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Sample records for additional therapeutic strategies

  1. Strategies for therapeutic hypometabothermia

    PubMed Central

    Liu, Shimin; Chen, Jiang-Fan

    2013-01-01

    Although therapeutic hypothermia and metabolic suppression have shown robust neuroprotection in experimental brain ischemia, systemic complications have limited their use in treating acute stroke patients. The core temperature and basic metabolic rate are tightly regulated and maintained in a very stable level in mammals. Simply lowering body temperature or metabolic rate is actually a brutal therapy that may cause more systemic as well as regional problems other than providing protection. These problems are commonly seen in hypothermia and barbiturate coma. The main innovative concept of this review is to propose thermogenically optimal and synergistic reduction of core temperature and metabolic rate in therapeutic hypometabothermia using novel and clinically practical approaches. When metabolism and body temperature are reduced in a systematically synergistic manner, the outcome will be maximal protection and safe recovery, which happen in natural process, such as in hibernation, daily torpor and estivation. PMID:24179563

  2. [Liver metastasis: therapeutic strategy].

    PubMed

    Gennari, L; Doci, R; Bignami, P

    1996-01-01

    The liver is one of the most frequent sites of metastatic growth, in particular from digestive malignancies (DM). The first goal is to reduce the incidence of metastases. Adjuvant systemic chemotherapies have been demonstrated to reduce the recurrence rate and to improve survival in Dukes C colon cancer. Fluorouracil is the pivot of adjuvant treatment modulated by Leucovorin or Levamisol. A short postoperative administration of fluorouracil by intraportal route has been tested, but the results are controversial. Adjuvant treatments for different DM are under investigation. When hepatic metastases are clinically evident, therapeutic decisions depend on several factors: site and nature of primary, extent of hepatic and extrahepatic disease, patient characteristics, efficacy of treatments. A staging system should be adopted to allow a rational approach. In selected cases a locoregional treatment can achieve consistent results. Hepatic Intrarterial Chemotherapy (HIAC) for colorectal metastases achieves objective responses in more than 50% of patients. Survival seems positively affected. When feasible, Ro hepatic resection is the most effective treatment, five-year survival rate being about 30% when metastases are from colorectal cancer. Since the liver is the most frequent site of recurrence after resection, repeat resection have been successfully performed. PMID:9214269

  3. [Other therapeutic strategies].

    PubMed

    Saba, Ghassen; Nieto, Isabel; Bation, Rémy; Allaïli, Najib; Bennabi, Djamila; Moliere, Fanny; Richieri, Raphaëlle; Holtzmann, Jérôme; Bubrovszky, Maxime; Camus, Vincent; Charpeaud, Thomas; Courtet, Philippe; Courvoisier, Pierre; Haesebaert, Frédéric; Doumy, Olivier; El-Hage, Wissam; Garnier, Marion; d'Amato, Thierry; Bougerol, Thierry; Lançon, Christophe; Haffen, Emmanuel; Llorca, Pierre-Michel; Vaiva, Guillaume; Bellivier, Frank; Leboyer, Marion; Aouizerate, Bruno

    2016-03-01

    Non-selective and irreversible MAOI have become as third or fourth-line strategy for the management of treatment-resistant depression. Non-selective and irreversible MAOI requires careful monitoring of drug interactions and dietary restrictions. Nutritional supplements such as omega-3 have been found to produce beneficial effects in the management of treatment-resistant depression when administered in combination with the ongoing antidepressant treatment. The glutamate antagonist ketamine has been found to produce beneficial effects in the management of treatment-resistant depression while administered alone. Dopamine and/or norepinephrine agonists, such as methylphenidate, modafinil or pramipexole, have been found to produce beneficial effects in the management of treatment-resistant depression when administered in combination with the ongoing antidepressant treatment. PMID:26995510

  4. Therapeutic Strategies in Huntington's Disease

    PubMed Central

    2006-01-01

    This article provides an overview of the therapeutic strategies, from ordinary classical drugs to the modern molecular strategy at experimental level, for Huntington's disease. The disease is characterized by choreic movements, psychiatric disorders, striatal atrophy with selective small neuronal loss, and autosomal dominant inheritance. The genetic abnormality is CAG expansion in huntingtin gene. Mutant huntingtin with abnormally long glutamine stretch aggregates and forms intranuclear inclusions. In this review, I summarize the results of previous trials from the following aspects; 1. symptomatic/palliative therapies including drugs, stereotaxic surgery and repetitive transcranial magnetic stimulation, 2. anti-degenerative therapies including anti-excitotoxicity, reversal of mitochondrial dysfunction and anti-apoptosis, 3. restorative/reparative therapies including neural trophic factors and tissue or stem cell transplantation, and 4. molecular targets in specific and radical therapies including inhibition of truncation of huntingtin, inhibition of aggregate formation, normalization of transcriptional dysregulation, enhancement of autophagic clearance of mutant huntingtin, and specific inhibition of huntingtin expression by sRNAi. Although the strategies mentioned in the latter two categories are mostly at laboratory level at present, we are pleased that one can discuss such "therapeutic strategies", a matter absolutely impossible before the causal gene of Huntington's disease was identified more than 10 years ago. It is also true, however, that some of the "therapeutic strategies" mentioned here would be found difficult to implement and abandoned in the future. PMID:20396523

  5. Follicular lymphoma: evolving therapeutic strategies.

    PubMed

    Kahl, Brad S; Yang, David T

    2016-04-28

    Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. After decades of stagnation, the natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival. Even chemotherapy platforms have changed in the past 5 years, as bendamustine combined with rituximab has rapidly become a standard frontline strategy in North America and parts of Europe. Recent discoveries have identified patients at high risk for poor outcomes to first-line therapy (m7-Follicular Lymphoma International Prognostic Index [m7-FLIPI]) and for poor outcomes after frontline therapy (National LymphoCare Study). However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. The development of targeted agents, exploiting our current understanding of FL biology, is a high research priority. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate end points, so that novel agents can be tested (and adopted, if appropriate) efficiently. PMID:26989204

  6. [Therapeutic strategy against multiple sclerosis].

    PubMed

    Suzumura, Akio

    2008-11-01

    The pathogenesis of multiple sclerosis (MS) remains to be elucidated and there is no curative therapy against MS, though we have several disease modifying drugs. In this symposium. I introduce several new strategies against development of autoimmune processes and axonal degeneration in MS. Several mechanisms regulate immune system not to attack self components. One of the most potent regulatory cells is CD4 + CD25 + FoxP + regulatory T cells (Treg), which suppress development of both T helper 1 and 2. Thus, to increase the number and function of Treg is an approach to suppress autoimmune diseases. We have found recently that midkine suppresses the development of Treg. and that suppression of midkine by RNA aptamer alleviates symptoms of experimental autoimmune encephalomyetitis, an animal model of MS. by expanding Treg. Another important strategy against MS is to suppress axonal degeneration which reportedly occurs from an early stage of MS. We have found that the most toxic agent from activated macrophages and microglia is glutamate that was produced by glutaminase and released through gap-junction. Thus, inhibitor for glutaminase and gap-junction may be other candidates to treat MS. Interferon-beta also effectively suppress glutamate production by these cells and subsequently suppress development of axonal degeneration. PMID:19198124

  7. [Therapeutic strategies against myasthenia gravis].

