 0.826, 95% CI 0.481 to 1.170 and dynamic balance (SMD -0.808, 95% CI -1.192 to -0.424 in healthy older adults. Two PD studies showed an improvement in static balance (SMD 0.124, 95% CI -0.581 to 0.828 and postural control (SMD 2.576, 95% CI 1.534 to 3.599. Our findings suggest that exergaming might be an appropriate therapeutic tool for improving balance and postural control in older adults, but more large-scale trials are needed to determine if the same is true for people with IPD.

  3. Diffusion MRI: A New Strategy for Assessment of Cancer Therapeutic Efficacy

    Directory of Open Access Journals (Sweden)

    Thomas L. Chenevert


    Full Text Available The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator of treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a non-volumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

  4. Adenosine can thwart antitumor immune responses elicited by radiotherapy. Therapeutic strategies alleviating protumor ADO activities

    Energy Technology Data Exchange (ETDEWEB)

    Vaupel, Peter [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Multhoff, Gabriele [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Helmholtz Zentrum Muenchen, Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Neuherberg (Germany)


    By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT. An overview of the generation, accumulation, and ADO-related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided. Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 + T and CD8 + T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis. ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters. (orig.) [German] Untersuchungen des bioenergetischen Status ergaben, dass Tumorhypoxie neben vielen anderen bedeutsamen biologischen Effekten zu einem starken

  5. RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

    NARCIS (Netherlands)

    Temming, K; Molema, G; Kok, RJ


    During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to a(v)beta(3)-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to

  6. In Vitro Evaluation of Biofilm Dispersal as a Therapeutic Strategy To Restore Antimicrobial Efficacy

    DEFF Research Database (Denmark)

    Roizman, Dan; Vidaillac, Celine; Givskov, Michael


    engineered strain PAO1/pBAD-yhjH resulted in increased antimicrobial efficacy and synergy of the imipenem-tobramycin combination. These results support the use of biofilm dispersal to enhance antimicrobial efficacy in the treatment of biofilm-associated infections, representing a promising therapeutic...

  7. Emerging nanotechnology based strategies for diagnosis and therapeutics of urinary tract infections: A review. (United States)

    Kumar, M S; Das, A P


    At present, various diagnostic and therapeutic approaches are available for urinary tract infections. But, still the quest for development of more rapid, accurate and reliable approach is an unending process. The pathogens, especially uropathogens are adapting to new environments and antibiotics day by day rapidly. Therefore, urinary tract infections are evolving as hectic and difficult to eradicate, increasing the economic burden to the society. The technological advances should be able to compete the adaptability characteristics of microorganisms to combat their growth in new environments and thereby preventing their infections. Nanotechnology is at present an extensively developing area of immense scientific interest since it has diverse potential applications in biomedical field. Nanotechnology may be combined with cellular therapy approaches to overcome the limitations caused by conventional therapeutics. Nanoantibiotics and drug delivery using nanotechnology are currently growing areas of research in biomedical field. Recently, various categories of antibacterial nanoparticles and nanocarriers for drug delivery have shown their potential in the treatment of infectious diseases. Nanoparticles, compared to conventional antibiotics, are more beneficial in terms of decreasing toxicity, prevailing over resistance and lessening costs. Nanoparticles present long term therapeutic effects since they are retained in body for relatively longer periods. This review focuses on recent advances in the field of nanotechnology, principally emphasizing diagnostics and therapeutics of urinary tract infections. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies. (United States)

    Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah


    Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

  9. Myocardial Bridging: Contemporary Understanding of Pathophysiology with Implications for Diagnostic and Therapeutic Strategies (United States)

    Eshtehardi, Parham; Rasoul-Arzrumly, Emad; McDaniel, Michael; Mekonnen, Girum; Timmins, Lucas H.; Lutz, Jerre; Guyton, Robert A; Samady, Habib


    Patients with myocardial bridges are often asymptomatic but this anomaly may be associated with exertional angina, acute coronary syndromes, cardiac arrhythmias, syncope or even sudden cardiac death. This review presents our understanding of the pathophysiology of myocardial bridging and describes prevailing diagnostic modalities and therapeutic options for this challenging clinical entity. PMID:24583304

  10. Repetition priming in oral text reading: a therapeutic strategy for phonologic text alexia. (United States)

    Lott, Susan Nitzberg; Sperling, Anne J; Watson, Nora L; Friedman, Rhonda B


    BACKGROUND: Phonologic text alexia (PhTA) is a reading disorder in which reading of pseudowords is impaired, but reading of real words is impaired only when reading text. Oral reading accuracy remains well preserved when words are presented individually, but when presented in text the part-of-speech effect that is often seen in phonologic alexia (PhA) emerges. AIMS: To determine whether repetition priming could strengthen and/or maintain the activation of words during text reading. METHODS #ENTITYSTARTX00026; PROCEDURES: We trained NYR, a patient with PhTA, to use a strategy, Sentence Building, designed to improve accuracy of reading words in text. The strategy required NYR to first read the initial word, and then build up the sentence by adding on sequential words, in a step-wise manner, utilizing the benefits of repetition priming to enhance accuracy. OUTCOMES #ENTITYSTARTX00026; RESULTS: When using the strategy, NYR displayed improved accuracy not only for sentences she practiced using the strategy, but unpracticed sentences as well. Additionally, NYR performed better on a test of comprehension when using the strategy, as compared to without the strategy. CONCLUSIONS: In light of research linking repetition priming to increased neural processing efficiency, our results suggest that use of this compensatory strategy improves reading accuracy and comprehension by temporarily boosting phonologic activation levels.

  11. TriVax: an improved peptide-based therapeutic vaccination strategy against Human Papillomavirus-induced cancers (United States)

    Barrios, Kelly; Celis, Esteban


    Background Therapeutic vaccines for cancer are an attractive alternative to conventional therapies, since the later result in serious adverse effects and in most cases are not effective against advanced disease. Human Papillomavirus (HPV) is responsible for several malignancies such as cervical carcinoma. Vaccines targeting oncogenic viral proteins like HPV16-E6 and -E7 are ideal candidates to elicit strong immune responses without generating autoimmunity because: i) these products are not expressed in normal cells; and ii) their expression is required to maintain the malignant phenotype. Our group has developed peptide vaccination strategy called TriVax, which is effective in generating vast numbers of antigen-specific T cells in mice capable of persisting for long time periods. Materials and methods We have used two HPV-induced mouse cancer models (TC-1 and C3.43) to evaluate the immunogenicity and therapeutic efficacy of TriVax prepared with the immunodominant CD8 T cell epitope HPV16-E749–57, mixed with poly-IC adjuvant and costimulatory anti-CD40 antibodies. Results TriVax using HPV16-E749–57 induced large and persistent T cell responses that were therapeutically effective against established HPV16-E7 expressing tumors. In most cases, TriVax was successful in attaining complete rejections of 6–11 day established tumors. In addition, TriVax induced long-term immunological memory, which prevented tumor recurrences. The antitumor effects of TriVax were independent of NK and CD4 T cells and surprisingly, did not rely to a great extent on type-I or type-II interferon. Conclusions These findings indicate that the TriVax strategy is an appealing immunotherapeutic approach for the treatment of established viral-induced tumors. We believe that these studies may help to launch more effective and less invasive therapeutic vaccines for HPV-mediated malignancies. PMID:22527249

  12. TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers. (United States)

    Barrios, Kelly; Celis, Esteban


    Therapeutic vaccines for cancer are an attractive alternative to conventional therapies, since the later result in serious adverse effects and in most cases are not effective against advanced disease. Human papillomavirus (HPV) is responsible for several malignancies such as cervical carcinoma. Vaccines targeting oncogenic viral proteins like HPV16-E6 and HPV16-E7 are ideal candidates to elicit strong immune responses without generating autoimmunity because: (1) these products are not expressed in normal cells and (2) their expression is required to maintain the malignant phenotype. Our group has developed peptide vaccination strategy called TriVax, which is effective in generating vast numbers of antigen-specific T cells in mice capable of persisting for long time periods. We have used two HPV-induced mouse cancer models (TC-1 and C3.43) to evaluate the immunogenicity and therapeutic efficacy of TriVax prepared with the immunodominant CD8 T-cell epitope HPV16-E7(49-57), mixed with poly-IC adjuvant and costimulatory anti-CD40 antibodies. TriVax using HPV16-E7(49-57) induced large and persistent T-cell responses that were therapeutically effective against established HPV16-E7 expressing tumors. In most cases, TriVax was successful in attaining complete rejections of 6-11-day established tumors. In addition, TriVax induced long-term immunological memory, which prevented tumor recurrences. The anti-tumor effects of TriVax were independent of NK and CD4 T cells and, surprisingly, did not rely to a great extent on type-I or type-II interferon. These findings indicate that the TriVax strategy is an appealing immunotherapeutic approach for the treatment of established viral-induced tumors. We believe that these studies may help to launch more effective and less invasive therapeutic vaccines for HPV-mediated malignancies.

  13. Artificial Cell Therapy: New Strategies for the Therapeutic Delivery of Live Bacteria (United States)


    There has been rapid growth in research regarding the use of live bacterial cells for therapeutic purposes. The recognition that these cells can be genetically engineered to synthesize products that have therapeutic potential has generated considerable interest and excitement among clinicians and health professionals. It is expected that a wide range of disease modifying substrates such as enzymes, hormones, antibodies, vaccines, and other genetic products will be used successfully and will impact upon health care substantially. However, a major limitation in the use of these bacterial cells is the complexity of delivering them to the correct target tissues. Oral delivery of live cells, lyophilized cells, and immobilized cells has been attempted but with limited success. Primarily, this is because bacterial cells are incapable of surviving passage through the gastrointestinal tract. In many occasions, when given orally, these cells have been found to provoke immunogenic responses that are undesirable. Recent studies show that these problems can be overcome by delivering live bacterial cells, such as genetically engineered cells, using artificial cell microcapsules. This review summarizes recent advances in the therapeutic use of live bacterial cells for therapy, discusses the principles of using artificial cells for the oral delivery of bacterial cells, outlines methods for preparing suitable artificial cells for this purpose, addresses potentials and limitations for their application in therapy, and provides insight for the future direction of this emergent and highly prospective technology. PMID:15689638

  14. Therapeutic step-up strategy for management of hereditary pancreatitis in children. (United States)

    Kargl, S; Kienbauer, M; Duba, H C; Schöfl, R; Pumberger, W


    Various different regimes exist for the treatment of hereditary pancreatitis in childhood. Here, we propose a therapeutic pathway with emphasis on endoscopic and surgical procedures. From 2006 to 2013, 12 patients with a diagnosis of hereditary pancreatitis were prospectively included in a therapeutic step-up schema. The treatment outcome was evaluated and correlated to aetiological factors and pathoanatomic findings. After diagnostic work-up (laboratory data, ultrasound examination, magnetic resonance cholangiopancreatography and genetic testing), all 12 patients underwent early endoscopic retrograde cholangiopancreatography (ERCP), which was successfully performed in ten children. Obstructive pancreatitis was found in eight children, and required sphincterotomy, dilation and stenting for 12 months. In two children with unsuccessful ERCP, open surgical drainage procedures were performed. After a mean follow-up of 32 months all children are free of recurrence of pancreatitis without any impairment of everyday activities. For children with hereditary pancreatitis, a therapeutic step plan with early ERCP and open surgical drainage procedures in case of impossible or insufficient endoscopic treatment prevents recurring pancreatitis and offers a normal quality of life without any major complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. [Therapeutic strategies. Evolution and current status of the European Guidelines on Cardiovascular disease prevention]. (United States)

    Guijarro, Carlos; García-Díaz, Juan de Dios


    The European Guidelines on Dyslipidaemias (2011) and Cardiovascular Prevention (2012) have incorporated important changes. Firstly, it highlights the identification of a group of "very high risk" patients: patients with atherosclerotic disease in any vascular area, diabetes with associated risk factors, advanced chronic renal failure, or a SCORE estimate >10%. Patients with diabetes and no other risk factors, moderate renal failure, severe hypertension, genetic dyslipidaemias, or a SCORE estimate 5-10%, are considered as "high risk". The HDL cholesterol and triglycerides levels are considered as modulators of risks, but not therapeutic objectives per se. The therapeutic objectives are set at LDL cholesterol levels < 70 mg/dl (or at least a reduction of at least 50%) for patients at very high risk, and an LDL < 100 mg/dl for high risk patients. As well as the changes in lifestyle, pharmacological treatment with statins is the focal point of lipid lowering treatments. Other pharmacological options may be considered if the treatment with the maximum tolerable doses of statins do not achieve the therapeutic objectives. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

  16. GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators. (United States)

    Filip, Małgorzata; Frankowska, Małgorzata; Sadakierska-Chudy, Anna; Suder, Agata; Szumiec, Lukasz; Mierzejewski, Paweł; Bienkowski, Przemyslaw; Przegaliński, Edmund; Cryan, John F


    γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted. Copyright © 2014. Published by Elsevier Ltd.

  17. Combination of multifaceted strategies to maximize the therapeutic benefits of neural stem cell transplantation for spinal cord repair. (United States)

    Hwang, Dong H; Kim, Hyuk M; Kang, Young M; Joo, In S; Cho, Chong-Su; Yoon, Byung-Woo; Kim, Seung U; Kim, Byung G


    Neural stem cells (NSCs) possess therapeutic potentials to reverse complex pathological processes following spinal cord injury (SCI), but many obstacles remain that could not be fully overcome by NSC transplantation alone. Combining complementary strategies might be required to advance NSC-based treatments to the clinical stage. The present study was undertaken to examine whether combination of NSCs, polymer scaffolds, neurotrophin-3 (NT3), and chondroitinase, which cleaves chondroitin sulfate proteoglycans at the interface between spinal cord and implanted scaffold, could provide additive therapeutic benefits. In a rat hemisection model, poly(ɛ-caprolactone) (PCL) was used as a bridging scaffold and as a vehicle for NSC delivery. The PCL scaffolds seeded with F3 NSCs or NT3 overexpressing F3 cells (F3.NT3) were implanted into hemisected cavities. F3.NT3 showed better survival and migration, and more frequently differentiated into neurons and oligodendrocytes than F3 cells. Animals with PCL scaffold containing F3.NT3 cells showed the best locomotor recovery, and motor evoked potentials (MEPs) following transcranial magnetic stimulation were recorded only in PCL-F3.NT3 group in contralateral, but not ipsilateral, hindlimbs. Implantation of PCL scaffold with F3.NT3 cells increased NT3 levels, promoted neuroplasticity, and enhanced remyelination of contralateral white matter. Combining chondroitinase treatment after PCL-F3.NT3 implantation further enhanced cell migration and promoted axonal remodeling, and this was accompanied by augmented locomotor recovery and restoration of MEPs in ipsilateral hindlimbs. We demonstrate that combining multifaceted strategies can maximize the therapeutic benefits of NSC transplantation for SCI. Our results may have important clinical implications for the design of future NSC-based strategies.

  18. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study. (United States)

    Sambola, A; Ferreira-González, I; Angel, J; Alfonso, F; Maristany, J; Rodríguez, O; Bueno, H; López-Minguez, J R; Zueco, J; Fernández-Avilés, F; San Román, A; Prendergast, B; Mainar, V; García-Dorado, D; Tornos, P


    To identify the therapeutic regimens used at discharge in patients receiving oral anticoagulant therapy (OAT) who undergo stenting percutaneous coronary intervention and stent implantation (PCI-S), and to assess the safety and efficacy associated with different therapeutic regimens according to thromboembolic risk. A prospective multicentre registry. In hospital, after discharge and follow-up by telephone call. 405 patients (328 male/77 female; mean (SD) age 71 (9) years) receiving OAT who underwent PCI-S between November 2003 and June 2006 from nine catheterisation laboratories of tertiary care teaching hospitals in Spain and one in the United Kingdom were included. Three therapeutic regimens were identified at discharge: triple therapy (TT) -- that is, any anticoagulant (AC) plus double antiplatelet therapy (DAT; 278 patients (68.6%); AC and a single antiplatelet (AC+AT; 46 (11.4%)) and DAT only (81 (20%)). At 6 months, patients receiving TT showed the greatest rate of bleeding events. No patients receiving DAT at low thromboembolic risk presented a bleeding event (14.8% receiving TT, 11.8% receiving AC+AT and 0% receiving DAT, p = 0.033) or cardiovascular event (6.7% receiving TT, 0% receiving AC+AT and 0% receiving DAT, p = 0.126). The combination of AC+AT showed the worst rate of adverse events in the whole cohort, especially in patients at moderate-high thromboembolic risk. In patients receiving OAT, TT was the most commonly used regimen after PCI-S. DAT was associated with the lowest rate of bleeding events and a similar efficacy to TT in patients at low thromboembolic risk. TT should probably be restricted to patients at moderate-high thromboembolic risk.

  19. Neuroimmunity dynamics and the development of therapeutic strategies for amyotrophic lateral sclerosis. (United States)

    Bowerman, Melissa; Vincent, Thierry; Scamps, Frédérique; Perrin, Florence E; Camu, William; Raoul, Cédric


    Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder characterized by the progressive and selective loss of both upper and lower motoneurons. The neurodegenerative process is accompanied by a sustained inflammation in the brain and spinal cord. The neuron-immune interaction, implicating resident microglia of the central nervous system and blood-derived immune cells, is highly dynamic over the course of the disease. Here, we discuss the timely controlled neuroprotective and neurotoxic cues that are provided by the immune environment of motoneurons and their potential therapeutic applications for ALS.

  20. Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing’s sarcoma (United States)

    Dai, Xing; Ma, Wei; He, Xijing; Jha, Rajiv Kumar


    Summary The most prevalent forms of bone cancer are osteosarcoma, chondrosarcoma, and Ewing’s sarcoma. Although chemotherapy and radiotherapy have replaced traditional surgical treatments, survival rates have undergone only marginal improvements. Current knowledge of the molecular pathways involved in each type of cancer has led to better approaches in cancer treatment. A number of cell signaling molecules are involved in tumorigenesis, and specific targets have been identified based on these signal transducers. This review highlights some of the important cellular pathways and potential therapeutic targets, tumor site-specific irradiation techniques, and novel drug delivery systems used to administer these drugs. PMID:21804475

  1. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress (United States)

    Booz, George W.


    Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and to initiate tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in these various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system, but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alzheimer’s disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain. PMID:21238581

  2. Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

    Directory of Open Access Journals (Sweden)

    Katherine R. Singleton


    Full Text Available Summary: Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC. MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution. : Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, but by combining statistical modeling of tumor data with functional interrogation of resistance models, Singleton et al. show that these pathways converge to activate MYC. BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, informing therapies that select against resistance. Keywords: melanoma, cancer therapeutics, therapeutic resistance, signaling networks, MYC, metabolism, synthetic lethality

  3. Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies. (United States)

    Mueller, Alan J; Peffers, Mandy J; Proctor, Carole J; Clegg, Peter D


    Systems orientated research offers the possibility of identifying novel therapeutic targets and relevant diagnostic markers for complex diseases such as osteoarthritis. This review demonstrates that the osteoarthritis research community has been slow to incorporate systems orientated approaches into research studies, although a number of key studies reveal novel insights into the regulatory mechanisms that contribute both to joint tissue homeostasis and its dysfunction. The review introduces both top-down and bottom-up approaches employed in the study of osteoarthritis. A holistic and multiscale approach, where clinical measurements may predict dysregulation and progression of joint degeneration, should be a key objective in future research. The review concludes with suggestions for further research and emerging trends not least of which is the coupled development of diagnostic tests and therapeutics as part of a concerted effort by the osteoarthritis research community to meet clinical needs. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1573-1588, 2017. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.

  4. Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis. (United States)

    Wang, Shu-Na; Xu, Tian-Ying; Li, Wen-Lin; Miao, Chao-Yu


    Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration. © 2016 John Wiley & Sons Ltd.

  5. Self-Microemulsifying Drug Delivery Systems: An Attractive Strategy for Enhanced Therapeutic Profile. (United States)

    Akula, Samatha; Gurram, Aravind Kumar; Devireddy, Srinivas Reddy


    Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modification, and cocrystals exist, lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-microemulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present paper gives exhaustive information on the formulation design and characterization of SMEDDS along with the probable mechanisms by which the bioavailability can be improved with SMEDDS.

  6. IL-10 as a therapeutic strategy in the treatment of rheumatoid arthritis. (United States)

    Keystone, E; Wherry, J; Grint, P


    IL-10 has anti-inflammatory and immunoregulatory properties that suggest a potential therapeutic role in RA. IL-10 inhibits proinflammatory cytokine and chemokine production in addition to blocking T-cell responses to specific antigens. It acts primarily through inhibition of costimulatory properties of macrophages. IL-10 stimulates proliferation and differentiation of antibody-forming B-cells. Preclinical studies in a variety of animal models, including collagen-induced arthritis, have shown that IL-10 is effective in preventing or inhibiting inflammation and autoreactivity. Although in RA, circulating and synovial levels of IL-10 are increased, accumulated evidence suggests that there may be a relative deficit of available IL-10. Moreover, exogenous addition of IL-10 in vitro has been shown to affect the immunopathological processes involved in RA. Preliminary studies of human recombinant IL-10 in patients with RA have demonstrated a trend towards efficacy with a good safety profile. Taken together, the data support a therapeutic role for IL-10 in the treatment of RA.

  7. Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases (United States)

    Haney, Matthew J.; Zhao, Yuling; Harrison, Emily B.; Mahajan, Vivek; Ahmed, Shaheen; He, Zhijian; Suresh, Poornima; Hingtgen, Shawn D.; Klyachko, Natalia L.; Mosley, R. Lee; Gendelman, Howard E.; Kabanov, Alexander V.; Batrakova, Elena V.


    The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA) encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD). This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders. PMID:23620794

  8. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. (United States)

    Booz, George W


    Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. The role of adipose stem cells in inflammatory bowel disease: From biology to novel therapeutic strategies. (United States)

    De Francesco, Francesco; Romano, Maurizio; Zarantonello, Laura; Ruffolo, Cesare; Neri, Daniele; Bassi, Nicolò; Giordano, Antonio; Zanus, Giacomo; Ferraro, Giuseppe A; Cillo, Umberto


    Inflammatory bowel diseases are an increasing phenomenon in western countries and in growing populations. The physiopathology of these conditions is linked to intestinal stem cells homeostasis and regenerative potential in a chronic inflammatory microenvironment. Patients with IBD present an increased risk of developing colorectal cancer (CRC), or colitis associated cancer (CAC). Conventional treatment for IBD target the inflammatory process (and include anti-inflammatory and immunosuppressive drugs) with biological agents emerging as a therapeutic approach for non-responders to traditional therapy. Conventional treatment provides scarce results and present severe complications. The intestinal environment may host incoming stem cells, able to engraft in the epithelial damaged sites and differentiate. Therefore, stem cell therapies represent an emerging alternative in inflammatory bowel diseases, with current investigations on the use of haematopoietic and mesenchymal stem cells, in particular adipose stem cells, apparently fundamental as regenerators and as immune-modulators. Here, we discuss stem cells in intestinal homeostasis and as therapeutic agents for the treatment of inflammatory bowel diseases.

  10. Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    Matthew J Haney

    Full Text Available The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD. This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.

  11. Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Jing Lin


    Full Text Available Self-renewing tumor-initiating cells (TICs are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC. GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3.5–7 nM, disrupt the open reading frame (ORF of GLDC transcript (predisposing it for nonsense-mediated decay, halt cell proliferation, and prevent colony formation in both A549 cells and TIC-enriched NSCLC tumor sphere cells (TS32. One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications.

  12. Strategy to prime the host and cells to augment therapeutic efficacy of progenitor cells for patients with myocardial infarction

    Directory of Open Access Journals (Sweden)

    Jeehoon Kang


    Full Text Available Cell therapy in myocardial infarction (MI is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming peripheral blood mononuclear cells or patients, as for cell therapy of MI.

  13. Anti-PD-1 Antibodies as a Therapeutic Strategy in Classical Hodgkin Lymphoma. (United States)

    Jain, Michael D; Kuruvilla, John


    Classical Hodgkin lymphoma (cHL) is defined by malignant Reed-Sternberg (RS) cells that recruit non-malignant immune cells into a supportive tumour microenvironment. In cHL, this is driven, in part, by genomic alterations of the 9p24.1 locus encoding the immune checkpoint ligands PD-L1 and PD-L2. Therapeutic anti-PD-1 antibodies have been developed that competitively inhibit the interaction between PD-1 and its ligands. Clinical trials of anti-PD-1 antibodies in cHL demonstrate high overall response rates but relapses still occur and new clinical challenges exist for toxicity management and response assessment. This review discusses the biological and clinical features of anti-PD-1 antibody therapy in cHL.

  14. Current diagnostics and treatment of fibrosarcoma –perspectives for future therapeutic targets and strategies (United States)

    Augsburger, Daniela; Nelson, Peter J.; Kalinski, Thomas; Udelnow, Andrej; Knösel, Thomas; Hofstetter, Monika; Qin, Ji Wei; Wang, Yan; Gupta, Arvid Sen; Bonifatius, Susanne; Li, Minglun; Bruns, Christiane J.; Zhao, Yue


    Adult-type fibrosarcoma is a rare and highly aggressive subtype of soft tissue sarcomas. Due to the existence of other spindle-cell shaped sarcomas, its diagnosis is always one of exclusion. The likelihood of misdiagnoses between similar tumour entities is high, and often leads to inappropriate tumour treatment. We summarize here the main features of fibrosarcoma. When fibrosarcoma is appropriately diagnosed, the patient`s overall prognosis is generally quite poor. Fibrosarcoma is characterized by its low sensitivity towards radio- and chemotherapy as well as by its high rate of tumour recurrences. Thus it is important to identify new methods to improve treatment of this tumour entity. We discuss some promising new directions in fibrosarcoma research, specifically focusing on more effective targeting of the tumour microenvironment. Communication between tumour cells and their surrounding stromal tissue play a crucial role in cancer progression, invasion, metastasis and chemosensitivity. The therapeutic potential of targeting the tumour microenvironment is addressed. PMID:29262667


    Directory of Open Access Journals (Sweden)

    M. M. Zafranskaya


    Full Text Available The ability of mesenchymal stem cells (MSC to influence the regulatory/suppressive effect in the autoimmune process and promote remyelination allows to consider them a new method of multiple sclerosis (MS therapy, by means of modifying the disease activity. Genetic stability, proliferative potential, ability to migrate into the damaged tissue areas and agreed protocols for isolation and culture are the main advantages for successful autologous, as well as allogeneic MSC therapy. Preliminary results from clinical studies using MSC application in MS patients show efficiency and safety of this therapeutic approach. Nevertheless, successful demonstration of the cell therapy in MS is only possible after detailed analysis and understanding of MSC biology and mechanisms of appropriate intercellular interactions. The article reviews general experience in usage of immunomodulatory and neuroprotective properties of MSС in MS, and highlights the issues of validity in cell-based therapy taking into account both in vitro и in vivo studies.

  16. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.

    LENUS (Irish Health Repository)

    Wander, Seth A


    Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

  17. Surgical and therapeutic strategy of recurrent malignant gliomas in intractable location

    Directory of Open Access Journals (Sweden)

    LU Yun-tao


    Full Text Available Objective Recurrent malignant gliomas often violate important neurological function parts or deep brain structures due to tumor invasion, further increasing the difficulty of reoperation and treatment. Therefore, how to develop a reasonable treatment strategy, maximize the removal of the tumor, and ensure a basic quality of life of the patient, is nowadays hotly debated by scholars from various countries. This article aims to explore the reasonable treatment and optimal surgical strategy of recurrent malignant gliomas. Methods Four cases of recurrent malignant glioma were collceted. A comprehensive assessment on preoperative imaging, intraoperative operation, postoperative complications and long-term follow-up was made, and treatment strategy was elaborated. Results Postoperative MRI in 2 cases showed the recurrent tumors located in remnant edema parts, which were revealed by T2WI after first resections. One case underwent expanded resection of edema parts according to T2WI. This patient suffered short-sensory aphasia and weakness of right limbs, but recovered by improving cerebral circulation, hyperbaric oxygen, auxiliary acupuncture and physical rehabilitation trainings. One case with brainstem glioma underwent precise resection by laser knife, without postoperative neurological disorders. All the 4 cases received postoperative chemotherapy with TMZ (200 mg/kg, 5 d/28 d. The average follow-up period was (14.00 ± 12.50 months. Conclusion For obvious recurrence of malignant glioma, reoperation is still the key factor to lengthen the survival of patients, and expanded resection of the edema area supplemented by T2WI can reduce recurrence. Under the precondition of maintaining the basic postoperative quality of life of patients (KPS > 70, expanded resection should be used. As for tumors adjacent to the eloquent areas, precise engraving resection should be used to minimize residual tumor cells.

  18. New strategies to direct therapeutic targeting of PML to treat cancers

    Directory of Open Access Journals (Sweden)

    Kamil eWolyniec


    Full Text Available The tumor suppressor function of the promyelocytic leukemia (PML protein was first identified as a result of its dysregulation in acute promyelocytic leukemia (APL, however, its importance is now emerging far beyond hematological neoplasms, to an extensive range of malignancies, including solid tumours. In response to stress signals, PML coordinates the regulation of numerous proteins, which activate fundamental cellular processes that suppress tumorigenesis. Importantly, PML itself is the subject of specific post-translational modifications, including ubiquitination, phosphorylation, acetylation and SUMOylation, which in turn control PML activity and stability and ultimately dictate cellular fate. Improved understanding of the regulation of this key tumor suppressor is uncovering potential opportunities for therapeutic intervention. Targeting the key negative regulators of PML in cancer cells such as CK2, BMK1 and E6AP, with specific inhibitors that are becoming available, provides unique and exciting avenues for restoring tumor suppression through the induction of apoptosis and senescence. These approaches could be combined with DNA damaging drugs and cytokines that are known to activate PML. Depending on the cellular context, reactivation or enhancement of tumor suppressive PML functions, or targeted elimination of aberrantly functioning PML, may provide clinical benefit.

  19. Immunohistochemical investigations and introduction of new therapeutic strategies in scleromyxoedema: Case report

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    Altmeyer Peter


    Full Text Available Abstract Background Scleromyxoedema is a rare chronic skin disease of obscure origin, which may often be associated with severe internal co-morbidity. Even though different casuistic treatment modalities have been described, to date, curing still seems to be impossible. Case presentation We report a 44-year-old Caucasian female presenting with remarkable circumscribed, erythematous to skin-coloured, indurated skin eruptions at the forehead, arms, shoulders, legs and the gluteal region. Routine histology and Alcian blue labelling confirmed a massive deposition of acid mucopolysaccharides. Immunohistochemical investigations revealed proliferating fibroblasts and a discrete lymphocytic infiltration as well as increased dermal expression of MIB-1+ and anti-mastcell-tryptase+ cells. Bone marrow biopsies confirmed a monoclonal gammopathy of undetermined significance without morphological characteristics of plasmocytoma; immunofixation unveiled the presence of IgG-kappa paraproteins. Conclusions Taking all data into account, our patient exhibited a complex form of lichen mxyoedematosus, which could most likely be linked a variant of scleromyxoedema. Experimental treatment with methotrexate resulted in a stabilisation of clinical symptoms but no improvement after five months of therapy. A subsequent therapeutic attempt by the use of medium-dose ultraviolet A1 cold-light photomonotherapy led to a further stabilisation of clinical symptoms, but could not induce a sustained amelioration of skin condition.

  20. Bariatric Surgery for Adolescents with Type 2 Diabetes: an Emerging Therapeutic Strategy. (United States)

    Stefater, M A; Inge, T H


    Type 2 diabetes (T2D) is a growing public health problem in youth, but conventional treatments are often insufficient to treat this disease and its comorbidities. We review evidence supporting an emerging role for bariatric surgery as a treatment for adolescent T2D. Paralleling what has been seen in adult patients, bariatric surgery dramatically improves glycemic control in patients with T2D. In fact, remission of T2D has been observed in as many as 95-100% of adolescents with diabetes after bariatric surgery, particularly vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) surgery. This striking outcome may be due to both weight-dependent- and weight-independent factors, and recent studies suggest that T2D-related comorbidities may also improve after surgery. Bariatric surgery including RYGB and VSG is a powerful therapeutic option for obese adolescents with T2D. Benefits must be weighed against risk for postoperative complications such as nutritional deficiencies, but earlier surgical intervention might lead to more complete metabolic remission in obese patients with T2D.

  1. Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway (United States)

    Oon, Shereen; Wilson, Nicholas J; Wicks, Ian


    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies. PMID:27350879

  2. Therapeutic strategies for a functional cure of chronic hepatitis B virus infection

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    Jinhong Chang


    Full Text Available Treatment of chronic hepatitis B virus (HBV infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus–host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.

  3. Stenotrophomonas, Achromobacter, and nonmelioid Burkholderia species: antimicrobial resistance and therapeutic strategies. (United States)

    Abbott, Iain J; Peleg, Anton Y


    Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and nonmelioid Burkholderia species, namely, Burkholderia cepacia complex, collectively are a group of troublesome nonfermenters. Although not inherently virulent organisms, these environmental Gram negatives can complicate treatment in those who are immunocompromised, critically ill in the intensive care unit and those patients with suppurative lung disease, such as cystic fibrosis. Through a range of intrinsic antimicrobial resistance mechanisms, virulence factors, and the ability to survive in biofilms, these opportunistic pathogens are well suited to persist, both in the environment and the host. Treatment recommendations are hindered by the difficulties in laboratory identification, the lack of reproducibility of antimicrobial susceptibility testing, the lack of clinical breakpoints, and the absence of clinical outcome data. Despite trimethoprim-sulfamethoxazole often being the mainstay of treatment, resistance is widely encountered, and alternative regimens, including combination therapy, are often used. This review will highlight the important aspects and unique challenges that these three nonfermenters pose, and, in the absence of clinical outcome data, our therapeutic recommendations will be based on reported antimicrobial susceptibility and pharmacokinetic/pharmacodynamic profiles. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. Gene Editing and CRISPR Therapeutics: Strategies Taught by Cell and Gene Therapy. (United States)

    Ramirez, Juan C


    A few years ago, we assisted in the demonstration for the first time of the revolutionary idea of a type of adaptive-immune system in the bacteria kingdom. This system, named CRISPR, and variants engineered in the lab, have been demonstrated as functional with extremely high frequency and fidelity in almost all eukaryotic cells studied to date. The capabilities of this RNA-guided nuclease have added to the interest that was announced with the advent of previous technologies for genome editing tools, such as ZFN and TALEN. The capabilities exhibited by these gene editors, opens up a novel scenario that indicates the promise of a next-generation medicine based on precision and personalized objectives, mostly due to the change in the paradigm regarding gene-surgery. This has certainly attracted, like never before, the attention of the biotech business and investor community. This chapter offers a brief overview of some of the factors that have contributed to a rapid entry into the biotech and pharmaceutical company's pipeline, focusing on how cell and gene therapies (CGT), collectively known as advanced therapies, have become the driving forces toward the therapeutic uses of gene editing technology. The sum of all those efforts for more than 30years has contributed to the new paradigm of considering genes as medicines. Copyright © 2017. Published by Elsevier Inc.

  5. Therapeutic strategies for chemotherapy-induced neutropenia in patients with solid tumors. (United States)

    Koinis, Filippos; Nintos, George; Georgoulias, Vassilis; Kotsakis, Athanasios


    Chemotherapy-induced neutropenia (CIN) is a common adverse event during treatment of cancer patients, associated with increased morbidity, mortality, health care costs and impairment of patients' quality of life which necessitate dose reductions. A computerized systematic literature search was performed through Medline, PubMed, Google Scholar and the Cochrane Library to identify peer reviewed publications relevant to CIN, pathophysiology and epidemiology, patient risk-assessment and existing treatment approaches. Additionally, emerging issues such as alternative therapeutic options and implications in elderly care were addressed. Although CIN represents a common adverse event in the management of patients with solid tumors, the heterogeneity in clinical practice across different settings underlines the need to improve existing tools for accurate patient classification. Moreover, the definition of the optimal implementation of out-patient treatment and the use of colony-stimulating factor as add-on treatment together with antibiotics should be further investigated in order to accumulate more solid data. Finally, physician education is required to ensure that scientific knowledge is implemented in the daily clinical practice.

  6. The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury

    Directory of Open Access Journals (Sweden)

    Seunghoon Lee


    Full Text Available Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS. Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural damage process is complex, involving a vast array of tissue structure, transcriptional/translational, electrochemical, metabolic, and functional events within the intact neighbors surrounding injured neural tissues. During aging, multiple changes involving physical, chemical, and biochemical processes occur from the molecular to the morphological levels in neural tissues. Among many recommended therapeutic candidates, melatonin also plays a role in protecting the nervous system from anti-inflammation and efficiently safeguards neuronal cells via antioxidants and other endogenous/exogenous beneficial factors. Therefore, given the wide range of mechanisms responsible for neuronal damage, multi-action drugs or therapies for the treatment of neural injury that make use of two or more agents and target several pathways may have greater efficacy in promoting functional recovery than a single therapy alone.