    PubMed

    Utsugisawa, Kimiaki; Nagane, Yuriko

    2013-05-01

    Many patients with myasthenia gravis (MG) still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of oral corticosteroids, since full remission is not common. Our analysis demonstrated that disease severity, oral corticosteroids, and depressive state are the major factors negatively associated with QOL, and that QOL of MM status patients taking < or = 5 mg prednisolne/day is identically good as that seen in CSR and is a target of treatment. In order to achieve early MM or better status with prednisolne < or = 5 mg/day, we advocate the early aggressive treatment strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved status using low-dose oral corticosteroids and calcineurin inhibitors. PMID:23777099

  8. International intellectual property strategies for therapeutic antibodies

    PubMed Central

    2011-01-01

    Therapeutic antibodies need international patent protection as their markets expand to include industrialized and emerging countries. Because international intellectual property strategies are frequently complex and costly, applicants require sound information as a basis for decisions regarding the countries in which to pursue patents. While the most important factor is the size of a given market, other factors should also be considered. PMID:22123063

  9. International intellectual property strategies for therapeutic antibodies.

    PubMed

    Storz, Ulrich

    2011-01-01

    Therapeutic antibodies need international patent protection as their markets expand to include industrialized and emerging countries. Because international intellectual property strategies are frequently complex and costly, applicants require sound information as a basis for decisions regarding the countries in which to pursue patents. While the most important factor is the size of a given market, other factors should also be considered. PMID:22123063

  10. [Progresses in therapeutic strategies for thymic rejuvenation].

    PubMed

    Tan, Jian-Xin; Wang, Ya-Jun; Zhu, Xi-Ke

    2016-02-25

    The thymus is a vital primary lymphoid organ that provides unique microenvironments for the proliferation, differentiation, and maturation of T cells. With advancing age, however, the thymus gradually undergoes age-related involution and reduction in immune function, which are characterized by decreases in tissue size, cellularity, and naïve T cell output. This dynamic process leads to the reduced efficacy of the immune system with age and contributes to the increased susceptibility to infection, autoimmune disease, and cancer. In addition, bone marrow transplantation, radio-chemotherapy and virus infection also impair the thymus and give rise to the decline in immune function. Therefore, understanding the molecular mechanisms involved in age-related thymic involution and development of novel therapeutic strategies for thymic rejuvenation have gained considerable interests in recent years. This review emphasizes thymic microenvironments and thymocyte-stromal cell interactions and summarizes our current knowledge about thymic rejuvenation in terms of sex steroid, cytokines, growth factors, hormones, transcription factors, cell graft, and microRNAs. At the end of each discussion, we also highlight unanswered issues and describe possible future research directions. PMID:26915325

  11. Jo Spence's auto-therapeutic survival strategies.

    PubMed

    Dennett, Terry

    2011-05-01

    The use of the camera as a therapeutic tool is now being increasingly applied within clinical practice (photo-therapy) and, by the public, is being used as a form of non-clinical therapeutic photography. The subject of the present article, the late Jo Spence, was a pioneer and advocate of this approach and worked out a number of strategies that might usefully be passed on to a younger generation. Jo Spence's work is complex and multi-sided. For this reason, this article expands on some of the categories discussed in earlier publications, placing them in their historical context, as well as adding key photographic illustrations. PMID:21335361

  12. Therapeutic strategies targeting cancer stem cells

    PubMed Central

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-01-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  13. [Therapeutic strategies for systemic lupus erythematosus].

    PubMed

    Schneider, M

    2015-04-01

    Therapeutic strategy means the definition of a long-term target, which should be reached by a chosen management. As for rheumatoid arthritis, the treat to target initiative recommends remission as the target for systemic lupus erythematosus (SLE) but the command variables of remission are not yet defined. The basis of a therapeutic strategy is first the analysis of those factors that may influence the achievement of the objectives: SLE disease activity, the differentiation of damage, organ manifestations, comorbidities, genetics, sex, age of onset and considering the pathophysiological basis are some of these factors. The next step is the analysis of the available substances and concepts that allow the target to be reached. Finally, rules for management (e.g. guidelines) are needed that enrich the possibility to reach the target and improve the prognosis of patients suffering from SLE. PMID:25854154

  14. Therapeutic strategies targeting cancer stem cells.

    PubMed

    Ning, Xiaoyan; Shu, Jianchang; Du, Yiqi; Ben, Qiwen; Li, Zhaoshen

    2013-04-01

    Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID:23358473

  15. Strategies for the discovery of therapeutic Aptamers

    PubMed Central

    Yang, Xianbin; Li, Na; Gorenstein, David G.

    2010-01-01

    Importance of the field Therapeutic aptamers are synthetic, structured oligonucleotides that bind to a very broad range of targets with high affinity and specificity. They are an emerging class of targeting ligand that show great promise for treating a number of diseases. A series of aptamers currently in various stages of clinical development highlights the potential of aptamers for therapeutic applications. Area covered in this review This review will cover in vitro selection of oligonucleotide ligands, called aptamers, from a combinatorial library using the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process as well as the other known strategies for finding aptamers against various targets. What the reader will gain Readers will gain an understanding of the highly useful strategies for successful aptamer discovery. They may also be able combine two or more of the presented strategies for their aptamer discovery projects. Take home message Although many processes are available for discovering aptamers, it is not trivial to discover an aptamer candidate that is ready to move toward pharmaceutical drug development. It is also apparent that there have been relatively few therapeutic advances and clinical trials undertaken due to the small number of companies that participate in aptamer development. PMID:21359096

  16. Therapeutic Strategies Based on Polymeric Microparticles

    PubMed Central

    Vilos, C.; Velasquez, L. A.

    2012-01-01

    The development of the field of materials science, the ability to perform multidisciplinary scientific work, and the need for novel administration technologies that maximize therapeutic effects and minimize adverse reactions to readily available drugs have led to the development of delivery systems based on microencapsulation, which has taken one step closer to the target of personalized medicine. Drug delivery systems based on polymeric microparticles are generating a strong impact on preclinical and clinical drug development and have reached a broad development in different fields supporting a critical role in the near future of medical practice. This paper presents the foundations of polymeric microparticles based on their formulation, mechanisms of drug release and some of their innovative therapeutic strategies to board multiple diseases. PMID:22665988

  17. Crizotinib resistance: implications for therapeutic strategies.

    PubMed

    Dagogo-Jack, I; Shaw, A T

    2016-09-01

    In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC. Despite dramatic and durable initial responses to crizotinib; however, the vast majority of patients will develop resistance within a few years. Diverse molecular mechanisms underlie resistance to crizotinib. This review will describe the clinical activity of crizotinib, review identified mechanisms of crizotinib resistance, and end with a survey of emerging therapeutic strategies aimed at overcoming crizotinib resistance. PMID:27573756

  18. [Type 2 diabetes: what therapeutic strategy?].

    PubMed

    Grimaldi, A; Hartemann-Heurtier, A

    2001-02-17

    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

  19. New Therapeutic Strategies for Primary Sclerosing Cholangitis.

    PubMed

    Williamson, Kate D; Chapman, Roger W

    2016-02-01

    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. PMID:26870928

  20. [Current therapeutic strategies in smoking cessation].

    PubMed

    Borgne, Anne; Aubin, Henri-Jean; Berlin, Ivan

    2004-11-15

    Smoking is a behaviour maintained and enhanced by a dependence mainly induced by nicotine. Despite awareness and knowledge of the associated health risks many smokers find it considerably difficult to quit. The untoward effects of nicotine withdrawal such as apparition of depressive mood, or weight gain, etc. justify the numerous unsuccessful attempts to quit smoking. Treatments with demonstrated efficacy are available and international evidence-based recommendations for cessation interventions have been established. These are: brief advice, assessing the smoking status of each patient and encouraging cessation; nicotine replacement therapies (NRT) [transdermal patch, gum, sublingual tablet or inhalator to be used at sufficiently individualised doses combining, if necessary, two or more NRT products]; bupropion, a more recent treatment: psychotropic drug, a noradrenaline and dopamine re-uptake inhibitor more recently approved for marketing; behavioural and cognitive therapies on their own or combined with pharmacotherapy. Measuring nicotine dependence using the Fagerström Test for Nicotine Dependence may help to define the therapeutic strategy. It is obvious that therapies can only work for smokers who are motivated to stop smoking. Before reaching the decision to quit, the smoker goes through a process in the course of which the role of health professionals' advice is paramount. PMID:15655912

  1. Diagnostic and therapeutic strategies for eosinophilic esophagitis

    PubMed Central

    Zaidi, Asifa K; Mussarat, Ahad; Mishra, Anil

    2014-01-01

    Eosinophilic esophagitis (EoE) is a recently recognized allergic disorder, characterized by eosophageal dysfunction, accumulation of ≥15 eosinophils/high-powered field, eosinophil microabssess, basal cell hyperplasia, extracellular eosinophilic granules in the esophageal epithelial mucosal biopsy and a lack of response to a 8-week proton pump inhibitor treatment. Despite the increased incidences and considerable progress made in understanding EoE pathogenesis, there are limited diagnostic and therapeutic options available for EoE. Currently, the only criterion for diagnosing EoE is repetitive esophageal endoscopic biopsies and histopathological evaluation. Antigen elimination or corticosteroid therapies are effective therapies for EoE but are expensive and have limitations, if continued in the long term. Hence, there is a great necessity for novel noninvasive diagnostic biomarkers that can easily diagnose EoE and assess effectiveness of therapy. Herein, we have provided an update on key molecules involved in the disease initiation, and progression and proposed novel noninvasive diagnostic molecules and strategies for EoE therapy. PMID:25400904

  2. Therapeutic vaccination strategies to treat nasopharyngeal carcinoma.

    PubMed

    Taylor, Graham S; Steven, Neil M

    2016-04-01

    Epstein-Barr virus (EBV) infects most people worldwide. EBV has oncogenic potential and is strongly associated with several lymphomas and carcinomas, including nasopharyngeal carcinoma (NPC), that together total 200,000 cases of cancer each year. All EBV-associated cancers express viral proteins that allow highly selective immunotherapeutic targeting of the malignant cells. A number of therapeutic EBV vaccines have been tested in clinical trials with evidence of immune boosting and clinical responses in NPC patients. Therapeutic vaccination could be used after adoptive T-cell transfer to increase and sustain the number of infused T-cells or combined with immunotherapies acting at different stages of the cancer immunity cycle to increase efficacy. The therapeutic EBV vaccines tested to date have been well tolerated with minimal off-target toxicity. A safe therapeutic vaccine that was also able to be mass produced could, in principle, be used to vaccinate large numbers of patients after first line therapy to reduce recurrence. PMID:27121883

  3. Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

    PubMed

    Vinay, Dass S; Ryan, Elizabeth P; Pawelec, Graham; Talib, Wamidh H; Stagg, John; Elkord, Eyad; Lichtor, Terry; Decker, William K; Whelan, Richard L; Kumara, H M C Shantha; Signori, Emanuela; Honoki, Kanya; Georgakilas, Alexandros G; Amin, Amr; Helferich, William G; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Keith, W Nicol; Bilsland, Alan; Bhakta, Dipita; Halicka, Dorota; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan; Choi, Beom K; Kwon, Byoung S

    2015-12-01

    Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. PMID:25818339

  4. Therapeutic strategies for cancer pain management.

    PubMed Central

    Miller, T. W.; Spiro, K.; Jay, L. L.

    1990-01-01

    Clinical issues related to treating the oncology pain patient have gained considerable attention in the medical and health care literature. Addressed are management strategies which focus specifically on cognitive-behavioral, psychosocial, and pharmacologic approaches to treating the oncology pain patient. Each strategy possesses unique qualities that can benefit the care and management of the cancer patient and provide a better understanding of the disease entity and the patient's ability to develop coping strategies that may be effective in understanding and confronting pain associated with cancer. PMID:2097904

  5. Novel therapeutic strategies for adult obese asthmatics

    PubMed Central

    Linderholm, Angela; Bratt, Jennifer; Schuster, Gertrud; Zeki, Amir; Kenyon, Nicholas J.

    2014-01-01

    Synopsis Asthma is a complex syndrome that affects an estimated 26 million people in the United States but gaps exist in the recognition and management of asthmatic subgroups. In this manuscript, we propose alternative approaches for future treatments of adult obese asthmatics that do not respond to standard controller therapies of inhaled corticosteroids, bronchodilators, and anti-leukotriene drugs. We draw parallels between seemingly disparate therapeutics through their common signaling pathways. Specifically, we describe how metformin and statins can potentially improve airway inflammation and suggest supplements, for example L-arginine, which can be used in combination with conventional therapies. A move towards more targeted therapies for asthma subgroups is needed. These therapies address asthma and the comorbidities that accompany obesity and metabolic syndrome to provide the greatest therapeutic potential. PMID:25282293

  6. Therapeutic Vaccine Strategies against Human Papillomavirus

    PubMed Central

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

    2014-01-01

    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

  7. Therapeutic Strategies in HCC: Radiation Modalities

    PubMed Central

    Gallicchio, R.; Nardelli, A.; Mainenti, P.; Nappi, A.; Capacchione, D.; Simeon, V.; Sirignano, C.; Abbruzzi, F.; Barbato, F.; Landriscina, M.

    2016-01-01

    Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with 131I Lipiodol or 90Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment. PMID:27563661

  8. Therapeutic Strategies in HCC: Radiation Modalities.

    PubMed

    Gallicchio, R; Nardelli, A; Mainenti, P; Nappi, A; Capacchione, D; Simeon, V; Sirignano, C; Abbruzzi, F; Barbato, F; Landriscina, M; Storto, G

    2016-01-01

    Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with (131)I Lipiodol or (90)Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment. PMID:27563661

  9. Therapeutic Strategies for Hereditary Kidney Cancer.

    PubMed

    Sidana, Abhinav; Srinivasan, Ramaprasad

    2016-08-01

    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. PMID:27325049

  10. Escherichia coli biofilm: development and therapeutic strategies.

    PubMed

    Sharma, G; Sharma, S; Sharma, P; Chandola, D; Dang, S; Gupta, S; Gabrani, R

    2016-08-01

    Escherichia coli biofilm consists of a bacterial colony embedded in a matrix of extracellular polymeric substances (EPS) which protects the microbes from adverse environmental conditions and results in infection. Besides being the major causative agent for recurrent urinary tract infections, E. coli biofilm is also responsible for indwelling medical device-related infectivity. The cell-to-cell communication within the biofilm occurs due to quorum sensors that can modulate the key biochemical players enabling the bacteria to proliferate and intensify the resultant infections. The diversity in structural components of biofilm gets compounded due to the development of antibiotic resistance, hampering its eradication. Conventionally used antimicrobial agents have a restricted range of cellular targets and limited efficacy on biofilms. This emphasizes the need to explore the alternate therapeuticals like anti-adhesion compounds, phytochemicals, nanomaterials for effective drug delivery to restrict the growth of biofilm. The current review focuses on various aspects of E. coli biofilm development and the possible therapeutic approaches for prevention and treatment of biofilm-related infections. PMID:26811181

  11. Immunological and Therapeutic Strategies against Salmonid Cryptobiosis

    PubMed Central

    Woo, Patrick T. K.