  7. Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies. (United States)

    Villa, Nancy Y; Rahman, Masmudur M; McFadden, Grant; Cogle, Christopher R


    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

  8. The impact of cellular senescence in skin ageing: A notion of mosaic and therapeutic strategies. (United States)

    Toutfaire, Marie; Bauwens, Emilie; Debacq-Chainiaux, Florence


    Cellular senescence is now recognized as one of the nine hallmarks of ageing. Recent data show the involvement of senescent cells in tissue ageing and some age-related diseases. Skin represents an ideal model for the study of ageing. Indeed, skin ageing varies between individuals depending on their chronological age but also on their exposure to various exogenous factors (mainly ultraviolet rays). If senescence traits can be detected with ageing in the skin, the senescent phenotype varies among the various skin cell types. Moreover, the origin of cellular senescence in the skin is still unknown, and multiple origins are possible. This reflects the mosaic of skin ageing. Senescent cells can interfere with their microenvironment, either via the direct secretion of factors (the senescence-associated secretory phenotype) or via other methods of communication, such as extracellular vesicles. Knowledge regarding the impact of cellular senescence on skin ageing could be integrated into dermatology research, especially to limit the appearance of senescent cells after photo(chemo)therapy or in age-related skin diseases. Therapeutic approaches include the clearance of senescent cells via the use of senolytics or via the cooperation with the immune system. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Nancy Y. Villa


    Full Text Available Allogeneic hematopoietic stem cell transplantation (allo-HSCT has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD, an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

  10. The Third Therapeutic System: Faith Healing Strategies in the Context of a Generalized AIDS Epidemic (United States)

    Manglos, Nicolette D.; Trinitapoli, Jenny


    Faith healing in sub-Saharan Africa has primarily been studied qualitatively among Pentecostal-Charismatic groups, and considered as its own phenomenon with little attention to its relationship to other modes of healing. Using data from Malawi, a religiously diverse African country with high HIV prevalence, we find that faith healing is pervasive across multiple religious traditions. For individuals, attending a faith healing congregation is associated with lower levels of generalized worry about AIDS, and this association is driven by those who switched churches before AIDS became widespread in rural areas. Use of condoms and traditional medicine are, on the other hand, positively associated with worry about AIDS. We argue that faith healing can be understood as a third therapeutic system that coexists with the well-documented biomedical and traditional systems. The success of faith healing approaches lies in their unique ability to combine individual-pragmatic and communal-ritualized aspects of healing to inform interpretations of the AIDS epidemic and its consequences. PMID:21362615

  11. Geroprotectors as a therapeutic strategy for COPD – where are we now?

    Directory of Open Access Journals (Sweden)

    Miłkowska-Dymanowska J


    Full Text Available Joanna Miłkowska-Dymanowska,1,2 Adam J Białas,1,2 Joanna Makowska,2,3 Aleksandra Wardzynska,2,4 Paweł Górski,1,2 Wojciech J Piotrowski1,2 1Department of Pneumology and Allergy, 1st Chair of Internal Medicine, 2Healthy Aging Research Centre, 3Department of Rheumatology, 4Department of Immunology, Rheumatology, and Allergy, Medical University of Lodz, Lodz, Poland Abstract: Although current therapies in chronic obstructive pulmonary disease (COPD improve the quality of life, they do not satisfactorily reduce disease progression or mortality. There are still many gaps in knowledge about the cellular, molecular, and genetic mechanisms contributing to pathobiology of this disease. However, increasing evidence suggests that accelerated aging, chronic systemic inflammation, and oxidative stress play major roles in pathogenesis in COPD, thus opening new opportunities in therapy. Therefore, the aim of our review was to describe and discuss some of the most widely used therapeutics that affect the root cause of aging and oxidative stress (metformin, melatonin, sirolimus, statins, vitamin D, and testosterone in context of COPD therapy. Keywords: COPD, metformin, melatonin, statins, vitamin D, testosterone

  12. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research (United States)

    Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda


    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID:25142460

  13. Current and Emerging Therapeutic Strategies for the Treatment of Meibomian Gland Dysfunction (MGD). (United States)

    Thode, Adam R; Latkany, Robert A


    Meibomian gland (MG) dysfunction (MGD) is a multifactorial, chronic condition of the eyelids, leading to eye irritation, inflammation and ocular surface disease. Initial conservative therapy often includes a combination of warm compresses in addition to baby shampoo or eyelid wipes. The practice of lid hygiene dates back to the 1950s, when selenium sulfide-based shampoo was first used to treat seborrhoeic dermatitis of the eyelids. Today, tear-free baby shampoo has replaced dandruff shampoo for MGD treatment and offers symptom relief in selected patients. However, many will not achieve significant improvement on this therapy alone; some may even develop an allergy to the added dyes and fragrances in these products. Other manual and mechanical techniques to treat MGD include MG expression and massage, MG probing and LipiFlow(®). While potentially effective in patients with moderate MGD, these procedures are more invasive and may be cost prohibitive. Pharmacological treatments are another course of action. Supplements rich in omega-3 fatty acids have been shown to improve both MGD and dry eye symptoms. Tea tree oil, specifically the terpenin-4-ol component, is especially effective in treating MGD associated with Demodex mites. Topical antibiotics, such as azithromycin, or systemic antibiotics, such as doxycycline or azithromycin, can improve MGD symptoms both by altering the ocular flora and through anti-inflammatory mechanisms. Addressing and treating concurrent ocular allergy is integral to symptom management. Topical N-acetylcysteine and topical cyclosporine can both be effective therapeutic adjuncts in patients with concurrent dry eye. A short course of topical steroid may be used in some severe cases, with monitoring for steroid-induced glaucoma and cataracts. While the standard method to treat MGD is simply warm compresses and baby shampoo, a more tailored approach to address the multiple aetiologies of the disease is suggested.

  14. Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies. (United States)

    McGraw, Christopher M; Ward, Christopher S; Samaco, Rodney C


    Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism-based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short-comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non-neurological diseases as well as to symptom-based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two-pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom-based approaches in addition to more mechanism-based approaches. © 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.

  15. CRISPR-Cas9 systems: versatile cancer modelling platforms and promising therapeutic strategies. (United States)

    Wen, Wan-Shun; Yuan, Zhi-Min; Ma, Shi-Jie; Xu, Jiang; Yuan, Dong-Tang


    The RNA-guided nuclease CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) and its variants such as nickase Cas9, dead Cas9, guide RNA scaffolds and RNA-targeting Cas9 are convenient and versatile platforms for site-specific genome editing and epigenome modulation. They are easy-to-use, simple-to-design and capable of targeting multiple loci simultaneously. Given that cancer develops from cumulative genetic and epigenetic alterations, CRISPR-Cas9 and its variants (hereafter referred to as CRISPR-Cas9 systems) hold extensive application potentials in cancer modeling and therapy. To date, they have already been applied to model oncogenic mutations in cell lines (e.g., Choi and Meyerson, Nat Commun 2014;5:3728) and in adult animals (e.g., Xue et al., Nature 2014;514:380-4), as well as to combat cancer by disabling oncogenic viruses (e.g., Hu et al., Biomed Res Int 2014;2014:612823) or by manipulating cancer genome (e.g., Liu et al., Nat Commun 2014;5:5393). Given the importance of epigenome and transcriptome in tumourigenesis, manipulation of cancer epigenome and transcriptome for cancer modeling and therapy is a promising area in the future. Whereas (epi)genetic modifications of cancer microenvironment with CRISPR-Cas9 systems for therapeutic purposes represent another promising area in cancer research. Herein, we introduce the functions and mechanisms of CRISPR-Cas9 systems in genome editing and epigenome modulation, retrospect their applications in cancer modelling and therapy, discuss limitations and possible solutions and propose future directions, in hope of providing concise and enlightening information for readers interested in this area. © 2015 UICC.

  16. Skeletal muscle homeostasis in Duchenne muscular dystrophy: modulating autophagy as a promising therapeutic strategy

    Directory of Open Access Journals (Sweden)

    Clara eDe Palma


    Full Text Available Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterised by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD, the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity and chronic local inflammation leading to substitution of myofibres by connective and adipose tissue. DMD patients suffer of continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. The autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels it can be detrimental and contribute to muscle wasting; at low levels it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular levels, the Akt axis is one of the key disregulated pathways, although the molecular events are not completely understood.The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signalling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.

  17. Advances in peripheral nervous system regenerative therapeutic strategies: A biomaterials approach. (United States)

    Dalamagkas, Kyriakos; Tsintou, Magdalini; Seifalian, Alexander


    Peripheral nerve injury is a very common medical condition with varying clinical severity but always great impact on the patients' productivity and the quality of life. Even the current 1st-choice surgical therapeutic approach or the "gold standard" as frequently called in clinical practice, is not addressing the problem efficiently and cost-effectively, increasing the mortality through the need of a second surgical intervention, while it does not take into account the several different types of nerves involved in peripheral nerve injuries. Neural tissue engineering approaches could potentially offer a very promising and attractive tool for the efficient peripheral nerve injury management, not only by mechanically building the gap, but also by inducing neuroregenerative mechanisms in a well-regulated microenvironment which would mimic the natural environment of the specific nerve type involved in the injury to obtain an optimum clinical outcome. There is still room for a lot of optimizations in regard to the conduits which have been developed with the help of neural engineering since many parameters affect the clinical outcome and the underlying mechanisms are still not well understood. Especially the intraluminal cues controlling the microenvironment of the conduits are in an infantile stage but there is profound potential in the application of the scaffolds. The aim of our review is to provide a quick reference to the recent advances in the field, focusing on the parameters that can significantly affect the clinical potentials of each approach, with suggestions for future improvements that could take the current work from bench to bedside. Thus, further research could shed light to those questions and it might hold the key to discover new more efficient and cost-effective therapies. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors

    Directory of Open Access Journals (Sweden)

    Kwai Fung Hui


    Full Text Available Epstein-Barr virus (EBV is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma. To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers.

  19. Preventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV (United States)

    Rodríguez, Sabrina M.; Florins, Arnaud; Gillet, Nicolas; de Brogniez, Alix; Sánchez-Alcaraz, María Teresa; Boxus, Mathieu; Boulanger, Fanny; Gutiérrez, Gerónimo; Trono, Karina; Alvarez, Irene; Vagnoni, Lucas; Willems, Luc


    Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads. PMID:21994777

  20. Preventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV

    Directory of Open Access Journals (Sweden)

    Lucas Vagnoni


    Full Text Available Bovine leukemia virus (BLV is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1. BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads.

  1. [Therapeutic strategies of atrial fibrillation in patients aged 65 and over. Report of 86 cases]. (United States)

    Jaafari, Aïcha; Zakhama, Lilia; Boussabah, Ehlem; Thameur, Moez; Boukhriss, Bessma; Amara, Yosser; Masmoudi, Mourad; Bencheikh, Mamoun; Benyoussef, Soraya


    Auricular fibrillation is the most common sustained cardiac arrhythmia, yet the optimal strategy for its management remains unclear. Since the study AFFIRM from which resulted them final were deferred in December 2002, the assumption of responsibility of the fibrillation of the old subject tends to become clarified. 86 patients at least 65 years or more were enrolled in our retrospective study from January 1997 to June 2003. The mean age is 70 years (65 to 82 years) and sex ratio to 0.79. 34% had a history of hypertension and 12% had a coronary artery disease. 2 groups were individualized, according to the year of admission before or after 2002. It comes out from these work 2 points: the restoration of the sinusal rhythm was the first choice. In the event of failure, the option was to maintain fibrillation and this, in the 2 groups. The AVK were founded in the large majority of the cases only after year 2002.

  2. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies (United States)

    Manna, Prasenjit


    Abstract Obesity is gaining acceptance as a serious primary health burden that impairs the quality of life because of its associated complications, including diabetes, cardiovascular diseases, cancer, asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and infertility. It is a complex metabolic disorder with a multifactorial origin. Growing evidence suggests that oxidative stress plays a role as the critical factor linking obesity with its associated complications. Obesity per se can induce systemic oxidative stress through various biochemical mechanisms, such as superoxide generation from NADPH oxidases, oxidative phosphorylation, glyceraldehyde auto-oxidation, protein kinase C activation, and polyol and hexosamine pathways. Other factors that also contribute to oxidative stress in obesity include hyperleptinemia, low antioxidant defense, chronic inflammation, and postprandial reactive oxygen species generation. In addition, recent studies suggest that adipose tissue plays a critical role in regulating the pathophysiological mechanisms of obesity and its related co-morbidities. To establish an adequate platform for the prevention of obesity and its associated health risks, understanding the factors that contribute to the cause of obesity is necessary. The most current list of obesity determinants includes genetic factors, dietary intake, physical activity, environmental and socioeconomic factors, eating disorders, and societal influences. On the basis of the currently identified predominant determinants of obesity, a broad range of strategies have been recommended to reduce the prevalence of obesity, such as regular physical activity, ad libitum food intake limiting to certain micronutrients, increased dietary intake of fruits and vegetables, and meal replacements. This review aims to highlight recent findings regarding the role of oxidative stress in the pathogenesis of obesity and its associated risk factors, the role of dysfunctional adipose tissue

  3. [Resistances to targeted therapies and strategy for following therapeutic lines in metastatic NSCLC]. (United States)

    Brosseau, Solenn; Oulkhouir, Youssef; Naltet, Charles; Zalcman, Gérard


    EGFR, ALK, ROS1 Tyrosine Kinase Inhibitors (TKis) have changed natural history of 12 to 15% of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) and molecular alterations (mutations or translocations) in these genes. Median Progression Free Survival (PFS) of these patients has increased from 12 months with a platinum-based chemotherapy associated with bevacizumab, to 18 months with TKIs, overall survival reaching several years in these patients. However, rare primary resistance have been described in less than 10% of patients with EGFR or ALK-mutated cancer, whereas secondary resistance occur systematically. New generations TKIs are currently in clinical development, which are active on tumor clones harboring a resistance mutation, and some of them diffuse perfectly well into brain, a classical sanctuary for metastasis. Strategies are developed to delay secondary resistance apparition, to prolong PFS, and then overall survival. These strategies use combinations, as soon as first linesetting, of TKIs with either an anti-angiogenic drug (bevacizumab), or with an immunological checkpoint inhibitors, or with Heat-Shock Protein (Hsp) inhibitors. In order to delay acquired resistance to EGFR TKIs, the French Intergroup (IFCT) has launched a combination trial of EGFR TKIs with an anti-estrogen (fulvestrant) in postmenopausal women, whereas other trials associate EGFR TKIs with EFGR monoclonal antibody cetuximab, or with a monoclonal antibody targeting c-met. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

  4. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies. (United States)

    Manna, Prasenjit; Jain, Sushil K


    Obesity is gaining acceptance as a serious primary health burden that impairs the quality of life because of its associated complications, including diabetes, cardiovascular diseases, cancer, asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and infertility. It is a complex metabolic disorder with a multifactorial origin. Growing evidence suggests that oxidative stress plays a role as the critical factor linking obesity with its associated complications. Obesity per se can induce systemic oxidative stress through various biochemical mechanisms, such as superoxide generation from NADPH oxidases, oxidative phosphorylation, glyceraldehyde auto-oxidation, protein kinase C activation, and polyol and hexosamine pathways. Other factors that also contribute to oxidative stress in obesity include hyperleptinemia, low antioxidant defense, chronic inflammation, and postprandial reactive oxygen species generation. In addition, recent studies suggest that adipose tissue plays a critical role in regulating the pathophysiological mechanisms of obesity and its related co-morbidities. To establish an adequate platform for the prevention of obesity and its associated health risks, understanding the factors that contribute to the cause of obesity is necessary. The most current list of obesity determinants includes genetic factors, dietary intake, physical activity, environmental and socioeconomic factors, eating disorders, and societal influences. On the basis of the currently identified predominant determinants of obesity, a broad range of strategies have been recommended to reduce the prevalence of obesity, such as regular physical activity, ad libitum food intake limiting to certain micronutrients, increased dietary intake of fruits and vegetables, and meal replacements. This review aims to highlight recent findings regarding the role of oxidative stress in the pathogenesis of obesity and its associated risk factors, the role of dysfunctional adipose tissue in

  5. Protein homeostasis disorders of key enzymes of amino acids metabolism: mutation-induced protein kinetic destabilization and new therapeutic strategies. (United States)

    Pey, Angel L


    Many inborn errors of amino acids metabolism are caused by single point mutations affecting the ability of proteins to fold properly (i.e., protein homeostasis), thus leading to enzyme loss-of-function. Mutations may affect protein homeostasis by altering intrinsic physical properties of the polypeptide (folding thermodynamics, and rates of folding/unfolding/misfolding) as well as the interaction of partially folded states with elements of the protein homeostasis network (such as molecular chaperones and proteolytic machineries). Understanding these mutational effects on protein homeostasis is required to develop new therapeutic strategies aimed to target specific features of the mutant polypeptide. Here, I review recent work in three different diseases of protein homeostasis associated to inborn errors of amino acids metabolism: phenylketonuria, inherited homocystinuria and primary hyperoxaluria type I. These three different genetic disorders involve proteins operating in different cell organelles and displaying different structural complexities. Mutations often decrease protein kinetic stability of the native state (i.e., its half-life for irreversible denaturation), which can be studied using simple kinetic models amenable to biophysical and biochemical characterization. Natural ligands and pharmacological chaperones are shown to stabilize mutant enzymes, thus supporting their therapeutic application to overcome protein kinetic destabilization. The role of molecular chaperones in protein folding and misfolding is also discussed as well as their potential pharmacological modulation as promising new therapeutic approaches. Since current available treatments for these diseases are either burdening or only successful in a fraction of patients, alternative treatments must be considered covering studies from protein structure and biophysics to studies in animal models and patients.

  6. Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model. (United States)

    Adriani, W; Laviola, G


    Adolescence comes in association with puberty, when maturation and rearrangement of major neurotransmitter pathways and functions are still taking place. The neurobiological processes occurring in the brain during this developmental period have been so far poorly investigated. Yet, it is during adolescence that some major neuropsychiatric disorders may become evident, including ADHD, schizophrenia, and drug abuse. Moreover, the age-related neurobehavioural plasticity renders adolescents particularly vulnerable to the consequences of psychoactive drug exposure. In this view, there is an increased likelihood that addiction will develop when psychoactive drug use starts early during adolescence. From all these observations adolescence emerges as a critical phase in development. In the present review, we focus on recent neurobiological characterization of adolescent rats and mice. As for vulnerability to addictive behaviour, nicotine exposure during adolescence dose-dependently down-regulated levels of AMPA GluR2/3 subunits in the striatum, suggesting a reduced neurobehavioural plasticity in adult subjects. Comparable exposure during adulthood had opposite effects. It was found consistently that exposure to nicotine during adolescence, but not similar exposure in the post-adolescent period, increased the expression of specific subunits of the acetylcholine receptor in adult rats, thus enhancing the reinforcing efficacy of nicotine in a self-administration paradigm. The present data identified a specific age-window, characterized by long-term effects on behavioural and neurochemical indexes, of vulnerability. With respect to potential therapeutic approaches in ADHD, we studied the adolescent spontaneously-hypertensive-rat (SHR) in an intolerance-to-delay operant-behaviour paradigm. The model was further validated by the finding that impulsivity was reduced by chronic methylphenidate administration. Impulsive SHR animals were characterized by reduced cannabinoid CB1

  7. Future Perspectives: Therapeutic Targeting of Notch Signalling May Become a Strategy in Patients Receiving Stem Cell Transplantation for Hematologic Malignancies

    Directory of Open Access Journals (Sweden)

    Elisabeth Ersvaer


    Full Text Available The human Notch system consists of 5 ligands and 4 membrane receptors with promiscuous ligand binding, and Notch-initiated signalling interacts with a wide range of other intracellular pathways. The receptor signalling seems important for regulation of normal and malignant hematopoiesis, development of the cellular immune system, and regulation of immune responses. Several Notch-targeting agents are now being developed, including natural receptor ligands, agonistic and antagonistic antibodies, and inhibitors of intracellular Notch-initiated signalling. Some of these agents are in clinical trials, and several therapeutic strategies seem possible in stem cell recipients: (i agonists may be used for stem cell expansion and possibly to enhance posttransplant lymphoid reconstitution; (ii receptor-specific agonists or antagonists can be used for immunomodulation; (iii Notch targeting may have direct anticancer effects. Although the effects of therapeutic targeting are difficult to predict due to promiscuous ligand binding, targeting of this system may represent an opportunity to achieve combined effects with earlier posttransplant reconstitution, immunomodulation, or direct anticancer effects.

  8. Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ion Cristóbal


    Full Text Available Protein phosphatase 2A (PP2A is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa. However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients.

  9. [Palbociclib combinations as new therapeutic strategies in the treatment of HR+/HER2- advanced breast cancer]. (United States)

    Boér, Katalin


    Until recently, the only endocrine agents used to treat HR+/HER2- advanced breast cancers were tamoxifen, aromatase inhibitors and fulvestrant, although a substantial proportion of patients relapse on these standard therapies. Intensive research has been conducted to develop new strategies to overcome endocrine resistance and to enhance the efficacy of endocrine treatments by combining hormone therapy with other targeted treatment approaches. The development of selective CDK4/6 inhibitors and the introduction of palbociclib, the first molecule in this class in clinical practice, represent an important step in the treatment of HR+ advanced breast cancer. High level evidence supports the use of palbociclib plus letrozole in the treatment of endocrine sensitive breast cancers, or palbociclib plus fulvestrant in tumors that develop acquired resistance to endocrine therapy. These combinations are effective and well tolerated therapeutic modalities. The new combination regimens with palbociclib represent an important addition to the therapeutic armamentarium in locally advanced and metastatic ER+/HER2- breast cancer. The article reviews the current role of palbociclib in combination with endocrine therapy in the therapy of HR+/HER2- advanced breast cancer.

  10. The Potential for iPS-Derived Stem Cells as a Therapeutic Strategy for Spinal Cord Injury: Opportunities and Challenges

    Directory of Open Access Journals (Sweden)

    Mohamad Khazaei


    Full Text Available Spinal cord injury (SCI is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is promising, particularly since it can target cell replacement, neuroprotection and regeneration. Cell therapies for treating SCI are limited due to several translational roadblocks, including ethical and practical concerns regarding cell sources. The use of iPSCs has been particularly attractive, since they avoid the ethical and moral concerns that surround other stem cells. Furthermore, various cell types with potential for application in the treatment of SCI can be created from autologous sources using iPSCs. For applications in SCI, the iPSCs can be differentiated into neural precursor cells, neurons, oligodendrocytes, astrocytes, neural crest cells and mesenchymal stromal cells that can act by replacing lost cells or providing environmental support. Some methods, such as direct reprogramming, are being investigated to reduce tumorigenicity and improve reprogramming efficiencies, which have been some of the issues surrounding the use of iPSCs clinically to date. Recently, iPSCs have entered clinical trials for use in age-related macular degeneration, further supporting their promise for translation in other conditions, including SCI.

  11. Targeting Leptin as a Therapeutic Strategy against Ovarian Cancer Peritoneal Metastasis. (United States)

    Wei, Xiao; Liu, Yi; Gong, Cheng; Ji, Teng; Zhou, Xiaoshui; Zhang, Taoran; Wan, Dongyi; Xu, Sen; Jin, Ping; Yang, Xin; Li, Xiaoting; Ma, Ding; Yang, Zongyuan; Gao, Qinglei


    Epithelial ovarian cancer (OC) is the leading cause of death in patients with gynecologic malignancy. Malignant ascites, a shared symptom of advanced OC patients, plays an important role in the peritoneal metastasis cascade of OC. Since leptin existed in great amount in malignant ascites, we speculated that it might be involved in the modulation of tumor cells malignant behavior. Here, we demonstrated that blocking of leptin could significantly suppress ovarian malignant ascitesinduced metastatic aggravation of OC cells. Furthermore, our results suggested that leptin was highly expressed in OC and correlated with poor outcome of OC patients. Recombinant leptin notably promoted the migration, invasion and proliferation of OC cells. Mechanistically, we found that leptin induced epithelial-mesenchymal transition (EMT) program in OC cells through the activation of the PI3K/Akt/mTOR pathway. Pharmacological inhibition of the PI3K/Akt/mTOR pathway partly impaired leptin-induced malignant transformation of OC cells. More importantly, our in vivo xenograft experiment showed that blocking of leptin could dramatically inhibit OC cells peritoneal dissemination. Collectively, this study emphasized the importance of leptin in OC progression and illustrated a novel mechanism that the PI3K/Akt/mTOR pathway was involved in leptin-induced EMT. Our findings provide new insights into leptin exertion on OC metastasis and identify the potential of leptin neutralizing as a novel strategy against OC peritoneal dissemination. Copyright© Bentham Science Publishers; For any queries, please email at

  12. Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders (United States)

    Mohammed Qasim Hussaini, Syed; Rigby, Michael J.; Jang, Mi-Hyeon


    Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment. PMID:23346419

  13. Leukotriene B4-loaded microspheres: a new therapeutic strategy to modulate cell activation

    Directory of Open Access Journals (Sweden)

    Sanz Maria J


    Full Text Available Abstract Background Leukotriene B4 (LTB4 is a potent inflammatory mediator that also stimulates the immune response. In addition, it promotes polymorphonuclear leukocyte phagocytosis, chemotaxis, chemokinesis and modulates cytokines release. Regarding chemical instability of the leukotriene molecule, in the present study we assessed the immunomodulatory activities conferred by LTB4 released from microspheres (MS. A previous oil-in-water emulsion solvent extraction-evaporation method was chosen to prepare LTB4-loaded MS. Results In the mice cremasteric microcirculation, intraescrotal injection of 0.1 ml of LTB4-loaded MS provoked significant increases in leukocyte rolling flux, adhesion and emigration besides significant decreases in the leukocyte rolling velocity. LTB4-loaded MS also increase peroxisome proliferator-activated receptor-α (PPARα expression by murine peritoneal macrophages and stimulate them to generate nitrite levels. Monocyte chemoattractant protein-1 (MCP-1 and nitric oxide (NO productions were also increased when human umbilical vein and artery endothelial cells (HUVECs and HUAECs, respectively were stimulated with LTB4-loaded MS. Conclusion LTB4-loaded MS preserve the biological activity of the encapsulated mediator indicating their use as a new strategy to modulate cell activation, especially in the innate immune response.

  14. Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Robin K. Kuriakose


    Full Text Available Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-induced cardiotoxicity (AIC was first suggested in 1979. Subsequent preclinical and clinical studies have supported the notion that hypertension is a major risk factor for AIC, along with the cumulative anthracycline dosage. There are several common or overlapping pathological mechanisms in AIC and hypertension, such as oxidative stress. Current evidence supports the utility of cardioprotective modalities as adjunct treatment prior to and during anthracycline chemotherapy. Several promising cardioprotective approaches against AIC pathologies include dexrazoxane, early hypertension management, and dietary supplementation of nitrate with beetroot juice or other medicinal botanical derivatives (e.g., visnagin and Danshen, which have both antihypertensive and anti-AIC properties. Future research is warranted to further elucidate the mechanisms of hypertension and AIC comorbidity and to conduct well-controlled clinical trials for identifying effective clinical strategies to improve long-term prognoses in this subgroup of cancer patients.

  15. House Dust Mite Respiratory Allergy: An Overview of Current Therapeutic Strategies. (United States)

    Calderón, Moisés A; Kleine-Tebbe, Jörg; Linneberg, Allan; De Blay, Frédéric; Hernandez Fernandez de Rojas, Dolores; Virchow, Johann Christian; Demoly, Pascal


    Although house dust mite (HDM) allergy is a major cause of respiratory allergic disease, specific diagnosis and effective treatment both present unresolved challenges. Guidelines for the treatment of allergic rhinitis and asthma are well supported in the literature, but specific evidence on the efficacy of pharmacotherapy treatment for known HDM-allergic patients is weaker. The standard diagnostic techniques--skin prick test and specific IgE testing--can be confounded by cross-reactivity. However, component-resolved diagnosis using purified and recombinant allergens can improve the accuracy of specific IgE testing, but availability is limited. Treatment options for HDM allergy are limited and include HDM avoidance, which is widely recommended as a strategy, although evidence for its efficacy is variable. Clinical efficacy of pharmacotherapy is well documented; however, symptom relief does not extend beyond the end of treatment. Finally, allergen immunotherapy has a poor but improving evidence base (notably on sublingual tablets) and its benefits last after treatment ends. This review identifies needs for deeper physician knowledge on the extent and impact of HDM allergy in respiratory disease, as well as further development and improved access to molecular allergy diagnosis. Furthermore, there is a need for the development of better-designed clinical trials to explore the utility of allergen-specific approaches, and uptake of data into guidance for physicians on more effective diagnosis and therapy of HDM respiratory allergy in practice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders

    Directory of Open Access Journals (Sweden)

    Heechul Jun


    Full Text Available Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

  17. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler


    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  18. Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections. (United States)

    Wares, Joanna R; Crivelli, Joseph J; Yun, Chae-Ok; Choi, Il-Kyu; Gevertz, Jana L; Kim, Peter S


    Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.

  19. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

    Directory of Open Access Journals (Sweden)

    Kenneth Maiese


    Full Text Available Throughout the globe, diabetes mellitus (DM is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1 and mTOR Complex 2 (mTORC2 and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K, protein kinase B (Akt, AMP activated protein kinase (AMPK, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae (SIRT1, Wnt1 inducible signaling pathway protein 1 (WISP1, and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

  20. Deciphering the therapeutic stem cell strategies of large and midsize pharmaceutical firms. (United States)

    Vertès, Alain A


    The slow adoption of cytotherapeutics remains a vexing hurdle given clinical progress achieved to date with a variety of stem cell lineages. Big and midsize pharmaceutical companies as an asset class still delay large-scale investments in this arena until technological and market risks will have been further reduced. Nonetheless, a handful of stem cell strategic alliance and licensing transactions have already been implemented, indicating that progress is actively monitored, although most of these involve midsize firms. The greatest difficulty is, perhaps, that the regenerative medicine industry is currently only approaching the point of inflexion of the technology development S-curve, as many more clinical trials read out. A path to accelerating technology adoption is to focus on innovation outliers among healthcare actors. These can be identified by analyzing systemic factors (e.g., national science policies and industry fragmentation) and intrinsic factors (corporate culture, e.g., nimble decision-making structures; corporate finance, e.g., opportunity costs and ownership structure; and operations, e.g., portfolio management strategies, threats on existing businesses and patent expirations). Another path is to accelerate the full clinical translation and commercialization of an allogeneic cytotherapeutic product in any indication to demonstrate the disease-modifying potential of the new products for treatment and prophylaxis, ideally for a large unmet medical need such as dry age-related macular degeneration, or for an orphan disease such as biologics-refractory acute graft-versus-host disease. In times of decreased industry average research productivities, regenerative medicine products provide important prospects for creating new franchises with a market potential that could very well mirror that achieved with the technology of monoclonal antibodies.

  1. Protein Misdirection Inside and Outside Motor Neurons in Amyotrophic Lateral Sclerosis (ALS: A Possible Clue for Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Akemi Ido


    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1 and TAR DNA binding protein 43kDa (TDP-43 are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.

  2. Viable Syntax: Rethinking Minimalist Architecture

    Directory of Open Access Journals (Sweden)

    Ken Safir


    Full Text Available Hauser et al. (2002 suggest that the human language faculty emerged as a genetic innovation in the form of what is called here a ‘keystone factor’—a single, simple, formal mental capability that, interacting with the pre-existing faculties of hominid ancestors, caused a cascade of effects resulting in the language faculty in modern humans. They take Merge to be the keystone factor, but instead it is posited here that Merge is the pre-existing mechanism of thought made viable by a principle that permits relations interpretable at the interfaces to be mapped onto c-command. The simplified minimalist architecture proposed here respects the keystone factor as closely as possible, but is justified on the basis of linguistic analyses it makes available, including a relativized intervention theory applicable across Case, scope, agreement, selection and linearization, a derivation of the A/A’-distinction from Case theory, and predictions such as why in situ wh-interpretation is island-insensitive, but susceptible to intervention effects.

  3. Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy. (United States)

    Richards, Patrick G; Dang, Kimberlyn M; Kauffman, Carol A; Stalker, Kay Lyn; Sudekum, David; Kerr, Lisa; Brinker-Bodley, Michelle; Cheriyan, Beena; West, Nina; Collins, Curtis D; Polega, Shikha; Malani, Anurag N


    A high-dose 12 mg/kg/day (6 mg/kg twice daily) voriconazole regimen was recommended by the CDC to treat patients injected with contaminated methylprednisolone acetate that caused a multi-state fungal outbreak in 2012-13. Therapeutic drug monitoring results of this unique regimen are unknown, as is the most appropriate dosing weight for obese patients. We evaluated voriconazole trough measurements for this dosing scheme, as well as the use of adjusted body weight dosing for obese patients. Voriconazole trough levels were analysed in obese (BMI ≥35 kg/m 2 ) and non-obese (BMI voriconazole troughs were supratherapeutic (>5 mg/L) in 65 (47%) patients, therapeutic (2-5 mg/L) in 57 (41%) patients and subtherapeutic (Voriconazole doses >11 and >8 mg/kg/day produced mainly first steady-state supratherapeutic troughs in 44 obese and 94 non-obese patients, respectively. An initial 12 mg/kg/day was progressively lowered to a median maintenance dose of 8.5 mg/kg/day in the obese and 8.6 mg/kg/day in the non-obese. A high-dose voriconazole regimen produced initial supratherapeutic troughs that required dose adjustment downward by nearly 30%. Adjusted body weight dosing in obese patients resulted in a similar maintenance dose to total body weight dosing in the non-obese, and appears to be a sensible dosing strategy for these patients.

  4. Initial therapeutic strategy of invasive candidiasis for intensive care unit patients: a retrospective analysis from the China-SCAN study. (United States)

    Cui, Na; Wang, Hao; Su, Longxiang; Qiu, Haibo; Li, Ruoyu; Liu, Dawei


    To investigate the impact of initial antifungal therapeutic strategies on the prognosis of invasive Candida infections (ICIs) in intensive care units (ICUs) in China. A total of 306 patients with proven ICIs in the China-SCAN study were analyzed retrospectively. Empiric, pre-emptive, and targeted therapy were adopted based on starting criteria including clinical, microbiological, and other conventional prediction rules. The primary outcome was hospital mortality and the secondary endpoints were duration days in ICU and duration days in hospital. The global responses (clinical and microbiological) at the end of the empirical therapy were also assessed. A total of 268/306 (87.6%) ICI patients received antifungal therapy, including 142/268 (53.0%) initial empirical therapy, 53/268 (19.8%) initial pre-emptive therapy, and 73/268 (27.2%) initial targeted therapy. Compared with the initial empirical antifungal therapy and targeted antifungal therapy, patients with initial pre-emptive antifungal therapy had significantly less clinical remission [11/53 (21.2%) vs. 61/142 (43.3%) vs. 22/73 (30.1%), P = 0.009], higher ICU [26/53 (57.8%) vs. 42/142 (32.2%) vs. 27/73 (43.5%), P = 0.008] and hospital mortality [27/53 (60.0%) vs. 43/142 (32.8%) vs. 29/73 (46.8%), P = 0.004] and more microbiological persistence [9/53 (17.0%) vs. 6/142 (4.2%) vs. 9/73 (12.3%), P = 0.011]. Kaplan-Meier survival analysis revealed that ICI patients with initial pre-emptive antifungal therapy and targeted antifungal therapy were associated with reduced hospital duration compared with patients with initial empirical antifungal therapy after confirmation of fungal infection (log-rank test: P = 0.021). Multivariate regression analysis provided evidence that initial empirical antifungal therapy was an independent predictor for DECREASING the hospital mortality in ICI patients on ICU admission and at ICI diagnosis (odds ratio 0.327, 95% confidence interval 0.160-0.667, P = 0

  5. A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90α

    Energy Technology Data Exchange (ETDEWEB)

    Mehta, Adi; Shervington, Leroy; Munje, Chinmay; Shervington, Amal, E-mail: [Brain Tumour North West, Faculty of Science and Technology, University of Central Lancashire, Preston, PR1 2HE (United Kingdom)


    Hsp90α's vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90α was downregulated using the post-transcriptional RNAi strategy (sihsp90α) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90α, 17-AAG and concurrent sihsp90α/17-AAG (combined treatment). Both Hsp90α gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90α, 17-AAG and a combination of sihsp90α/17-AAG, reduced cell viability by 27%, 75% and 88% (p < 0.001), respectively, after 72 h. hsp90α mRNA copy numbers were downregulated by 65%, 90% and 99% after 72 h treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG, respectively. The relationship between Hsp90α protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90α inhibition. Both Hsp90α and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90α protein and the Akt kinase levels, the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination treatment reduced the Hsp90α protein and Akt kinase levels to 4.3% and 43%, respectively, after 72 h. hsp90α mRNA expression detected in SVGp12 was negligible compared to U87-MG, also, the combination treatment did not compromise the normal cell viability. Taking into account the role of Hsp90α in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy.

  6. Proceedings of Therapeutic Strategies:

    DEFF Research Database (Denmark)

    Höök, Kristina Höök

    Managing chronic conditions can be challenging. People in such conditions, and the people around them, have to: deal with symptoms, adapt to the resulting disability, manage emotions, and change habits to keep the condition under control. Self-care technologies have the potential to support self-...

  7. [Hypertriglyceridemia: therapeutic strategy]. (United States)

    Cugnet-Anceau, Christine; Moret, Myriam; Moulin, Philippe


    Causes of hypertriglyceridemia (HTG) vary according to their severity and to their character pure or mixed. Environmental factors including caloric intake excess, fructose overload, alcohol consumption, metabolic syndrom, diabetes, and drug exposure are mostly involved in pure, mild HTG. In contrast, the main etiology of mixed HTG (combined dyslipidemia) is familial combined hyperlipidemia which is commonly associated with metabolic syndrome. Major HTG (> 10 g/L) results mostly from genetic disorder in lipid metabolism with a variable contribution of environmental factors. The complications of HTG are an increased risk of acute pancreatitis (TG > 10 g/L) and a controversial atherogenic risk. Lifestyle modification is the treatment cornerstone. Nevertheless, statins are generally considered as the first drug if a medication is necessary for mixed hyperlipidemia. Fibrates may be used in combination with statin for patient with high atherogenic risk and simultaneous residual hypertriglycéridémie and low HDLc or in high risk patient with severe pure hypertriglyceridemia.