    2010-01-01

    Salmonid cryptobiosis is caused by the haemoflagellate, Cryptobia salmositica. Clinical signs of the disease in salmon (Oncorhynchus spp.) include exophthalmia, general oedema, abdominal distension with ascites, anaemia, and anorexia. The disease-causing factor is a metalloprotease and the monoclonal antibody (mAb-001) against it is therapeutic. MAb-001 does not fix complement but agglutinates the parasite. Some brook charr, Salvelinus fontinalis cannot be infected (Cryptobia-resistant); this resistance is controlled by a dominant Mendelian locus and is inherited. In Cryptobia-resistant charr the pathogen is lysed via the Alternative Pathway of Complement Activation. However, some charr can be infected and they have high parasitaemias with no disease (Cryptobia-tolerant). In infected Cryptobia-tolerant charr the metalloprotease is neutralized by a natural antiprotease, α2 macroglobulin. Two vaccines have been developed. A single dose of the attenuated vaccine protects 100% of salmonids (juveniles and adults) for at least 24 months. Complement fixing antibody production and cell-mediated response in vaccinated fish rise significantly after challenge. Fish injected with the DNA vaccine initially have slight anaemias but they recover and have agglutinating antibodies. On challenge, DNA-vaccinated fish have lower parasitaemias, delayed peak parasitaemias and faster recoveries. Isometamidium chloride is therapeutic against the pathogen and its effectiveness is increased after conjugation to antibodies. PMID:20052385

  12. Immunological and therapeutic strategies against salmonid cryptobiosis.

    PubMed

    Woo, Patrick T K

    2010-01-01

    Salmonid cryptobiosis is caused by the haemoflagellate, Cryptobia salmositica. Clinical signs of the disease in salmon (Oncorhynchus spp.) include exophthalmia, general oedema, abdominal distension with ascites, anaemia, and anorexia. The disease-causing factor is a metalloprotease and the monoclonal antibody (mAb-001) against it is therapeutic. MAb-001 does not fix complement but agglutinates the parasite. Some brook charr, Salvelinus fontinalis cannot be infected (Cryptobia-resistant); this resistance is controlled by a dominant Mendelian locus and is inherited. In Cryptobia-resistant charr the pathogen is lysed via the Alternative Pathway of Complement Activation. However, some charr can be infected and they have high parasitaemias with no disease (Cryptobia-tolerant). In infected Cryptobia-tolerant charr the metalloprotease is neutralized by a natural antiprotease, alpha2 macroglobulin. Two vaccines have been developed. A single dose of the attenuated vaccine protects 100% of salmonids (juveniles and adults) for at least 24 months. Complement fixing antibody production and cell-mediated response in vaccinated fish rise significantly after challenge. Fish injected with the DNA vaccine initially have slight anaemias but they recover and have agglutinating antibodies. On challenge, DNA-vaccinated fish have lower parasitaemias, delayed peak parasitaemias and faster recoveries. Isometamidium chloride is therapeutic against the pathogen and its effectiveness is increased after conjugation to antibodies. PMID:20052385

  13. [Myeloproliferative neoplasms: pathophysiology and therapeutic strategy].

    PubMed

    Kubuki, Yoko; Hidaka, Tomonori; Shimoda, Kazuya

    2015-10-01

    Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells (HSCs) with genetic abnormalities in combination with mutations in JAK2, MPL or CALR, which induce autosomal JAK-STAT pathway activation, and mutations in epigenetic regulator genes such as TET2 or DNMT3A. The prognosis of patients with polycythemia vera (PV) or essential thrombocythemia (ET) is relatively good, and the therapeutic goal in cases with PV or ET is to prevent thrombohemorrhagic complications. PV or ET patients at least 60 years of age or with a history of thrombosis are in a high-risk category, and are managed with low dose aspirin and cytoreductive therapy. Phlebotomy to maintain Ht<0.45 is also used to manage PV patients. The median survival for Japanese primary myelofibrosis (MF) patients is 3.9 years. Several factors including age>65 years, Hb<10 g/dl, the presence of constitutional symptoms, and the presence of blasts in blood were identified as being associated with shorter survival in MF patients. Those patients in the high-risk category are candidates for allogenic HSC transplantation (allo-HSCT), which is potentially curative but is also associated with higher therapy-related mortality. High-risk MF patients without indications for allo-HSCT are treated with JAK inhibitors, which can markedly ameliorate constitutional symptoms and splenomegaly, and might thereby lead to a degree of improvement in survival. PMID:26458438

  14. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  15. Therapeutic strategy in unresectable metastatic colorectal cancer

    PubMed Central

    Tournigand, Christophe; André, Thierry; de Gramont, Aimery

    2012-01-01

    While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials. PMID:22423266

  16. [Therapeutic strategy for secondary lung cancer].

    PubMed

    Miura, Hiroyuki; Nakajima, Norio; Takahashi, Hidenobu; Kinoshita, Masao; Ikeda, Norihiko

    2010-10-01

    Among 659 resected lung cancer cases from 1994 to 2009, 57 secondary lung cancers (8.6%) were evaluated. The secondary tumors were synchronous, located in the same lobe in 10, the ipsilateral different lobe in 17, and the contralateral lobe in 13, or metachronous, located in the contralateral lobe in 15, and the ipsilateral different lobe in 5. Both the tumors were removed in 49 cases. Chemotherapy, stereotactic radiotherapy (SRT), photo dynamic therapy (PDT), or best supportive care (BSC) was selected after a lobectomy or segmentectomy of the 1st tumor in 8 cases considering the patient's condition. Lobectomy or segmentectomy should be indicated for the 1st tumor considering curability. Bilobectomy is adopted for multiple cancers involving middle lobe. According to the operability or pulmonary function, the same strategy is adopted for secondary cancer. Considering the patient's condition, possibility of metastases and the tumor location and histologic type, partial resection, SRT, PDT, or BSC could be selected. PMID:20954350

  17. Current and Potential Therapeutic Strategies for Hemodynamic Cardiorenal Syndrome

    PubMed Central

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

    2016-01-01

    Background 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. Summary 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. Key Messages 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

  18. Innovative therapeutic strategies for recessive dystrophic epidermolysis bullosa.

    PubMed

    Larcher, F; Del Río, M

    2015-06-01

    Recessive dystrophic epidermolysis bullosa (RDEB) is among the most serious rare skin diseases. It is also the rare skin disease for which most effort has been expended in developing advanced therapeutic interventions. RDEB is caused by collagen VII deficiency resulting from COL7A1 mutations. Therapeutic approaches seek to replenish collagen VII and thus restore dermal-epidermal adhesion. Therapeutic options under development include protein therapy and different cell-based and gene-based therapies. In addition to treating skin defects, some of these therapies may also target internal mucosa. In the coming years, these novel therapeutic approaches should substantially improve the quality of life of patients with RDEB. PMID:25796272

  19. Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

    PubMed Central

    2015-01-01

    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

  20. Novel Therapeutic Strategies in Acute Lymphoblastic Leukemia.

    PubMed

    Dias, Ajoy; Kenderian, Saad J; Westin, Gustavo F; Litzow, Mark R

    2016-08-01

    Chemotherapy cures only a minority of adult patients with acute lymphoblastic leukemia (ALL). In addition, relapsed ALL has a poor outcome with 5-year survival as low as 7 %. Hence, there is a need to develop effective therapies to treat relapsed disease and to combine these agents with chemotherapy to improve outcomes in newly diagnosed patients. ALL cells express several antigens amenable to target therapies including CD19, CD20, CD22, and CD52. Over the last decade, there has been a surge in the development of immune therapies which target these receptors and that have induced robust responses. In this manuscript, we review these novel immune agents in the treatment of B-ALL. As these new therapies mature, the challenge going forward will be to find safe and effective combinations of these agents with chemotherapy and to determine their place in the current treatment schema. PMID:27101015

  1. Therapeutic Strategies for Targeting Ras Proteins

    PubMed Central

    Gysin, Stephan; Salt, Megan; Young, Amy; McCormick, Frank

    2011-01-01

    Ras genes are frequently activated in cancer. Attempts to develop drugs that target mutant Ras proteins have, so far, been unsuccessful. Tumors bearing these mutations, therefore, remain among the most difficult to treat. Most efforts to block activated Ras have focused on pathways downstream. Drugs that inhibit Raf kinase have shown clinical benefit in the treatment of malignant melanoma. However, these drugs have failed to show clinical benefit in Ras mutant tumors. It remains unclear to what extent Ras depends on Raf kinase for transforming activity, even though Raf proteins bind directly to Ras and are certainly major effectors of Ras action in normal cells and in development. Furthermore, Raf kinase inhibitors can lead to paradoxical activation of the MAPK pathway. MEK inhibitors block the Ras-MAPK pathway, but often activate the PI3’-kinase, and have shown little clinical benefit as single agents. This activation is mediated by EGF-R and other receptor tyrosine kinases through relief of a negative feedback loop from ERK. Drug combinations that target multiple points within the Ras signaling network are likely to be necessary to achieve substantial clinical benefit. Other effectors may also contribute to Ras signaling and provide a source of targets. In addition, unbiased screens for genes necessary for Ras transformation have revealed new potential targets and have added to our understanding of Ras cancer biology. PMID:21779505