  8. A new therapeutic strategy against hormone-dependent breast cancer: the preclinical development of a dual aromatase and sulfatase inhibitor. (United States)

    Foster, Paul A; Chander, Surinder K; Newman, Simon P; Woo, L W Lawrence; Sutcliffe, Oliver B; Bubert, Christian; Zhou, Dujin; Chen, Shiuan; Potter, Barry V L; Reed, Michael J; Purohit, Atul


    The production of E2 is paramount for the growth of estrogen receptor-positive breast cancer. Various strategies have been used, including the use of enzyme inhibitors against either aromatase (AROM) or steroid sulfatase (STS), in an attempt to ablate E2 levels. Both these enzymes play a critical role in the formation of estrogenic steroids and their inhibitors are now showing success in the clinic. We show here, in a xenograft nude mouse model, that the inhibition of both enzymes using STX681, a dual AROM and STS inhibitor (DASI), is a potential new therapeutic strategy against HDBC. MCF-7 cells stably expressing either AROM cDNA (MCF-7(AROM)) or STS cDNA (MCF-7(STS)) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of either androstenedione (A(4)) or E2 sulfate and bearing either MCF-7(AROM) or MCF-7(STS) tumors were orally treated with STX64, letrozole, or STX681. Treatment was administered for 28 days. Mice were weighed and tumor measurements were taken weekly. STX64, a potent STS inhibitor, completely blocked MCF-7(STS) tumor growth but failed to attenuate MCF-7(AROM) tumor growth. In contrast, letrozole inhibited MCF-7(AROM) tumors but had no effect on MCF-7(STS) tumors. STX681 completely inhibited the growth of both tumors. AROM and STS activity was also completely inhibited by STX681, which was accompanied by a significant reduction in plasma E2 levels. This study indicates that targeting both the AROM and the STS enzyme with a DASI inhibits HDBC growth and is therefore a potentially novel treatment for this malignancy.

  9. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Motoo, Yoshiharu, E-mail: [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Shimasaki, Takeo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan); Ishigaki, Yasuhito [Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Nakajima, Hideo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Kawakami, Kazuyuki; Minamoto, Toshinari [Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan)


    Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

  10. Formal Modeling of mTOR Associated Biological Regulatory Network Reveals Novel Therapeutic Strategy for the Treatment of Cancer

    Directory of Open Access Journals (Sweden)

    Zurah Bibi


    activation of mTORC2 may be a better therapeutic strategy for the treatment of cancer.

  11. Experimental design for the optimization of propidium monoazide treatment to quantify viable and non-viable bacteria in piggery effluents. (United States)

    Desneux, Jérémy; Chemaly, Marianne; Pourcher, Anne-Marie


    Distinguishing between viable and dead bacteria in animal and urban effluents is a major challenge. Among existing methods, propidium monoazide (PMA)-qPCR is a promising way to quantify viable cells. However, its efficiency depends on the composition of the effluent, particularly on total suspended solids (TSS)) and on methodological parameters. The aim of this study was evaluate the influence of three methodological factors (concentration of PMA, incubation time and photoactivation time) on the efficiency of PMA-qPCR to quantify viable and dead cells of Listeria monocytogenes used as a microorganism model, in two piggery effluents (manure and lagoon effluent containing 20 and 0.4 TSS, respectively). An experimental design strategy (Doehlert design and desirability function) was used to identify the experimental conditions to achieve optimal PMA-qPCR results. The quantification of viable cells of L. monocytogenes was mainly influenced by the concentration of PMA in the manure and by the duration of photoactivation in the lagoon effluent. Optimal values differed with the matrix: 55 μM PMA, 5 min incubation and 56 min photoactivation for manure and 20 μM PMA, 20 min incubation and 30 min photoactivation for lagoon effluent. Applied to five manure and four lagoon samples, these conditions resulted in satisfactory quantification of viable and dead cells. PMA-qPCR can be used on undiluted turbid effluent with high levels of TSS, provided preliminary tests are performed to identify the optimal conditions.

  12. Albumin-binding domain from Streptococcus zooepidemicus protein Zag as a novel strategy to improve the half-life of therapeutic proteins. (United States)

    Cantante, Cátia; Lourenço, Sara; Morais, Maurício; Leandro, João; Gano, Lurdes; Silva, Nuno; Leandro, Paula; Serrano, Mónica; Henriques, Adriano O; Andre, Ana; Cunha-Santos, Catarina; Fontes, Carlos; Correia, João D G; Aires-da-Silva, Frederico; Goncalves, Joao


    Recombinant antibody fragments belong to the promising class of biopharmaceuticals with high potential for future therapeutic applications. However, due to their small size they are rapidly cleared from circulation. Binding to serum proteins can be an effective approach to improve pharmacokinetic properties of short half-life molecules. Herein, we have investigated the Zag albumin-binding domain (ABD) derived from Streptococcus zooepidemicus as a novel strategy to improve the pharmacokinetic properties of therapeutic molecules. To validate our approach, the Zag ABD was fused with an anti-TNFα single-domain antibody (sdAb). Our results demonstrated that the sdAb-Zag fusion protein was highly expressed and specifically recognizes human, rat and mouse serum albumins with affinities in the nanomolar range. Moreover, data also demonstrated that the sdAb activity against the therapeutic target (TNFα) was not affected when fused with Zag ABD. Importantly, the Zag ABD increased the sdAb half-life ∼39-fold (47min for sdAb versus 31h for sdAb-Zag). These findings demonstrate that the Zag ABD fusion is a promising approach to increase the half-life of small recombinant antibodies molecules without affecting their therapeutic efficacy. Moreover, the present study strongly suggests that the Zag ABD fusion strategy can be potentially used as a universal method to improve the pharmokinetics properties of many others therapeutics proteins and peptides in order to improve their dosing schedule and clinical effects. Copyright © 2017. Published by Elsevier B.V.

  13. An Optimized Voriconazole Dosing Strategy to Achieve Therapeutic Serum Concentrations in Children Younger than 2 Years Old. (United States)

    Zembles, Tracy N; Thompson, Nathan E; Havens, Peter L; Kaufman, Bruce A; Huppler, Anna R


    To describe our experience with voriconazole in three patients younger than 2 years using an optimized dosing strategy for voriconazole that incorporates intensive therapeutic drug monitoring (TDM). Case series. Large pediatric hospital. Three patients younger than 2 years who received voriconazole therapy and had serum trough concentrations measured between January 1, 2010, and October 31, 2015. A clinical practice guideline developed at our institution was used to standardize initial dosing, appropriate use and timing of TDM, and dosage modifications based on TDM. TDM was used to guide dosing to achieve a target voriconazole serum trough concentration of 2-6 μg/ml. Voriconazole samples were assayed by using a high-performance liquid chromatography analytical method with solid-phase extraction. Initial dosages for the three patients were 9 mg/kg intravenously every 12 hours (one patient) and 9 mg/kg enterally twice/day (two patients). Multiple dose escalations and a more frequent dosing interval were required to achieve trough concentrations within the target range. The final dosages were 12 mg/kg intravenously every 8 hours, 17.7 mg/kg enterally 3 times/day, and 8.5 mg/kg enterally 3 times/day, respectively. In addition to voriconazole trough concentrations, TDM included evaluations for drug toxicities. Visual, neurologic, or hepatic adverse effects were not encountered in the three patients. Our data support higher initial doses and perhaps a 3 times/day dosing schedule to achieve voriconazole serum concentrations in the target range for children younger than 2 years. Implementation of a clinical practice guideline with the participation of pharmacists specializing in pharmacokinetics allows for effective use of voriconazole in young children. © 2016 Pharmacotherapy Publications, Inc.

  14. Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Hanumantha Rao Madala


    Full Text Available Isocitrate dehydrogenases 1 and 2 (IDH1,2, the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs and gain an unusual new activity of reducing the α-ketoglutarate (α-KG to D-2 hydroxyglutarate (D-2HG in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation, JmjC domain-containing KDMs (histone lysine demethylases, and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.

  15. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies. (United States)

    Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr


    Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Viable group A streptococci in macrophages during acute soft tissue infection.

    Directory of Open Access Journals (Sweden)

    Pontus Thulin


    highlights a need for alternative therapeutic strategies.

  17. Viable Group A Streptococci in Macrophages during Acute Soft Tissue Infection.

    Directory of Open Access Journals (Sweden)


    of streptococcal soft tissue infections highlights a need for alternative therapeutic strategies.

  18. Epstein-Barr virus-encoded EBNA1 and ZEBRA: targets for therapeutic strategies against EBV-carrying cancers. (United States)

    Daskalogianni, Chrysoula; Pyndiah, Slovénie; Apcher, Sébastien; Mazars, Anne; Manoury, Bénédicte; Ammari, Nisrine; Nylander, Karin; Voisset, Cécile; Blondel, Marc; Fåhraeus, Robin


    The EBV-encoded EBNA1 was first discovered 40 years ago, approximately 10 years after the presence of EBV had been demonstrated in Burkitt's lymphoma cells. It took another 10 years before the functions of EBNA1 in maintaining the viral genome were revealed, and it has since been shown to be an essential viral factor expressed in all EBV-carrying cells. Apart from serving to maintain the viral episome and to control viral replication and gene expression, EBNA1 also harbours a cis-acting mechanism that allows virus-carrying host cells to evade the immune system. This relates to a particular glycine-alanine repeat (GAr) within EBNA1 that has the capacity to suppress antigen presentation to the major histocompatibility complex (MHC) class I pathway. We discuss the role of the GAr sequence at the level of mRNA translation initiation, rather than at the protein level, as at least part of the mechanism to avoid MHC presentation. Interfering with this mechanism has become the focus of the development of immune-based therapies against EBV-carrying cancers, and some lead compounds that affect translation of GAr-carrying mRNAs have been identified. In addition, we describe the EBV-encoded ZEBRA factor and the switch from the latent to the lytic cycle as an alternative virus-specific target for treating EBV-carrying cancers. Understanding the molecular mechanisms of how EBNA1 and ZEBRA interfere with cellular pathways not only opens new therapeutic approaches but continues to reveal new cell-biological insights on the interplay between host and virus. This review is a tale of discoveries relating to how EBNA1 and ZEBRA have emerged as targets for specific cancer therapies against EBV-carrying diseases, and serves as an illustration of how mRNA translation can play roles in future immune-based strategies to target viral disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  19. Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function. (United States)

    Han, Myung-Hoon; Lee, Eun-Hye; Koh, Seong-Ho


    Neurological diseases such as Alzheimer, Parkinson, and ischemic stroke have increased in occurrence and become important health issues throughout the world. There is currently no effective therapeutic strategy for addressing neurological deficits after the development of these major neurological disorders. In recent years, it has become accepted that adult neural stem cells located in the subventricular and subgranular zones have the ability to proliferate and differentiate in order to replace lost or damaged neural cells. There have been many limitations in the clinical application of both endogenous and exogenous neurogenesis for neurological disorders. However, many studies have investigated novel mechanisms in neurogenesis and have shown that these limitations can potentially be overcome with appropriate stimulation and various approaches. We will review concepts related to possible therapeutic strategies focused on the perspective of neurogenesis for the treatment of patients diagnosed with Alzheimer disease, Parkinson disease, and ischemic stroke based on current reports.

  20. Pure Quantum Interpretations Are not Viable (United States)

    Schmelzer, I.


    Pure interpretations of quantum theory, which throw away the classical part of the Copenhagen interpretation without adding new structure to its quantum part, are not viable. This is a consequence of a non-uniqueness result for the canonical operators.



    Soumya Kanti Biswas1 , Sanjay Kundu2 , Monojit Debnath3* , Moulisha Biswas3 , Tuhin kanti Biswas4


    Guggulu (Commiphora wightii) is a common medicinal preparation widely used in Ayurveda since time immemorial. The quality extraction and preparation are important for proper therapeutic outcome as well marketing strategy. Many varieties of guggulu are available in market for the treatment of different diseases. Scientific validation for extraction and therapeutic evaluation are essentially needed for viable marketing of the plant. Keywords: Guggulu, Commiphera wightii, guggulosterone, market ...

  2. Unique strategies for therapeutic gene transfer in haemophilia A and haemophilia BWFH State-of-the-Art Session on Therapeutic Gene Transfer Buenos Aires, Argentina. (United States)

    Montgomery, R R; Monahan, P E; Ozelo, M C


    Gene therapy of haemophilia has been initiated through a number of approaches including expression in muscle, liver and omental implanted fibroblasts, or i.v. injection of an expression construct under the control of a ubiquitous promoter. In all these approaches, the goal was to have factor VIII (FVIII) or factor IX (FIX) synthesized so that it restored the levels of the missing protein in blood. The three talks in this session are totally, or at least in part, directed at strategies that may be clinically effective even in the absence of correction of the missing plasma clotting factor, although the haematopoietic stem cell or blood outgrowth endothelial cell therapy could achieve plasma correction as well. Two of the approaches achieve localized coagulation factor expression without necessarily correcting the systemic defect--one is with synthesis of FVIII or FIX within the joint space and the other is with the local release of FVIII (or FIX) by platelets at the site of vascular injury. All of the three approaches have demonstrated efficacy in small animal models and are now the subject of larger animal studies. None has yet to progress to human trials.

  3. A psychological effect of having a potentially viable sequestration strategy. (United States)

    Matsumoto, Katsumi


    Purposeful carbon sequestration by direct injection into the deep ocean can store carbon for centuries. Even after injected carbon begins to leak back out to the atmosphere, much of the injected carbon will remain sequestered because of the acid neutralizing capacity of seawater. The slow leakage that occurs centuries into the future can give a false sense of security that the carbon and climate problem is under control. If this were to cause policy makers to become less vigilant about reducing the total emissions of anthropogenic carbon, our descendants would be penalized with having much higher carbon dioxide content in the atmosphere when leakage begins. This "carelessness feedback" would apply to other forms of sequestration that are not permanent. To avoid falling into this trap requires generations of policy makers to be aware of the feedback and committed to intergenerational equity.

  4. A psychological effect of having a potentially viable sequestration strategy

    Directory of Open Access Journals (Sweden)

    Matsumoto Katsumi


    Full Text Available Abstract Purposeful carbon sequestration by direct injection into the deep ocean can store carbon for centuries. Even after injected carbon begins to leak back out to the atmosphere, much of the injected carbon will remain sequestered because of the acid neutralizing capacity of seawater. The slow leakage that occurs centuries into the future can give a false sense of security that the carbon and climate problem is under control. If this were to cause policy makers to become less vigilant about reducing the total emissions of anthropogenic carbon, our descendants would be penalized with having much higher carbon dioxide content in the atmosphere when leakage begins. This "carelessness feedback" would apply to other forms of sequestration that are not permanent. To avoid falling into this trap requires generations of policy makers to be aware of the feedback and committed to intergenerational equity.

  5. A psychological effect of having a potentially viable sequestration strategy


    Matsumoto Katsumi


    Abstract Purposeful carbon sequestration by direct injection into the deep ocean can store carbon for centuries. Even after injected carbon begins to leak back out to the atmosphere, much of the injected carbon will remain sequestered because of the acid neutralizing capacity of seawater. The slow leakage that occurs centuries into the future can give a false sense of security that the carbon and climate problem is under control. If this were to cause policy makers to become less vigilant abo...

  6. Skills training workshops as a viable strategy for improving ...

    African Journals Online (AJOL)

    Empirical evidence from this study shows that six months after attending the workshops, project managers introduced positive changes in the personnel and financial management of their projects, and increased the volume and value of their projects outputs. They also undertook new investments, obtained new loans and ...

  7. The STARS Alliance: Viable Strategies for Broadening Participation in Computing (United States)

    Dahlberg, Teresa; Barnes, Tiffany; Buch, Kim; Rorrer, Audrey


    The Students and Technology in Academia, Research, and Service (STARS) Alliance is a nationally-connected system of regional partnerships among higher education, K-12 schools, industry and the community with a mission to broaden the participation of women, under-represented minorities and persons with disabilities in computing (BPC). Each regional…

  8. Biodiversity information resource sharing as a viable strategy for ...

    African Journals Online (AJOL)

    Availability of accurate biodiversity information is a paramount necessity in facilitating the process of decision making on biodiversity resource use and protection. In Tanzania, like other countries in East Africa, a lot of biodiversity data and information is produced, analysed and disseminated as reports, seminars, ...

  9. Is Microcredit a Viable Strategy for Empowering Women? | Al ...

    African Journals Online (AJOL)

    Microfinance institutions (MFIs) grant microcredits to hundreds of thousands of people, particularly women in developing countries with the aim of empowering them. The microcredits in the form of small loans to women are considered a tool for empowering women toward change in their socio-economic conditions.

  10. Functionalized bioengineered spider silk spheres improve nuclease resistance and activity of oligonucleotide therapeutics providing a strategy for cancer treatment. (United States)

    Kozlowska, Anna Karolina; Florczak, Anna; Smialek, Maciej; Dondajewska, Ewelina; Mackiewicz, Andrzej; Kortylewski, Marcin; Dams-Kozlowska, Hanna


    Cell-selective delivery and sensitivity to serum nucleases remain major hurdles to the clinical application of RNA-based oligonucleotide therapeutics, such as siRNA. Spider silk shows great potential as a biomaterial due to its biocompatibility and biodegradability. Self-assembling properties of silk proteins allow for processing into several different morphologies such as fibers, scaffolds, films, hydrogels, capsules and spheres. Moreover, bioengineering of spider silk protein sequences can functionalize silk by adding peptide moieties with specific features including binding or cell recognition domains. We demonstrated that modification of silk protein by adding the nucleic acid binding domain enabled the development of a novel oligonucleotide delivery system that can be utilized to improve pharmacokinetics of RNA-based therapeutics, such as CpG-siRNA. The MS2 bioengineered silk was functionalized with poly-lysine domain (KN) to generate hybrid silk MS2KN. CpG-siRNA efficiently bound to MS2KN in contrary to control MS2. Both MS2KN complexes and spheres protected CpG-siRNA from degradation by serum nucleases. CpG-siRNA molecules encapsulated into MS2KN spheres were efficiently internalized and processed by TLR9-positive macrophages. Importantly, CpG-STAT3siRNA loaded in silk spheres showed delayed and extended target gene silencing compared to naked oligonucleotides. The prolonged Stat3 silencing resulted in the more pronounced downregulation of interleukin 6 (IL-6), a proinflammatory cytokine and upstream activator of STAT3, which limits the efficacy of TLR9 immunostimulation. Our results demonstrate the feasibility of using spider silk spheres as a carrier of therapeutic nucleic acids. Moreover, the modified kinetic and activity of the CpG-STAT3siRNA embedded into silk spheres is likely to improve immunotherapeutic effects in vivo. We demonstrated that modification of silk protein by adding the nucleic acid binding domain enabled the development of a novel

  11. Research strategy of the therapeutic quality of mud and salty water from Ursu(Bear) Lake, Sovata, 


    Munteanu Constantin; Cinteza Delia; Pretorian Suzana; Lazarescu Horia; Poenaru Daniela; Hoteteu Mihai; Munteanu Diana


    Infertility (sterility) is a health problem affecting 15% of couples of reproductive age. Today only a few are known about causes and treatment options involved in the pathology of infertility, while a number of issues remain unknown. Currently natural therapeutic factors from Sovata are used, based on experience over the years, for the following causes of infertility: tubal obstruction, laparoscopic postneosalpingostomiei recovery treatment (prevention of restenozations), sequelae after pelv...

  12. Therapeutic microRNA Delivery Strategies with Special Emphasis on Cancer Therapy and Tumorigenesis: Current Trends and Future Challenges. (United States)

    Chakraborty, Chiranjib; Wen, Zhi-Hong; Agoramoorthy, Govindasamy; Lin, Chan-Shing


    Over the decade, miRNAs are the most important molecules for the biopharmaceutical industry due to their relation with several human diseases. Presently, the phase-II clinical trial has been initiated for the first miRNA-based therapeutics ("Miravirsen") to treat HCV infection. It has been expected that many more miRNA-based therapeutics will enter the clinical trials. Therefore, it is important to develop different kinds of novel delivery systems with better efficacy and more efficiency, but fewer side effects. We have undertaken a structured search of bibliographic databases for peer-reviewed research literature to solve our review question. Literature survey was performed widely to write this review article. In this review, we have discussed the various types of miRNA delivery systems such as viral vectors, lipid-based systems, nanocarriers, and LNA-customized DNA delivery without any delivery-mediated agent. Current status, technical support, and the future challenges for miRNA-based delivery are also discussed. Recent development and understanding of miRNA had shown the therapeutic potentiality of miRNA.

  13. Recent Perspectives on Genome, Transmission, Clinical Manifestation, Diagnosis, Therapeutic Strategies, Vaccine Developments, and Challenges of Zika Virus Research

    Directory of Open Access Journals (Sweden)

    Apoorva Shankar


    Full Text Available One of the potential threats to public health microbiology in 21st century is the increased mortality rate caused by Zika virus (ZIKV, a mosquito-borne flavivirus. The severity of ZIKV infection urged World Health Organization (WHO to declare this virus as a global concern. The limited knowledge on the structure, virulent factors, and replication mechanism of the virus posed as hindrance for vaccine development. Several vector and non-vector-borne mode of transmission are observed for spreading the disease. The similarities of the virus with other flaviviruses such as dengue and West Nile virus are worrisome; hence, there is high scope to undertake ZIKV research that probably provide insight for novel therapeutic intervention. Thus, this review focuses on the recent aspect of ZIKV research which includes the outbreak, genome structure, multiplication and propagation of the virus, current animal models, clinical manifestations, available treatment options (probable vaccines and therapeutics, and the recent advancements in computational drug discovery pipelines, challenges and limitation to undertake ZIKV research. The review suggests that the infection due to ZIKV became one of the universal concerns and an interdisciplinary environment of in vitro cellular assays, genomics, proteomics, and computational biology approaches probably contribute insights for screening of novel molecular targets for drug design. The review tried to provide cutting edge knowledge in ZIKV research with future insights required for the development of novel therapeutic remedies to curtail ZIKV infection.

  14. Recent Perspectives on Genome, Transmission, Clinical Manifestation, Diagnosis, Therapeutic Strategies, Vaccine Developments, and Challenges of Zika Virus Research (United States)

    Shankar, Apoorva; Patil, Amulya A.; Skariyachan, Sinosh


    One of the potential threats to public health microbiology in 21st century is the increased mortality rate caused by Zika virus (ZIKV), a mosquito-borne flavivirus. The severity of ZIKV infection urged World Health Organization (WHO) to declare this virus as a global concern. The limited knowledge on the structure, virulent factors, and replication mechanism of the virus posed as hindrance for vaccine development. Several vector and non-vector-borne mode of transmission are observed for spreading the disease. The similarities of the virus with other flaviviruses such as dengue and West Nile virus are worrisome; hence, there is high scope to undertake ZIKV research that probably provide insight for novel therapeutic intervention. Thus, this review focuses on the recent aspect of ZIKV research which includes the outbreak, genome structure, multiplication and propagation of the virus, current animal models, clinical manifestations, available treatment options (probable vaccines and therapeutics), and the recent advancements in computational drug discovery pipelines, challenges and limitation to undertake ZIKV research. The review suggests that the infection due to ZIKV became one of the universal concerns and an interdisciplinary environment of in vitro cellular assays, genomics, proteomics, and computational biology approaches probably contribute insights for screening of novel molecular targets for drug design. The review tried to provide cutting edge knowledge in ZIKV research with future insights required for the development of novel therapeutic remedies to curtail ZIKV infection. PMID:28959246

  15. Using Generic Examples to Make Viable Arguments (United States)

    Adams, Anne E.; Ely, Rob; Yopp, David


    The twenty-first century has seen an increased call to train students to craft mathematical arguments. The third of the Common Core's (CCSS) Standards for Mathematical Practice (SMP 3) (CCSSI 2010) calls for all mathematically proficient students to "construct viable arguments" to support the truth of their ideas and to "critique…

  16. 3p22.1p21.31 microdeletion identifies CCK as Asperger syndrome candidate gene and shows the way for therapeutic strategies in chromosome imbalances. (United States)

    Iourov, Ivan Y; Vorsanova, Svetlana G; Voinova, Victoria Y; Yurov, Yuri B


    In contrast to other autism spectrum disorders, chromosome abnormalities are rare in Asperger syndrome (AS) or high-functioning autism. Consequently, AS was occasionally subjected to classical positional cloning. Here, we report on a case of AS associated with a deletion of the short arm of chromosome 3. Further in silico analysis has identified a candidate gene for AS and has suggested a therapeutic strategy for manifestations of the chromosome rearrangement. Using array comparative genomic hybridization, an interstitial deletion of 3p22.1p21.31 (~2.5 Mb in size) in a child with Asperger's syndrome, seborrheic dermatitis and chronic pancreatitis was detected. Original bioinformatic approach to the prioritization of candidate genes/processes identified CCK (cholecystokinin) as a candidate gene for AS. In addition to processes associated with deleted genes, bioinformatic analysis of CCK gene interactome indicated that zinc deficiency might be a pathogenic mechanism in this case. This suggestion was supported by plasma zinc concentration measurements. The increase of zinc intake produced a rise in zinc plasma concentration and the improvement in the patient's condition. Our study supported previous linkage findings and had suggested a new candidate gene in AS. Moreover, bioinformatic analysis identified the pathogenic mechanism, which was used to propose a therapeutic strategy for manifestations of the deletion. The relative success of this strategy allows speculating that therapeutic or dietary normalization of metabolic processes altered by a chromosome imbalance or genomic copy number variations may be a way for treating at least a small proportion of cases of these presumably incurable genetic conditions.

  17. Research strategy of the therapeutic quality of mud and salty water from Ursu(Bear Lake, Sovata, 

    Directory of Open Access Journals (Sweden)

    Munteanu Constantin


    Full Text Available Infertility (sterility is a health problem affecting 15% of couples of reproductive age. Today only a few are known about causes and treatment options involved in the pathology of infertility, while a number of issues remain unknown. Currently natural therapeutic factors from Sovata are used, based on experience over the years, for the following causes of infertility: tubal obstruction, laparoscopic postneosalpingostomiei recovery treatment (prevention of restenozations, sequelae after pelvic inflammatory disease, peritonitis, post-inflammatory adhesions; secretory ovarian dysfunction (estrogen, progesterone, polycystic ovarian syndrome, endometriosis, infertility induced by stress.

  18. Assessment of refractive astigmatism and simulated therapeutic refractive surgery strategies in coma-like-aberrations-dominant corneal optics. (United States)

    Zhou, Wen; Stojanovic, Aleksandar; Utheim, Tor Paaske


    The aim of the study is to raise the awareness of the influence of coma-like higher-order aberrations (HOAs) on power and orientation of refractive astigmatism (RA) and to explore how to account for that influence in the planning of topography-guided refractive surgery in eyes with coma-like-aberrations-dominant corneal optics. Eleven eyes with coma-like-aberrations-dominant corneal optics and with low lenticular astigmatism (LA) were selected for astigmatism analysis and for treatment simulations with topography-guided custom ablation. Vector analysis was used to evaluate the contribution of coma-like corneal HOAs to RA. Two different strategies were used for simulated treatments aiming to regularize irregular corneal optics: With both strategies correction of anterior corneal surface irregularities (corneal HOAs) were intended. Correction of total corneal astigmatism (TCA) and RA was intended as well with strategies 1 and 2, respectively. Axis of discrepant astigmatism (RA minus TCA minus LA) correlated strongly with axis of coma. Vertical coma influenced RA by canceling the effect of the with-the-rule astigmatism and increasing the effect of the against-the-rule astigmatism. After simulated correction of anterior corneal HOAs along with TCA and RA (strategies 1 and 2), only a small amount of anterior corneal astigmatism (ACA) and no TCA remained after strategy 1, while considerable amount of ACA and TCA remained after strategy 2. Coma-like corneal aberrations seem to contribute a considerable astigmatic component to RA in eyes with coma-like-aberrations dominant corneal optics. If topography-guided ablation is programmed to correct the corneal HOAs and RA, the astigmatic component caused by the coma-like corneal HOAs will be treated twice and will result in induced astigmatism. Disregarding RA and treating TCA along with the corneal HOAs is recommended instead.

  19. The network model of depression as a basis for new therapeutic strategies for treating major depressive disorder in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Kevin eD'Ostilio


    Full Text Available The high prevalence of major depressive disorder in people with Parkinson's disease, its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with Parkinson's disease within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation using high frequency repetitive transcranial magnetic stimulation over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes non-invasive brain stimulation together with cognitive and behavioral interventions.

  20. The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson’s Disease (United States)

    D’Ostilio, Kevin; Garraux, Gaëtan


    The high prevalence of major depressive disorder in people with Parkinson’s disease (PD), its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with PD within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation (NIBS) using high frequency repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes NIBS together with cognitive and behavioral interventions. PMID:27148016

  1. Anti-MMP-9 Antibody: A Promising Therapeutic Strategy for Treatment of Inflammatory Bowel Disease Complications with Fibrosis. (United States)

    Goffin, Laurence; Fagagnini, Stefania; Vicari, Alain; Mamie, Céline; Melhem, Hassan; Weder, Bruce; Lutz, Christian; Lang, Silvia; Scharl, Michael; Rogler, Gerhard; Chvatchko, Yolande; Hausmann, Martin


    Despite medical treatments or surgical options, more than one-third of patients with Crohn's disease suffer from recurring fistulae. Matrix metalloprotease 9 (MMP-9), a type IV collagenase that cleaves components of the extracellular matrix leading to tissue remodeling, is upregulated in crypt abscesses and around fistulae suggesting an important role for this enzyme in fistula formation. Our aims were (1) to correlate serum levels of MMP-9 degradation products in patients with CD with the presence of fistulae and (2) to investigate the impact of selective MMP-9 inhibition in a mouse model of intestinal fibrosis. Serum MMP-9 degradation products were quantified in subjects affected with nonstricturing and nonpenetrating CD (n = 50), stricturing CD (n = 41), penetrating CD (n = 22), CD with perianal fistula (n = 29), and healthy controls (n = 10). Therapeutic efficacy of anti-MMP-9 monoclonal antibodies was assessed in a heterotopic xenograft model of intestinal fibrosis. C3M, an MMP-9 degradation product of collagen III, demonstrated the highest serum levels in patients with penetrating CD and differentiated penetrating CD from other CD subgroups and healthy controls, P = 0.0005. Anti-MMP-9 treatments reduced collagen deposition and hydroxyproline content in day-14 intestinal grafts indicating reduced fibrosis. The serologic biomarker C3M can discriminate penetrating CD from other CD subgroups and could serve as marker for the development of penetrating CD. Anti-MMP-9 antibody has therapeutic potential to prevent intestinal fibrosis in CD complications.

  2. Significance of Glucose Transporter Type 1 (GLUT-1) Expression in the Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma. (United States)

    Kurahara, Hiroshi; Maemura, Kosei; Mataki, Yuko; Sakoda, Masahiko; Iino, Satoshi; Kawasaki, Yota; Arigami, Takaaki; Mori, Shinichiro; Kijima, Yuko; Ueno, Shinichi; Shinchi, Hiroyuki; Natsugoe, Shoji


    This study aimed to examine the prognostic relevance of glucose transporter type 1 (GLUT-1), which is a key regulator of the glucose metabolism. In particular, the study aimed to examine the association between GLUT-1 expression and the therapeutic effect of chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC were enrolled in the study. Patients with distant metastases and those who received only chemotherapy as treatment were excluded from the study. Specimens for immunohistochemical evaluations were obtained through surgical resection and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the primary tumor before any treatment. This study included 197 patients. Of these 197 patients, 100 underwent upfront surgery, and 97 received neoadjuvant CRT (NACRT), which was performed mainly for patients with locally advanced tumors. Of the 97 patients who received NACRT, 21 later underwent surgical resection. For the patients who underwent upfront surgery, low GLUT-1 expression was an independent factor for a better prognosis. For the patients who underwent NACRT, low GLUT-1 expression was significantly associated with greater tumor size reduction, a higher resection rate, and a better prognosis. Additionally, GLUT-1 expression was significantly increased after NACRT treatment. Among the patients with PDAC, those with low GLUT-1 expression in the primary tumor had a better prognosis those with high GLUT-1 expression. Moreover, the patients with low GLUT-1 expression displayed a better therapeutic response to NACRT.

  3. Intercellular Interactomics of Human Brain Endothelial Cells and Th17 Lymphocytes: A Novel Strategy for Identifying Therapeutic Targets of CNS Inflammation

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    Arsalan S. Haqqani


    Full Text Available Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells possess brain-homing capability and contribute to the pathogenesis of multiple sclerosis and cerebral ischemia. The leukocyte transmigration across the endothelium is a highly regulated, multistep process involving intercellular communications and interactions between the leukocytes and endothelial cells. The molecules involved in the process are attractive therapeutic targets for inhibiting leukocyte brain migration. We hypothesized and have been successful in demonstrating that molecules of potential therapeutic significance involved in Th17-brain endothelial cell (BEC communications and interactions can be discovered through the combination of advanced membrane/submembrane proteomic and interactomic methods. We describe elements of this strategy and preliminary results obtained in method and approach development. The Th17-BEC interaction network provides new insights into the complexity of the transmigration process mediated by well-organized, subcellularly localized molecular interactions. These molecules and interactions are potential diagnostic, therapeutic, or theranostic targets for treatment of neurological conditions accompanied or caused by leukocyte infiltration.

  4. Monotone viable trajectories for functional differential inclusions (United States)

    Haddad, Georges

    This paper is a study on functional differential inclusions with memory which represent the multivalued version of retarded functional differential equations. The main result gives a necessary and sufficient equations. The main result gives a necessary and sufficient condition ensuring the existence of viable trajectories; that means trajectories remaining in a given nonempty closed convex set defined by given constraints the system must satisfy to be viable. Some motivations for this paper can be found in control theory where F( t, φ) = { f( t, φ, u)} uɛU is the set of possible velocities of the system at time t, depending on the past history represented by the function φ and on a control u ranging over a set U of controls. Other motivations can be found in planning procedures in microeconomics and in biological evolutions where problems with memory do effectively appear in a multivalued version. All these models require viability constraints represented by a closed convex set.

  5. A triple suicide gene strategy that improves therapeutic effects and incorporates multimodality molecular imaging for monitoring gene functions. (United States)

    Xing, L; Sun, X; Deng, X; Kotedia, K; Zanzonico, P B; Ackerstaff, E; Koutcher, J A; Ling, C C; Li, G C


    Gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, has shown promise in clinical trials. In this preclinical study using stable cell lines and xenograft tumor models, we show that a triple-suicide-gene GDEPT approach produce enhanced therapeutic efficacy over previous methods. Importantly, all the three genes (thymidine kinase, cytosine deaminase and uracil phosphoribosyltransferase) function simultaneously as effectors for GDEPT and markers for multimodality molecular imaging (MMI), using positron emission tomography, magnetic resonance spectroscopy and optical (fluorescent and bioluminescent) techniques. It was demonstrated that MMI can evaluate the distribution and function/activity of the triple suicide gene. The concomitant expression of these genes significantly enhances prodrug cytotoxicity and radiosensitivity in vitro and in vivo.

  6. Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy. (United States)

    Timpani, Cara A; Hayes, Alan; Rybalka, Emma


    Duchenne Muscular Dystrophy is a rare and fatal neuromuscular disease in which the absence of dystrophin from the muscle membrane induces a secondary loss of neuronal nitric oxide synthase and the muscles capacity for endogenous nitric oxide synthesis. Since nitric oxide is a potent regulator of skeletal muscle metabolism, mass, function and regeneration, the loss of nitric oxide bioavailability is likely a key contributor to the chronic pathological wasting evident in Duchenne Muscular Dystrophy. As such, various therapeutic interventions to re-establish either the neuronal nitric oxide synthase protein deficit or the consequential loss of nitric oxide synthesis and bioavailability have been investigated in both animal models of Duchenne Muscular Dystrophy and in human clinical trials. Notably, the efficacy of these interventions are varied and not always translatable from animal model to human patients, highlighting a complex interplay of factors which determine the downstream modulatory effects of nitric oxide. We review these studies herein.

  7. Nanoparticle strategies for cancer therapeutics: Nucleic acids, polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review). (United States)

    Agostinelli, Enzo; Vianello, Fabio; Magliulo, Giuseppe; Thomas, Thresia; Thomas, T J


    Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, polyamine analogues and cytotoxic products of polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other

  8. A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. (United States)

    Crighton, Gemma L; Estcourt, Lise J; Wood, Erica M; Trivella, Marialena; Doree, Carolyn; Stanworth, Simon


    therapeutic platelet transfusions to prophylactic platelet transfusions in haematology patients undergoing myelosuppressive chemotherapy or HSCT. One trial is still ongoing, leaving six trials eligible with a total of 1195 participants. These trials were conducted between 1978 and 2013 and enrolled participants from fairly comparable patient populations. We were able to critically appraise five of these studies, which contained separate data for each arm, and were unable to perform quantitative analysis on one study that did not report the numbers of participants in each treatment arm.Overall the quality of evidence per outcome was low to moderate according to the GRADE approach. None of the included studies were at low risk of bias in every domain, and all the studies identified had some threats to validity. We deemed only one study to be at low risk of bias in all domains other than blinding.Two RCTs (801 participants) reported at least one bleeding episode within 30 days of the start of the study. We were unable to perform a meta-analysis due to considerable statistical heterogeneity between studies. The statistical heterogeneity seen may relate to the different methods used in studies for the assessment and grading of bleeding. The underlying patient diagnostic and treatment categories also appeared to have some effect on bleeding risk. Individually these studies showed a similar effect, that a therapeutic-only platelet transfusion strategy was associated with an increased risk of clinically significant bleeding compared with a prophylactic platelet transfusion policy. Number of days with a clinically significant bleeding event per participant was higher in the therapeutic-only group than in the prophylactic group (one RCT; 600 participants; mean difference 0.50, 95% confidence interval (CI) 0.10 to 0.90; moderate-quality evidence). There was insufficient evidence to determine whether there was any difference in the number of participants with severe or life

  9. A Novel EphA4 Based Small Molecule Based Therapeutic Strategy for Prevention and Treatment of Post Traumatic Osteoarthritis (United States)


    whether EfnA4-fc treatment of monocytes/macrophages and inflamed synovial fibroblasts would reduce release of pro-inflammatory cytokines and MMPs as...and optimize a small molecule- and EphA4-based strategy involving injection of an EphA4-binding EfnA-fc chimeric protein into the inflamed joint for...therefore, been aimed to complete the remaining work of subtask 2.2 (Demonstration that EfnA4-fc inhibits activity activity of the inflamed synoviocytes

  10. Therapeutic Patient Education in Cancer Pain Management: from Practice to Research: Proposals and Strategy of the French EFFADOL Program. (United States)

    Prevost, Virginie; Clarisse, Bénédicte; Heutte, Natacha; Leconte, Alexandra; Bisson, Cécile; Bignon, Rachel; Cauchin, Sonia; Feuillet, Maryline; Gehanne, Sylvie; Gicquère, Maud; Grach, Marie-Christine; Guillaumé, Cyril; Le Gal, Christine; Le Garrec, Joelle; Lecaer, Franck; Lepleux, Isabelle; Millet, Anne-Laure; Ropartz, Marie-Claude; Roux, Nathalie; Hieng, Virith Sep; Van Delook, Carole; Le Chevalier, Aline; Delorme, Claire


    In the field of cancer pain, therapeutic patient education (TPE) allows patients to develop skills to better manage their pain. In the Lower Normandy region of France, the management of pain is based on networking, thus allowing proximity and accessibility for all concerned. We have thus designed and initiated a broad five-stage research program that includes the following: (1) training for caregivers in TPE; (2) identifying the educational expectations of patients and their relatives with regard to cancer pain; (3) the design of a TPE program; (4) the evaluation of its quality; and (5) the evaluation of its effectiveness by comparative randomization. This article presents this approach and more particularly the research phases (stages 2, 4, 5) for which the objectives, the methodology, and the expected results are justified. Among the key points, particular attention is paid to the evaluation of the educational dimension that provides patients with self-efficacy to participate actively in the management of their pain, their perception of changes in relation to it and its impact. The choice of a specific assessment criterion (subscale 9 of the Brief Pain Inventory) and of the step-wedge design are thus argued. This approach, which is based on a partnership between health care professionals and researchers, aims to demonstrate the benefits provided by TPE to patients in order to enable them to better manage their pain on a daily basis.

  11. Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

    Directory of Open Access Journals (Sweden)

    Bernard Waeber


    Full Text Available Bernard Waeber1, Jean-Jacques Mourad21Division de Physiopathologie Clinique, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland; 2Hôpital Avicienne, Bobigny, FranceAbstract: A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118, a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108, or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103. The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 ± 70.5 (mean ± SD using the fixed-dose combination strategy, compared with –7.2 ± 81.0 using the sequential monotherapy approach and –17.5 ± 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril and a diuretic (indapamide.Keywords: antihypertensive therapy, tolerability, antihypertensive efficacy, fixed-dose combination, sequential monotherapy, stepped-care treatment

  12. Fear of hypoglycemia in adults with type 1 diabetes: impact of therapeutic advances and strategies for prevention - a review. (United States)

    Martyn-Nemeth, Pamela; Schwarz Farabi, Sarah; Mihailescu, Dan; Nemeth, Jeffrey; Quinn, Laurie


    This review summarizes the current state of the science related to fear of hypoglycemia (FOH) in adults with type 1 diabetes. Fear of hypoglycemia is a critical deterrent to diabetes self-management, psychological well-being, and quality of life. We examine the influence of contemporary treatment regimens, technology, and interventions to identify gaps in knowledge and opportunities for research and practice. A literature search was conducted of MEDLINE, PsycINFO, and EMBASE. Fifty-three studies that examined fear of hypoglycemia were included. Fear of hypoglycemia influences diabetes management and quality of life. Gender and age differences exist in experiences and responses. Responses vary from increased vigilance to potentially immobilizing distress. Fear of hypoglycemia is greater at night and may contribute to poor sleep quality. Strategies to reduce fear of hypoglycemia have had varying success. Newer technologies hold promise but require further examination. Fear of hypoglycemia remains a problem, despite advances in technology, insulin analogs, and evidence-based diabetes management. Clinical care should consistently include assessment for its influence on diabetes self-management and psychological health. Further research is needed regarding the influence of newer technologies and individualized strategies to reduce fear of hypoglycemia while maintaining optimal glucose control. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Air-spore in Cartagena, Spain: viable and non-viable sampling methods. (United States)

    Elvira-Rendueles, Belen; Moreno, Jose; Garcia-Sanchez, Antonio; Vergara, Nuria; Martinez-Garcia, Maria Jose; Moreno-Grau, Stella


    In the presented study the airborne fungal spores of the semiarid city of Cartagena, Spain, are identified and quantified by means of viable or non-viable sampling methods. Airborne fungal samples were collected simultaneously using a filtration method and a pollen and particle sampler based on the Hirst methodology. This information is very useful for elucidating geographical patterns of hay fever and asthma. The qualitative results showed that when the non-viable methodology was employed, Cladosporium, Ustilago, and Alternaria were the most abundant spores identified in the atmosphere of Cartagena, while the viable methodology showed that the most abundant taxa were: Cladosporium, Penicillium, Aspergillus and Alternaria. The quantitative results of airborne fungal spores identified by the Hirst-type air sampler (non-viable method), showed that Deuteromycetes represented 74% of total annual spore counts, Cladosporium being the major component of the fungal spectrum (62.2%), followed by Alternaria (5.3%), and Stemphylium (1.3%). The Basidiomycetes group represented 18.9% of total annual spore counts, Ustilago (7.1%) being the most representative taxon of this group and the second most abundant spore type. Ascomycetes accounted for 6.9%, Nectria (2.3%) being the principal taxon. Oomycetes (0.2%) and Zygomycestes and Myxomycestes (0.06%) were scarce. The prevailing species define our bioaerosol as typical of dry air. The viable methodology was better at identifying small hyaline spores and allowed for the discrimination of the genus of some spore types. However, non-viable methods revealed the richness of fungal types present in the bioaerosol. Thus, the use of both methodologies provides a more comprehensive characterization of the spore profile.

  14. The Wound Healing and Antibacterial Activity of Five Ethnomedical Calophyllum inophyllum Oils: An Alternative Therapeutic Strategy to Treat Infected Wounds (United States)

    Léguillier, Teddy; Lecsö-Bornet, Marylin; Lémus, Christelle; Rousseau-Ralliard, Delphine; Lebouvier, Nicolas; Hnawia, Edouard; Nour, Mohammed; Aalbersberg, William; Ghazi, Kamelia; Raharivelomanana, Phila; Rat, Patrice


    Background Calophyllum inophyllum L. (Calophyllaceae) is an evergreen tree ethno-medically used along the seashores and islands of the Indian and Pacific Oceans, especially in Polynesia. Oil extracted from the seeds is traditionally used topically to treat a wide range of skin injuries from burn, scar and infected wounds to skin diseases such as dermatosis, urticaria and eczema. However, very few scientific studies reported and quantified the therapeutic properties of Calophyllum inophyllum oil (CIO). In this work, five CIO from Indonesia (CIO1), Tahiti (CIO2, 3), Fiji islands (CIO4) and New Caledonia (CIO5) were studied and their cytotoxic, wound healing, and antibacterial properties were presented in order to provide a scientific support to their traditional use and verify their safety. Methods The safety of the five CIO was ascertained using the Alamar blue assay on human keratinocyte cells. CIO wound healing properties were determined using the scratch test assay on human keratinocyte cells. CIO-stimulated antibacterial innate immune response was evaluated using ELISA by measuring β defensin-2 release in human derivative macrophage cells. CIO antibacterial activity was tested using oilogramme against twenty aerobic Gram- bacteria species, twenty aerobic Gram+ bacteria species, including a multi-drug resistant Staphylococcus aureus strain and two anaerobic Gram+ bacteria species e.g. Propionibacterium acnes and Propionibacterium granulosum. To detect polarity profile of the components responsible of the antibacterial activity, we performed bioautography against a Staphylococcus aureus strain. Results Based on Alamar Blue assay, we showed that CIO can be safely used on keratinocyte cells between 2.7% and 11.2% depending on CIO origin. Concerning the healing activity, all the CIO tested accelerated in vitro wound closure, the healing factor being 1.3 to 2.1 higher compared to control when keratinocytes were incubated after scratch with CIO at 0.1%. Furthermore

  15. The Wound Healing and Antibacterial Activity of Five Ethnomedical Calophyllum inophyllum Oils: An Alternative Therapeutic Strategy to Treat Infected Wounds.

    Directory of Open Access Journals (Sweden)

    Teddy Léguillier

    Full Text Available Calophyllum inophyllum L. (Calophyllaceae is an evergreen tree ethno-medically used along the seashores and islands of the Indian and Pacific Oceans, especially in Polynesia. Oil extracted from the seeds is traditionally used topically to treat a wide range of skin injuries from burn, scar and infected wounds to skin diseases such as dermatosis, urticaria and eczema. However, very few scientific studies reported and quantified the therapeutic properties of Calophyllum inophyllum oil (CIO. In this work, five CIO from Indonesia (CIO1, Tahiti (CIO2, 3, Fiji islands (CIO4 and New Caledonia (CIO5 were studied and their cytotoxic, wound healing, and antibacterial properties were presented in order to provide a scientific support to their traditional use and verify their safety.The safety of the five CIO was ascertained using the Alamar blue assay on human keratinocyte cells. CIO wound healing properties were determined using the scratch test assay on human keratinocyte cells. CIO-stimulated antibacterial innate immune response was evaluated using ELISA by measuring β defensin-2 release in human derivative macrophage cells. CIO antibacterial activity was tested using oilogramme against twenty aerobic Gram- bacteria species, twenty aerobic Gram+ bacteria species, including a multi-drug resistant Staphylococcus aureus strain and two anaerobic Gram+ bacteria species e.g. Propionibacterium acnes and Propionibacterium granulosum. To detect polarity profile of the components responsible of the antibacterial activity, we performed bioautography against a Staphylococcus aureus strain.Based on Alamar Blue assay, we showed that CIO can be safely used on keratinocyte cells between 2.7% and 11.2% depending on CIO origin. Concerning the healing activity, all the CIO tested accelerated in vitro wound closure, the healing factor being 1.3 to 2.1 higher compared to control when keratinocytes were incubated after scratch with CIO at 0.1%. Furthermore, our results

  16. The Wound Healing and Antibacterial Activity of Five Ethnomedical Calophyllum inophyllum Oils: An Alternative Therapeutic Strategy to Treat Infected Wounds. (United States)

    Léguillier, Teddy; Lecsö-Bornet, Marylin; Lémus, Christelle; Rousseau-Ralliard, Delphine; Lebouvier, Nicolas; Hnawia, Edouard; Nour, Mohammed; Aalbersberg, William; Ghazi, Kamelia; Raharivelomanana, Phila; Rat, Patrice


    Calophyllum inophyllum L. (Calophyllaceae) is an evergreen tree ethno-medically used along the seashores and islands of the Indian and Pacific Oceans, especially in Polynesia. Oil extracted from the seeds is traditionally used topically to treat a wide range of skin injuries from burn, scar and infected wounds to skin diseases such as dermatosis, urticaria and eczema. However, very few scientific studies reported and quantified the therapeutic properties of Calophyllum inophyllum oil (CIO). In this work, five CIO from Indonesia (CIO1), Tahiti (CIO2, 3), Fiji islands (CIO4) and New Caledonia (CIO5) were studied and their cytotoxic, wound healing, and antibacterial properties were presented in order to provide a scientific support to their traditional use and verify their safety. The safety of the five CIO was ascertained using the Alamar blue assay on human keratinocyte cells. CIO wound healing properties were determined using the scratch test assay on human keratinocyte cells. CIO-stimulated antibacterial innate immune response was evaluated using ELISA by measuring β defensin-2 release in human derivative macrophage cells. CIO antibacterial activity was tested using oilogramme against twenty aerobic Gram- bacteria species, twenty aerobic Gram+ bacteria species, including a multi-drug resistant Staphylococcus aureus strain and two anaerobic Gram+ bacteria species e.g. Propionibacterium acnes and Propionibacterium granulosum. To detect polarity profile of the components responsible of the antibacterial activity, we performed bioautography against a Staphylococcus aureus strain. Based on Alamar Blue assay, we showed that CIO can be safely used on keratinocyte cells between 2.7% and 11.2% depending on CIO origin. Concerning the healing activity, all the CIO tested accelerated in vitro wound closure, the healing factor being 1.3 to 2.1 higher compared to control when keratinocytes were incubated after scratch with CIO at 0.1%. Furthermore, our results showed that CIO

  17. The use of steroid sulfatase inhibitors as a novel therapeutic strategy against hormone-dependent endometrial cancer. (United States)

    Foster, Paul A; Woo, L W Lawrence; Potter, Barry V L; Reed, Michael J; Purohit, Atul


    The past few years have seen an increase in the reported incidence of endometrial carcinoma, one of the most frequently diagnosed malignancies of the female genital tract. Estrogen production is vital for the mitogenesis of endometrial tumors. Inhibition of steroid sulfatase (STS), an enzyme responsible for the synthesis of steroids with estrogenic properties, may represent a novel therapeutic target for this type of cancer. This study investigates the effects of STX64 (also known as 667Coumate and BN83495) and STX213, two potent STS inhibitors, on hormone-dependent endometrial cancer cell growth in vivo. When tested in intact mice with endometrial cancer xenografts, STX64 had limited effect on tumor growth. In contrast, the microtubule disruptor STX140 reduced tumor growth by 55%. In a hormone-dependent endometrial xenograft model in ovariectomized mice, both STX64 and STX213 given orally, daily at 1 mg/kg significantly inhibited tumor growth by 48 and 67%, respectively. However, when given orally at 1 mg/kg once weekly, only STX213 still inhibited tumor proliferation. At a higher dose of STX64 (10 mg/kg, orally, daily), a greater tumor growth inhibition of 59% was observed. Liver and tumor STS activity was completely inhibited in all daily treatment groups. Plasma estradiol (E2) levels were also significantly decreased. A significant correlation was observed between plasma E2 concentrations and STS activity, indicating the importance of circulating E2 on tumor growth. This novel study demonstrates for the first time that STS inhibitors are potent inhibitors of endometrial cancer growth in nude mice.

  18. Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy.

    Directory of Open Access Journals (Sweden)

    Protim Sarker

    Full Text Available BACKGROUND: Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18 in the large intestinal epithelia. AIMS: To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB, a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. METHODS: The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR and release of the CAP-18 peptide/protein in stool (Western blot. PRINCIPAL FINDINGS: Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. CONCLUSION: Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from

  19. Parejas viables que perduran en el tiempo


    Juan José Cuervo Rodríguez


    El presente artículo científico presenta resultados del proceso llevado a cabo en el proyecto de investigación docente "Mecanismos de autorregulación en parejas viables que perduran en el tiempo". Se soporta en una mirada compleja de la psicología basada en una epistemología de la construcción. En el ámbito metodológico, se inscribe en los estudios de terapia familiar desde una perspectiva de la comunicación humana como un todo integrado. Participaron nueve parejas. Los criterios de inclusión...

  20. Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus

    DEFF Research Database (Denmark)

    Sigges, Johanna; Biazar, Cyrus; Landmann, Aysche


    The aim of this prospective, cross-sectional, multicentre study performed by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) was to investigate different therapeutic strategies and their efficacies in cutaneous lupus erythematosus (CLE) throughout Europe. Using the EUSCLE Core Set...... Questionnaire, topical and systemic treatment options were analysed in a total of 1002 patients (768 females and 234 males) with different CLE subtypes. The data were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the criteria of the American College...... of Rheumatology (ACR) for the classification of systemic lupus erythematosus. Sunscreens were applied by 84.0% of the study cohort and showed a high efficacy in preventing skin lesions in all disease subtypes, correlating with a lower CLASI activity score. Topical steroids were used in 81.5% of the patients...

  1. [Change in the therapeutic strategy when faced with an inadequate response to the pharmacological treatment of attention deficit hyperactivity disorder]. (United States)

    Gandía-Benetó, Rubén; Mulas, Fernando; Roca, Patricia; Ortiz-Sánchez, Pedro; Abad-Mas, Luis


    Attention deficit hyperactivity disorder (ADHD) is a disorder of a biological origin affecting the neurodevelopment of the brain. It is estimated that 3-7% of school-age children present ADHD. The most commonly used pharmacological treatments are amphetamines and methylphenidate (MPH). Although response rates to MPH are high, full remission rates reach only 56%. The 25% of patients who do not respond to MPH would show a response to other stimulants and vice-versa. AIMS. To clinically evaluate patients by detecting inadequate responses and the efficacy of a change to lisdexamfetamine dimesylate (LDX). The study was prospective and observation-based. Inadequate responses were considered to be those that presented non-coverage or no effect. The Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) and Clinical Global Impression-Severity (CGI-S) assessment scales were used for the clinical assessment, together with the Weiss Functional Impairment Rating Scale (WFIRS) and the Child Health and Illness Profile (CHIP-AE). Data regarding adverse side effects were also collected. Forty-one patients met criteria for inadequate response to treatment: 13.6 ± 3.4 years, 54.6 ± 13.2 kg, 158.5 ± 17.2 cm and body mass index of 20.9 ± 3.5 kg/m2. Reasons for change (non-exclusive): non-coverage (76%), lack of intensity of effect (68%) and presence of adverse side effects with the previous medication (16%). The mean score both at baseline and at nine months, on the ADHD-RS, was 24.54 ± 6.3 versus 12.01 ± 3.2 (p ADHD. When the response to MPH presents non-coverage or lack of effect, changing to LDX has proved to be effective, with an improvement in 86.7% of cases, which is similar to that of other studies. It is therefore a good therapeutic option in these patients.

  2. Enzymatic isolation of viable human odontoblasts. (United States)

    Cuffaro, H M; Pääkkönen, V; Tjäderhane, L


    To improve an enzymatic method previously used for isolation of rat odontoblasts to isolate viable mature human odontoblasts. Collagenase I, collagenase I/hyaluronidase mixture and hyaluronidase were used to extract mature human odontoblasts from the pulp chamber. Detachment of odontoblasts from dentine was determined with field emission scanning electron microscopy (FESEM) and to analyse the significance of differences in tubular diameter, and the t-test was used. MTT-reaction was used to analyse cell viability, and nonparametric Kruskal-Wallis and Mann-Whitney post hoc tests were used to analyse the data. Immunofluorescent staining of dentine sialoprotein (DSP), aquaporin-4 (AQP4) and matrix metalloproteinase-20 (MMP-20) and quantitative PCR (qPCR) of dentine sialophosphoprotein (DSPP) were used to confirm the odontoblastic nature of the cells. MTT-reaction and FESEM demonstrated collagenase I/hyaluronidase resulted in more effective detachment and higher viability than collagenase I alone. Hyaluronidase alone was not able to detach odontoblasts. Immunofluorescence revealed the typical odontoblastic-morphology with one process, and DSP, AQP4 and MMP-20 were detected. Quantitative PCR of DSPP confirmed that the isolated cells expressed this odontoblast-specific gene. The isolation of viable human odontoblasts was successful. The cells demonstrated morphology typical for odontoblasts and expressed characteristic odontoblast-type genes and proteins. This method will enable new approaches, such as apoptosis analysis, for studies using fully differentiated odontoblasts. © 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  3. Determination of therapeutic strategy for adhesive small bowel obstruction using water-soluble contrast agents: An audit of 776 cases in a single center. (United States)

    Mori, Haruki; Kaneoka, Yuji; Maeda, Atsuyuki; Takayama, Yuichi; Takahashi, Takamasa; Onoe, Shunsuke; Fukami, Yasuyuki


    Several studies have investigated the diagnostic and therapeutic role of water-soluble contrast agents in adhesive small bowel obstruction, but there is no clear diagnostic classification for the determination of therapeutic strategy. The aim of this study was to clarify the clinical value of classification using water-soluble contrast agents in patients with adhesive small bowel obstruction. Between January 2009 and December 2015, 776 consecutive patients with adhesive small bowel obstruction were managed initially with water-soluble contrast agents and were included in the study. Abdominal x-rays were taken 5 hours after administration of 100 mL water-soluble contrast agents and classified into 4 types. The medical records of the patients with adhesive small bowel obstruction were analyzed retrospectively and divided into 2 groups of patients with complete obstruction (ie, the absence of contrast agent in the colon) with (type I) or without (type II) a detectable point of obstruction and a group with an incomplete obstruction (ie, the presence of contrast agent in the colon) with (type IIIA) or without (type IIIB) dilated small intestine. Types I, II, IIIA, and IIIB were identified in 27, 90, 358, and 301 patients, respectively. The overall operative rate was 16.6%. In the patients treated conservatively (types IIIA and IIIB), 647 patients (98.2%) were treated successfully without operative intervention. The operative rate was 3.4% (n = 12/358) in type IIIA vs 0% (n = 0/301) in the type IIIB group (P = .001). Compared with type IIIA, type IIIB was associated with earlier initiation of oral intake (2.1 vs 2.6 days, P strategy for adhesive small bowel obstruction. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Isotype Diversification of IgG Antibodies to HIV Gag Proteins as a Therapeutic Vaccination Strategy for HIV Infection

    Directory of Open Access Journals (Sweden)

    Sonia Fernandez


    Full Text Available The development of vaccines to treat and prevent human immunodeficiency virus (HIV infection has been hampered by an incomplete understanding of “protective” immune responses against HIV. Natural control of HIV-1 infection is associated with T-cell responses against HIV-1 Gag proteins, particularly CD8+ T-cell responses restricted by “protective” HLA-B alleles, but other immune responses also contribute to immune control. These immune responses appear to include IgG antibodies to HIV-1 Gag proteins, interferon-a-dependant natural killer (NK cell responses and plasmacytoid dendritic cell (pDC responses. Here, it is proposed that isotype diversification of IgG antibodies against HIV-1 Gag proteins, to include IgG2, as well as IgG3 and IgG1 antibodies, will broaden the function of the antibody response and facilitate accessory cell responses against HIV-1 by NK cells and pDCs. We suggest that this should be investigated as a vaccination strategy for HIV-1 infection.

  5. Novel Drug Delivery System Based on Docetaxel-Loaded Nanocapsules as a Therapeutic Strategy Against Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Antonia Aránega


    Full Text Available In the field of cancer therapy, lipid nanocapsules based on a core-shell structure are promising vehicles for the delivery of hydrophobic drugs such as docetaxel. The main aim of this work was to evaluate whether docetaxel-loaded lipid nanocapsules improved the anti-tumor effect of free docetaxel in breast cancer cells. Three docetaxel-loaded lipid nanocapsules were synthesized by solvent displacement method. Cytotoxic assays were evaluated in breast carcinoma (MCF-7 cells treated by the sulforhodamine B colorimetric method. Cell cycle was studied by flow cytometry and Annexin V-FITC, and apoptosis was evaluated by using propidium iodide assays. The anti-proliferative effect of docetaxel appeared much earlier when the drug was encapsulated in lipid nanoparticles than when it was free. Docetaxel-loaded lipid nanocapsules significantly enhanced the decrease in IC50 rate, and the treated cells evidenced apoptosis and a premature progression of the cell cycle from G(1 to G(2-M phase. The chemotherapeutic effect of free docetaxel on breast cancer cells is improved by its encapsulation in lipid nanocapsules. This approach has the potential to overcome some major limitations of conventional chemotherapy and may be a promising strategy for future applications in breast cancer therapy.

  6. Therapeutic Strategy for Cavernous Sinus-Invading Non-Functioning Pituitary Adenomas Based on the Modified Knosp Grading System. (United States)

    Hwang, Juyoung; Seol, Ho Jun; Nam, Do-Hyun; Lee, Jung-Il; Lee, Min Ho; Kong, Doo-Sik


    Non-functioning pituitary adenomas (NFPA) invading into the cavernous sinus are surgically challenging. To decrease recurrence rate, surgeon makes a strong endeavor to resect tumor gross totally. However, gross total resection (GTR) is difficult to achieve with cavernous sinus invasion. Recently, a new classification system for cavernous invasion of pituitary adenomas was suggested. The aim of this study is to validate this new classification system and to identify limitations and considerations in designing treatment strategies for patients with NFPA involving the cavernous sinus. Between January 2000 and January 2012, 275 patients who underwent operation for NFPA were enrolled in the study. Median age was 50 years (15-79 years). There were 145 males and 130 females. The median follow-up duration was 4 years (range 1-12.5 years). Related to extent of tumor removal, GTR was obtained in 184 patients (66.9%), near total resection (NTR) was obtained in 45 patients (16.3%), and sub-total resection (STR) was obtained in 46 patients (16.7%) of a total 275 patients. There were statistically significant differences between the extent of resection and the new Knosp classification (pcavernous-invading adenomas.

  7. Human immunodeficiency virus: 25 years of diagnostic and therapeutic strategies and their impact on hepatitis B and C virus. (United States)

    Stürmer, Martin; Doerr, Hans Wilhelm; Gürtler, Lutz


    The human immunodeficiency virus (HIV) had spread unrecognized in the human population as sexually transmitted disease and was finally identified by its disease AIDS in 1981. Even after the isolation of the causative agent in 1983, the burden and death rate of AIDS accelerated worldwide especially in young people despite the confection of new drugs capable to inhibit virus replication since 1997. However, at least in industrialised countries, this trend could be reversed by the introduction of combination therapy strategies. The design of new drugs is on going; besides the inhibition of the three enzymes of HIV for replication and maturation (reverse transcriptase, integrase and protease), further drugs inhibits fusion of viral and cellular membranes and virus maturation. On the other hand, viral diagnostics had been considerably improved since the emergence of HIV. There was a need to identify infected people correctly, to follow up the course of immune reconstitution of patients by measuring viral load and CD4 cells, and to analyse drug escape mutations leading to drug resistance. Both the development of drugs and the refined diagnostics have been transferred to the treatment of patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). This progress is not completed; there are beneficial aspects in the response of the scientific community to the HIV burden for the management of other viral diseases. These aspects are described in this contribution. Further aspects as handling a stigmatising disease, education of self-responsiveness within sexual relationships, and ways for confection of a protective vaccine are not covered.

  8. [Identification, during development, of a methodology targeted at determining the positioning of new drugs for therapeutic strategies: examples of rheumatoid arthritis and cardiac insufficiency]. (United States)

    Le Jeunne, C; Plétan, Y; Boissel, J P


    The Marketing Authorization (MA) granted to a new molecular entity does not allow for proper anticipation of its future positioning within the therapeutic strategy. A specific methodology should be devised as early as during the pre-MA development phase that could result in an initial positioning that should be subjected to further reappraisal with regard to scientific advances, the arrival of new treatments and further developments with this molecule. A methodology is thus proposed, based on early optimisation of the development plan, the granting of subsequent MAs, and reappraisal of the positioning within the strategy, based on analysis of all available data. It should be possible to take into account the economic context, within an agreed system with pre-defined medico-economic criteria. This may in turn raise the issue of the role of the various parties involved in this assessment, as well as how to understand the respective opinions of stakeholders: authorities, sponsors, prescribers and patients, each of whom has a specific view of the definition of the strategic objective that should apply to the disease concerned.

  9. Roots of success: cultivating viable community forestry

    Energy Technology Data Exchange (ETDEWEB)

    MacQueen, Duncan


    Is community forestry emerging from the shadows? The evidence shows that locally controlled enterprises can be economically viable, and often build on stronger social and environmental foundations than the big private-sector players. Certainly this is an industry in need of a shakeup. Many forests have become flashpoints where agro-industry, large-scale logging concerns and conservation interests clash, while forest-dependent communities are left out in the cold. Meanwhile, governments – driven by concerns over the climate impacts of deforestation – are having to gear up for legal, sustainable forestry production. Community forestry could be crucial to solving many of these challenges. By building on local core capabilities and developing strategic partnerships, they are forging key new business models that could transform the sector.


    Iorio, Silvia


    This article addresses the strategies employed by Nahua community of Mexixo to deal with health problems. Drawing on qualitative research, it discusses the choice of plural therapeutic itineraries, including the use of informal and formal healthcare.

  11. Social Networking and Smart Technology: Viable Environmental Communication Tools…? (United States)

    Montain, J.; Byrne, J. M.


    To what extent do popular social networking channels represent a viable means for disseminating information regarding environmental change to the general public? Are new forms of communication such as YouTube™, Facebook™, MySpace™ and Twitter™ and smart devices such as iPhone™ and BlackBerry™ useful and effective in terms motivating people into social action and behavioural modification; or do they simply pay ‘lip service’ to these pressing environmental issues? This project will explore the background connections between social networking and environmental communication and education; and outline why such tools might be an appropriate way to connect to a broad audience in an efficient and unconventional manner. Further, research will survey the current prevalence of reliable environmental change information on social networking Internet-based media; and finally, suggestions for improved strategies and new directions will be provided.

  12. Enumeration of viable and non-viable larvated Ascaris eggs with quantitative PCR. (United States)

    Raynal, Maria; Villegas, Eric N; Nelson, Kara L


    The goal of this study was to further develop an incubation-quantitative polymerase chain reaction (qPCR) method for quantifying viable Ascaris eggs by characterizing the detection limit and number of template copies per egg, determining the specificity of the method, and testing the method with viable and inactivated larvated eggs. The number of template copies per cell was determined by amplifying DNA from known numbers of eggs at different development stages; the value was estimated to be 32 copies. The specificity of the method was tested against a panel of bacteria, fungi, protozoa and helminths, and no amplification was found with non-target DNA. Finally, fully larvated eggs were inactivated by four different treatments: 254 nm ultraviolet light, 2,000 ppm NH(3)-N at pH 9, moderate heat (48 °C) and high heat (70 °C). Concentrations of treated eggs were measured by direct microscopy and incubation-qPCR. The qPCR signal decreased following all four treatments, and was in general agreement with the decrease in viable eggs determined by microscopy. The incubation-qPCR method for enumerating viable Ascaris eggs is a promising approach that can produce results faster than direct microscopy, and may have benefits for applications such as assessing biosolids.

  13. Polymerase chain reaction-based discrimination of viable from non-viable Mycoplasma gallisepticum

    Directory of Open Access Journals (Sweden)

    Ching Giap Tan


    Full Text Available The present study was based on the reverse transcription polymerase chain reaction (RT-PCR of the 16S ribosomal nucleic acid (rRNA of Mycoplasma for detection of viable Mycoplasma gallisepticum. To determine the stability of M. gallisepticum 16S rRNA in vitro, three inactivation methods were used and the suspensions were stored at different temperatures. The 16S rRNA of M. gallisepticum was detected up to approximately 20–25 h at 37 °C, 22–25 h at 16 °C, and 23–27 h at 4 °C. The test, therefore, could detect viable or recently dead M. gallisepticum (< 20 h. The RT-PCR method was applied during an in vivo study of drug efficacy under experimental conditions, where commercial broiler-breeder eggs were inoculated with M. gallisepticum into the yolk. Hatched chicks that had been inoculated in ovo were treated with Macrolide 1. The method was then applied in a flock of day 0 chicks with naturally acquired vertical transmission of M. gallisepticum, treated with Macrolide 2. Swabs of the respiratory tract were obtained for PCR and RT-PCR evaluations to determine the viability of M. gallisepticum. This study proved that the combination of both PCR and RT-PCR enables detection and differentiation of viable from non-viable M. gallisepticum.

  14. Adeno-associated virus-mediated neuroglobin overexpression ameliorates the N-methyl-N-nitrosourea-induced retinal impairments: a novel therapeutic strategy against photoreceptor degeneration

    Directory of Open Access Journals (Sweden)

    Tao Y


    Full Text Available Ye Tao,1,* Zhen Yang,2,* Wei Fang,2 Zhao Ma,3 Yi Fei Huang,1 Zhengwei Li4 1Department of Ophthalmology, Key Lab of Ophthalmology and Visual Science, Chinese PLA General Hospital, Beijing, 2Department of Neurosurgery, Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi’an, 3Department of Neurosurgery, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 4Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: Retinal degeneration (RD is a heterogeneous group of inherited dystrophies leading to blindness. The N-methyl-N-nitrosourea (MNU-administered mouse is used as a pharmacologically induced RD animal model in various therapeutic investigations. The present study found the retinal neuroglobin (NGB expression in the MNU-administered mice was significantly lower than in normal controls, suggesting NGB was correlated with RD. Subsequently, an adeno-associated virus (AAV-2-mCMV-NGB vector was delivered into the subretinal space of the MNU-administered mice. The retinal NGB expression of the treated eye was upregulated significantly in both protein and mRNA levels. Further, we found NGB overexpression could alleviate visual impairments and morphological devastations in MNU-administered mice. NGB overexpression could rectify apoptotic abnormalities and ameliorate oxidative stress in MNU-administered mice, thereby promoting photoreceptor survival. The cone photoreceptors in MNU-administered mice were also sensitive to AAV-mediated NGB overexpression. Taken together, our findings suggest that manipulating NGB bioactivity via gene therapy may represent a novel therapeutic strategy against RD. Future elucidation of the exact role of NGB would advance our knowledge about the pathological mechanisms underlying RD. Keywords: neuroglobin, retinal degeneration

  15. Role of Pre-therapeutic 18F-FDG PET/CT in Guiding the Treatment Strategy and Predicting Prognosis in Patients with Esophageal Carcinoma

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    Teik Hin Tan


    Full Text Available Objective(s: The present study aimed to evaluate the role of pretherapeutic 18fluorine-fluorodeoxyglucose positron emission tomographycomputed tomography (18F-FDG PET-CT and maximum standardized uptake value (SUVmax in guiding the treatment strategy and predicting the prognosis of esophageal carcinoma, using the survival data of thepatients.Methods: The present retrospective, cohort study was performed on 40 consecutive patients with esophageal carcinoma (confirmed by endoscopic biopsy, who underwent pre-operative 18F-FDG PET-CTstaging between January 2009 and June 2014. All the patients underwent contrast-enhanced CT and non-contrasted 18F-FDG PET-CT evaluations.The patients were followed-up over 12 months to assess the changes in therapeutic strategies. Survival analysis was done considering the primary tumor SUVmax, using the Kaplan–Meier product-limit method.Results: In a total of 40 patients, 18F-FDG PET-CT scan led to changes in disease stage in 26n (65.0% cases, with upstaging and downstaging reported in 10n (25.0% and 16n (40.0% patients, respectively. The management strategy changed from palliative to curative in 10 out of 24 patients and from curative to palliative in 7 out of 16 cases. Based on the18F-FDG PET-CT scan alone, the median survival of patients in the palliative group was 4.0n (95 % CI 3.0-5.0 months, whereas the median survival in the curative group has not been reached, based on the 12-month followup.Selection of treatment strategy on the basis of 18F-FDG PET/CT alone was significantly associated with the survival outcomes at nine months (P=0.03 and marginally significant at 12 months (P=0.05. On the basisof SUVmax, the relation between survival and SUVmax was not statistically significant.Conclusion: 18F-FDG PET/CT scan had a significant impact on stage stratification and subsequently, selection of a stage-specific treatment approach and the overall survival outcome in patients with esophageal carcinoma. However, pre

  16. The Conceptual Mechanism for Viable Organizational Learning Based on Complex System Theory and the Viable System Model (United States)

    Sung, Dia; You, Yeongmahn; Song, Ji Hoon


    The purpose of this research is to explore the possibility of viable learning organizations based on identifying viable organizational learning mechanisms. Two theoretical foundations, complex system theory and viable system theory, have been integrated to provide the rationale for building the sustainable organizational learning mechanism. The…

  17. Deletion of ultraconserved elements yields viable mice

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel; Holt, Amy; Afzal, Veena; Pennacchio, Len A.; Rubin, Edward M.


    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lacking these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.

  18. Is Greenberg's "Macro-Carib" viable?

    Directory of Open Access Journals (Sweden)

    Spike Gildea

    Full Text Available In his landmark work Language in the Americas, Greenberg (1987 proposed that Macro-Carib was one of the major low-level stocks of South America, which together with Macro-Panoan and Macro-Ge-Bororo were claimed to comprise the putative Ge-Pano-Carib Phylum. His Macro-Carib includes the isolates Andoke and Kukura, and the Witotoan, Peba-Yaguan, and Cariban families. Greenberg's primary evidence came from person-marking paradigms in individual languages, plus scattered words from individual languages collected into 79 Macro-Carib 'etymologies' and another 64 Amerind 'etymologies'. The goal of this paper is to re-evaluate Greenberg's Macro-Carib claim in the light of the much more extensive and reliable language data that has become available largely since 1987. Based on full person-marking paradigms for Proto-Cariban, Yagua, Bora and Andoke, we conclude that Greenberg's morphological claims are unfounded. For our lexical comparison, we created lexical lists for Proto-Cariban, Proto-Witotoan, Yagua and Andoke, for both Greenberg's 143 putative etymologies and for the Swadesh 100 list. From both lists, a total of 23 potential cognates were found, but no consonantal correspondences were repeated even once. We conclude that our greatly expanded and improved database does not provide sufficient evidence to convince the skeptic that the Macro-Carib hypothesis is viable

  19. Economically viable large-scale hydrogen liquefaction (United States)

    Cardella, U.; Decker, L.; Klein, H.


    The liquid hydrogen demand, particularly driven by clean energy applications, will rise in the near future. As industrial large scale liquefiers will play a major role within the hydrogen supply chain, production capacity will have to increase by a multiple of today’s typical sizes. The main goal is to reduce the total cost of ownership for these plants by increasing energy efficiency with innovative and simple process designs, optimized in capital expenditure. New concepts must ensure a manageable plant complexity and flexible operability. In the phase of process development and selection, a dimensioning of key equipment for large scale liquefiers, such as turbines and compressors as well as heat exchangers, must be performed iteratively to ensure technological feasibility and maturity. Further critical aspects related to hydrogen liquefaction, e.g. fluid properties, ortho-para hydrogen conversion, and coldbox configuration, must be analysed in detail. This paper provides an overview on the approach, challenges and preliminary results in the development of efficient as well as economically viable concepts for large-scale hydrogen liquefaction.