  2. Non-coding RNAs: Therapeutic Strategies and Delivery Systems.

    PubMed

    Ling, Hui

    2016-01-01

    The vast majority of the human genome is transcribed into RNA molecules that do not code for proteins, which could be small ones approximately 20 nucleotide in length, known as microRNAs, or transcripts longer than 200 bp, defined as long noncoding RNAs. The prevalent deregulation of microRNAs in human cancers prompted immediate interest on the therapeutic value of microRNAs as drugs and drug targets. Many features of microRNAs such as well-defined mechanisms, and straightforward oligonucleotide design further make them attractive candidates for therapeutic development. The intensive efforts of exploring microRNA therapeutics are reflected by the large body of preclinical studies using oligonucleotide-based mimicking and blocking, culminated by the recent entry of microRNA therapeutics in clinical trial for several human diseases including cancer. Meanwhile, microRNA therapeutics faces the challenge of effective and safe delivery of nucleic acid therapeutics into the target site. Various chemical modifications of nucleic acids and delivery systems have been developed to increase targeting specificity and efficacy, and reduce the associated side effects including activation of immune response. Recently, long noncoding RNAs become attractive targets for therapeutic intervention because of their association with complex and delicate phenotypes, and their unconventional pharmaceutical activities such as capacity of increasing output of proteins. Here I discuss the general therapeutic strategies targeting noncoding RNAs, review delivery systems developed to maximize noncoding RNA therapeutic efficacy, and offer perspectives on the future development of noncoding RNA targeting agents for colorectal cancer. PMID:27573903

  3. New strategies and patent therapeutics in EBV-associated diseases.

    PubMed

    Villegas, E; Santiago, O; Sorlózano, A; Gutierrez, J

    2010-09-01

    Epstein-Barr virus (EBV) is a virus present all throughout the world that causes infectious mononucleosis (IM) and is highly associated with certain malignancies. This study is a review of current knowledge concerning the pathogenic mechanisms of EBV in tumor and auto-immune diseases and the different new strategies to treat EBV associated pathologies. Phenomena surrounding the proliferation and immortalization of B lymphocytes, the mechanisms of immune escape and the role of CD8+ and CD4+ T cells in the infection by EBV are explained. An analysis is made of the role of EBV proteins during the biological events that take place in primary infection, persistent chronic infection together with an update of the approaches of novel patented therapeutics. Currently there is no vaccine protecting against EBV-associated disorders and no treatment that may inhibit or eliminate their progression. Thus, it is crucial to obtain additional information on the function and importance of genes that play a role on the development of those diseases with which it is associated, as well as on the humoral and cellular immune processes involved in them. PMID:21034415

  4. New therapeutic strategies for BRAF mutant colorectal cancers

    PubMed Central

    2015-01-01

    Oncogenic BRAF mutations are found in ~10% of colorectal cancers (CRCs) and predict poor prognosis. Although BRAF inhibitors have demonstrated striking efficacy in BRAF mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF mutant CRC. Over the past few years, studies have begun to define the molecular mechanisms underlying the relative resistance of BRAF mutant CRC to BRAF inhibitors, leading to the development of novel therapeutic strategies that are showing promising clinical activity in initial clinical trials. Our current understanding of the mechanisms of BRAF inhibitor resistance in BRAF mutant CRC and the therapeutic approaches currently in clinical trials for BRAF mutant CRC are reviewed herein. PMID:26697198

  5. Therapeutic and prevention strategies against human enterovirus 71 infection.

    PubMed

    Kok, Chee Choy

    2015-05-12

    Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. PMID:25964873

  6. Therapeutic and prevention strategies against human enterovirus 71 infection

    PubMed Central

    Kok, Chee Choy

    2015-01-01

    Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. PMID:25964873

  7. [Pleural mesothelioma: impact of the staging for the therapeutic strategy].

    PubMed

    Greillier, L; Scherpereel, A; Astoul, P

    2007-10-01

    Realistic improvement has been recently done for the treatment of malignant pleural mesothelioma. Besides new findings for the epidemiology of the disease, medico-social impact for patients, the knowledge of biological parameters for diagnosis, prognosis and future therapeutic targets as well, the early diagnosis of the disease mainly based on more extended practice of thoracoscopy allows in association with new imaging techniques a careful staging of the disease and consequently new therapeutic implications. Indeed if new balistic assessment of the disease improves the efficacy of radiotherapy and new combined chemotherapy have shown antitumoral responses, surgical strategy takes part in the armamenterium for this disease and combined with others therapeutic modalities seems to be a raisonnable approach despite the lack of prospective, comparative, randomized study and the drawback of current staging. However, the most important point is the multidisciplinary concertation induced by the management of this disease which represents a "model" in thoracic oncology. PMID:18235408

  8. Glycosylation of Therapeutic Proteins: An Effective Strategy to Optimize Efficacy

    PubMed Central

    Solá, Ricardo J.; Griebenow, Kai

    2009-01-01

    During their development and administration, protein-based drugs routinely display suboptimum therapeutic efficacies due to their poor physicochemical and pharmacological properties. These innate liabilities have driven the development of molecular level strategies to improve the therapeutic behavior of protein drugs. Among, the currently developed approaches, glycoengineering is one of the most promising due fact that it has been shown to simultaneously afford improvements over most of the parameters necessary for optimization of protein drug in vivo efficacy (e.g., in vitro and in vivo molecular stability, pharmacodynamic responses, and pharmacokinetic profiles) while allowing for targeting to the desired site of action. The intent of this article is to provide an account of the effects that glycosylation has on the therapeutic efficacy of protein drugs and to describe the current understanding of the mechanisms by which glycosylation leads to such effects. PMID:20055529

  9. Novel therapeutic strategies for treatment of visceral leishmaniasis.

    PubMed

    Jain, Keerti; Jain, Narendra K

    2013-12-01

    Leishmaniasis reveals itself in two forms, cutaneous and visceral, but the later exerts serious complications and may lead to death, if untreated. The availability of limited number of antileishmanial chemotherapeutic agents, the high cost of treatment, growing incidences of resistance to first line drugs as well as severe toxicities associated with the drugs complicate the treatment of visceral leishmaniasis. To overcome these problems, critical investigation of new therapeutic strategies with potential antileishmanial activity and good tolerability are essential. In this review we explore the different facets of novel therapeutic strategies for treatment of visceral leishmaniasis with a purpose to summarize all the possible treatment tactics, which will help scientists working in this arena to implement their research in a systematic manner. PMID:23973338

  10. Survivin and Tumorigenesis: Molecular Mechanisms and Therapeutic Strategies

    PubMed Central

    Chen, Xun; Duan, Ning; Zhang, Caiguo; Zhang, Wentao

    2016-01-01

    Survivin is the smallest member of the inhibitor of apoptosis protein family, which has key roles in regulating cell division and inhibiting apoptosis by blocking caspase activation. Survivin is highly expressed in most human cancers, such as lung, pancreatic and breast cancers, relative to normal tissues. Aberrant survivin expression is associated with tumor cell proliferation, progression, angiogenesis, therapeutic resistance, and poor prognosis. Studies on the underlying molecular mechanisms indicate that survivin is involved in the regulation of cytokinesis and cell cycle progression, as well as participates in a variety of signaling pathways such as the p53, Wnt, hypoxia, transforming growth factor, and Notch signaling pathways. In this review, recent progress in understanding the molecular basis of survivin is discussed. Therapeutic strategies targeting survivin in preclinical studies are also briefly summarized. PMID:26918045