  20. [Breast cancer: new therapeutic strategies]. (United States)

    Espie, M


    NEED FOR NEW CHEMOTHERAPY AGENTS: Metastasic breast cancer is an excellent model for studying anticancer agents: chemotherapy or hormonotherapy or compounds modifying the organism's response. If no adjuvant treatment is given after locoregional treatment of breast cancer, metastasis will develop within 10 years in 30% of the patients free of initial nodal invasion and within 5 years in 50% of the patients with initial nodal invasion. ADJUVANT TREATMENTS: Hormonotherapy and chemotherapy reduce mortality due to breast cancer by 10%. New adjuvant agents have been recently introduced. Taxans (docetaxel, paclitaxel) are the most active molecules since antracyclines. New aromataase inhibitors include letrozole and anastrozole. Their efficacy has been demonstrated in phase II and phase III trials, allowing their experimentation as adjuvant treatments.

  1. Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age. (United States)

    Rigaud, Charlotte; Barkaoui, Mohamed A; Thomas, Caroline; Bertrand, Yves; Lambilliotte, Anne; Miron, Jean; Aladjidi, Nathalie; Plat, Geneviève; Jeziorski, Eric; Galambrun, Claire; Mansuy, Ludovic; Lutz, Patrick; Deville, Anne; Armari-Alla, Corinne; Reguerre, Yves; Fraitag, Sylvie; Coulomb, Aurore; Gandemer, Virginie; Leboulanger, Nicolas; Moshous, Despina; Hoang-Xuan, Khe; Tazi, Abdellatif; Heritier, Sébastien; Emile, Jean-François; Donadieu, Jean


    The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent. © 2016 John Wiley & Sons Ltd.

  2. Diagnostic and therapeutic strategy in Menière's disease. Guidelines of the French Otorhinolaryngology-Head and Neck Surgery Society (SFORL). (United States)

    Nevoux, J; Franco-Vidal, V; Bouccara, D; Parietti-Winkler, C; Uziel, A; Chays, A; Dubernard, X; Couloigner, V; Darrouzet, V; Mom, T


    The authors present the guidelines of the French Otorhinolaryngology-Head and Neck Surgery Society (Société française d'oto-rhino-laryngologie et de chirurgie de la face et du cou: SFORL) for diagnostic and therapeutic strategy in Menière's disease. A work group was entrusted with a review of the scientific literature on the above topic. Guidelines were drawn up, then read over by an editorial group independent of the work group. The guidelines were graded according to the literature analysis and recommendations grading guide published by the French National Agency for Accreditation and Evaluation in Health (January 2000). Menière's disease is diagnosed in the presence of the association of four classical clinical items and after eliminating differential diagnoses on MRI. In case of partial presentation, objective audiovestibular tests are recommended. Therapy comprises medical treatment and surgery, either conservative or sacrificing vestibular function. Medical treatment is based on lifestyle improvement, betahistine, diuretics or transtympanic injection of corticosteroids or gentamicin. The main surgical treatments, in order of increasing aggressiveness, are endolymphatic sac surgery, vestibular neurotomy and labyrinthectomy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Is mental practice an effective adjunct therapeutic strategy for upper limb motor restoration after stroke? A systematic review and meta- analysis. (United States)

    Machado, Sergio; Lattari, Eduardo; de Sá, Alberto Souza; Rocha, Nuno B F; Yuan, Ti-Fei; Paes, Flávia; Wegner, Mirko; Budde, Henning; Nardi, Antonio E; Arias-Carrión, Oscar


    Stroke is one of the most common conditions requiring rehabilitation, and its motor impairments are a major cause of permanent disability. Hemiparesis is observed by 80% of the patients after acute stroke. Neuroimaging studies showed that real and imagined movements have similarities regarding brain activation, supplying evidence that those similarities are based on the same process. Within this context, the combination of mental practice (MP) with physical and occupational therapy appears to be a natural complement based on neurorehabilitation concepts. Our study seeks to investigate if MP for stroke rehabilitation of upper limbs is an effective adjunct therapy. PubMed (Medline), ISI knowledge (Institute for Scientific Information) and SciELO (Scientific Electronic Library) were terminated on 20 February 2015. Data were collected on variables as follows: sample size, type of supervision, configuration of mental practice, setting the physical practice (intensity, number of sets and repetitions, duration of contractions, rest interval between sets, weekly and total duration), measures of sensorimotor deficits used in the main studies and significant results. Random effects models were used that take into account the variance within and between studies. Seven articles were selected. As there was no statistically significant difference between the two groups (MP vs control), showed a - 0.6 (95% CI: -1.27 to 0.04), for upper limb motor restoration after stroke. The present meta-analysis concluded that MP is not effective as adjunct therapeutic strategy for upper limb motor restoration after stroke.

  4. Exploiting the therapeutic potential of leptin signaling in cachexia. (United States)

    Mak, Robert H; Cheung, Wai W; Gertler, Arieh


    The anorexia-cachexia syndrome is a complication of many chronic conditions including cancer, chronic obstructive pulmonary disease, congestive heart failure, and chronic kidney disease (CKD). Leptin levels are significantly elevated in CKD patients and are associated with markers of poor nutritional status as well as mortality and morbidity. This review will focus on the mechanism and exploit the therapeutic potential of leptin signaling in CKD-associated cachexia. Studies in db/db mice show that the lack of leptin receptor is protective against CKD-induced cachexia. Blockade of leptin's downstream mediators, such as melanocortin-4 receptor, attenuated CKD-associated cachexia. Pegylation of leptin antagonists resulted in a potent and effective long-acting reagents suitable for in-vivo studies or therapies. Pegylated leptin antagonist treatment ameliorates CKD-associated cachexia in mice. Leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.

  5. Parejas viables que perduran en el tiempo

    Directory of Open Access Journals (Sweden)

    Juan José Cuervo Rodríguez


    Full Text Available El presente artículo científico presenta resultados del proceso llevado a cabo en el proyecto de investigación docente "Mecanismos de autorregulación en parejas viables que perduran en el tiempo". Se soporta en una mirada compleja de la psicología basada en una epistemología de la construcción. En el ámbito metodológico, se inscribe en los estudios de terapia familiar desde una perspectiva de la comunicación humana como un todo integrado. Participaron nueve parejas. Los criterios de inclusión fueron: cinco o más años de convivencia, participación voluntaria, no presentar (ni haber presentado problemáticas especiales que ameriten intervención psicoterapéutica y la obtención de un porcentaje significativo en el uso de estrategias de comunicación asertiva en la resolución de conflictos. El método general utilizado fue el análisis de la comunicación en tarea de conversación. Los principales hallazgos señalan una estrecha relación entre el contexto de desarrollo de las parejas, la emergencia de códigos comunicacionales propios y la posibilidad de perdurar en el tiempo; también, se resalta el tipo de comunicación asertiva o constructiva, la construcción de valores como el respeto y la aceptación de las diferencias, y el deseo por vivir y construir bienestar común, como elementos constitutivos de su identidad como pareja.

  6. Is telomerase a viable target in cancer? (United States)

    Buseman, C.M.; Wright, W.E.; Shay, J.W.


    The ideal cancer treatment would specifically target cancer cells yet have minimal or no adverse effects on normal somatic cells. Telomerase, the ribonucleoprotein reverse transcriptase that maintains the ends of human chromosome, is an attractive cancer therapeutic target for exactly this reason [1]. Telomerase is expressed in more than 85% of cancer cells, making it a nearly universal cancer marker, while the majority of normal somatic cells are telomerase negative. Telomerase activity confers limitless replicative potential to cancer cells, a hallmark of cancer which must be attained for the continued growth that characterizes almost all advanced neoplasms [2]. In this review we will summarize the role of telomeres and telomerase in cancer cells, and how properties of telomerase are being exploited to create targeted cancer therapies including telomerase inhibitors, telomerase-targeted immunotherapies and telomerase-driven virotherapies. A frank and balanced assessment of the current state of telomerase inhibitors with caveats and potential limitations will be included. PMID:21802433

  7. PMA-Linked Fluorescence for Rapid Detection of Viable Bacterial Endospores (United States)

    LaDuc, Myron T.; Venkateswaran, Kasthuri; Mohapatra, Bidyut


    The most common approach for assessing the abundance of viable bacterial endospores is the culture-based plating method. However, culture-based approaches are heavily biased and oftentimes incompatible with upstream sample processing strategies, which make viable cells/spores uncultivable. This shortcoming highlights the need for rapid molecular diagnostic tools to assess more accurately the abundance of viable spacecraft-associated microbiota, perhaps most importantly bacterial endospores. Propidium monoazide (PMA) has received a great deal of attention due to its ability to differentiate live, viable bacterial cells from dead ones. PMA gains access to the DNA of dead cells through compromised membranes. Once inside the cell, it intercalates and eventually covalently bonds with the double-helix structures upon photoactivation with visible light. The covalently bound DNA is significantly altered, and unavailable to downstream molecular-based manipulations and analyses. Microbiological samples can be treated with appropriate concentrations of PMA and exposed to visible light prior to undergoing total genomic DNA extraction, resulting in an extract comprised solely of DNA arising from viable cells. This ability to extract DNA selectively from living cells is extremely powerful, and bears great relevance to many microbiological arenas.

  8. Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db/db mouse. (United States)

    Jin, Hai-Rong; Kim, Woo Jean; Song, Jae Sook; Piao, Shuguang; Tumurbaatar, Munkhbayar; Shin, Sun Hwa; Choi, Min Ji; Tuvshintur, Buyankhuu; Song, Kang-Moon; Kwon, Mi-Hye; Yin, Guo Nan; Koh, Gou Young; Ryu, Ji-Kan; Suh, Jun-Kyu


    immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay, whereas a single injection of COMP-Ang1 protein elicited partial improvement. Cavernous neovascularization using recombinant Ang1 protein is a novel therapeutic strategy for the treatment of ED resulting from type II diabetes. © 2010 International Society for Sexual Medicine.

  9. Wharton’s Jelly-Derived Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for the Management of Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Joseph P. McGuirk


    Full Text Available Allogeneic hematopoietic cell transplantation (allo-HCT, a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD. The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ-derived mesenchymal stromal cells (MSCs as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

  10. Double guidewire endoscopic technique, a major evolution in endoscopic retrograde cholangiopancreatography: Results of a retrospective study with historical controls comparing two therapeutic sequential strategies. (United States)

    Laquiere, Arthur; Desilets, Etienne; Belle, Arthur; Castellani, Paul; Grandval, Philippe; Laugier, René; Penaranda, Guillaume; Lecomte, Laurence; Boustiere, Christian


    Endoscopic access to the common bile duct (CBD) remains difficult in 10% of cases, requiring alternative techniques .CBD access was difficult after either five unsuccessful attempts, five unintentional insertions into the pancreatic duct or >10-min-long unsuccessful attempts. This retrospective study with historical controls aimed to evaluate the benefit of the double guidewire (DGW) technique after failure of standard CBD cannulation. From January 2012 to December 2014, all patients requiring therapeutic endoscopic retrograde cholangiopancreatography (ERCP) with difficult access to CBD were included in a Studied group. This group was compared to a historical ERCP control group from January 2009 to December 2011. In the Studied group, a sequential strategy including DGW technique was done when the guidewire was unintentionally passed into the pancreatic duct. In the control group, only pre-cut technique was used. Among the 538 patients with naive papilla eligible for ERCP, 73 had difficult CBD access. Successful CBD access rate was higher in the Studied group: 91% (50/55) versus 67% (12/18) P = 0.0215. Complication rates were similar in both groups: 28% versus 20%, P = 0.5207. LOS was shorter in the Studied group (9.2 ± 8.5 vs 14.4 ± 7.4 days, P = 0.0028). Post-ERCP cholangitis were lower in the Studied group: 2% (1/55) versus 22% (4/18), P = 0.0118. After standard cannulation failure, DGW technique increased successful CBD access rate and decreased LOS without increasing complications. © 2016 Japan Gastroenterological Endoscopy Society.

  11. Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies. (United States)

    Deng, Changchun; Lipstein, Mark R; Scotto, Luigi; Jirau Serrano, Xavier O; Mangone, Michael A; Li, Shirong; Vendome, Jeremie; Hao, Yun; Xu, Xiaoming; Deng, Shi-Xian; Realubit, Ronald B; Tatonetti, Nicholas P; Karan, Charles; Lentzsch, Suzanne; Fruman, David A; Honig, Barry; Landry, Donald W; O'Connor, Owen A


    Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kδ inhibitors, inhibited casein kinase-1 ε (CK1ε). Targeting CK1ε using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kδ/CK1ε inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1ε should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc. © 2017 by The American Society of Hematology.

  12. Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells (United States)

    Cengiz, Bagdat Burcu; Asik, Mehmet Dogan; Kara, Goknur; Turk, Mustafa; Denkbas, Emir Baki


    In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

  13. Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cengiz, Bagdat Burcu; Asik, Mehmet Dogan [Hacettepe University, Nanotechnology and Nanomedicine Division (Turkey); Kara, Goknur [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey); Turk, Mustafa [Kirikkale University, Bioengineering Department (Turkey); Denkbas, Emir Baki, E-mail: [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey)


    In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

  14. Separable Bilayer Microfiltration Device for Viable Label-free Enrichment of Circulating Tumour Cells (United States)

    Zhou, Ming-Da; Hao, Sijie; Williams, Anthony J.; Harouaka, Ramdane A.; Schrand, Brett; Rawal, Siddarth; Ao, Zheng; Brennaman, Randall; Gilboa, Eli; Lu, Bo; Wang, Shuwen; Zhu, Jiyue; Datar, Ram; Cote, Richard; Tai, Yu-Chong; Zheng, Si-Yang


    The analysis of circulating tumour cells (CTCs) in cancer patients could provide important information for therapeutic management. Enrichment of viable CTCs could permit performance of functional analyses on CTCs to broaden understanding of metastatic disease. However, this has not been widely accomplished. Addressing this challenge, we present a separable bilayer (SB) microfilter for viable size-based CTC capture. Unlike other single-layer CTC microfilters, the precise gap between the two layers and the architecture of pore alignment result in drastic reduction in mechanical stress on CTCs, capturing them viably. Using multiple cancer cell lines spiked in healthy donor blood, the SB microfilter demonstrated high capture efficiency (78-83%), high retention of cell viability (71-74%), high tumour cell enrichment against leukocytes (1.7-2 × 103), and widespread ability to establish cultures post-capture (100% of cell lines tested). In a metastatic mouse model, SB microfilters successfully enriched viable mouse CTCs from 0.4-0.6 mL whole mouse blood samples and established in vitro cultures for further genetic and functional analysis. Our preliminary studies reflect the efficacy of the SB microfilter device to efficiently and reliably enrich viable CTCs in animal model studies, constituting an exciting technology for new insights in cancer research.

  15. Asouzu's Complementary Ontology as a Foundation for a Viable ...

    African Journals Online (AJOL)

    This paper on “Asouzu's Complementary Ontology as a foundation for a viable Ethic of the Environment”, posits that an ethic of the environment can be seen as viable if it considers the whole of reality as ontologically relevant. This point of view would free environmental ethics of anthropocentric bias and its attendant ...

  16. Designing Viable Business Models for Living Labs

    Directory of Open Access Journals (Sweden)

    Bernhard R. Katzy


    Full Text Available Over 300 regions have integrated the concept of living labs into their economic development strategy since 2006, when the former Finnish Prime Minister Esko Aho launched the living lab innovation policy initiative during his term of European presidency. Despite motivating initial results, however, success cases of turning research into usable new products and services remain few and uncertainty remains on what living labs actually do and contribute. This practitioner-oriented article presents a business excellence model that shows processes of idea creation and team mobilization, new product development, user involvement, and entrepreneurship through which living labs deliver high-potential investment opportunities. Customers of living labs are identified as investors such as venture capitalists or industrial firms because living labs can generate revenue from them to create their own sustainable business model. The article concludes that living labs provide extensive support “lab” infrastructure and that it remains a formidable challenge to finance it, which calls for a more intensive debate.

  17. Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines. (United States)

    Criscione, S M


    There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity

  18. Treatment with Rutin - A Therapeutic Strategy for Neutrophil-Mediated Inflammatory and Autoimmune Diseases - Anti-inflammatory Effects of Rutin on Neutrophils -

    Directory of Open Access Journals (Sweden)

    Bahareh Abd Nikfarjam


    due to its inhibiting NO and TNF-α productions, as well as MPO activity, in activated human neutrophils. Treatment with rutin may be considered as a therapeutic strategy for neutrophil-mediated inflammatory/ autoimmune diseases.

  19. A new era of therapeutic strategies for chronic thromboembolic pulmonary hypertension by two different interventional therapies; pulmonary endarterectomy and percutaneous transluminal pulmonary angioplasty.

    Directory of Open Access Journals (Sweden)

    Takumi Inami

    and catheter-based interventional therapies leads us to expect the dawn of a new era of therapeutic strategies for CTEPH.

  20. Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement. (United States)

    Kandalam, Saikrishna; Sindji, Laurence; Delcroix, Gaëtan J-R; Violet, Fabien; Garric, Xavier; André, Emilie M; Schiller, Paul C; Venier-Julienne, Marie-Claire; des Rieux, Anne; Guicheux, Jérôme; Montero-Menei, Claudia N


    Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device. It should direct the survival and/or neuronal differentiation of the grafted cells, to safely transplant them in the central nervous system, and enhance their tissue repair properties. A model protein was used to optimize the nanoprecipitation conditions of the neuroprotective brain-derived neurotrophic factor (BDNF). BDNF nanoprecipitate was encapsulated in fibronectin-coated (FN) PAMs and the in vitro release profile evaluated. It showed a prolonged, bi-phasic, release of bioactive BDNF, without burst effect. We demonstrated that PAMs and the Si-HPMC hydrogel increased the expression of neural/neuronal differentiation markers of MIAMI cells after 1week. Moreover, the 3D environment (PAMs or hydrogel) increased MIAMI cells secretion of growth factors (b-NGF, SCF, HGF, LIF, PlGF-1, SDF-1α, VEGF-A & D) and chemokines (MIP-1α & β, RANTES, IL-8). These results show that PAMs delivering BDNF combined with Si-HPMC hydrogel represent a useful novel local delivery tool in the context of neurological disorders. It not only provides neuroprotective BDNF but also bone marrow-derived stem cells that benefit from that environment by displaying neural commitment and an improved neuroprotective/reparative secretome. It provides preliminary evidence of a promising pro-angiogenic, neuroprotective and axonal growth-promoting device for the nervous system. Combinatorial tissue engineering strategies for the central nervous system are scarce. We developed and characterized a novel

  1. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Su [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jeon, Seong-Uk; Lee, Chan-Ju; Kim, Young-Eun; Bok, Seoyeon; Hong, Beom-Ju; Park, Dong-Young [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Ahn, G-One, E-mail: [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Kim, Hak Jae, E-mail: [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)


    in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.

  2. Separation of viable and non-viable tomato (Solanum lycopersicum L.) seeds using single seed near-infrared spectroscopy

    DEFF Research Database (Denmark)

    Shrestha, Santosh; Deleuran, Lise Christina; Gislum, René


    -viable tomato seeds of two cultivars using chemometrics. The data exploration were performed by principal component analysis (PCA). Subsequently, viable and non-viable seeds were classified by partial least squares-discriminant analysis (PLS-DA) and interval PLS-DA (iPLS-DA). The indication of clustering...... of viable and non-viable seeds were observed in the PCA of each cultivar and the pooled samples. However, the PCA did not exhibit a pattern of separation among the early, normal and late germinated tomato seeds. The NIR spectral regions of 1160–1170, 1383–1397, 1647–1666, 1860–1884 and 1915–1940 nm were...... identified as important for classification of viable and non-viable tomato seeds by iPLS-DA. The sensitivity i.e. ability to correctly identify the positive samples and specificity i.e. ability to reject the negative samples of the (iPLS-DA) model on identified spectral regions for prediction of viable...

  3. Massive Ethylene Glycol Ingestion Treated with Fomepizole Alone—A Viable Therapeutic Option

    National Research Council Canada - National Science Library

    Buchanan, Jennie A; Alhelail, Mohammed; Cetaruk, Edward W; Schaeffer, Tammi H; Palmer, Robert B; Kulig, Ken; Brent, Jeffrey


    Fomepizole is used to treat and prevent toxicity from ethylene glycol poisoning. Treatment with fomepizole without hemodialysis in massive ethylene glycol ingestion has been rarely reported in the literature...

  4. Determination of viable Salmonellae from potable and source water through PMA assisted qPCR. (United States)

    Singh, Gulshan; Vajpayee, Poornima; Bhatti, Saurabh; Ronnie, Nirmala; Shah, Nimish; McClure, Peter; Shanker, Rishi


    Resource constrained countries identified as endemic zones for pathogenicity of Salmonella bear an economic burden due to recurring expenditure on medical treatment. qPCR used for Salmonella detection could not discriminate between viable and nonviable cells. Propidium monoazide (PMA) that selectively penetrates nonviable cells to cross-link their DNA, was coupled with ttr gene specific qPCR for quantifying viable salmonellae in source/potable waters collected from a north Indian city. Source water (raw water for urban potable water supply) and urban potable water exhibited viable salmonellae in the range of 2.1×10(4)-2.6×10(6) and 2-7160CFU/100mL, respectively. Potable water at water works exhibited DNA from dead cells but no viable cells were detected. PMA assisted qPCR could specifically detect low numbers of live salmonellae in Source and potable waters. This strategy can be used in surveillance of urban potable water distribution networks to map contamination points for better microbial risk management. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Viable Cell Culture Banking for Biodiversity Characterization and Conservation. (United States)

    Ryder, Oliver A; Onuma, Manabu


    Because living cells can be saved for indefinite periods, unprecedented opportunities for characterizing, cataloging, and conserving biological diversity have emerged as advanced cellular and genetic technologies portend new options for preventing species extinction. Crucial to realizing the potential impacts of stem cells and assisted reproductive technologies on biodiversity conservation is the cryobanking of viable cell cultures from diverse species, especially those identified as vulnerable to extinction in the near future. The advent of in vitro cell culture and cryobanking is reviewed here in the context of biodiversity collections of viable cell cultures that represent the progress and limitations of current efforts. The prospects for incorporating collections of frozen viable cell cultures into efforts to characterize the genetic changes that have produced the diversity of species on Earth and contribute to new initiatives in conservation argue strongly for a global network of facilities for establishing and cryobanking collections of viable cells.

  6. The Medicinal Chemistry of Therapeutic Peptides: Recent Developments in Synthesis and Design Optimizations. (United States)

    Parthasarathy, Anutthaman; Anandamma, Sasikala K; Kalesh, Karunakaran A


    Peptide therapeutics have made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, high-resolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with select examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered 'undruggable'. Copyright© Bentham Science Publishers; For any queries, please email at

  7. PTP1B: a new therapeutic target for Rett syndrome. (United States)

    Tautz, Lutz


    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is characterized by successive loss of acquired cognitive, social, and motor skills and development of autistic behavior. RTT affects approximately 1 in 10,000 live female births and is the second most common cause of severe mental retardation in females, after Down syndrome. Currently, there is no cure or effective therapy for RTT. Approved treatment regimens are presently limited to supportive management of specific physical and mental disabilities. In this issue, Krishnan and colleagues reveal that the protein tyrosine phosphatase PTP1B is upregulated in patients with RTT and in murine models and provide strong evidence that targeting PTP1B has potential as a viable therapeutic strategy for the treatment of RTT.

  8. Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative

    NARCIS (Netherlands)

    Cuppens, T.; Annibali, D.; Coosemans, A.; Trovik, J.; Haar, N. Ter; Colas, E.; Garcia-Jimenez, A.; Vijver, K. van der; Kruitwagen, R.P.; Brinkhuis, M.; Zikan, M.; Dundr, P.; Huvila, J.; Carpen, O.; Haybaeck, J.; Moinfar, F.; Salvesen, H.B.; Stukan, M.; Mestdagh, C.; Zweemer, R.P.; Massuger, L.F.A.G.; Mallmann, M.R.; Wardelmann, E.; Mints, M.; Verbist, G.; Thomas, D; Gomme, E.; Hermans, E; Moerman, P.; Bosse, T.; Amant, F.


    Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive

  9. Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC)


    Jay Overholser; Kristen Henkins Ambegaokar; Siobhan M. Eze; Eduardo Sanabria-Figueroa; Rita Nahta; Tanios Bekaii-Saab; Pravin T.P. Kaumaya


    Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, pot...

  10. Therapeutic Nanodevices (United States)

    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.

  11. The transcorneal electrical stimulation as a novel therapeutic strategy against retinal and optic neuropathy: a review of experimental and clinical trials

    Directory of Open Access Journals (Sweden)

    Ye Tao


    Full Text Available Transcorneal electrical stimulation (TES is a novel therapeutic approach to activate the retina and related downstream structures. TES has multiple advantages over traditional treatments, such as being minimally invasive and readily applicable in a routine manner. Series of animal experiments have shown that TES protects the retinal neuron from traumatic or genetic induced degeneration. These laboratory evidences support its utilization in ophthalmological therapies against various retinal and optical diseases including retinitis pigmentosa (RP, traumatic optic neuropathy, anterior ischemic optic neuropathy (AION, and retinal artery occlusions (RAOs. Several pioneering explorations sought to clarify the functional mechanism underlying the neuroprotective effects of TES. It seems that the neuroprotective effects should not be attributed to a solitary pathway, on the contrary, multiple mechanisms might contribute collectively to maintain cellular homeostasis and promote cell survival in the retina. More precise evaluations via functional and morphological techniques would determine the exact mechanism underlying the remarkable neuroprotective effect of TES. Further studies to determine the optimal parameters and the long-term stability of TES are crucial to justify the clinical significance and to establish TES as a popularized therapeutic modality against retinal and optic neuropathy.

  12. microRNAs as a New Mechanism Regulating Adipose Tissue Inflammation in Obesity and as a Novel Therapeutic Strategy in the Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Qian Ge


    Full Text Available Obesity is associated closely with the metabolic syndrome (MS. It is well known that obesity-induced chronic inflammation plays a fundamental role in the pathogenesis of MS. White adipose tissue (AT is the primary site for the initiation and exacerbation of obesity-associated inflammation. Exploring the mechanisms of white AT inflammation and resetting the immunological balance in white AT could be crucial for the management of MS. Several prominent molecular mechanisms have been proposed to mediate inflammation in white AT, including hypoxia, endoplasmic reticulum stress, lipotoxicity, and metabolic endotoxemia. Recently, a growing body of evidence supports the role of miRNAs as a new important inflammatory mediator by regulating both the adaptive and innate immunity. This review will focus on the implication of miRNAs in white AT inflammation in obesity, and will also highlight the potential of miRNAs as targets for therapeutic intervention in MS as well as the challenges lying in miRNA-targeting therapeutics.

  13. microRNAs as a new mechanism regulating adipose tissue inflammation in obesity and as a novel therapeutic strategy in the metabolic syndrome. (United States)

    Ge, Qian; Brichard, Sonia; Yi, Xu; Li, QiFu


    Obesity is associated closely with the metabolic syndrome (MS). It is well known that obesity-induced chronic inflammation plays a fundamental role in the pathogenesis of MS. White adipose tissue (AT) is the primary site for the initiation and exacerbation of obesity-associated inflammation. Exploring the mechanisms of white AT inflammation and resetting the immunological balance in white AT could be crucial for the management of MS. Several prominent molecular mechanisms have been proposed to mediate inflammation in white AT, including hypoxia, endoplasmic reticulum stress, lipotoxicity, and metabolic endotoxemia. Recently, a growing body of evidence supports the role of miRNAs as a new important inflammatory mediator by regulating both the adaptive and innate immunity. This review will focus on the implication of miRNAs in white AT inflammation in obesity, and will also highlight the potential of miRNAs as targets for therapeutic intervention in MS as well as the challenges lying in miRNA-targeting therapeutics.

  14. The search for viable local government system in Nigeria: an ...

    African Journals Online (AJOL)

    The history of the Nigerian local government system has been one long episode of trails and errors aimed at achieving viable local government institution without much success. Local government in the country began its long series of reforms from the colonial period when the colonial government attempted to ...

  15. Detection of viable toxigenic Vibrio cholerae and virulent Shigella ...

    African Journals Online (AJOL)

    A rapid and sensitive assay was developed for the detection of low numbers of viable Vibrio cholerae and Shigella spp. cells in environmental and drinking water samples. Water samples were filtered, and the filters were enriched in a non-selective medium. The enrichment cultures were prepared for polymerase chain ...

  16. Comment: Towards a Viable Local Government Structure in Nigeria ...

    African Journals Online (AJOL)

    Local governments are principally established for development at the grassroots and they must be structured in a manner that makes them viable and capable of achieving this purpose. The objective of this comment is to appraise the current local government structure under the Nigerian constitutional framework with a view ...

  17. Cultivation and multiplication of viable axenic Trypanosoma vivax in ...

    African Journals Online (AJOL)



    Sep 1, 2009 ... Cultivation and multiplication of viable axenic. Trypanosoma vivax in vitro and in vivo. O. A. Idowu, A. B. Idowu, C. F. Mafiana and S. O. Sam-Wobo*. Parasitology Laboratory, Department of Biological Sciences, University of Agriculture, Abeokuta, Nigeria. Accepted 13 April, 2006. Trypanosoma vivax was ...

  18. Detection of viable toxigenic Vibrio cholerae and virulent Shigella ...

    African Journals Online (AJOL)



    Apr 2, 2003 ... A rapid and sensitive assay was developed for the detection of low numbers of viable Vibrio cholerae and Shigella spp. cells in environmental and drinking water samples. Water samples were filtered, and the filters were enriched in a non-selective medium. The enrichment cultures were prepared for ...

  19. High speed flow cytometric separation of viable cells (United States)

    Sasaki, Dennis T.; Van den Engh, Gerrit J.; Buckie, Anne-Marie


    Hematopoietic cell populations are separated to provide cell sets and subsets as viable cells with high purity and high yields, based on the number of original cells present in the mixture. High-speed flow cytometry is employed using light characteristics of the cells to separate the cells, where high flow speeds are used to reduce the sorting time.

  20. Examination of nanoformulated crosslinked polymers complexed with copper/zinc superoxide dismutase as a therapeutic strategy for angiotensin II-mediated hypertension (United States)

    Savalia, Krupa

    Excessive generation of superoxide (O2·-) has been extensively implicated as a signaling molecule in cardiovascular pathologies, including hypertension. As a major risk factor for myocardial infarction, stroke, and heart failure, the morbidity and mortality associated with hypertension is a worldwide epidemic. Although there are several standard therapies that effectively lower blood pressure, many hypertensive patients have uncontrolled blood pressure despite taking available medications. Thus, there is a necessity to develop new pharmacotherapies that target novel molecular effectors (e.g. O2·-) that have been implicated to be integral in the pathogenesis of hypertension. To overcome the failed therapeutic impact of currently available antioxidants in cardiovascular disease, we developed a nanomedicine-based delivery system for the O2 ·- scavenging enzyme, copper/zinc superoxide dismutase (CuZnSOD), in which CuZnSOD protein is electrostatically bound to poly-L-lysine (PLL 50)-polyethylene glycol (PEG) block co-polymer to form CuZnSOD nanozyme. Different formulations of CuZnSOD nanozyme are covalently stabilized by either reducible or non-reducible crosslinked bonds between the PLL50-PEG polymers. Herein, we tested the overall hypothesis that PLL50-PEG CuZnSOD nanozyme delivers active CuZnSOD protein to neurons and decreases blood pressure in a model of Angll-dependent hypertension. As determined by electron paramagnetic resonance (EPR) spectroscopy, nanozymes retain full SOD enzymatic activity. Furthermore, non-reducible crosslinked nanozyme delivers active CuZnSOD protein to central neurons in culture (CATH.a neurons) without inducing significant neuronal toxicity. In vivo studies conducted in Angll-mediated hypertensive adult male C57BL/6 mice demonstrate that the non-reducible crosslinked nanozyme significantly attenuates blood pressure when given directly into the brain and prevents the further increase in hypertension when intravenously (IV) administered

  1. Current progress and challenges in engineering viable artificial leaf for solar water splitting

    Directory of Open Access Journals (Sweden)

    Phuc D. Nguyen


    Full Text Available Large scale production of H2, a clean fuel, can be realized with just water and solar light energy by employing a viable energy conversion device called artificial leaf. In this tutorial review, we discuss on advances achieved recently and technical challenges remained toward the creation of such a leaf. Development of key components like catalysts for water electrolysis process and light harvester for harvesting solar energy as well as strategies being developed for assembling these components to create a complete artificial leaf will be highlighted.

  2. Antiviral cationic peptides as a strategy for innovation in global health therapeutics for dengue virus: high yield production of the biologically active recombinant plectasin peptide. (United States)

    Rothan, Hussin A; Mohamed, Zulqarnain; Suhaeb, Abdulrazzaq M; Rahman, Noorsaadah Abd; Yusof, Rohana


    Dengue virus infects millions of people worldwide, and there is no vaccine or anti-dengue therapeutic available. Antimicrobial peptides have been shown to possess effective antiviral activity against various viruses. One of the main limitations of developing these peptides as potent antiviral drugs is the high cost of production. In this study, high yield production of biologically active plectasin peptide was inexpensively achieved by producing tandem plectasin peptides as inclusion bodies in E. coli. Antiviral activity of the recombinant peptide towards dengue serotype-2 NS2B-NS3 protease (DENV2 NS2B-NS3pro) was assessed as a target to inhibit dengue virus replication in Vero cells. Single units of recombinant plectasin were collected after applying consecutive steps of refolding, cleaving by Factor Xa, and nickel column purification to obtain recombinant proteins of high purity. The maximal nontoxic dose (MNTD) of the recombinant peptide against Vero cells was 20 μM (100 μg/mL). The reaction velocity of DENV2 NS2B-NS3pro decreased significantly after increasing concentrations of recombinant plectasin were applied to the reaction mixture. Plectasin peptide noncompetitively inhibited DENV2 NS2B-NS3pro at Ki value of 5.03 ± 0.98 μM. The percentage of viral inhibition was more than 80% at the MNTD value of plectasin. In this study, biologically active recombinant plectasin which was able to inhibit dengue protease and viral replication in Vero cells was successfully produced in E. coli in a time- and cost- effective method. These findings are potentially important in the development of potent therapeutics against dengue infection.

  3. Molecular approaches for viable bacterial population and transcriptional analyses in a rodent model of dental caries. (United States)

    Klein, M I; Scott-Anne, K M; Gregoire, S; Rosalen, P L; Koo, H


    Culturing methods are the primary approach for microbiological analysis of plaque biofilms in rodent models of dental caries. In this study, we developed strategies for the isolation of DNA and RNA from plaque biofilms formed in vivo to analyse the viable bacterial population and gene expression. Plaque biofilm samples from rats were treated with propidium monoazide to isolate DNA from viable cells, and the purified DNA was used to quantify total bacteria and the Streptococcus mutans population via quantitative polymerase chain reaction (qPCR) and specific primers; the same samples were also analysed by counting colony-forming units (CFU). In parallel, RNA was isolated from plaque-biofilm samples (from the same animals) and used for transcriptional analyses via reverse transcription-qPCR. The viable populations of both S. mutans and total bacteria assessed by qPCR were positively correlated with the CFU data (P  0.8). However, the qPCR data showed higher bacterial cell counts, particularly for total bacteria (vs. CFU). Moreover, S. mutans proportion in the plaque biofilm determined by qPCR analysis showed strong correlation with incidence of smooth-surface caries (P = 0.0022, r = 0.71). The purified RNAs presented high RNA integrity numbers (> 7), which allowed measurement of the expression of genes that are critical for S. mutans virulence (e.g. gtfB and gtfC). Our data show that the viable microbial population and the gene expression can be analysed simultaneously, providing a global assessment of the infectious aspect of dental caries. Our approach could enhance the value of the current rodent model in further understanding the pathophysiology of this disease and facilitating the exploration of novel anti-caries therapies. © 2012 John Wiley & Sons A/S.

  4. A Translational Medicine perspective of the development of torcetrapib: Does the failure of torcetrapib development cast a shadow on future development of lipid modifying agents, HDL elevation strategies or CETP as a viable molecular target for atherosclerosis? A case study of the use of biomarkers and Translational Medicine in atherosclerosis drug discovery and development. (United States)

    Zhao, Lei; Jin, Weijun; Rader, Daniel; Packard, Chris; Feuerstein, Giora


    Although the relationship between HDL (high density lipoprotein) function and cardiovascular (CV) risk has been extensively explored, the premise that HDL elevation is linked to reduced CV risks and that high HDL cholesterol (HDL-C) might be a potential surrogate biomarker for reduced CV risk remains controversial. Substantial genetic, molecular, biochemical and preclinical evidence have raised the hope that HDL-C elevation via CETP inhibition might generate clinical benefits. However, four large-scale clinical trials with the CETP inhibitor torcetrapib failed to demonstrate benefits on CV clinical outcomes. Likewise, biomarkers that were supposed to predict vascular risk reduction provided disappointing results. The sad tale of torcetrapib development emphasizes the need for a paradigm shift from the conventional drug development mode to a biomarker-based Translational Medicine (TMed) strategy. Emergence of further CETP inhibitors encourage continued development of such compounds for cardiovascular risk management. However, there is a need to adopt biomarker-driven TMed strategies in target validation, target-compound interaction, pharmacodynamic activities, disease modification and patient selection to guide future drug development efforts. This commentary analyzes the issues surrounding the demise of torcetrapib and proposes a TMed-based road map towards successful development of new CETP inhibitors.

  5. Modeling the Normal and Neoplastic Cell Cycle with 'Realistic Boolean Genetic Networks': Their Application for Understanding Carcinogenesis and Assessing Therapeutic Strategies (United States)

    Szallasi, Zoltan; Liang, Shoudan


    In this paper we show how Boolean genetic networks could be used to address complex problems in cancer biology. First, we describe a general strategy to generate Boolean genetic networks that incorporate all relevant biochemical and physiological parameters and cover all of their regulatory interactions in a deterministic manner. Second, we introduce 'realistic Boolean genetic networks' that produce time series measurements very similar to those detected in actual biological systems. Third, we outline a series of essential questions related to cancer biology and cancer therapy that could be addressed by the use of 'realistic Boolean genetic network' modeling.