  11. Targeting ischemic penumbra: part I - from pathophysiology to therapeutic strategy

    PubMed Central

    Liu, Shimin; Levine, Steven R.; Winn, H. Richard

    2010-01-01

    Penumbra is the viable tissue around the irreversibly damaged ischemic core. The purpose of acute stroke treatment is to salvage penumbral tissue and to improve brain function. However, the majority of acute stroke patients who have treatable penumbra are left untreated. Therefore, developing an effective non-recanalizational therapeutics, such as neuroprotective agents, has significant clinical applications. Part I of this serial review on “targeting penumbra” puts special emphases on penumbral pathophysiology and the development of therapeutic strategies. Bioenergetic intervention by massive metabolic suppression and direct energy delivery would be a promising future direction. An effective drug delivery system for this purpose should be able to penetrate BBB and achieve high local tissue drug levels while non-ischemic region being largely unaffected. Selective drug delivery to ischemic stroke penumbra is feasible and deserves intensive research. PMID:20607107

  12. Targeting histone deacetylases: A novel therapeutic strategy for atrial fibrillation.

    PubMed

    Lkhagva, Baigalmaa; Kao, Yu-Hsun; Chen, Yao-Chang; Chao, Tze-Fan; Chen, Shih-Ann; Chen, Yi-Jen

    2016-06-15

    Atrial fibrillation (AF) is a common cardiac arrhythmia associated with high mortality and morbidity. Current treatments of AF have limited efficacy and considerable side effects. Histone deacetylases (HDACs) play critical roles in the pathophysiology of cardiovascular diseases and contribute to the genesis of AF. Therefore, HDAC inhibition may prove a novel therapeutic strategy for AF through upstream therapy and modifications of AF electrical and structural remodeling. In this review, we provide an update of the knowledge of the effects of HDACs and HDAC inhibitors on AF, and dissect potential underlying mechanisms. PMID:27089819

  13. Potential therapeutic strategy to treat substance abuse related disorders.

    PubMed

    Chang, Sulie L

    2013-12-01

    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). PMID:25267886

  14. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses.

    PubMed

    Sekijima, Yoshiki; Kelly, Jeffery W; Ikeda, Shu-ichi

    2008-01-01

    Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials. PMID:19075702

  15. Faster, better, stronger: towards new antidepressant therapeutic strategies.

    PubMed

    O'Leary, Olivia F; Dinan, Timothy G; Cryan, John F

    2015-04-15

    Major depression is a highly prevalent disorder and is predicted to be the second leading cause of disease burden by 2020. Although many antidepressant drugs are currently available, they are far from optimal. Approximately 50% of patients do not respond to initial first line antidepressant treatment, while approximately one third fail to achieve remission following several pharmacological interventions. Furthermore, several weeks or months of treatment are often required before clinical improvement, if any, is reported. Moreover, most of the commonly used antidepressants have been primarily designed to increase synaptic availability of serotonin and/or noradrenaline and although they are of therapeutic benefit to many patients, it is clear that other therapeutic targets are required if we are going to improve the response and remission rates. It is clear that more effective, rapid-acting antidepressants with novel mechanisms of action are required. The purpose of this review is to outline the current strategies that are being taken in both preclinical and clinical settings for identifying superior antidepressant drugs. The realisation that ketamine has rapid antidepressant-like effects in treatment resistant patients has reenergised the field. Further, developing an understanding of the mechanisms underlying the rapid antidepressant effects in treatment-resistant patients by drugs such as ketamine may uncover novel therapeutic targets that can be exploited to meet the Olympian challenge of developing faster, better and stronger antidepressant drugs. PMID:25092200

  16. Therapeutic Strategies to Alter Oxygen Affinity of Sickle Hemoglobin

    PubMed Central

    Safo, Martin K.; Kato, Gregory J.

    2014-01-01

    The fundamental pathophysiology of sickle cell disease involves the polymerization of sickle hemoglobin in its T-state which develops under low oxygen saturation. One therapeutic strategy is to develop pharmacologic agents to stabilize the R-state of hemoglobin, which has higher oxygen affinity and would be expected to have slower kinetics of polymerization, potentially delaying the sickling of red cells during circulation. This therapeutic strategy has stimulated the laboratory investigation of aromatic aldehydes, aspirin derivatives, thiols and isothiocyanates that can stabilize the R-state of hemoglobin in vitro. One representative aromatic aldehyde agent, 5-hydoxymethyl-2-furfural (5-HMF, also known as Aes-103) increases oxygen affinity of sickle hemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials. The development of Hb allosteric modifiers as direct anti-sickling agents is an attractive investigational goal for the treatment of sickle cell disease. PMID:24589263

  17. Oligo/Polynucleotide-Based Gene Modification: Strategies and Therapeutic Potential

    PubMed Central

    Sargent, R. Geoffrey; Kim, Soya

    2011-01-01

    Oligonucleotide- and polynucleotide-based gene modification strategies were developed as an alternative to transgene-based and classical gene targeting-based gene therapy approaches for treatment of genetic disorders. Unlike the transgene-based strategies, oligo/polynucleotide gene targeting approaches maintain gene integrity and the relationship between the protein coding and gene-specific regulatory sequences. Oligo/polynucleotide-based gene modification also has several advantages over classical vector-based homologous recombination approaches. These include essentially complete homology to the target sequence and the potential to rapidly engineer patient-specific oligo/polynucleotide gene modification reagents. Several oligo/polynucleotide-based approaches have been shown to successfully mediate sequence-specific modification of genomic DNA in mammalian cells. The strategies involve the use of polynucleotide small DNA fragments, triplex-forming oligonucleotides, and single-stranded oligodeoxynucleotides to mediate homologous exchange. The primary focus of this review will be on the mechanistic aspects of the small fragment homologous replacement, triplex-forming oligonucleotide-mediated, and single-stranded oligodeoxynucleotide-mediated gene modification strategies as it relates to their therapeutic potential. PMID:21417933

  18. Antioxidants as a Potential Preventive and Therapeutic Strategy for Cadmium.

    PubMed

    Brzóska, Malgorzata M; Borowska, Sylwia; Tomczyk, Michal

    2016-01-01

    Epidemiological studies provide a growing number of evidences that chronic exposure to relatively low levels of cadmium (Cd), nowadays taking place in industrialized countries, may cause health hazard. Thus, growing interest has been focused on effective ways of protection from adverse effects of exposure to this heavy metal. Because numerous effects to Cd's toxic action result from its prooxidative properties, it seems reasonable that special attention should be directed to agents that can prevent or reduce this metal-induced oxidative stress and its consequences in tissues, organs and systems at risk of toxicity, including liver, kidneys, testes, ears, eyes, cardiovascular system and nervous system as well as bone tissue. This review discusses a wide range of natural (plant and animal origin) and synthetic antioxidants together with many plant extracts (e.g. black and green tea, Aronia melanocarpa, Allium sativum, Allium cepa, Ocimum sanctum, Phoenix dactylifera, Physalis peruviana, Zingiber officinale) that have been shown to prevent from Cd toxicity. Moreover, some attention has been focused on the fact that substances not possessing antioxidative potential may also prevent Cd-induced oxidative stress and its consequences. So far, most of the data on the protective effects of the natural and synthetic antioxidants and plant extracts come from studies in animals' models; however, numerous of them seem to be promising preventive/therapeutic strategies for Cd toxicity in humans. Further investigation of prophylactic and therapeutic use of antioxidants in populations exposed to Cd environmentally and occupationally is warranted, given that therapeutically effective chelation therapy for this toxic metal is currently lacking. PMID:25944010

  19. Current therapeutic strategies for premature ejaculation and future perspectives

    PubMed Central

    Xin, Zhong-Cheng; Zhu, Yi-Chen; Yuan, Yi-Ming; Cui, Wan-Shou; Jin, Zhe; Li, Wei-Ren; Liu, Tao