  6. Treatment of venous thromboembolism – effects of different therapeutic strategies on bleeding and recurrence rates and considerations for future anticoagulant management

    Directory of Open Access Journals (Sweden)

    Hass Bastian


    Full Text Available Abstract Effective treatment of venous thromboembolism (VTE strikes a balance between prevention of recurrence and bleeding complications. The current standard of care is heparin followed by a vitamin K antagonist such as warfarin. However, this option is not without its limitations, as the anticoagulant effect of warfarin is associated with high inter- and intra-patient variability and patients must be regularly monitored to ensure that anticoagulation is within the narrow target therapeutic range. Several novel oral anticoagulant agents are in the advanced stages of development for VTE treatment, some of which are given after an initial period of heparin treatment, in line with current practice, while others switch from high to low doses after the initial phase of treatment. In this review we assess the critical considerations for treating VTE in light of emerging clinical data for new oral agents and discuss the merits of novel treatment regimens for patients who have experienced an episode of deep vein thrombosis or pulmonary embolism.

  7. Removal of viable bacteria and endotoxins by Electro Deionization (EDI). (United States)

    Harada, Norimitsu; Otomo, Teruo; Watabe, Tomoichi; Ase, Tomonobu; Takemura, Takuto; Sato, Toshio


    Viable bacteria and endotoxins in water sometimes cause problems for human health. Endotoxins are major components of the outer cell wall of gram-negative bacteria (lipopolysaccharides). In medical procedures, especially haemodialysis (HD) and related therapies (haemodiafiltration (HDF), haemofiltration (HF)), endotoxins in the water for haemodialysis can permeate through the haemodialysis membrane and cause microinflammation or various haemodialysis-related illnesses. To decrease such a biological risk, RO and UF membranes are generally used. Also, hot water disinfection or the chemical disinfection is regularly executed to kill bacteria which produce endotoxins. However, simple treatment methods and equipment may be able to decrease the biological risk more efficiently. In our experiments, we confirmed that viable bacteria and endotoxins were removed by Electro Deionization (EDI) technology and also clarified the desorption mechanisms.

  8. Acupuntura un tratamiento viable para las adicciones en Colombia

    Directory of Open Access Journals (Sweden)

    Hernán López Seuscún


    Los tratamientos con auriculoterapia, como el protocolo NADA (National Acupuncture Detoxification Association, son los métodos más usados para las adicciones en el mundo, y aunque no se ha logrado evidenciar su efectividad, por su costo, facilidad y el poco riesgo de efectos adversos se hace viable en un país con pocos recursos económicos como Colombia.

  9. Academic Pediatric Dentistry is a Rewarding, Financially Viable Career Path. (United States)

    Townsend, Janice A; Chi, Donald L


    Newly graduated pediatric dentists have unprecedented levels of debt. High levels of student debt may be perceived as an obstacle to pursue an academic career. However, opportunities exist through faculty compensation models and loan repayment programs that make an academic career financially viable. The purpose of this paper is to outline the benefits of a career in academic dentistry and provide examples of young pediatric dentistry faculty members who have been able to manage student debt while pursuing meaningful and rewarding careers.

  10. Clinical Strategy for Optimal Traditional Chinese Medicine (TCM) Herbal Dose Selection in Disease Therapeutics: Expert Consensus on Classic TCM Herbal Formula Dose Conversion. (United States)

    Zha, Lin-Hua; He, Li-Sha; Lian, Feng-Mei; Zhen, Zhong; Ji, Hang-Yu; Xu, Li-Peng; Tong, Xiao-Lin


    The clinical therapeutics of traditional Chinese medicine (TCM) constitutes a complicated process which involves theory, diagnosis, and formula prescription with specific herbal dosage. Zhang Zhong-Jing's classic work, Treatise on Febrile and Miscellaneous Diseases, has been influencing TCM practice for almost 2000 years. However, during this extended period of time in Chinese history, the Chinese weight measurement system experienced noticeable changes. This change in the weight measurement system inevitably, and perhaps even negatively, affected TCM herbal dosage determination and treatment outcome. Thus, in modern society, a full understanding of the accuracy of herbal dose selection has a critical importance in the TCM daily practice of delivering the best treatment to the patients suffering from different illnesses. In the 973 Project of the Chinese National Basic Research Program, expert consensus on classic TCM formula dose conversion has been reached based on extensive literature review and discussion on the dose-effect relationship of classic TCM formulas. One "liang" in classic TCM formulas is equivalent to 13.8 g. However, based on many TCM basic and clinical studies of variable herbal formula prescriptions and herbal drug preparations, the rule of one liang equals 13.8 g should be adjusted according to different disease conditions. Recommended by the committee on TCM formula dose-effect relationship of the China Association of Chinese Medicine and the World Federation of Chinese Medicine Societies, the following expert consensus has been reached: (i) One liang converts to 6-9 g for the severely and critically ill patients. (ii) One liang converts to 3-6 g for the patients suffering from chronic diseases. (iii) One liang converts to 1-3 g in preventive medicine. The above conversions should be used as a future TCM practice guideline. Using this recommended guideline should enhance the effectiveness of daily TCM practice.

  11. Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer. (United States)

    Ma, Sisi; Sun, Jiazeng; Guo, Yabin; Zhang, Peng; Liu, Yanxin; Zheng, Dexian; Shi, Juan


    TNF-related apoptosis-inducing ligand (TRAIL) possesses the capacity to induce apoptosis in a wide variety of tumor cells without affecting most normal cells. However, it has now emerged that many primary cancer cells are resistant to TRAIL monotherapy. Overcoming the intrinsic or acquired TRAIL resistance is desirable for TRAIL-mediated cancer therapy. In this study, we found that the miR-221/222 cluster was up-regulated in TRAIL-resistant liver cancer cells. Specific inhibitors of miR-221 and/or miR-222, called sponge, TuD and miR-Zip were constructed, and their ability to overcome TRAIL resistance was compared. Among them, AAV-mediated gene therapy using co-expression of TRAIL with miR-221-Zip showed the most synergistic activity in the induction of apoptosis in vitro. In vivo treatment of nude mice bearing human TRAIL-resistant liver cancer xenografts with AAV-TRAIL-miR-221-Zip also led to growth inhibition. This sensitizing effect of miR-221-Zip was associated with increased expression of PTEN, the miR-221 target, as well as with decreasing levels of Survivin. Moreover, miR-221 expression was concomitant with promotion of Survivin expression and suppression of PTEN expression. TRAIL sensitivity of cancer cells isolated from liver cancer tissues or from patients was significantly correlated with miR-221 expression. And miR-221 blood expression levels in liver cancer patients were correlated with TRAIL sensitivity, thus it had the potential to be a predictor of TRAIL sensitivity in liver cancer. These data suggested the potential of combining AAV-TRAIL with miR-221-Zip as a therapeutic intervention for liver cancer.

  12. Control of Granule Cell Dispersion by Natural Materials Such as Eugenol and Naringin: A Potential Therapeutic Strategy Against Temporal Lobe Epilepsy. (United States)

    Kim, Sang Ryong


    The hippocampus is an important brain area where abnormal morphological characteristics are often observed in patients with temporal lobe epilepsy (TLE), typically showing the loss of the principal neurons in the CA1 and CA3 areas of the hippocampus. TLE is frequently associated with widening of the granule cell layer of the dentate gyrus (DG), termed granule cell dispersion (GCD), in the hippocampus, suggesting that the control of GCD with protection of hippocampal neurons may be useful for preventing and inhibiting epileptic seizures. We previously reported that eugenol (EUG), which is an essential component of medicinal herbs and has anticonvulsant activity, is beneficial for treating epilepsy through its ability to inhibit GCD via suppression of mammalian target of rapamycin complex 1 (mTORC1) activation in the hippocampal DG in a kainic acid (KA)-treated mouse model of epilepsy in vivo. In addition, we reported that naringin, a bioflavonoid in citrus fruits, could exert beneficial effects, such as antiautophagic stress and antineuroinflammation, in the KA mouse model of epilepsy, even though it was unclear whether naringin might also attenuate the seizure-induced morphological changes of GCD in the DG. Similar to the effects of EUG, we recently observed that naringin treatment significantly reduced KA-induced GCD and mTORC1 activation, which are both involved in epileptic seizures, in the hippocampus of mouse brain. Therefore, these observations suggest that the utilization of natural materials, which have beneficial properties such as inhibition of GCD formation and protection of hippocampal neurons, may be useful in developing a novel therapeutic agent against TLE.

  13. Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis. (United States)

    Iizuka, Masahiro; Etou, Takeshi; Kumagai, Makoto; Matsuoka, Atsushi; Numata, Yuka; Sagara, Shiho


    Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed "long-interval cytapheresis (LI-CAP)", in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (psteroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC.

  14. A rapid biosensor for viable B. anthracis spores. (United States)

    Baeumner, Antje J; Leonard, Barbara; McElwee, John; Montagna, Richard A


    A simple membrane-strip-based biosensor assay has been combined with a nucleic acid sequence-based amplification (NASBA) reaction for rapid (4 h) detection of a small number (ten) of viable B. anthracis spores. The biosensor is based on identification of a unique mRNA sequence from one of the anthrax toxin genes, the protective antigen ( pag), encoded on the toxin plasmid, pXO1, and thus provides high specificity toward B. anthracis. Previously, the anthrax toxins activator ( atxA) mRNA had been used in our laboratory for the development of a biosensor for the detection of a single B. anthracis spore within 12 h. Changing the target sequence to the pag mRNA provided the ability to shorten the overall assay time significantly. The vaccine strain of B. anthracis (Sterne strain) was used in all experiments. A 500-microL sample containing as few as ten spores was mixed with 500 microL growth medium and incubated for 30 min for spore germination and mRNA production. Thus, only spores that are viable were detected. Subsequently, RNA was extracted from lysed cells, selectively amplified using NASBA, and rapidly identified by the biosensor. While the biosensor assay requires only 15 min assay time, the overall process takes 4 h for detection of ten viable B. anthracis spores, and is shortened significantly if more spores are present. The biosensor is based on an oligonucleotide sandwich-hybridization assay format. It uses a membrane flow-through system with an immobilized DNA probe that hybridizes with the target sequence. Signal amplification is provided when the target sequence hybridizes to a second DNA probe that has been coupled to liposomes encapsulating the dye sulforhodamine B. The amount of liposomes captured in the detection zone can be read visually or quantified with a hand-held reflectometer. The biosensor can detect as little as 1 fmol target mRNA (1 nmol L(-1)). Specificity analysis revealed no cross-reactivity with 11 organisms tested, among them closely

  15. Therapeutic Vaccines for Chronic Infections (United States)

    Autran, Brigitte; Carcelain, Guislaine; Combadiere, Béhazine; Debre, Patrice


    Therapeutic vaccines aim to prevent severe complications of a chronic infection by reinforcing host defenses when some immune control, albeit insufficient, can already be demonstrated and when a conventional antimicrobial therapy either is not available or has limited efficacy. We focus on the rationale and challenges behind this still controversial strategy and provide examples from three major chronic infectious diseases-human immunodeficiency virus, hepatitis B virus, and human papillomavirus-for which the efficacy of therapeutic vaccines is currently being evaluated.

  16. Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer

    Directory of Open Access Journals (Sweden)

    Fávaro Wagner J


    . The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases.

  17. Significantly enhanced biomass production of a novel bio-therapeutic strain Lactobacillus plantarum (AS-14) by developing low cost media cultivation strategy. (United States)

    Manzoor, Asma; Qazi, Javed Iqbal; Haq, Ikram Ul; Mukhtar, Hamid; Rasool, Akhtar


    Probiotic bacteria are becoming an important tool for improving human health, controlling diseases and enhancing immune responses. The availability of a cost effective cultivation conditions has profound effect on the efficiency and role of probiotic bacteria. Therefore the current study was conducted with an objective to develop a low cost growth medium for enhancing the biomass production of a bio-therapeutic bacterial strain Lactobacillus plantarum AS-14. In this work the isolation of Lactobacillus plantarum AS-14 bacterial strain was carried out from brinjal using cheese whey as a main carbon source. Moreover, the effect of four other nutritional factors besides cheese whey was investigated on the enhanced cell mass production by using response surface methodology (RSM). The best culture medium contained 60 g/l cheese whey, 15 g/l glucose and 15 g/l corn steep liquor in addition to other minor ingredients and it resulted in maximum dry cell mass (15.41 g/l). The second-order polynomial regression model determined that the maximum cell mass production (16.02 g/l) would be obtained at temperature 40°C and pH 6.2. Comparative studies showed that cultivation using cheese whey and corn steep liquor with other components of the selected medium generated higher biomass with lower cost than that of De Man, Rogosa and Sharpe (MRS) medium under similar cultivation conditions (pH 6.2 and temperature 40°C). It is evident that the cell biomass of L. Plantarum AS-14 was enhanced by low cost cultivation conditions. Moreover, corn steep liquor and ammonium bisulphate were perceived as low-cost nitrogen sources in combination with other components to substitute yeast extract. Of all these factors, cheese whey, corn steep liquor, yeast extract and two operating conditions (temperature and pH) were found to be the most significant parameters. Thus the cost effective medium developed in this research might be used for large-scale commercial application where economics is quite

  18. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Alberto Malerba


    Full Text Available The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD. In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO. Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.

  19. Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital. (United States)

    Hotham, James E; Simpson, Patrick J D; Brooman-White, Rosalie S; Basu, Amlan; Ross, Callum C; Humphreys, Sharon A; Larkin, Fintan; Gupta, Nitin; Das, Mrigendra


    Clozapine is used in the management of treatment-resistant schizophrenia and is effective in reducing aggression; however a subgroup of patients is poorly responsive. For violent patients in this group, there is limited literature on the use of strategies to augment clozapine with other agents. Here we present a case series of 6 schizophrenia patients, within a high-security hospital, who have a history of serious violence and who were treated with clozapine augmented with amisulpride. We reviewed case notes and health records for evidence of violence/aggression and positive factors such as engagement in activities, and Clinical Global Impression (CGI) scores were formulated. We also examined metabolic parameters before and after augmentation. All 6 of the patients showed clinical improvement in symptoms and a reduction in their risk of violence to others. Five patients had a reduction in number of violent/aggressive incidents, and all patients showed improvement in engagement in occupational, vocational, and/or psychological work. Metabolic parameters were largely unchanged except for 1 patient whose Body Mass Index (BMI) increased. Five patients reported side effects as unchanged or improved. These schizophrenia patients with a history of violence showed clinical improvement and reduced aggression and violence with amisulpride augmentation of clozapine. To our knowledge, this is the first report of an antiaggressive benefit of this combination in forensic psychiatric patients. Further studies are warranted to establish the efficacy and anti-aggressive effects of amisulpride augmentation of clozapine.

  20. Liquid biopsy in cancer patients: advances in capturing viable CTCs for functional studies using the EPISPOT assay. (United States)

    Alix-Panabières, Catherine; Pantel, Klaus


    Circulating tumor cells (CTCs) in the blood of cancer patients have received increasing attention as new diagnostic tool enabling 'liquid biopsies'. In contrast to the wealth of descriptive studies demonstrating the clinical relevance of CTCs as biomarkers, the extremely low concentration of CTCs in the peripheral blood of most cancer patients challenges further functional studies. This article discusses the current possibilities to enrich and, in particular, detect viable CTCs with emphasis on the EPithelial ImmunoSPOT technology. This functional assay detects viable CTCs at the single-cell level and has been used on hundreds of patients with different tumor types including epithelial tumors (breast, prostate and colon cancer) and melanomas. Moreover, the article summarizes recent advances in the in vitro and in vivo expansion of CTCs from cancer patients. These functional analyses will contribute to identifying the biological properties of metastatic cells and reveal new therapeutic targets against disseminating cancer cells.

  1. Modulation of the endocannabinoid system in viable and non-viable first trimester pregnancies by pregnancy-related hormones

    Directory of Open Access Journals (Sweden)

    Taylor Anthony H


    Full Text Available Abstract Background In early pregnancy, increased plasma levels of the endocannabinoid anandamide (AEA are associated with miscarriage through mechanisms that might affect the developing placenta or maternal decidua. Methods In this study, we compare AEA levels in failed and viable pregnancies with the levels of the trophoblastic hormones (beta-human chorionic gonadotrophin (beta-hCG, progesterone (P4 and (pregnancy-associated placental protein-A (PAPP-A essential for early pregnancy success and relate that to the expression of the cannabinoid receptors and enzymes that modulate AEA levels. Results The median plasma AEA level in non-viable pregnancies (1.48 nM; n = 20 was higher than in viable pregnancies (1.21 nM; n = 25; P = 0.013, as were progesterone and beta-hCG levels (41.0 vs 51.5 ng/mL; P = 0.052 for P4 and 28,650 vs 6,560 mIU/L; P = 0.144 for beta-hCG, respectively, but were not statistically significant. Serum PAPP-A levels in the viable group were approximately 6.8 times lower than those in the non-viable group (1.82 vs 12.25 mg/L; P = 0.071, but again these differences were statistically insignificant. In the spontaneous miscarriage group, significant correlations between P4 and beta-hCG, P4 and PAPP-A and AEA and PAPP-A levels were observed. Simultaneously, immunohistochemical distributions of the two main cannabinoid receptors and the AEA-modifying enzymes, fatty acid amide hydrolase (FAAH and N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, changed within both the decidua and trophoblast. Conclusions The association of higher AEA levels with early pregnancy failure and with beta-hCG and PAPP-A, but not with progesterone concentrations suggest that plasma AEA levels and pregnancy failure are linked via a mechanism that may involve trophoblastic beta-hCG, and PAPP-A, but not, progesterone production. Although the trophoblast, decidua and embryo contain receptors for AEA, the main AEA target in early pregnancy failure

  2. Inkjet printing of viable human dental follicle stem cells

    Directory of Open Access Journals (Sweden)

    Mau Robert


    Full Text Available Inkjet printing technology has the potential to be used for seeding of viable cells for tissue engineering approaches. For this reason, a piezoelectrically actuated, drop-on-demand inkjet printing system was applied to deliver viable human dental follicle stem cells (hDFSC of sizes of about 15 μm up to 20 μm in diameter. The purpose of these investigations was to verify the stability of the printing process and to evaluate cell viability post printing. Using a Nanoplotter 2.1 (Gesim, Germany equipped with the piezoelectric printhead NanoTip HV (Gesim, Germany, a concentration of 6.6 ×106 cells ml−1 in DMEM with 10% fetal calf serum (FCS could be dispensed. The piezoelectric printhead has a nominal droplet volume of ~ 400 pl and was set to a voltage of 75 V and a pulse of 50 μs while dosing 50 000 droplets over a time of 100 seconds. The volume and trajectory of the droplet were checked by a stroboscope test right before and after the printing process. It was found that the droplet volume decreases significantly by 35% during printing process, while the trajectory of the droplets remains stable with only an insignificant number of degrees deviation from the vertical line. It is highly probable that some cell sedimentations or agglomerations affect the printing performance. The cell viability post printing was assessed by using the Trypan Blue dye exclusion test. The printing process was found to have no significant influence on cell survival. In conclusion, drop-on-demand inkjet printing can be a potent tool for the seeding of viable cells.

  3. Molar Pregnancy with a Co-Existing Viable Fetus

    Directory of Open Access Journals (Sweden)

    Ruya Deveer


    Full Text Available     The aim of this study was to report the clinical features, management, and outcome of a case of molar pregnancy with a coexisting viable fetus and to review the literature. In this article, we report a case of pregnancy with diffuse placental molar change and a normal fetus which presented with hyperemesis gravidarum and hyperthyroidism. Genetic amniocentesis showed normal fetal karyotype. A healthy full-term live male infant was delivered by cesarean section. In molar pregnancies with a normal karyotype fetus, with intensive maternal follow-up, continuation of pregnancy can be suggested.

  4. Mobilization of Viable Tumor Cells Into the Circulation During Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Olga A. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (Australia); Anderson, Robin L. [The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (Australia); Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Russell, Prudence A. [Department of Anatomical Pathology, St. Vincent Hospital, Fitzroy, VIC (Australia); Ashley Cox, R. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Ivashkevich, Alesia [Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Laboratory of DNA Repair and Genomics, Centre for Innate Immunity and Infectious Disease, Monash Institute for Medical Research, Monash University, Clayton, VIC (Australia); Swierczak, Agnieszka; Doherty, Judy P. [Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Jacobs, Daphne H.M. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Smith, Jai [Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Siva, Shankar; Daly, Patricia E. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); Ball, David L. [Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia); The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (Australia); and others


    Purpose: To determine whether radiation therapy (RT) could mobilize viable tumor cells into the circulation of non-small cell lung cancer (NSCLC) patients. Methods and Materials: We enumerated circulating tumor cells (CTCs) by fluorescence microscopy of blood samples immunostained with conventional CTC markers. We measured their DNA damage levels using γ-H2AX, a biomarker for radiation-induced DNA double-strand breaks, either by fluorescence-activated cell sorting or by immunofluorescence microscopy. Results: Twenty-seven RT-treated NSCLC patients had blood samples analyzed by 1 or more methods. We identified increased CTC numbers after commencement of RT in 7 of 9 patients treated with palliative RT, and in 4 of 8 patients treated with curative-intent RT. Circulating tumor cells were also identified, singly and in clumps in large numbers, during RT by cytopathologic examination (in all 5 cases studied). Elevated γ-H2AX signal in post-RT blood samples signified the presence of CTCs derived from irradiated tumors. Blood taken after the commencement of RT contained tumor cells that proliferated extensively in vitro (in all 6 cases studied). Circulating tumor cells formed γ-H2AX foci in response to ex vivo irradiation, providing further evidence of their viability. Conclusions: Our findings provide a rationale for the development of strategies to reduce the concentration of viable CTCs by modulating RT fractionation or by coadministering systemic therapies.

  5. Therapeutic misadventure. (United States)

    Langford, N J


    Therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Within the National Health Service there were over 86,000 reported adverse incidents in 2007. In the USA medication errors have been rated as the fourth highest cause of death. Unfortunately one of the greatest contributors to iatrogenic injury is human error. The potential types of misadventure are infinite. Medication errors are a major part of this, being responsible for over 70% of cases that cause serious harm. However, many medication errors caused by slips, lapses, technical errors and mistakes are preventable; intentional violations of safe operating procedures are not. While medication errors were tolerated by society in the past, the readiness to institute criminal proceedings against health-care professionals has increased greatly in the UK over the last decade. The medication process consists of writing prescriptions, dispensing the product, administering it and monitoring its effects. Prescription errors arise owing to incomplete information, lack of appropriate labelling, environmental factors and human blunders. Even with a perfect prescription the right medication must be dispensed and appropriately labelled. Dispensing errors are not uncommon and may be compounded by non-clinical considerations. Administration of a drug by injection is one of the most dangerous aspects of the medication process, especially in inexperienced hands. The final component of medication supply is monitoring the effect of the medication. With short courses of medication such monitoring is easy, but with long-term medication, particularly with potent drugs where the margin between efficacy and toxicity is small, active procedures may be required to ensure toxicity does not ensue. Despite the endeavour of health-care professions to stick to the rule of 'first, do no harm', in reality this is difficult to achieve all of the time. When

  6. Effective and viable mind-body stress reduction in the workplace: a randomized controlled trial. (United States)

    Wolever, Ruth Q; Bobinet, Kyra J; McCabe, Kelley; Mackenzie, Elizabeth R; Fekete, Erin; Kusnick, Catherine A; Baime, Michael


    Highly stressed employees are subject to greater health risks, increased cost, and productivity losses than those with normal stress levels. To address this issue in an evidence-based manner, worksite stress management programs must be able to engage individuals as well as capture data on stress, health indices, work productivity, and health care costs. In this randomized controlled pilot, our primary objective was to evaluate the viability and proof of concept for two mind-body workplace stress reduction programs (one therapeutic yoga-based and the other mindfulness-based), in order to set the stage for larger cost-effectiveness trials. A second objective was to evaluate 2 delivery venues of the mindfulness-based intervention (online vs. in-person). Intention-to-treat principles and 2 (pre and post) × 3 (group) repeated-measures analysis of covariance procedures examined group differences over time on perceived stress and secondary measures to clarify which variables to include in future studies: sleep quality, mood, pain levels, work productivity, mindfulness, blood pressure, breathing rate, and heart rate variability (a measure of autonomic balance). Two hundred and thirty-nine employee volunteers were randomized into a therapeutic yoga worksite stress reduction program, 1 of 2 mindfulness-based programs, or a control group that participated only in assessment. Compared with the control group, the mind-body interventions showed significantly greater improvements on perceived stress, sleep quality, and the heart rhythm coherence ratio of heart rate variability. The two delivery venues for the mindfulness program produced basically equivalent results. Both the mindfulness-based and therapeutic yoga programs may provide viable and effective interventions to target high stress levels, sleep quality, and autonomic balance in employees. PsycINFO Database Record (c) 2012 APA, all rights reserved.

  7. Dissolvable tattoo sensors: from science fiction to a viable technology (United States)

    Cheng, Huanyu; Yi, Ning


    Early surrealistic painting and science fiction movies have envisioned dissolvable tattoo electronic devices. In this paper, we will review the recent advances that transform that vision into a viable technology, with extended capabilities even beyond the early vision. Specifically, we focus on the discussion of a stretchable design for tattoo sensors and degradable materials for dissolvable sensors, in the form of inorganic devices with a performance comparable to modern electronics. Integration of these two technologies as well as the future developments of bio-integrated devices is also discussed. Many of the appealing ideas behind developments of these devices are drawn from nature and especially biological systems. Thus, bio-inspiration is believed to continue playing a key role in future devices for bio-integration and beyond.

  8. A viable logarithmic f(R) model for inflation

    Energy Technology Data Exchange (ETDEWEB)

    Amin, M.; Khalil, S. [Center for Fundamental Physics, Zewail City of Science and Technology,6 October City, Giza (Egypt); Salah, M. [Center for Fundamental Physics, Zewail City of Science and Technology,6 October City, Giza (Egypt); Department of Mathematics, Faculty of Science, Cairo University,Giza (Egypt)


    Inflation in the framework of f(R) modified gravity is revisited. We study the conditions that f(R) should satisfy in order to lead to a viable inflationary model in the original form and in the Einstein frame. Based on these criteria we propose a new logarithmic model as a potential candidate for f(R) theories aiming to describe inflation consistent with observations from Planck satellite (2015). The model predicts scalar spectral index 0.9615

  9. Simultaneous pyometra and viable puppies’ gestation in a bitch

    Directory of Open Access Journals (Sweden)

    A. Risso


    Full Text Available Here we describe a case of pyometra coexisting with gestation in a 4.5 year-old miniature short-haired Dachshund. The dog exhibited depression, vaginal discharge, polydipsia and dehydration. Ultrasound examination revealed the presence of low to moderate anechoic fluid collection in the left uterine horn. Blood analysis revealed mild neutrophilia with a left shift. Based on these findings a presumptive diagnosis of pyometra was made and the bitch was treated using amoxicillin-clavulanate with dopaminergic agonist (cabergoline. A second ultrasound scan revealed the presence of two gestational vesicles in the right uterine horn that were successfully carried to term. Unusually, while pyometra persisted in the left uterine horn, two viable puppies were delivered by caesarean section from the right uterine horn.

  10. Avian Diagnostic and Therapeutic Antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Bradley, David Sherman [UND SMHS


    A number of infectious agents have the potential of causing significant clinical symptomology and even death, but dispite this, the number of incidence remain below the level that supports producing a vaccine. Therapeutic antibodies provide a viable treatment option for many of these diseases. We proposed that antibodies derived from West Nile Virus (WNV) immunized geese would be able to treat WNV infection in mammals and potential humans. We demonstrated that WNV specific goose antibodies are indeed successful in treating WNV infection both prophylactically and therapeutically in a golden hamster model. We demonstrated that the goose derived antibodies are non-reactogenic, i.e. do not cause an inflammatory response with multiple exposures in mammals. We also developed both a specific pathogen free facility to house the geese during the antibody production phase and a patent-pending purification process to purify the antibodies to greater than 99% purity. Therefore, the success of these study will allow a cost effective rapidly producible therapeutic toward clinical testing with the necessary infrastructure and processes developed and in place.

  11. Profiling Total Viable Bacteria in a Hemodialysis Water Treatment System. (United States)

    Chen, Lihua; Zhu, Xuan; Zhang, Menglu; Wang, Yuxin; Lv, Tianyu; Zhang, Shenghua; Yu, Xin


    Culture-dependent methods, such as heterotrophic plate counting (HPC), are usually applied to evaluate the bacteriological quality of hemodialysis water. However, these methods cannot detect the uncultured or viable but non-culturable (VBNC) bacteria, both of which may be quantitatively predominant throughout the hemodialysis water treatment system. Therefore, propidium monoazide (PMA)-qPCR associated with HPC was used together to profile the distribution of the total viable bacteria in such a system. Moreover, high-throughput sequencing of 16S rRNA gene amplicons was utilized to analyze the microbial community structure and diversity. The HPC results indicated that the total bacterial counts conformed to the standards, yet the bacteria amounts were abruptly enhanced after carbon filter treatment. Nevertheless, the bacterial counts detected by PMA-qPCR, with the highest levels of 2.14 × 10 7 copies/100 ml in softener water, were much higher than the corresponding HPC results, which demonstrated the occurrence of numerous uncultured or VBNC bacteria among the entire system before reverse osmosis (RO). In addition, the microbial community structure was very different and the diversity was enhanced after the carbon filter. Although the diversity was minimized after RO treatment, pathogens such as Escherichia could still be detected in the RO effluent. In general, both the amounts of bacteria and the complexity of microbial community in the hemodialysis water treatment system revealed by molecular approaches were much higher than by traditional method. These results suggested the higher health risk potential for hemodialysis patients from the up-to-standard water. The treatment process could also be optimized, based on the results of this study.

  12. Psicoterapia psicodinâmica breve: estratégia terapêutica e mudança no padrão de relacionamento conflituoso Brief psychodynamic therapy: therapeutic strategy and change in the conflictual relationship pattern

    Directory of Open Access Journals (Sweden)

    Elisa Medici Pizão Yoshida


    Full Text Available Examinaram-se possíveis relações entre mudanças no padrão de relacionamento conflituoso de paciente, de 48 anos, submetida a psicoterapia breve psicodinâmica, e a estratégia terapêutica adotada pela terapeuta. Foi também avaliada a "magnitude" da mudança em sintomas psicopatológicos ao final do processo e entrevistas de acompanhamento (3 e 6 meses, com instrumentos de autorrelato: Inventário Beck de Depressão (BDI, Escala de Alexitimia de Toronto (TAS, Escala de Avaliação de Sintomas-40 (EAS-40, Escala Fatorial de Ajustamento Emocional/ Neuroticismo (EFN. A avaliação do padrão relacional baseou-se no Tema Central de Relacionamento Conflituoso - CCRT e a estratégia terapêutica, no grau de "expressividade vs. apoio" das intervenções. Os resultados mostraram melhoras clinicamente significantes nos sintomas e mudança parcial do padrão central de relacionamento. As intervenções terapêuticas foram mais expressivas no início e mais suportivas à medida que mudanças positivas eram observadas. É necessária cautela na generalização dos resultados. A abordagem metodológica permite comparar diferentes indivíduos.This study aimed to evaluate possible association between change in the conflictual relationship pattern of a 48 year-old, woman, assisted on brief psychodynamic therapy, and the therapist's therapeutic strategy. Yet it was evaluated the magnitude of change of psychopathological symptoms at the end and follow-up interviews (3 and 6 months according to self-report measures: Beck Depression Inventory (BDI, Toronto Alexithymia Scale (TAS, Symptom Assessment Scale40 (EAS-40, Emotional Adjustment/ Neuroticism Factorial Scale (EFN. The relationship pattern was assessed based on the Core Conflictual Relationship Theme - CCRT method and the therapeutic strategy according to the degree of expressiveness vs supportiveness of the therapist's interventions. Results pointed out to clinically significant improvement on symptoms


    Directory of Open Access Journals (Sweden)

    Andreea MANOLIU


    Full Text Available The Romanian tourism industry has an increasing importance over the economic growth and it currently represents one of the best opportunities to create revenues and workplaces for the country. However, the competitive advantage no longer relies on the natural potential; it is gradually replaced by the anthropical one, represented mainly by science and the information and communication technology (ICT. Therefore, an important topic in relation to changing and renewing the tourism industry regards the use of the information and communication technology. What seems to be necessary for tourism is an intense familiarization with the consumers’ needs and preferences, as well as a quick and fictional approach of the way in which these needs could be met in a more efficient, more attractive way. The use of ICT among the specialized economy agents becomes a strategic priority for the Romanian market, its extremely beneficial effects being well-known for the performance of the sector.

  14. Neurocysticercosis: Diagnostic problems & current therapeutic strategies. (United States)

    Rajshekhar, Vedantam


    Neurocysticercosis (NCC) is the most common single cause of seizures/epilepsy in India and several other endemic countries throughout the world. It is also the most common parasitic disease of the brain caused by the cestode Taenia solium or pork tapeworm. The diagnosis of NCC and the tapeworm carrier (taeniasis) can be relatively inaccessible and expensive for most of the patients. In spite of the introduction of several new immunological tests, neuroimaging remains the main diagnostic test for NCC. The treatment of NCC is also mired in controversy although, there is emerging evidence that albendazole (a cysticidal drug) may be beneficial for patients by reducing the number of seizures and hastening the resolution of live cysts. Currently, there are several diagnostic and management issues which remain unresolved. This review will highlight some of these issues.

  15. Therapeutic strategies in symptomatic portal biliopathy

    National Research Council Canada - National Science Library

    Vibert, Eric; Azoulay, Daniel; Aloia, Thomas; Pascal, Gérard; Veilhan, Luc-Antoine; Adam, René; Samuel, Didier; Castaing, Denis


    Chronic portal obstruction can lead to formation of portal cavernoma (PC). Half of all patients with PC will develop cholestasis, termed portal biliopathy, and some will progress to symptomatic biliary obstruction...

  16. Optimization of Therapeutic Strategies for Organophosphate Poisoning (United States)


    an anticonvulsant, and diazepam is the preferred medicine (Cannard, 2006:92). Diazepam reduces the severity of seizures and epilepsy, which are...addition, medical doctors may administer 5 mg of diazepam intravenously for patients with convulsions (CDC, 2008:19). The New York Department of Health...Initial concentration, synthesis constants, and degradation constants for the esterases were obtained from literature data, experiment, and model

  17. New therapeutic strategies for prostate cancer


    Zalazar, Florencia


    El cáncer de próstata (PCa) es la segunda causa de muerte por cáncer en los hombres en la población argentina. El instituto Nacional del Cáncer (USA) describe diferentes tratamientos para los pacientes con PCa: cirugía, radiación y hormono-terapia. Para los pacientes con PCa avanzado, el tratamiento más común es el docetaxel, sin embargo esta terapia no extiende significativamente la sobrevida de los pacientes. Por lo tanto, es crítico el desarrollo de nuevos agentes y combinaciones para el t...

  18. New therapeutic strategies for postoperative ileus

    NARCIS (Netherlands)

    van Bree, Sjoerd H. W.; Nemethova, Andrea; Cailotto, Cathy; Gomez-Pinilla, Pedro J.; Matteoli, Gianluca; Boeckxstaens, Guy E.


    Patients undergoing an abdominal surgical procedure develop a transient episode of impaired gastrointestinal motility or postoperative ileus. Importantly, postoperative ileus is a major determinant of recovery after intestinal surgery and leads to increased morbidity and prolonged hospitalization,

  19. Presacral Ganglioneuroma: Diagnostic Considerations and Therapeutic Strategy

    Directory of Open Access Journals (Sweden)

    Konstantinos Vardas


    Full Text Available Presacral ganglioneuroma is an extremely rare tumor of neural crest origin. To the best of our knowledge, less than 20 cases have been reported previously. The present study reports on a presacral ganglioneuroma, 10.5 × 8 × 4 cm in size, that was found incidentally in a 35-year-old man with prior history of diverticulitis. He was admitted to our hospital due to lower left abdominal pain. Abdominal computed tomography and magnetic resonance imaging confirmed the extension of the lesion from the S2 level to the coccyx. The mass had low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images with no intraspinal or rectal extension. T2-weighted images demonstrated a compartmentalized solid tumor with cystic components. Complete tumor resection with free surgical margins was achieved using an abdominal approach. The patient remains asymptomatic 2 years after surgery. We emphasize on clinical features, radiologic appearance and surgical treatment of this rare entity. The clinical and pathologic features of previously reported studies are also briefly reviewed.

  20. Therapeutic Strategies Targeting Cariogenic Biofilm Microenvironment

    National Research Council Canada - National Science Library

    Liu, Y; Ren, Z; Hwang, G; Koo, H


    Cariogenic biofilms are highly structured microbial communities embedded in an extracellular matrix, a multifunctional scaffold that is essential for the existence of the biofilm lifestyle and full...

  1. Therapeutic Adherence in Smoking Therapy

    Directory of Open Access Journals (Sweden)

    María Salvador Manzano


    Full Text Available Therapeutic adherence is a complex and multidimensional concept. The percentage of adherence to treatments involving a change in lifestyle, such as quitting smoking, is lower than in other disorders, a fact which has relevant clinical, psychological and economic consequences. This paper aims to review the associated factors with adherence to therapy in smoking treatment. Strategies to enhance therapeutic adherence involve the adequate choice of treatment, to know the smoker´s characteristics, breaking down organizational barriers in health system and the training of health professionals in communication skills with patients.

  2. The elusive minimum viable population size for white sturgeon

    Energy Technology Data Exchange (ETDEWEB)

    Jager, Yetta [ORNL; Lepla, Ken B. [Idaho Power Company; Van Winkle, Webb [Van Windle Environmental Consulting; James, Mr Brad [Washington Department of Fish and Wildlife; McAdam, Dr Steve [University of British Columbia, Vancouver


    Biological conservation of sturgeon populations is a concern for many species. Those responsible for managing the white sturgeon (Acipenser transmontanus) and similar species are interested in identifying extinction thresholds to avoid. Two thresholds that exist in theory are the minimum viable population size (MVP) and minimum amount of suitable habitat. In this paper, we present both model and empirical estimates of these thresholds. We modified a population viability analysis (PVA) model for white sturgeon to include two new Allee mechanisms. Despite this, PVA-based MVP estimates were unrealistically low compared with empirical estimates unless opportunities for spawning were assumed to be less frequent. PVA results revealed a trade-off between MVP and habitat thresholds; smaller populations persisted in longer river segments and vice versa. Our empirical analyses suggested (1) a MVP range based on population trends from 1,194 to 27,700 individuals, and (2) a MVP estimate of 4,000 individuals based on recruitment. Long-term historical population surveys are needed for more populations to pinpoint an MVP based on trends, whereas the available data were sufficient to estimate MVP based on recruitment. Beyond the MVP, we developed a hierarchical model for population status based on empirical data. Metapopulation support was the most important predictor of population health, followed by the length of free-flowing habitat, with habitat thresholds at 26 and 150 km. Together, these results suggest that habitat and connectivity are important determinants of population status that likely influence the site-specific MVP thresholds.

  3. Towards a viable and just global nursing ethics. (United States)

    Crigger, Nancy J


    Globalization, an outgrowth of technology, while informing us about people throughout the world, also raises our awareness of the extreme economic and social disparities that exist among nations. As part of a global discipline, nurses are vitally interested in reducing and eliminating disparities so that better health is achieved for all people. Recent literature in nursing encourages our discipline to engage more actively with social justice issues. Justice in health care is a major commitment of nursing; thus questions in the larger sphere of globalization, justice and ethics, are our discipline's questions also. Global justice, or fairness, is not an issue for some groups or institutions, but a deeper human rights issue that is a responsibility for everyone. What can we do to help reduce or eliminate the social and economic disparities that are so evident? What kind of ethical milieu is needed to address the threat that globalization imposes on justice and fairness? This article enriches the conceptualization of globalization by investigating recent work by Schweiker and Twiss. In addition, I discuss five qualities or characteristics that will facilitate the development of a viable and just global ethic. A global ethic guides all people in their response to human rights and poverty. Technology and business, two major forces in globalization that are generally considered beneficial, are critiqued as barriers to social justice and the common good.

  4. Keeping checkpoint/restart viable for exascale systems.

    Energy Technology Data Exchange (ETDEWEB)

    Riesen, Rolf E.; Bridges, Patrick G. (IBM Research, Ireland, Mulhuddart, Dublin); Stearley, Jon R.; Laros, James H., III; Oldfield, Ron A.; Arnold, Dorian (University of New Mexico, Albuquerque, NM); Pedretti, Kevin Thomas Tauke; Ferreira, Kurt Brian; Brightwell, Ronald Brian


    Next-generation exascale systems, those capable of performing a quintillion (10{sup 18}) operations per second, are expected to be delivered in the next 8-10 years. These systems, which will be 1,000 times faster than current systems, will be of unprecedented scale. As these systems continue to grow in size, faults will become increasingly common, even over the course of small calculations. Therefore, issues such as fault tolerance and reliability will limit application scalability. Current techniques to ensure progress across faults like checkpoint/restart, the dominant fault tolerance mechanism for the last 25 years, are increasingly problematic at the scales of future systems due to their excessive overheads. In this work, we evaluate a number of techniques to decrease the overhead of checkpoint/restart and keep this method viable for future exascale systems. More specifically, this work evaluates state-machine replication to dramatically increase the checkpoint interval (the time between successive checkpoint) and hash-based, probabilistic incremental checkpointing using graphics processing units to decrease the checkpoint commit time (the time to save one checkpoint). Using a combination of empirical analysis, modeling, and simulation, we study the costs and benefits of these approaches on a wide range of parameters. These results, which cover of number of high-performance computing capability workloads, different failure distributions, hardware mean time to failures, and I/O bandwidths, show the potential benefits of these techniques for meeting the reliability demands of future exascale platforms.

  5. Is Greenberg’s “Macro-Carib” viable?

    Directory of Open Access Journals (Sweden)

    Spike Gildea


    Full Text Available In his landmark work Language in the Americas, Greenberg (1987 proposed that Macro-Carib was one of the major low-level stocks of South America, which together with Macro-Panoan and Macro-Ge-Bororo were claimed to comprise the putative Ge-Pano-Carib Phylum. His Macro-Carib includes the isolates Andoke and Kukura, and the Witotoan, Peba-Yaguan, and Cariban families. Greenberg’s primary evidence came from person-marking paradigms in individual languages, plus scattered words from individual languages collected into 79 Macro-Carib ‘etymologies’ and another 64 Amerind ‘etymologies’. The goal of this paper is to re-evaluate Greenberg’s Macro-Carib claim in the light of the much more extensive and reliable language data that has become available largely since 1987. Based on full person-marking paradigms for Proto-Cariban, Yagua, Bora and Andoke, we conclude that Greenberg’s morphological claims are unfounded. For our lexical comparison, we created lexical lists for Proto-Cariban, Proto-Witotoan, Yagua and Andoke, for both Greenberg’s 143 putative etymologies and for the Swadesh 100 list. From both lists, a total of 23 potential cognates were found, but no consonantal correspondences were repeated even once. We conclude that our greatly expanded and improved database does not provide sufficient evidence to convince the skeptic that the Macro-Carib hypothesis is viable.

  6. Case-based anatomy teaching: a viable alternative? (United States)

    Eseonu, Onyedikachi; Carachi, Robert; Brindley, Nicola


    Over the last two decades, there has been a decline in the amount of time available for anatomy teaching in the medical undergraduate curriculum, and new methods of anatomy teaching have been adopted for pragmatic reasons, with little evidence base to support their proposed educational benefits. This study seeks to establish the effect of a case-based teaching method on students' confidence in anatomy. Forty-three student volunteers in the clinical phase of the Glasgow medical course were given weekly anatomy teaching sessions based on clinical case presentations over 4 weeks. The students were given an anatomy test, and were asked to rate their confidence in their anatomy knowledge before and after the teaching sessions. There was a two-point increase in students' self-rated confidence, and a 10.9 per cent increase in average test score after the case-based anatomy teaching sessions. Both of these increases were statistically significant (p teaching was also highly rated by students, which may make it a viable option for the teaching of anatomy in the modern medical curriculum. © 2013 John Wiley & Sons Ltd.

  7. Protein design algorithms predict viable resistance to an experimental antifolate. (United States)

    Reeve, Stephanie M; Gainza, Pablo; Frey, Kathleen M; Georgiev, Ivelin; Donald, Bruce R; Anderson, Amy C


    Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure.

  8. Towards viable cosmological models of disformal theories of gravity (United States)

    Sakstein, Jeremy


    The late-time cosmological dynamics of disformal gravity are investigated using dynamical systems methods. It is shown that in the general case there are no stable attractors that screen fifth forces locally and simultaneously describe a dark energy dominated universe. Viable scenarios have late-time properties that are independent of the disformal parameters and are identical to the equivalent conformal quintessence model. Our analysis reveals that configurations where the Jordan frame metric becomes singular are only reached in the infinite future, thus explaining the natural pathology resistance observed numerically by several previous works. The viability of models where this can happen is discussed in terms of both the cosmological dynamics and local phenomena. We identify a special parameter tuning such that there is a new fixed point that can match the presently observed dark energy density and equation of state. This model is unviable when the scalar couples to the visible sector but may provide a good candidate model for theories where only dark matter is disformally coupled.

  9. SMA actuators: a viable practical technology (Presentation Video) (United States)

    Browne, Alan L.; Brown, Jeffrey; Hodgson, Darel E.


    Diverse products either based solely on or incorporating Shape Memory Alloys (SMA) have and are being made in a wide range of industries, and IP is being captured. Why then compared to SE (superelastic) Nitinol, and especially conventional technology, do so few ideas reach production? This presentation delves deeply into this topic in reaching the final assessment that SMA actuators are indeed now a viable practical technology. The presentation begins with an introduction to and description of the fundamental basis of SMA actuator technology. Examples of multiple commercially available geometric forms of SMA actuators are given and the functionalities that they provide are described. This is followed by examples of multiple commercial products incorporating such SMA actuators. Given that there are literally millions of commercial products incorporating conventional actuator technologies, indications are given as to why there are their less than 1000 that utilize SMA. Experience based challenges to the commercial use of SMA actuators are described. Besides having to compete with existing non-SMA technology which is quite mature additional challenges that are unique to SM actuators are indicated these including a wider than expected set of technical engineering problems and challenges and that a broader scope of dynamics is required.

  10. Enhanced inhibition of murine prostatic carcinoma growth by immunization with or administration of viable human umbilical vein endothelial cells and CRM197

    Directory of Open Access Journals (Sweden)

    Zhang Huiyong


    Full Text Available Vaccination with xenogeneic and syngeneic endothelial cells is effective for inhibiting tumor growth. Nontoxic diphtheria toxin (CRM197, as an immunogen or as a specific inhibitor of heparin-binding EGF-like growth factor, has shown promising antitumor activity. Therefore, immunization with or administration of viable human umbilical vein endothelial cells (HUVECs combined with CRM197 could have an enhanced antitumor effect. Six-week-old C57BL/6J male mice were vaccinated with viable HUVECs, 1 x 10(6 viable HUVECs combined with 100 μg CRM197, or 100 μg CRM197 alone by ip injections once a week for 4 consecutive weeks. RM-1 cells (5 x 10(5 were inoculated by sc injection as a preventive procedure. During the therapeutic procedure, 6-week-old male C57BL/6J mice were challenged with 1 x 10(5 RM-1 cells, then injected sc with 1 x 10(6 viable HUVECs, 1 x 10(6 viable HUVECs + 100 μg CRM197, and 100 μg CRM197 alone twice a week for 4 consecutive weeks. Tumor volume and life span were monitored. We also investigated the effects of immunization with HUVECs on the aortic arch wall and on wound healing. Vaccination with or administration of viable HUVECs+CRM197 enhanced the inhibition of RM-1 prostatic carcinoma by 24 and 29%, respectively, and prolonged the life span for 3 and 4 days, respectively, compared with those of only vaccination or administration with viable HUVECs of tumor-bearing C57BL/6J mice. Furthermore, HUVEC immunization caused some damage to the aortic arch wall but did not have remarkable effects on the rate of wound healing; the wounds healed in approximately 13 days. Treatment with CRM197 in combination with viable HUVECs resulted in a marked enhancement of the antitumor effect in the preventive or therapeutic treatment for prostatic carcinoma in vivo, suggesting a novel combination for anti-cancer therapy.

  11. Acupuntura un tratamiento viable para las adicciones en Colombia

    Directory of Open Access Journals (Sweden)

    Hernán López-Suescún


    Full Text Available Resumen La acupuntura es una antigua técnica terapéutica desarrollada en China, que ha evidenciado ser efectiva en síntomas como las náuseas, vómito y dolor dentario. A pesar del sustento fisiológico que posibilitaría un uso efectivo en otras patologías, incluyendo el campo de las adicciones, los estudios son contradictorios, posiblemente por la diferencias de visión entre la medicina oriental y la occidental. El consumo de psicoactivos es un problema de salud pública en Colombia y en el mundo que genera grandes costos tangibles e intangibles, los cuales, en países desarrollados, puede llegar hasta el 1,6 % del PIB. En contraste, el beneficio económico del tratamiento de las adicciones, según las Naciones Unidas Contra la Droga y el Delito (UNODC, está entre 1:3 a 1:13; por lo tanto, cualquier esfuerzo que se realice en favor de los consumidores es una ganancia. Con base en estos datos, los organismos internacionales han generado políticas que ayudan a aminorar estos efectos. Colombia, como integrante de estos organismos, ha realizado varios compromisos para llevar a cabo dichas metas. Los tratamientos con auriculoterapia, como el protocolo NADA (National Acupuncture Detoxification Association, son los métodos más usados para las adicciones en el mundo, y aunque no se ha logrado evidenciar su efectividad, por su costo, facilidad y el poco riesgo de efectos adversos se hace viable en un país con pocos recursos económicos como Colombia.

  12. Determining size and dispersion of minimum viable populations for land management planning and species conservation (United States)

    Lehmkuhl, John F.


    The concept of minimum populations of wildlife and plants has only recently been discussed in the literature. Population genetics has emerged as a basic underlying criterion for determining minimum population size. This paper presents a genetic framework and procedure for determining minimum viable population size and dispersion strategies in the context of multiple-use land management planning. A procedure is presented for determining minimum population size based on maintenance of genetic heterozygosity and reduction of inbreeding. A minimum effective population size ( N e ) of 50 breeding animals is taken from the literature as the minimum shortterm size to keep inbreeding below 1% per generation. Steps in the procedure adjust N e to account for variance in progeny number, unequal sex ratios, overlapping generations, population fluctuations, and period of habitat/population constraint. The result is an approximate census number that falls within a range of effective population size of 50 500 individuals. This population range defines the time range of short- to long-term population fitness and evolutionary potential. The length of the term is a relative function of the species generation time. Two population dispersion strategies are proposed: core population and dispersed population.

  13. Remote sensing is a viable tool for mapping soil salinity in agricultural lands

    Directory of Open Access Journals (Sweden)

    Elia Scudiero


    Full Text Available Soil salinity negatively impacts the productivity and profitability of western San Joaquin Valley (WSJV farmland. Many factors, including drought, climate change, reduced water allocations, and land-use changes could worsen salinity conditions there, and in other agricultural lands in the state. Mapping soil salinity at regional and state levels is essential for identifying drivers and trends in agricultural soil salinity, and for developing mitigation strategies, but traditional soil sampling for salinity does not allow for accurate large-scale mapping. We tested remote-sensing modeling to map root zone soil salinity for farmland in the WSJV. According to our map, 0.78 million acres are salt affected (i.e., ECe > 4 dS/m, which represents 45% of the mapped farmland; 30% of that acreage is strongly or extremely saline. Independent validations of the remote-sensing estimations indicated acceptable to excellent correspondences, except in areas of low salinity and high soil heterogeneity. Remote sensing is a viable tool for helping landowners make decisions about land use and also for helping water districts and state agencies develop salinity mitigation strategies.

  14. Recent Advances on Inorganic Nanoparticle-Based Cancer Therapeutic Agents

    National Research Council Canada - National Science Library

    Wang, Fenglin; Li, Chengyao; Cheng, Jing; Yuan, Zhiqin


      Inorganic nanoparticles have been widely investigated as therapeutic agents for cancer treatments in biomedical fields due to their unique physical/chemical properties, versatile synthetic strategies...

  15. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

    National Research Council Canada - National Science Library

    Chen, Zhongyi; Guo, Lilu; Zhang, Yongqin; Walzem, Rosemary L; Pendergast, Julie S; Printz, Richard L; Morris, Lindsey C; Matafonova, Elena; Stien, Xavier; Kang, Li; Coulon, Denis; McGuinness, Owen P; Niswender, Kevin D; Davies, Sean S


    ...; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota...

  16. Poverty alleviation in Uganda: the case for a viable optimum ...

    African Journals Online (AJOL)

    Poverty alleviation is a long and painstaking process. It involves knowing what poverty is, its causes and means of alleviating it. Poverty is one of the scourges including disease and ignorance a combination of which deprives humanity of the basic needs for living. Among the strategies to alleviate poverty is effective ...

  17. Social Enterprise in Higher Education: A Viable Venture? (United States)

    Hoefer, Richard A.; Sliva, Shannon M.


    Social enterprise is a burgeoning, although nebulously defined, strategy for linking market-based revenues with social good in nonprofit, for-profit, and public organizations. This article offers a unifying definition of social enterprise, tracks its development throughout traditional sectors, and takes a first step in extending the concepts of…

  18. Promoting Women Participation in Aquaculture as a Viable Tool for ...

    African Journals Online (AJOL)

    This paper therefore review the potential of aquaculture in reducing poverty by enhancing food security and as a source of income, also the paper focus on the roles of women in aquaculture, factors limiting their participation in fish farming and the strategies for promoting women participation in aquaculture as a veritable ...

  19. Proteomic identification of nitrated brain proteins in traumatic brain-injured rats treated postinjury with gamma-glutamylcysteine ethyl ester: insights into the role of elevation of glutathione as a potential therapeutic strategy for traumatic brain injury. (United States)

    Reed, Tanea T; Owen, Joshua; Pierce, William M; Sebastian, Andrea; Sullivan, Patrick G; Butterfield, D Allan


    Traumatic brain injury (TBI) occurs suddenly and has damaging effects to the brain that are dependent on the severity of insult. Symptoms can be mild, moderate, or severe. Oxidative damage is associated with traumatic brain injury through reactive oxygen/nitrogen species production. One such species, peroxynitrite, is elevated in TBI brain tissue (Orihara et al. [2001] Forensic Sci. Int. 123:142-149; Deng et al. [2007] Exp. Neurol. 205:154-165). Peroxynitrite can react with carbon dioxide and decompose to produce NO(2) and carbonate radicals, which in turn can lead to 3-nitrotyrosine, an index of protein nitration. Gamma-glutamylcysteine ethyl ester (GCEE) is an ethyl ester moiety of gamma-glutamylcysteine, an agent that up-regulates glutathione (GSH) production in brain (Drake et al. [2002] J. Neurosci. Res. 68:776-784). Many preclinical studies of TBI have employed pretreatment of animals with proposed beneficial agents prior to the injury itself. However, in the real world of TBI, treatment begins postinjury. Hence, insights into agents that improve outcome following injury are desperately needed. This study is one of the first to investigate a potential GSH-based therapy for TBI postinjury. Protein carbonyls, an index of protein oxidation, were significantly elevated in brain of animals subjected to TBI. However, if, after TBI, GCEE was administered i.p., protein carbonyl levels were significantly reduced. Similarly, 3-nitrotyrosine levels were elevated in brain following TBI but significantly decreased following TBI if GCEE was administered i.p. Redox proteomics analysis showed that several brain proteins were nitrated after TBI. However, if GCEE was given i.p. following TBI, many of these proteins were protected from nitration. The results are encouraging and are discussed with reference to potential therapeutic strategies for TBI involving elevated GSH. 2008 Wiley-Liss, Inc.

  20. Therapeutic vaccines for leishmaniasis. (United States)

    Khamesipour, Ali


    Numerous therapeutic strategies are used to treat leishmaniasis. The treatment of cutaneous leishmaniasis (CL) is solely depends on antimonate derivatives with safety issues and questionable efficacy and there is no fully effective modality to treat CL caused by Leishmania tropica and Leishmania braziliensis. There is no prophylactic vaccine available against any form of leishmaniasis. Immunotherapy for CL has a long history; immunotherapy trials of first and second generation vaccines showed promising results. The current article briefly covers the prophylactic vaccines and explains different immunotherapy strategies that have been used to treat leishmaniasis. This paper does not include experimental vaccines and only lays emphasis on human trials and those vaccines which reached human trials. Immunotherapy is currently used to successfully treat several disorders; Low cost, limited side effects and no possibility to develop resistance make immunotherapy a valuable choice especially for infectious disease with chemotherapy problems. Efforts are needed to explore the immunological surrogate marker(s) of cure and protection in leishmaniasis and overcome the difficulties in standardization of crude Leishmania vaccines. One of the reasons for anti-leishmaniasis vaccine failure is lack of an appropriate adjuvant. So far, not enough attention has been paid to develop vaccines for immunotherapy of leishmaniasis.

  1. Viable business models for public utilities; Zukunftsfaehige Geschaeftsmodelle fuer Stadtwerke

    Energy Technology Data Exchange (ETDEWEB)

    Gebhardt, Andreas; Weiss, Claudia [Buelow und Consorten GmbH, Hamburg (Germany)


    Small suppliers are faced with mounting pressures from an increasingly complex regulatory regime and a market that rewards size. Many have been able to adapt to the new framework conditions by successively optimizing existing activities. However, when change takes hold of all stages of the value chain it is no longer enough to merely modify one's previous strategies. It rather becomes necessary to review one's business model for its sustainability, take stock of the company's competencies and set priorities along the value chain. This is where a network-oriented focussing strategy can assist in ensuring efficient delivery of services in core areas while enabling the company to present itself on the market with a full range of services.

  2. Coscheduling in Clusters: Is It a Viable Alternative?

    Energy Technology Data Exchange (ETDEWEB)

    Choi, G S; Kim, J H; Ersoz, D; Yoo, A B; Das, C R


    than spin-based techniques like PB on a Linux platform. Third, the proposed HYBRID scheduling provides the best performance-energy behavior and can be implemented on any cluster with little effort. All these results suggest that blocking-based coscheduling techniques are viable candidates to be used instead of batching scheme for significant performance-energy benefits.

  3. Effect of myocardial revascularisation on left ventricular systolic function in patients with and without viable myocardium: should non-viable segments be revascularised? (United States)

    Stipac, Alja Vlahovic; Stankovic, Ivan; Vidakovic, Radosav; Putnikovic, Biljana; Ilic, Ivan; Milicic, Biljana; Neskovic, Aleksandar N


    To assess the effect of surgical revascularisation on left ventricular (LV) systolic function in patients with viable and non-viable dysfunctional LV segments determined by low dose dobutamine stress echocardiography (DSE). Prospective observational cohort study. Single tertiary care centre. Consecutive patients referred to surgical revascularisation (n=115). DSE and surgical revascularisation. Functional recovery defined as increase in ejection fraction ≥ 5% 1 year after revascularisation in patients with and without viable myocardium (viability defined as improvement of contractility in ≥ 4 LV segments on DSE). The mean age, ejection fraction and wall motion score index (WMSi) of patients were 59 ± 9 years, 44 ± 9% and 1.82 ± 0.31, respectively. There was no difference between DSE positive and DSE negative patients for any of those parameters at baseline study (p>0.05 for all). After 12 months, the ejection fraction increased 11 ± 1% in patients with viable myocardium vs 7 ± 1% in patients without viable myocardium (p=0.002). Moreover, in patients with viable myocardium, the greatest increase of ejection fraction occurred 1 month after surgery (9 ± 1%), whereas in those patients with negative DSE the ejection fraction increased more gradually (2±1% after 1 month, p=0.002 between groups for 1 month vs preoperative value), but still improved after 12 months follow-up (pmyocardial revascularisation. Functional recovery continuously occurs throughout the first year after surgical treatment.

  4. Human therapeutic cloning (NTSC): applying research from mammalian reproductive cloning. (United States)

    French, Andrew J; Wood, Samuel H; Trounson, Alan O


    Human therapeutic cloning or nuclear transfer stem cells (NTSC) to produce patient-specific stem cells, holds considerable promise in the field of regenerative medicine. The recent withdrawal of the only scientific publications claiming the successful generation of NTSC lines afford an opportunity to review the available research in mammalian reproductive somatic cell nuclear transfer (SCNT) with the goal of progressing human NTSC. The process of SCNT is prone to epigenetic abnormalities that contribute to very low success rates. Although there are high mortality rates in some species of cloned animals, most surviving clones have been shown to have normal phenotypic and physiological characteristics and to produce healthy offspring. This technology has been applied to an increasing number of mammals for utility in research, agriculture, conservation, and biomedicine. In contrast, attempts at SCNT to produce human embryonic stem cells (hESCs) have been disappointing. Only one group has published reliable evidence of success in deriving a cloned human blastocyst, using an undifferentiated hESC donor cell, and it failed to develop into a hESC line. When optimal conditions are present, it appears that in vitro development of cloned and parthenogenetic embryos, both of which may be utilized to produce hESCs, may be similar to in vitro fertilized embryos. The derivation of ESC lines from cloned embryos is substantially more efficient than the production of viable offspring. This review summarizes developments in mammalian reproductive cloning, cell-to-cell fusion alternatives, and strategies for oocyte procurement that may provide important clues facilitating progress in human therapeutic cloning leading to the successful application of cell-based therapies utilizing autologous hESC lines.

  5. A technique for determining viable military logistics support alternatives (United States)

    Hester, Jesse Stuart

    A look at today's US military will see them operating much beyond the scope of protecting and defending the United States. These operations now consist of, but are not limited to humanitarian aid, disaster relief, peace keeping, and conflict resolution. This broad spectrum of operational environments has necessitated a transformation of the individual military services to a hybrid force that is attempting to leverage the inherent and emerging capabilities and strengths of all those under the umbrella of the Department of Defense (DOD), this concept has been coined Joint Operations. Supporting Joint Operations requires a new approach to determining a viable military logistics support system. The logistics architecture for these operations has to accommodate scale, time, varied mission objectives, and imperfect information. Compounding the problem is the human in the loop (HITL) decision maker (DM) who is a necessary component for quickly assessing and planning logistics support activities. Past outcomes are not necessarily good indicators of future results, but they can provide a reasonable starting point for planning and prediction of specific needs for future requirements. Adequately forecasting the necessary logistical support structure and commodities needed for any resource intensive environment has progressed well beyond stable demand assumptions to one in which dynamic and nonlinear environments can be captured with some degree of fidelity and accuracy. While these advances are important, a holistic approach that allows exploration of the operational environment or design space does not exist to guide the military logistician in a methodical way to support military forecasting activities. To bridge this capability gap, a method called Adaptive Technique for Logistics Architecture Solutions (ATLAS) has been developed. This method provides a process that facilitates the use of techniques and tools that filter and provide relevant information to the DM. By doing

  6. Determine separations process strategy decision

    Energy Technology Data Exchange (ETDEWEB)

    Slaathaug, E.J.


    This study provides a summary level comparative analysis of selected, top-level, waste treatment strategies. These strategies include No Separations, Separations (high-level/low-level separations), and Deferred Separations of the tank waste. These three strategies encompass the full range of viable processing alternatives based upon full retrieval of the tank wastes. The assumption of full retrieval of the tank wastes is a predecessor decision and will not be revisited in this study.

  7. Sensitive and Specific Biomimetic Lipid Coated Microfluidics to Isolate Viable Circulating Tumor Cells and Microemboli for Cancer Detection.

    Directory of Open Access Journals (Sweden)

    Jia-Yang Chen

    Full Text Available Here we presented a simple and effective membrane mimetic microfluidic device with antibody conjugated supported lipid bilayer (SLB "smart coating" to capture viable circulating tumor cells (CTCs and circulating tumor microemboli (CTM directly from whole blood of all stage clinical cancer patients. The non-covalently bound SLB was able to promote dynamic clustering of lipid-tethered antibodies to CTC antigens and minimized non-specific blood cells retention through its non-fouling nature. A gentle flow further flushed away loosely-bound blood cells to achieve high purity of CTCs, and a stream of air foam injected disintegrate the SLB assemblies to release intact and viable CTCs from the chip. Human blood spiked cancer cell line test showed the ~95% overall efficiency to recover both CTCs and CTMs. Live/dead assay showed that at least 86% of recovered cells maintain viability. By using 2 mL of peripheral blood, the CTCs and CTMs counts of 63 healthy and colorectal cancer donors were positively correlated with the cancer progression. In summary, a simple and effective strategy utilizing biomimetic principle was developed to retrieve viable CTCs for enumeration, molecular analysis, as well as ex vivo culture over weeks. Due to the high sensitivity and specificity, it is the first time to show the high detection rates and quantity of CTCs in non-metastatic cancer patients. This work offers the values in both early cancer detection and prognosis of CTC and provides an accurate non-invasive strategy for routine clinical investigation on CTCs.

  8. Grazing of particle-associated bacteria-an elimination of the non-viable fraction. (United States)

    Gonsalves, Maria-Judith; Fernandes, Sheryl Oliveira; Priya, Madasamy Lakshmi; LokaBharathi, Ponnapakkam Adikesavan

    Quantification of bacteria being grazed by microzooplankton is gaining importance since they serve as energy subsidies for higher trophic levels which consequently influence fish production. Hence, grazing pressure on viable and non-viable fraction of free and particle-associated bacteria in a tropical estuary controlled mainly by protist grazers was estimated using the seawater dilution technique. In vitro incubations over a period of 42h showed that at the end of 24h, growth coefficient (k) of particle-associated bacteria was 9 times higher at 0.546 than that of free forms. Further, 'k' value of viable cells on particles was double that of free forms at 0.016 and 0.007, respectively. While bacteria associated with particles were grazed (coefficient of removal (g)=0.564), the free forms were relatively less grazed indicating that particle-associated bacteria were exposed to grazers in these waters. Among the viable and non-viable forms, 'g' of non-viable fraction (particle-associated bacteria=0.615, Free=0.0086) was much greater than the viable fraction (particle-associated bacteria=0.056, Free=0.068). Thus, grazing on viable cells was relatively low in both the free and attached states. These observations suggest that non-viable forms of particle-associated bacteria were more prone to grazing and were weeded out leaving the viable cells to replenish the bacterial standing stock. Particle colonization could thus be a temporary refuge for the "persistent variants" where the viable fraction multiply and release their progeny. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

  9. Significance of Viable but Nonculturable Escherichia coli: Induction, Detection, and Control. (United States)

    Ding, Tian; Suo, Yuanjie; Xiang, Qisen; Zhao, Xihong; Chen, Shiguo; Ye, Xingqian; Liu, Donghong


    Diseases caused by foodborne or waterborne pathogens are emerging. Many pathogens can enter into the viable but nonculturable (VBNC) state, which is a survival strategy when exposed to harsh environmental stresses. Pathogens in the VBNC state have the ability to evade conventional microbiological detection methods, posing a significant and potential health risk. Therefore, controlling VBNC bacteria in food processing and the environment is of great importance. As the typical one of the gram-negatives, Escherichia coli (E. coli) is a widespread foodborne and waterborne pathogenic bacterium and is able to enter into a VBNC state in extreme conditions (similar to the other gram-negative bacteria), including inducing factors and resuscitation stimulus. VBNC E. coli has the ability to recover both culturability and pathogenicity, which may bring potential health risk. This review describes the concrete factors (nonthermal treatment, chemical agents, and environmental factors) that induce E. coli into the VBNC state, the condition or stimulus required for resuscitation of VBNC E. coli, and the methods for detecting VBNC E. coli. Furthermore, the mechanism of genes and proteins involved in the VBNC E. coli is also discussed in this review.

  10. Cybernetically sound organizational structures II: Relating de Sitter's design theory to Beer's viable system model

    NARCIS (Netherlands)

    Achterbergh, J.M.I.M.; Vriens, D.J.


    - Purpose – The purpose of this paper is to show how the viable system model (VSM) and de Sitter's design theory can complement each other in the context of the diagnosis and design of viable organizations. - Design/methodology/approach – Key concepts from Beer's model and de Sitter's design

  11. Professional judgment and the interpretation of viable mold air sampling data. (United States)

    Johnson, David; Thompson, David; Clinkenbeard, Rodney; Redus, Jason


    Although mold air sampling is technically straightforward, interpreting the results to decide if there is an indoor source is not. Applying formal statistical tests to mold sampling data is an error-prone practice due to the extreme data variability. With neither established exposure limits nor useful statistical techniques, indoor air quality investigators often must rely on their professional judgment, but the lack of a consensus "decision strategy" incorporating explicit decision criteria requires professionals to establish their own personal set of criteria when interpreting air sampling data. This study examined the level of agreement among indoor air quality practitioners in their evaluation of airborne mold sampling data and explored differences in inter-evaluator assessments. Eighteen investigators independently judged 30 sets of viable mold air sampling results to indicate: "definite indoor mold source," "likely indoor mold source," "not enough information to decide," "likely no indoor mold source," or "definitely no indoor mold source." Kappa coefficient analysis indicated weak inter-observer reliability, and comparison of evaluator mean scores showed clear inter-evaluator differences in their overall scoring patterns. The responses were modeled on indicator "traits" of the data sets using a generalized, linear mixed model approach and showed several traits to be associated with respondents' ratings, but they also demonstrated distinct and divergent inter-evaluator response patterns. Conclusions were that there was only weak overall agreement in evaluation of the mold sampling data, that particular traits of the data were associated with the conclusions reached, and that there were substantial inter-evaluator differences that were likely due to differences in the personal decision criteria employed by the individual evaluators. The overall conclusion was that there is a need for additional work to rigorously explore the constellation of decision criteria

  12. Hymenolepis nana: immunity against oncosphere challenge in mice previously given viable or non-viable oncospheres of H. nana, H. diminuta, H. microstoma and Taenia taeniaeformis. (United States)

    Ito, A; Onitake, K; Sasaki, J; Takami, T


    When mice, previously given oral inoculation with viable oncospheres of the heterologous cestode species (Hymenolepis diminuta, H. microstoma, Taenia taeniaeformis) and the homologous one (H. nana), were challenged with oncospheres of H. nana 4 days after the primary inoculation, they showed strong and complete resistance to H. nana challenge, respectively. However, the resistance was not evoked in mice given either infective eggs of Toxocara canis or non-viable oncospheres of all cestode species examined. Congenitally athymic nude mice given viable oncospheres did not show any resistance to H. nana either. Eosinophil infiltration around cysticercoids of H. nana in the intestinal villi appeared to be more prominent in mice previously given viable oncospheres of H. diminuta than in mice given non-viable oncospheres or PBS only. Some of the eosinophils in the villus harboring cysticercoid(s) of H. nana invaded the epithelia in the former, whereas all eosinophils remained in the lamina propria in the latter. There was almost no eosinophil infiltration in nude mice. Microscopic observations revealed that oncospheres of H. diminuta, which require beetles as the intermediate host like H. microstoma, could invade the mouse intestinal tissue. Therefore, it is strongly suggested that the strong cross resistance to H. nana in mice, induced by oncospheres of all heterologous cestode species, is thymus-dependent and due to oncospheral invasion into the intestinal tissue of mice.

  13. Liposomal systems as viable drug delivery technology for skin cancer sites with an outlook on lipid-based delivery vehicles and diagnostic imaging inputs for skin conditions'. (United States)

    Akhtar, Naseem; Khan, Riaz A


    Skin cancer is among one of the most common human malignancies wide-spread world-over with mortality statistics rising continuously at an alarming rate. The increasing frequency of these malignancies has marked the need for adopting effective treatment plan coupled with better and site-specific delivery options for the desired therapeutic agent's availability at the affected site. The concurrent delivery approaches to cancerous tissues are under constant challenge and, as a result, are evolving and gaining advancements in terms of delivery modes, therapeutic agents and site-specificity of the therapeutics delivery. The lipid-based liposomal drug delivery is an attractive and emerging option, and which is meticulously shaping up beyond a threshold level to a promising, and viable route for the effective delivery of therapeutic agents and other required injuctions to the skin cancer. An update on liposomal delivery of chemotherapeutic agents, natural-origin compounds, photosensitizer, and DNA repair enzymes as well as other desirable and typical delivery modes employed in drug delivery and in the treatment of skin cancers is discussed in details. Moreover, liposomal delivery of nucleic acid-based therapeutics, i.e., small interfering RNA (siRNA), mRNA therapy, and RGD-linked liposomes are among the other promising novel technology under constant development. The current clinical applicability, viable clinical plans, future prospects including transport feasibility of delivery vesicles and imaging techniques in conjunction with the therapeutic agents is also discussed. The ongoing innovations in liposomal drug delivery technology for skin cancers hold promise for further development of the methodology for better, more effective and site-specific delivery as part of the better treatment plan by ensuring faster drug transport, better and full payload delivery with enough and required concentration of the dose. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Two ways to the top: evidence that dominance and prestige are distinct yet viable avenues to social rank and influence. (United States)

    Cheng, Joey T; Tracy, Jessica L; Foulsham, Tom; Kingstone, Alan; Henrich, Joseph


    The pursuit of social rank is a recurrent and pervasive challenge faced by individuals in all human societies. Yet, the precise means through which individuals compete for social standing remains unclear. In 2 studies, we investigated the impact of 2 fundamental strategies-Dominance (the use of force and intimidation to induce fear) and Prestige (the sharing of expertise or know-how to gain respect)-on the attainment of social rank, which we conceptualized as the acquisition of (a) perceived influence over others (Study 1), (b) actual influence over others' behaviors (Study 1), and (c) others' visual attention (Study 2). Study 1 examined the process of hierarchy formation among a group of previously unacquainted individuals, who provided round-robin judgments of each other after completing a group task. Results indicated that the adoption of either a Dominance or Prestige strategy promoted perceptions of greater influence, by both group members and outside observers, and higher levels of actual influence, based on a behavioral measure. These effects were not driven by popularity; in fact, those who adopted a Prestige strategy were viewed as likable, whereas those who adopted a Dominance strategy were not well liked. In Study 2, participants viewed brief video clips of group interactions from Study 1 while their gaze was monitored with an eye tracker. Dominant and Prestigious targets each received greater visual attention than targets low on either dimension. Together, these findings demonstrate that Dominance and Prestige are distinct yet viable strategies for ascending the social hierarchy, consistent with evolutionary theory.

  15. Therapeutic approaches for celiac disease (United States)

    Plugis, Nicholas M.; Khosla, Chaitan


    Celiac disease is a common, lifelong autoimmune disorder for which dietary control is the only accepted form of therapy. A strict gluten-free diet is burdensome to patients and can be limited in efficacy, indicating there is an unmet need for novel therapeutic approaches to supplement or supplant dietary therapy. Many molecular events required for disease pathogenesis have been recently characterized and inspire most current and emerging drug-discovery efforts. Genome-wide association studies (GWAS) confirm the importance of human leukocyte antigen genes in our pathogenic model and identify a number of new risk loci in this complex disease. Here, we review the status of both emerging and potential therapeutic strategies in the context of disease pathophysiology. We conclude with a discussion of how genes identified during GWAS and follow-up studies that enhance susceptibility may offer insight into developing novel therapies. PMID:26060114

  16. Real-time detection of viable microorganisms by intracellular phototautomerism

    Directory of Open Access Journals (Sweden)

    Schuren Frank


    preservation strategies and membrane permeation and stability. The assay allows for high-throughput applications and has great potential for rapid monitoring of microbial content in air, liquids or on surfaces.