    2011-01-01

    Premature ejaculation (PE) is a common sexual disorder in men that is mediated by disturbances in the peripheral and central nervous systems. Although all pharmaceutical treatments for PE are currently used ‘off-label', some novel oral agents and some newer methods of drug administration now provide important relief to PE patients. However, the aetiology of this condition has still not been unified, primarily because of the lack of a standard animal model for basic research and the absence of a widely accepted definition and assessment tool for evidence-based clinical studies in patients with PE. In this review, we focus on the current therapeutic strategies and future treatment perspectives for PE. PMID:21532601

  20. Therapeutic strategies for Leber's hereditary optic neuropathy: A current update.

    PubMed

    Gueven, Nuri; Faldu, Dharmesh

    2013-11-01

    Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial retinopathy, caused by mutations in subunits of complex I of the respiratory chain, which leads to elevated levels of oxidative stress and an insufficient energy supply. This molecular pathology is thought to be responsible for the dysfunction and eventual apoptotic loss of retinal ganglion cells in the eye, which ultimately results in blindness. Many strategies, ranging from neuroprotectants, antioxidants, anti-apoptotic- and anti-inflammatory compounds have been tested with mixed results. Currently, the most promising compounds are short-chain quinones that have been shown to protect the vision of LHON patients during the early stages of the disease. This commentary gives a brief overview on the current status of tested therapeutics and also addresses future developments such as the use of gene therapy that hopefully will provide safe and efficient therapy options for all LHON patients. PMID:25343117

  1. Molecular pathogenesis and therapeutic strategies of human osteosarcoma

    PubMed Central

    Denduluri, Sahitya K; Wang, Zhongliang; Yan, Zhengjian; Wang, Jing; Wei, Qiang; Mohammed, Maryam K; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan

    2016-01-01

    Abstract Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies. Born out of these and similar investigations, a variety of emerging therapies are now undergoing various phases of OS clinical testing. They broadly include angiogenesis inhibitors, drugs that act on the bone microenvironment, receptor tyrosine kinase inhibitors, immune system modulators, and other radio- or chemo-sensitizing agents. As new forms of drug delivery are being developed simultaneously, the possibility of targeting tumors locally while minimizing systemic toxicityis is seemingly more achievable now than ever. In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

  2. Notochordal Cell-Derived Therapeutic Strategies for Discogenic Back Pain

    PubMed Central

    Purmessur, D.; Cornejo, M. C.; Cho, S. K.; Hecht, A. C.; Iatridis, J. C.

    2013-01-01

    An understanding of the processes that occur during development of the intervertebral disk can help inform therapeutic strategies for discogenic pain. This article reviews the literature to identify candidates that are found in or derived from the notochord or notochordal cells and evaluates the theory that such factors could be isolated and used as biologics to target the structural disruption, inflammation, and neurovascular ingrowth often associated with discogenic back pain. A systematic review using PubMed was performed with a primary search using keywords “(notochordal OR notochord) And (nerves OR blood vessels OR SHH OR chondroitin sulfate OR notch OR CTGF) NOT chordoma.” Secondary searches involved keywords associated with the intervertebral disk and pain. Several potential therapeutic candidates from the notochord and their possible targets were identified. Studies are needed to further identify candidates, explore mechanisms for effect, and to validate the theory that these candidates can promote structural restoration and limit or inhibit neurovascular ingrowth using in vivo studies. PMID:24436871

  3. Cell encapsulation technology as a therapeutic strategy for CNS malignancies.

    PubMed Central

    Visted, T.; Bjerkvig, R.; Enger, P. O.

    2001-01-01

    Gene therapy using viral vectors has to date failed to reveal its definitive clinical usefulness. Cell encapsulation technology represents an alternative, nonviral approach for the delivery of biologically active compounds to tumors. This strategy involves the use of genetically engineered producer cells that secrete a protein with therapeutic potential. The cells are encapsulated in an immunoisolating material that makes them suitable for transplantation. The capsules, or bioreactors, permit the release of recombinant proteins that may assert their effects in the tumor microenvironment. During the last decades, there has been significant progress in the development of encapsulation technologies that comprise devices for both macro- and microencapsulation. The polysaccharide alginate is the most commonly used material for cell encapsulation and is well tolerated by various tissues. A wide spectrum of cells and tissues has been encapsulated and implanted, both in animals and humans, indicating the general applicability of this approach for both research and medical purposes, including CNS malignancies. Gliomas most frequently recur at the resection site. To provide local and sustained drug delivery, the bioreactors can be implanted in the brain parenchyma or in the ventricular system. The development of comprehensive analyses of geno- and phenotypic profiles of a tumor (genomics and proteomics) may provide new and important guidelines for choosing the optimal combination of bioreactors and recombinant proteins for therapeutic use. PMID:11465401

  4. DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

    PubMed Central

    Wang, Qi-En

    2015-01-01

    The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored. PMID:26322164

  5. The immune system and cancer evasion strategies: therapeutic concepts.

    PubMed

    Muenst, S; Läubli, H; Soysal, S D; Zippelius, A; Tzankov, A; Hoeller, S

    2016-06-01

    The complicated interplay between cancer and the host immune system has been studied for decades. New insights into the human immune system as well as the mechanisms by which tumours evade immune control have led to the new and innovative therapeutic strategies that are considered amongst the medical breakthroughs of the last few years. Here, we will review the current understanding of cancer immunology in general, including immune surveillance and immunoediting, with a detailed look at immune cells (T cells, B cells, natural killer cells, macrophages and dendritic cells), immune checkpoints and regulators, sialic acid-binding immunoglobulin-like lectins (Siglecs) and other mechanisms. We will also present examples of new immune therapies able to reverse immune evasion strategies of tumour cells. Finally, we will focus on therapies that are already used in daily oncological practice such as the blockade of immune checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) in patients with metastatic melanoma or advanced lung cancer, or therapies currently being tested in clinical trials such as adoptive T-cell transfer. PMID:26748421

  6. Pharmacological Drug Delivery Strategies for Improved Therapeutic Effects: Recent Advances.

    PubMed

    Savaliya, Reema; Singh, Poornima; Singh, Sanjay

    2016-01-01

    The latest pharmacologic research has resulted number of new molecules with the potential to modernize the prevention or treatment of different complex diseases, including cancer. The therapeutics generally include moieties such as proteins, drugs and genes, etc. Current activities in the pharmacological field include the development of novel drug-delivery systems to overcome pharmacokinetic glitches such as limited bioavailability, unwanted distribution, drug resistant, and stability, etc. Therefore, to address these issues various biotechnological and pharmacological techniques has been introduced. However, effective drug delivery with improved efficacy remains challenging. This review is focused towards different strategies such as physical and biological methods for efficacious delivery at desired tissues and even sub-cellular targeting. Emphasis is also given about nanotechnology based drug or gene delivery strategies and co-delivery of drug-drug; gene-gene or combinations of drug-gene, etc. are the current cuttingedge methods, which are under clinical or pre-clinical stage of research. Uses of biodegradable materials, such as liposomes and polymeric particles are another class of drug delivery vehicles, which have shown tremendous success, are also discussed. Towards the end, future directions of pharmacological drug delivery methods have also been summarized. PMID:26654439

  7. Tackling Ebola: new insights into prophylactic and therapeutic intervention strategies.

    PubMed

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

    2011-01-01

    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

  8. Hepatitis C virus-host interactions: Etiopathogenesis and therapeutic strategies

    PubMed Central

    Hassan, Mohamed; Selimovic, Denis; El-Khattouti, Abdelouahid; Ghozlan, Hanan; Haikel, Youssef; Abdelkader, Ola