  17. Fertility-Sparing Surgery in Early Epithelial Ovarian Cancer: A Viable Option?

    Directory of Open Access Journals (Sweden)

    Christina Fotopoulou


    Full Text Available Epithelial ovarian cancer (EOC continues to represent one of the most lethal conditions in women in the western countries. With the shifting of childbearing towards higher age, EOC increasingly affects women with active childbearing wish, resulting in major impacts on treatment management. Next to the optimal therapeutic treatment strategies, gynecologic oncologists are being asked to incorporate into their decision-making processes the patients' wish for fertility preserving alternatives ideally without compromising oncologic safety. Nowadays, fertility-sparing surgery represents an effective alternative to conventional radical cytoreduction in younger women with early stages of the disease. As such, this paper considers indications for fertility sparing surgery in EOC, reflects on outcomes from the oncologic and reproductive data of the largest and most relevant series outcomes data, reporting on fertility sparing techniques in EOC, reviews medicamentous efforts to prevent chemotherapy induced gonadotoxicity, and discusses future aspects in the gynecologic cancer management.

  18. [Therapeutic possibilities after traumatic experiences]. (United States)

    Kapfhammer, Hans-Peter


    Acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) are frequent, but not obligatory psychological sequelae following trauma. A major subgroup of patients face a chronic course of illness associated with an increased psychiatric comorbidity and significant impairments in psychosocial adaptation. The typical psychopathological symptoms of ASD and PTSD are best described within a multifactorial model integrating both neurobiological and psychosocial influences. The complex etiopathogenesis of acute and posttraumatic stress disorder favours multimodal approaches in the treatment. Differential psychotherapeutic and pharmacological strategies are available. In a critical survey on empirical studies, psychological debriefing cannot be considered as a positive approach to be recommended as general preventive measure during the immediate posttraumatic phase. Positive effects of cognitive-behavioral interventions can be established for ASD. Psychodynamic psychotherapy, cognitive-behavioral therapy and EMDR show promising results in the treatment of PTSD. Major clinical restrictions of patient sampling within special research facilities, however, do not allow an unconditional generalization of these data to psychiatric routine care. In an empirical analysis the SSRIs are the most and best studied medications for ASD and PTSD. In comparison to tricyclic antidepressants SSRIs demonstrate a broader spectrum of therapeutic effects and are better tolerated. The substance classes of SSNRI, DAS, SARI and NaSSA are to be considered as drugs of second choice. They promise a therapeutic efficacy equivalent to the SSRIs, being investigated so far only in open studies. MAO-inhibitors may dispose of a positive therapeutic potential, their profile of side effects must be respected, however. Mood stabilizers and atypical neuroleptics may be used first and foremost in add-on strategies. Benzodiazepines should be used only with increased caution for a short time in states of

  19. Exploring Oxidative Reactions in Hemoglobin Variants Using Mass Spectrometry: Lessons for Engineering Oxidatively Stable Oxygen Therapeutics. (United States)

    Strader, Michael Brad; Alayash, Abdu I


    Worldwide demand has driven the development of hemoglobin (Hb)-based oxygen carriers (HBOCs) as potential acellular oxygen therapeutics. HBOCs have the potential to provide an oxygen bridge to patients and minimize current problems associated with supply and storage of donated blood. However, to date, safety and efficacy issues have hampered the approval of viable HBOCs in the United States. These previous efforts have underscored the need for a better molecular understanding of toxicity to design safe and oxidatively stable HBOCs. Recent Advances: High-resolution accurate mass (HRAM) mass spectrometry (MS) has recently become a versatile tool in characterizing oxidative post-translational modifications that occur in Hb. When integrated with other analytical techniques, HRAM data have been invaluable in providing mechanistic insight into the extent of oxidative modification by quantifying oxidation in amino acids near the reactive heme or at specific "oxidative hotspots." In addition to providing a deeper understanding of Hb oxidative toxicity, HRAM MS studies are currently being used toward developing suitable HBOCs using a "two-prong" strategy that involves (i) understanding the mechanism of Hb toxicity by evaluating mutant Hbs identified in patients with hemoglobinopathies and (ii) utilizing this information toward designing against (or for) these reactions in acellular oxygen therapeutics that will result in oxidatively stable protein. Future HRAM studies are aimed at fully characterizing engineered candidate HBOCs to determine the most oxidatively stable protein while retaining oxygen carrying function in vivo. Antioxid. Redox Signal. 26, 777-793.

  20. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer's disease. (United States)

    Kobayashi, Yodai; Sugahara, Hirosuke; Shimada, Kousuke; Mitsuyama, Eri; Kuhara, Tetsuya; Yasuoka, Akihito; Kondo, Takashi; Abe, Keiko; Xiao, Jin-Zhong


    It has previously been shown that the consumption of probiotics may have beneficial effects not only on peripheral tissues but also on the central nervous system and behavior via the microbiota-gut-brain axis, raising the possibility that treatment with probiotics could be an effective therapeutic strategy for managing neurodegenerative disorders. In this study, we investigated the effects of oral administration of Bifidobacterium breve strain A1 (B. breve A1) on behavior and physiological processes in Alzheimer's disease (AD) model mice. We found that administration of B. breve A1 to AD mice reversed the impairment of alternation behavior in a Y maze test and the reduced latency time in a passive avoidance test, indicating that it prevented cognitive dysfunction. We also demonstrated that non-viable components of the bacterium or its metabolite acetate partially ameliorated the cognitive decline observed in AD mice. Gene profiling analysis revealed that the consumption of B. breve A1 suppressed the hippocampal expressions of inflammation and immune-reactive genes that are induced by amyloid-β. Together, these findings suggest that B. breve A1 has therapeutic potential for preventing cognitive impairment in AD.

  1. Non-viable antagonist cells are associated with reduced biocontrol performance by viable cells of the yeast Papiliotrema flavescens against Fusarium head blight of wheat. (United States)

    Microbially-based plant disease control products have achieved commercial market success, but the efficacy of such biocontrol products is sometimes deemed inconsistent. Improper processing of harvested microbial biomass or long-term storage can reduce the proportion of viable cells and necessitate t...

  2. Therapeutic use exemption (United States)

    Dvorak, J; Kirkendall, D; Vouillamoz, M


    Football players who have either physical symptoms or disease after injury may need to be treated with specific medicines that are on the list of prohibited substances. Therapeutic use exemption may be granted to such players, in accordance with strictly defined criteria—these are presented in this article. Procedures of how to request for an abbreviated or a standard therapeutic use exemption are explained, and data on therapeutic use exemptions (UEFA and FIFA, 2004 and 2005) are also presented. PMID:16799102

  3. Novel strategies for anti-aging drug discovery. (United States)

    Saraswat, Komal; Rizvi, Syed Ibrahim


    Scientific achievements in the last few decades, leading to effective therapeutic interventions, have dramatically improved human life expectancy. Consequently, aging has become a significant problem and represents the major risk factor for most human pathologies including diabetes, cardiovascular diseases, neurological disorders, and cancer. Scientific discoveries over the past two decades have been instrumental in dissecting molecular mechanism(s) which play important roles in determining longevity. The same understanding has also led to the acknowledgement of the plurality of 'causes' which act either alone or in combination to create the condition which can be defined as 'aging'. Areas covered: Over the years, several concepts have been put forward for the development of a viable anti-aging regimen. In this review, the authors extensively review anti aging interventions based on caloric restriction, activation of telomerase, autophagy inducers, senolytic therapeutics, plasma membrane redox system (PMRS) activators, epigenetic modulators, and stem cell therapies. Expert opinion: Based upon our current understanding, one of the most promising approaches for a successful anti-aging strategy includes the activation of adenosine monophosphate dependent protein kinase (AMPK). Another strategy may involve activation of PMRS. Future research efforts are likely to focus on nutrient and energy sensing molecular pathways which include mTOR, IGF-1, AMPK and the sirtuins.

  4. Immediate natural tooth pontic: A viable yet temporary prosthetic solution: A patient reported outcome

    Directory of Open Access Journals (Sweden)

    Sudhir Bhandari


    Conclusion: The concept of immediate pontic placement is surely a viable treatment option and promises an excellent transient esthetic solution for a lost tooth as well as enables good preparation of the extraction site for future prosthetic replacement.

  5. Improved identification of viable myocardium using second harmonic imaging during dobutamine stress echocardiography

    NARCIS (Netherlands)

    F. Sozzi (Fabiola); D. Poldermans (Don); J.J. Bax (Jeroen); A. Elhendy (Abdou); E.C. Vourvouri (Eleni); R. Valkema (Roelf); J. de Sutter; A.F.L. Schinkel (Arend); A. Borghetti; J.R.T.C. Roelandt (Jos)


    textabstractOBJECTIVE: To determine whether, compared with fundamental imaging, second harmonic imaging can improve the accuracy of dobutamine stress echocardiography for identifying viable myocardium, using nuclear imaging as a reference. PATIENTS: 30 patients with chronic left

  6. Marine environmental pollution stress detection through direct viable counts of bacteria

    Digital Repository Service at National Institute of Oceanography (India)

    Ramaiah, N.; Kenkre, V.D.; Verlecar, X.N.

    Direct viable counts (DVC) of bacteria were quantified from polluted and relatively less/non-polluted coastal locations during different seasons to assess whether they can be routinely monitored for an understanding of environmental stress(es...

  7. Combustion aspects of the reapplication of energetic materials as fuels as a viable demil technology

    Energy Technology Data Exchange (ETDEWEB)

    Baxter, L.; Davis, K.; Sinquefield, S.; Huey, S.; Lipkin, J.; Shah, D.; Ross, J.; Sclippa, G. [Sandia National Labs., Livermore, CA (United States). Combustion Research Facility


    This investigation addresses the combustion-related aspects of the reapplication of energetic materials as fuels in boilers as an economically viable and environmentally acceptable use of excess energetic materials. The economics of this approach indicate that the revenues from power generation and chemical recovery approximately equal the costs of boiler modification and changes in operation. The primary tradeoff is the cost of desensitizing the fuels against the cost of open burn/open detonation (OB/OD) or other disposal techniques. Two principal combustion-related obstacles to the use of energetic-material-derived fuels are NO{sub x} generation and the behavior of metals. NO{sub x} measurements obtained in this investigation indicate that the nitrated components (nitrocellulose, nitroglycerin, etc.) of energetic materials decompose with NO{sub x} as the primary product. This can lead to high uncontrolled NO{sub x} levels (as high as 2,600 ppm on a 3% O{sub 2} basis for a 5% blend of energetic material in the fuel). NO{sub x} levels are sensitive to local stoichiometry and temperature. The observed trends resemble those common during the combustion of other nitrogen-containing fuels. Implications for NO{sub x} control strategies are discussed. The behavior of inorganic components in energetic materials tested in this investigation could lead to boiler maintenance problems such as deposition, grate failure, and bed agglomeration. The root cause of the problem is the potentially extreme temperature generated during metal combustion. Implications for furnace selection and operation are discussed.

  8. Immunization of rodents against Hymenolepis infections using non-viable homologous oncospheres. (United States)

    Fan, Ping-Chin; Chung, Wen-Cheng; Ito, Akira


    Immunity to Taiwan Taenia infection in pigs can be stimulated using homologous or heterologous non-viable Taenia oncospheres. This study was designed to determine whether homologous non-viable oncospheres could stimulate immunity to Hymenolepis infection in rodents. Hatched oncospheres were prepared from eggs of Hymenolepis diminuta, Hymenolepis nana, and Hymenolepis microstoma and kept at -70 degrees C for more than 1 month. A mixture of 500 non-viable oncospheres of each tapeworm and complete Freund's adjuvant was injected subcutaneously in four groups of Sprague-Dawley rats or ICR mice one to four times at an interval of 1 week; controls were not immunized. After immunization, each rodent was orally inoculated with three fresh active cysticercoids of H. diminuta or H. microstoma or 500 fresh eggs of H. nana. The animals were then necropsied for adult tapeworms. No rats or mice immunized with non-viable oncospheres of H. diminuta or H. nana were infected by the challenge inoculation. However, 28 of 34 mice immunized with non-viable H. microstoma oncospheres were infected after inoculation with cysticercoids. This study demonstrated complete protection against infection by homologous parasites in rats or mice immunized with non-viable oncospheres of H. diminuta and H. nana, respectively. Repeated immunization may not be required if resistance is stimulated in rodent hosts.

  9. [Viable myocardium detecting by CARTO voltage mapping in swine model of acute myocardial infarction]. (United States)

    Lin, Tao; Ma, Yi-Tong; Yang, Yi-Ning; Mu, Hu-Yati; He, Peng-Yi; Yang, Yu-Chun; Chou, Ping; Liu, Fen; Zhang, Yan-Yi


    To evaluate the accuracy and practicability of detecting viable myocardium by CARTO voltage mapping in swine model of acute myocardial infarction (MI). MI was induced in 13 anesthetized swines via occluding the distal of left anterior descending coronary arteries by angioplasty balloon for 60-90 minutes. The viable myocardium detection by CARTO voltage mapping was made after reconstruction of the left ventricle using CARTO and the results were compared with TTC staining. The standard of CARTO voltage to detect viable myocardium was 0.5 - 1.5 mV while viable myocardium showed pink color by TTC staining. Eleven out of 13 swines survived the operation and 2 swines died of ventricular fibrillation at 45 and 65 minutes post ischemia. Left ventricle was divided into 16 segments and 176 segments from 11 swines were analyzed. Viable myocardium detected by CARTO voltage mapping was identical as identified by TTC staining (Kappa = 0.816, P < 0.001). Taken the TTC result as standard, the sensitivity, specificity and accuracy rate of CARTO voltage mapping are 71.8%, 96.5% and 90.9% respectively. CARTO voltage mapping could be used as a reliable tool to detect viable myocardium in this model.

  10. Chicanoizing the Therapeutic Community (United States)

    Aron, William S.; And Others


    Focusing on the drug addiction problem and its antecedent conditions in a Chicano population, the article examines several therapeutic interventions suggested by these conditions and indicates how they might be incorporated into a drug addiction Therapeutic Community treatment program designed to meet the needs of Chicano drug addicts. (Author/NQ)

  11. Therapeutic Crisis Intervention. (United States)

    Holden, Martha J.; Powers, Jane Levine


    Describes Therapeutic Crisis Intervention (TCI) program as providing staff with skills, knowledge, and confidence to manage child in crisis to bring about a "maximum amount of lasting response." Contends that, by applying principles of TCI training, direct care worker can attain therapeutic control and maintain dignity of both adult and child…

  12. Trends in Therapeutic Recreation. (United States)

    Smith, Ralph W.


    Discusses the implications of the rapid, dramatic changes taking place in therapeutic recreation for individuals with physical disabilities. The article notes the impact of changes in managed care, examines programming trends in therapeutic recreation (adventure/outdoor education, competitive sports, handcycling, health enhancement activities, and…

  13. GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth. (United States)

    Esquerré, Michaël; Momot, Marie; Goubier, Anne; Gonindard, Christophe; Leung-Theung-Long, Stéphane; Misseri, Yolande; Bissery, Marie-Christine


    GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8+ T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8+ T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Therapeutic angiogenesis: a fantastic new adventure. (United States)

    Harjai, Kishore J; Chowdhury, Pertha; Grines, Cindy L


    A significant proportion of patients with coronary artery disease have symptoms refractory to medical treatment, yet are unsuitable for conventional revascularization techniques, like percutaneous coronary intervention and coronary artery bypass surgery. Such patients are potential candidates for alternative forms of coronary revascularization, like therapeutic angiogenesis. This strategy is designed to promote the development of supplemental collateral blood vessels that will act as endogenous bypass conduits. Two major avenues for achieving therapeutic angiogenesis are currently under intense investigation: gene therapy (the introduction of new genetic material into somatic cells to synthesize proteins that are missing, defective, or desired for specific therapeutic purposes) and protein-based therapy (administration of the growth factors, instead of the genes encoding for the growth factors responsible for angiogenesis). This article provides a concise review of the "components" of gene and protein-based therapy, namely, the growth factors, the vector (for gene therapy), the route of delivery, the therapeutic target, the desired therapeutic effect, and quantifiable clinical end points for trials of angiogenesis. Based on preliminary studies, the authors believe that therapeutic angiogenesis represents a promising novel therapy for treatment of the ischemic heart. In the future, angiogenesis will likely be offered as an adjunct to conventional revascularization strategies in subsets of patients who are only "suboptimally" revascularized with conventional techniques, and might evolve into a stand-alone treatment for some patients with nonrevascularizable disease.

  15. Reporting therapeutic discourse in a therapeutic community. (United States)

    Chapman, G E


    Research in nurses' communications has concentrated on nurse to patient interactions. Those few studies which focus on nurse to nurse communications seem to be generated by a pragmatic and normative concern with effective information sharing. In this paper, which describes one aspect of a larger case study of a hospital-based therapeutic community, the description and analysis of nurses' reports flows not from a normative model of professional practice, but rather an exploration of how professional practice is articulated as discourse in nurses' written accounts. Foucault's ideas about therapeutic discourse inform the theoretical framework of the research. Ethnomethodological concerns with the importance of documentary analysis provide the methodological rationale for examining nurses' 24-hour report documents, as official discourse, reflecting therapeutic practice in this setting. A content analysis of nurses' reports, collected over a period of 4 months, demonstrated the importance of domesticity and ordinary everyday activities in nurses' accounts of hospital life. Disruption to the 'life as usual' domesticity in the community seemed to be associated with admission to and discharge from the hospital when interpersonal and interactional changes between patients occur. It is suggested that nurses in general hospital wards and more orthodox psychiatric settings might usefully consider the impact of admissions and discharges on the group of patients they manage, and make this a discursive focus of their work.

  16. Humor: A Therapeutic Intervention for Child Counseling (United States)

    Berg, Rachelle G.; Parr, Gerald; Bradley, Loretta J.; Berry, Jeremy J.


    Counselors utilize many strategies, techniques, and tools when building a therapeutic alliance or addressing children's issues. Due to the serious nature of discussing problems or perhaps because of the fear of seeming insensitive, counselors often overlook humor as a means to enhance therapy. Whether deliberate or spontaneous, humor can add…

  17. BUD31 and Lipid Metabolism: A New Potential Therapeutic Entry Point for Myc-Driven Breast Cancer (United States)


    AWARD NUMBER: W81XWH-14-1-0039 TITLE: BUD31 and Lipid Metabolism: A New Potential Therapeutic Entry Point for Myc-Driven Breast Cancer...TITLE AND SUBTITLE 5a. CONTRACT NUMBER BUD31 and Lipid Metabolism: A New Potential Therapeutic Entry Point for Myc-Driven Breast Cancer 5b. GRANT...manuscript in Nature detailing a role for BUD31 in splicing and shown more broadly that splicing is a viable therapeutic intervention point for myc

  18. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors (United States)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  19. Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Kristine Yee

    Full Text Available Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI, but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy.We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22 post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled ("dose optimization" study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16. Finally, the superior product and dose (150 million cardiospheres were tested in a blinded, randomized, placebo-controlled ("pivotal" study (n = 22. Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo.Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.

  20. Immunization of Rodents Against Hymenolepis Infections using Non-Viable Homologous Oncospheres

    Directory of Open Access Journals (Sweden)

    Ping-Chin Fan


    Full Text Available Immunity to Taiwan Taenia infection in pigs can be stimulated using homologous or heterologous nonviable Taenia oncospheres. This study was designed to determine whether homologous non-viable oncospheres could stimulate immunity to Hymenolepis infection in rodents. Hatched oncospheres were prepared from eggs of Hymenolepis diminuta, Hymenolepis nana, and Hymenolepis microstoma and kept at −70°C for more than 1 month. A mixture of 500 non-viable oncospheres of each tapeworm and complete Freund's adjuvant was injected subcutaneously in four groups of Sprague-Dawley rats or ICR mice one to four times at an interval of 1 week; controls were not immunized. After immunization, each rodent was orally inoculated with three fresh active cysticercoids of H. diminuta or H. microstoma or 500 fresh eggs of H. nana. The animals were then necropsied for adult tapeworms. No rats or mice immunized with non-viable oncospheres of H. diminuta or H. nana were infected by the challenge inoculation. However, 28 of 34 mice immunized with non-viable H. microstoma oncospheres were infected after inoculation with cysticercoids. This study demonstrated complete protection against infection by homologous parasites in rats or mice immunized with non-viable oncospheres of H. diminuta and H. nana, respectively. Repeated immunization may not be required if resistance is stimulated in rodent hosts.

  1. Airborne viable fungi in school environments in different climatic regions - A review (United States)

    Salonen, Heidi; Duchaine, Caroline; Mazaheri, Mandana; Clifford, Sam; Lappalainen, Sanna; Reijula, Kari; Morawska, Lidia


    Elevated levels of fungi in indoor environments have been linked with mould/moisture damage in building structures. However, there is a lack of information about "normal" concentrations and flora as well as guidelines of viable fungi in the school environment in different climatic conditions. We have reviewed existing guidelines for indoor fungi and the current knowledge of the concentrations and flora of viable fungi in different climatic areas, the impact of the local factors on concentrations and flora of viable fungi in school environments. Meta-regression was performed to estimate the average behaviour for each analysis of interest, showing wide variation in the mean concentrations in outdoor and indoor school environments (range: 101-103 cfu/m3). These concentrations were significantly higher for both outdoors and indoors in the moderate than in the continental climatic area, showing that the climatic condition was a determinant for the concentrations of airborne viable fungi. The most common fungal species both in the moderate and continental area were Cladosporium spp. and Penicillium spp. The suggested few quantitative guidelines for indoor air viable fungi for school buildings are much lower than for residential areas. This review provides a synthesis, which can be used to guide the interpretation of the fungi measurements results and help to find indications of mould/moisture in school building structures.

  2. Rapid quantification of viable Campylobacter bacteria on chicken carcasses, using real-time PCR and propidium monoazide treatment, as a tool for quantitative risk assessment. (United States)

    Josefsen, M H; Löfström, C; Hansen, T B; Christensen, L S; Olsen, J E; Hoorfar, J


    A number of intervention strategies against Campylobacter-contaminated poultry focus on postslaughter reduction of the number of cells, emphasizing the need for rapid and reliable quantitative detection of only viable Campylobacter bacteria. We present a new and rapid quantitative approach to the enumeration of food-borne Campylobacter bacteria that combines real-time quantitative PCR (Q-PCR) with simple propidium monoazide (PMA) sample treatment. In less than 3 h, this method generates a signal from only viable and viable but nonculturable (VBNC) Campylobacter bacteria with an intact membrane. The method's performance was evaluated by assessing the contributions to variability by individual chicken carcass rinse matrices, species of Campylobacter, and differences in efficiency of DNA extraction with differing cell inputs. The method was compared with culture-based enumeration on 50 naturally infected chickens. The cell contents correlated with cycle threshold (C(T)) values (R(2) = 0.993), with a quantification range of 1 x 10(2) to 1 x 10(7) CFU/ml. The correlation between the Campylobacter counts obtained by PMA-PCR and culture on naturally contaminated chickens was high (R(2) = 0.844). The amplification efficiency of the Q-PCR method was not affected by the chicken rinse matrix or by the species of Campylobacter. No Q-PCR signals were obtained from artificially inoculated chicken rinse when PMA sample treatment was applied. In conclusion, this study presents a rapid tool for producing reliable quantitative data on viable Campylobacter bacteria in chicken carcass rinse. The proposed method does not detect DNA from dead Campylobacter bacteria but recognizes the infectious potential of the VBNC state and is thereby able to assess the effect of control strategies and provide trustworthy data for risk assessment.

  3. Combining ethidium monoazide treatment with real-time PCR selectively quantifies viable Batrachochytrium dendrobatidis cells. (United States)

    Blooi, Mark; Martel, An; Vercammen, Francis; Pasmans, Frank


    Detection of the lethal amphibian fungus Batrachochytrium dendrobatidis relies on PCR-based techniques. Although highly accurate and sensitive, these methods fail to distinguish between viable and dead cells. In this study a novel approach combining the DNA intercalating dye ethidium monoazide (EMA) and real-time PCR is presented that allows quantification of viable B. dendrobatidis cells without the need for culturing. The developed method is able to suppress real-time PCR signals of heat-killed B. dendrobatidis zoospores by 99.9 % and is able to discriminate viable from heat-killed B. dendrobatidis zoospores in mixed samples. Furthermore, the novel approach was applied to assess the antifungal activity of the veterinary antiseptic F10(®) Antiseptic Solution. This disinfectant killed B. dendrobatidis zoospores effectively within 1 min at concentrations as low as 1:6400. Copyright © 2013 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

  4. A multicenter study of viable PCR using propidium monoazide to detect Legionella in water samples. (United States)

    Scaturro, Maria; Fontana, Stefano; Dell'eva, Italo; Helfer, Fabrizia; Marchio, Michele; Stefanetti, Maria Vittoria; Cavallaro, Mario; Miglietta, Marilena; Montagna, Maria Teresa; De Giglio, Osvalda; Cuna, Teresa; Chetti, Leonarda; Sabattini, Maria Antonietta Bucci; Carlotti, Michela; Viggiani, Mariagabriella; Stenico, Alberta; Romanin, Elisa; Bonanni, Emma; Ottaviano, Claudio; Franzin, Laura; Avanzini, Claudio; Demarie, Valerio; Corbella, Marta; Cambieri, Patrizia; Marone, Piero; Rota, Maria Cristina; Bella, Antonino; Ricci, Maria Luisa


    Legionella quantification in environmental samples is overestimated by qPCR. Combination with a viable dye, such as Propidium monoazide (PMA), could make qPCR (named then vPCR) very reliable. In this multicentre study 717 artificial water samples, spiked with fixed concentrations of Legionella and interfering bacterial flora, were analysed by qPCR, vPCR and culture and data were compared by statistical analysis. A heat-treatment at 55 °C for 10 minutes was also performed to obtain viable and not-viable bacteria. When data of vPCR were compared with those of culture and qPCR, statistical analysis showed significant differences (P 0.05). Overall this study provided a good experimental reproducibility of vPCR but also highlighted limits of PMA in the discriminating capability of dead and live bacteria, making vPCR not completely reliable. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Issues of organizational cybernetics and viability beyond Beer's viable systems model (United States)

    Nechansky, Helmut


    The paper starts summarizing the claims of Beer's viable systems model to identify five issues any viable organizations has to deal with in an unequivocal hierarchical structure of five interrelated systems. Then the evidence is introduced for additional issues and related viable structures of organizations, which deviate from Beer's model. These issues are: (1) the establishment and (2) evolution of an organization; (3) systems for independent top-down control (like "Six Sigma"); (4) systems for independent bottom-up correction of performance problems (like "Kaizen"), both working outside a hierarchical structure; (5) pull production systems ("Just in Time") and (6) systems for checks and balances of top-level power (like boards and shareholder meetings). Based on that an evolutionary approach to organizational cybernetics is outlined, addressing the establishment of organizations and possible courses of developments, including recent developments in quality and production engineering, as well as problems of setting and changing goal values determining organizational policies.

  6. Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

    NARCIS (Netherlands)

    Rizzo, L.Y.; Theek, B.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria


    In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-)

  7. Proteasome inhibitors as experimental therapeutics of autoimmune diseases

    NARCIS (Netherlands)

    Verbrugge, C.S.E.; Scheper, R.J.; Lems, W.F.; de Gruijl, T.D.; Jansen, G.


    Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received

  8. Breaking the LSD1/KDM1A Addiction: Therapeutic Targeting of the Epigenetic Modifier in AML


    Lokken, Alyson A.; Zeleznik-Le, Nancy J.


    KDM1A/LSD1, a histone H3K4/K9 demethylase and epigenetic regulator with roles in both gene activation and repression, has increased expression in multiple cancer types. Harris et al., in this issue of Cancer Cell, and Schenk et al. show that KDM1A may be a viable therapeutic target in treating AML.

  9. Evaluation of respiratory route as a viable portal of entry for Salmonella in poultry

    Directory of Open Access Journals (Sweden)

    Kallapura G


    Full Text Available Gopala Kallapura,1 Xochitl Hernandez-Velasco,2 Neil R Pumford,1 Lisa R Bielke,1 Billy M Hargis,1 Guillermo Tellez1 1Department of Poultry Science, University of Arkansas, Fayetteville, AR, USA; 2College of Veterinary Medicine and Animal Husbandry, The National Autonomous University of Mexico, Mexico Abstract: With increasing reports of Salmonella infection, we are forced to question whether the fecal–oral route is the major route of infection and consider the possibility that airborne Salmonella infections might have a major unappreciated role. Today's large-scale poultry production, with densely stocked and enclosed production buildings, is often accompanied by very high concentrations of airborne microorganisms. Considering that the upper and lower respiratory lymphoid tissue requires up to 6 weeks to be fully developed, these immune structures seem to have a very minor role in preventing pathogen infection. In addition, the avian respiratory system in commercial poultry has anatomic and physiologic properties that present no challenge to the highly adapted Salmonella. The present review evaluates the hypothesis that transmission by the fecal–respiratory route may theoretically be a viable portal of entry for Salmonella in poultry. First, we update the current knowledge on generation of Salmonella bioaerosols, and the transport and fate of Salmonella at various stages of commercial poultry production. Further, emphasis is placed on survivability of Salmonella in these bioaerosols, as a means to assess the transport and subsequent risk of exposure and infection of poultry. Additionally, the main anatomic structures, physiologic functions, and immunologic defense in the avian respiratory system are discussed to understand the potential entry points inherent in each component that could potentially lead to infection and subsequent systemic infection of poultry by Salmonella. In this context, we also evaluate the role of the mucosal immune

  10. Blogging as a viable research methodology for young people with arthritis: a qualitative study. (United States)

    Prescott, Julie; Gray, Nicola J; Smith, Felicity J; McDonagh, Janet E


    The development of services that are responsive to the needs of users is a health policy priority. Finding ways of engaging young people in research to gain insights into their particular experiences, perspectives, and needs is vital but challenging. These data are critical to improving services in ways that meet the needs of young people. Our aim was to evaluate Web-based blogging as a viable method for understanding the daily experiences and condition management strategies of young people with juvenile arthritis. To meet the objectives of the study, a qualitative approach was required to gather information on the experiences and perspectives of young people regarding the management of their condition and its daily impact. In collaboration with a group of young people with arthritis, a custom website was developed. This website provided the opportunity for young people (aged 11-19) with arthritis from a United Kingdom pediatric hospital to contribute blogs. It was designed so that young people were free to write about whatever was important to them, but the site also included some structure and prompts to facilitate the writing of blogs. Qualitative analytical procedures were employed, supported by NVivo software. Engagement in the study by young people was variable in terms of their participation rates, frequency of website visits, and the length of their blogs. Young people used the site in different ways, some responding to the website categories and prompts that the team created, while others used it as a diary to record their experiences and thoughts. In line with principles of qualitative inquiry, the data collection was participant-led. Young people were in control of what, how much, and how often they wrote. However, some young people expressed difficulty regarding knowing what they should blog about. For a number of reasons, discussed here, the blogs may also not be fully reflective of experiences and perspectives of the participants. However, the data

  11. Theranostics Using Antibodies and Antibody-Related Therapeutics

    NARCIS (Netherlands)

    Moek, Kirsten L; Giesen, Danique; Kok, Iris C; de Groot, Derk Jan A; Jalving, Mathilde; Fehrmann, Rudolf S N; Lub-de Hooge, Marjolijn N; Brouwers, Adrienne H; de Vries, Elisabeth G E

    In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these

  12. Recent novel tumor gatekeepers and potential therapeutic approaches

    African Journals Online (AJOL)

    ... have been made to present some of the latest knowledge about novel tumor gatekeepers and new therapeutic strategies to improve the efficacy of chemotherapy and give new hope to cancer patients to fight against cancer. Keywords: Cancer, Potent inhibitors, Gatekeepers, Therapeutic approaches, Oncogenic pathways ...

  13. El modelo de sistema viable: un instrumento para la organización efectiva

    Directory of Open Access Journals (Sweden)

    Norlando Sánchez Rueda


    Full Text Available RESUMEN En este ensayo se presenta una interpretación teórica del denominado Modelo de Sistema Viable (MSV, de Stafford Beer y su Potencial Aplicación en Tareas de Diagnóstico  y diseño empresarial, al igual que para Mejorar las capacidades Organizacionales de Auto- Regulación  y Auto- Organización. Se explica como el Modelo del Sistema Viable permite conocer e interpretar  los mecanismos de estabilidad y adaptabilidad de las organizaciones, pilares para el crecimiento de una verdadera organización Efectiva.

  14. Process Improvement for Maximized Therapeutic Innovation Outcome. (United States)

    Waldman, Scott A; Terzic, Andre


    Deconvoluting key biological mechanisms forms the framework for therapeutic discovery. Strategies that enable effective translation of those insights along the development and regulatory path ultimately drive validated clinical application in patients and populations. Accordingly, parity in What vs. How we transform novel mechanistic insights into therapeutic paradigms is essential in achieving success. Aligning molecular discovery with innovations in structures and processes along the discovery-development-regulation-utilization continuum maximizes the return on public and private investments for next-generation solutions in managing health and disease. © 2017 ASCPT.

  15. Postoperative Ileus: Pathophysiology, Current Therapeutic Approaches. (United States)

    Stakenborg, N; Gomez-Pinilla, P J; Boeckxstaens, G E


    Postoperative ileus, which develops after each abdominal surgical procedure, is an iatrogenic disorder characterized by a transient inhibition of gastrointestinal motility. Its pathophysiology is complex involving pharmacological (opioids, anesthetics), neural, and immune-mediated mechanisms. The early neural phase, triggered by activation of afferent nerves during the surgical procedure, is short lasting compared to the later inflammatory phase. The latter starts after 3-6 h and lasts several days, making it a more interesting target for treatment. Insight into the triggers and immune cells involved is of great importance for the development of new therapeutic strategies. In this chapter, the pathogenesis and the current therapeutic approaches to treat postoperative ileus are discussed.

  16. Are big potassium-type Ca(2+)-activated potassium channels a viable target for the treatment of epilepsy? (United States)

    Leo, Antonio; Citraro, Rita; Constanti, Andrew; De Sarro, Giovambattista; Russo, Emilio


    BK (big potassium) channels are Ca(2+)-activated K(+) channels widely expressed in mammalian cells. They are extensively distributed in the CNS, the most abundant level being found in brain areas largely involved in epilepsy, namely cortex, hippocampus, piriform cortex, and other limbic structures. BK channels control action potential shape/duration, thereby regulating membrane excitability and Ca(2+) signaling. The potassium channel superfamily represents a rich source of potential targets for therapeutic intervention in epilepsy. Some studies have identified alterations in BK channel function, therefore, supporting the development of drugs acting on these channels for epilepsy treatment. The actual sketch is intriguing and controversial, since mechanisms altering the physiological role of BK channels leading to either a loss- or gain-of-function have both been linked to seizure onset. Not many studies have been performed to unravel the efficacy of drugs acting on these channels as potential antiepileptics; however, paradoxically, efficacy has been demonstrated for both BK channel openers and blockers. Furthermore, their potential usefulness in preventing epileptogenesis has not been investigated at all. Substantial data on risks and benefits of modulating these channels are urgently needed to draw a definitive conclusion on whether BK channels are a viable future target for the treatment of epilepsy.

  17. Brain plasticity-based therapeutics (United States)

    Merzenich, Michael M.; Van Vleet, Thomas M.; Nahum, Mor


    The primary objective of this review article is to summarize how the neuroscience of brain plasticity, exploiting new findings in fundamental, integrative and cognitive neuroscience, is changing the therapeutic landscape for professional communities addressing brain-based disorders and disease. After considering the neurological bases of training-driven neuroplasticity, we shall describe how this neuroscience-guided perspective distinguishes this new approach from (a) the more-behavioral, traditional clinical strategies of professional therapy practitioners, and (b) an even more widely applied pharmaceutical treatment model for neurological and psychiatric treatment domains. With that background, we shall argue that neuroplasticity-based treatments will be an important part of future best-treatment practices in neurological and psychiatric medicine. PMID:25018719

  18. Brain Plasticity-Based Therapeutics

    Directory of Open Access Journals (Sweden)

    Michael eMerzenich


    Full Text Available The primary objective of this review article is to summarize how the neuroscience of brain plasticity, exploiting new findings in fundamental, integrative and cognitive neuroscience, is changing the therapeutic landscape for professional communities addressing brain-based disorders and disease. After considering the neurological bases of training-driven neuroplasticity, we shall describe how this neuroscience-guided perspective distinguishes this new approach from a the more-behavioral, traditional clinical strategies of professional therapy practitioners, and b an even more widely applied pharmaceutical treatment model for neurological and psychiatric treatment domains. With that background, we shall argue that neuroplasticity-based treatments will be an important part of future best-treatment practices in neurological and psychiatric medicine.

  19. Kant and therapeutic privilege. (United States)

    Brown, Chris


    Given Kant's exceptionless moral prohibition on lying, one might suspect that he is committed to a similar prohibition on withholding diagnostic and prognostic information from patients. I confirm this suspicion by adapting arguments against therapeutic privilege from his arguments against lying. However, I show that all these arguments are importantly flawed and submit that they should be rejected. A more compelling Kantian take on informed consent and therapeutic privilege is achievable, I argue, by focusing on Kant's duty of beneficence, which requires us to aim at furthering others' ends. But I show that there are some cases in which furthering a patient's ends requires withholding material medical information from her. Although I concede that these cases are probably quite rare, I conclude that the best Kantian thinking agrees with that of therapeutic privilege's advocates.

  20. Lymphedema and Therapeutic Lymphangiogenesis

    Directory of Open Access Journals (Sweden)

    Yukihiro Saito


    Full Text Available Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return and swelling of the extremities. Lymphedema is divided into primary and secondary forms based on the underlying etiology. Despite substantial advances in both surgical and conservative techniques, therapeutic options for the management of lymphedema are limited. Although rarely lethal, lymphedema is a disfiguring and disabling condition with an associated decrease in the quality of life. The recent impressive expansion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities for the treatment of lymphedema. This review highlights the lymphatic biology, the pathophysiology of lymphedema, and the therapeutic lymphangiogenesis using hepatocyte growth factor.