    2012-01-01

    Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies. PMID:24520529

  9. The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies

    PubMed Central

    2014-01-01

    Subarachnoid hemorrhage (SAH) represents a considerable health problem. To date, limited therapeutic options are available. In order to develop effective therapeutic strategies for SAH, the mechanisms involved in SAH brain damage should be fully explored. Here we review the mechanisms of SAH brain damage induced by the experimental endovascular puncture model. We have included a description of similarities and distinctions between experimental SAH in animals and human SAH pathology. Moreover, several novel treatment options to diminish SAH brain damage are discussed. SAH is accompanied by cerebral inflammation as demonstrated by an influx of inflammatory cells into the cerebral parenchyma, upregulation of inflammatory transcriptional pathways and increased expression of cytokines and chemokines. Additionally, various cell death pathways including cerebral apoptosis, necrosis, necroptosis and autophagy are involved in neuronal damage caused by SAH. Treatment strategies aiming at inhibition of inflammatory or cell death pathways demonstrate the importance of these mechanisms for survival after experimental SAH. Moreover, neuroregenerative therapies using stem cells are discussed as a possible strategy to repair the brain after SAH since this therapy may extend the window of treatment considerably. We propose the endovascular puncture model as a suitable animal model which resembles the human pathology of SAH and which could be applied to investigate novel therapeutic therapies to combat this debilitating insult. PMID:24386932

  10. Drugs or diet? – Developing novel therapeutic strategies targeting the free fatty acid family of GPCRs

    PubMed Central

    Dranse, H J; Kelly, M E M; Hudson, B D

    2013-01-01

    Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet, synthesized endogenously, or produced via fermentation of carbohydrates by gut microbiota. In addition to serving as an important source of energy, FFAs are known to produce a variety of both beneficial and detrimental effects on metabolic and inflammatory processes. While historically, FFAs were believed to produce these effects only through intracellular targets such as peroxisome proliferator-activated receptors, it has now become clear that FFAs are also agonists for several GPCRs, including a family of four receptors now termed FFA1-4. Increasing evidence suggests that FFA1-4 mediate many of the beneficial properties of FFAs and not surprisingly, this has generated significant interest in the potential of these receptors as therapeutic targets for the treatment of a variety of metabolic and inflammatory disorders. In addition to the traditional strategy of developing small-molecule therapeutics targeting these receptors, there has also been some consideration given to alternate therapeutic approaches, specifically by manipulating endogenous FFA concentrations through alteration of either dietary intake, or production by gut microbiota. In this review, the current state of knowledge for FFA1-4 will be discussed, together with their potential as therapeutic targets in the treatment of metabolic and inflammatory disorders. In particular, the evidence in support of small molecule versus dietary and microbiota-based therapeutic approaches will be considered to provide insight into the development of novel multifaceted strategies targeting the FFA receptors for the treatment of metabolic and inflammatory disorders. PMID:23937426

  11. Managing fatigue: clinical correlates, assessment procedures and therapeutic strategies.

    PubMed

    Penner, Ik; Calabrese, P

    2010-01-01

    The majority of patients with Multiple Sclerosis (MS) experience fatigue and for many susabjects concerned it is the most disabling symptom. Fatigue is most prominent in the afternoon and may be aggravated by heat. It has a tremendous negative impact on quality of life and is often one of the major reasons for early retirement and unemployment. Against further assumptions, fatigue can occur at all stages and is often present at the onset of the disease. Reliable assessment however, is difficult as it is a subjectively perceived lack of physical and/or mental energy interfering with intended activities and has to be differentiated from depression, consequences of sleep disorders, cognitive decline, and side-effects of medication. Moreover, fatigue is not directly related to overall disease evolution, to disability levels or localized lesions, although an association with dysfunction of fronto-thalamo-basal-ganglia circuits seems likely. Several therapeutic approaches including pharmacological as well as non-pharmacological strategies are available but an evidence-based specific gold-standard for the treatment of fatigue is still missing. PMID:20663419

  12. MicroRNA: A new therapeutic strategy for cardiovascular diseases.

    PubMed

    Samanta, Saheli; Balasubramanian, Sathyamoorthy; Rajasingh, Sheeja; Patel, Urmi; Dhanasekaran, Anuradha; Dawn, Buddhadeb; Rajasingh, Johnson

    2016-07-01

    Myocardial infarction, atherosclerosis, and hypertension are the most common heart-related diseases that affect both the heart and the blood vessels. Multiple independent risk factors have been shown to be responsible for cardiovascular diseases. The combination of a healthy diet, exercise, and smoking cessation keeps these risk factors in check and helps maintain homeostasis. The dynamic monolayer endothelial cell integrity and cell-cell communication are the fundamental mechanisms in maintaining homeostasis. Recently, it has been revealed that small noncoding RNAs (ncRNAs) play a critical role in regulation of genes involved in either posttranscriptional or pretranslational modifications. They also control diverse biological functions like development, differentiation, growth, and metabolism. Among ncRNAs, the short interfering RNAs (siRNAs), and microRNAs (miRNAs) have been extensively studied, but their specific functions remain largely unknown. In recent years, miRNAs are efficiently studied as one of the important candidates for involvement in most biological processes and have been implicated in many human diseases. Thus, the identification and the respective targets of miRNAs may provide novel molecular insight and new therapeutic strategies to treat diseases. This review summarizes the recent developments and insight on the role of miRNAs in cardiovascular disease prognosis, diagnostic and clinical applications. PMID:27013138

  13. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies

    PubMed Central

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

    2016-01-01

    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. Sarcopenia in heart failure: mechanisms and therapeutic strategies

    PubMed Central

    Collamati, Agnese; Marzetti, Emanuele; Calvani, Riccardo; Tosato, Matteo; D'Angelo, Emanuela; Sisto, Alex N; Landi, Francesco

    2016-01-01

    Chronic heart failure (CHF) is a highly prevalent condition among the elderly and is associated with considerable morbidity, institutionalization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Malnutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment. PMID:27605943

  15. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies.

    PubMed

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

    2016-02-21

    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

  16. Sarcopenia in heart failure: mechanisms and therapeutic strategies.

    PubMed

    Collamati, Agnese; Marzetti, Emanuele; Calvani, Riccardo; Tosato, Matteo; D'Angelo, Emanuela; Sisto, Alex N; Landi, Francesco

    2016-07-01

    Chronic heart failure (CHF) is a highly prevalent condition among the elderly and is associated with considerable morbidity, institutionalization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Malnutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment. PMID:27605943

  17. Therapeutic strategies for Alzheimer's disease in clinical trials.

    PubMed

    Godyń, Justyna; Jończyk, Jakub; Panek, Dawid; Malawska, Barbara

    2016-02-01

    Alzheimer's disease (AD) is considered to be the most common cause of dementia and is an incurable, progressive neurodegenerative disorder. Current treatment of the disease, essentially symptomatic, is based on three cholinesterase inhibitors and memantine, affecting the glutamatergic system. Since 2003, no new drugs have been approved for treatment of AD. This article presents current directions in the search for novel, potentially effective agents for the treatment of AD, as well as selected promising treatment strategies. These include agents acting upon the beta-amyloid, such as vaccines, antibodies and inhibitors or modulators of γ- and β-secretase; agents directed against the tau protein as well as compounds acting as antagonists of neurotransmitter systems (serotoninergic 5-HT6 and histaminergic H3). Ongoing clinical trials with Aβ antibodies (solanezumab, gantenerumab, crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials. Interesting results have also been achieved in trials involving small molecules such as inhibitors of β-secretase (MK-8931, E2609), a combination of 5-HT6 antagonist (idalopirdine) with donepezil, inhibition of advanced glycation end product receptors by azeliragon or modulation of the acetylcholine response of α-7 nicotinic acetylcholine receptors by encenicline. Development of new effective drugs acting upon the central nervous system is usually a difficult and time-consuming process, and in the case of AD to-date clinical trials have had a very high failure rate. Most phase II clinical trials ending with a positive outcome do not succeed in phase III, often due to serious adverse effects or lack of therapeutic efficacy. PMID:26721364

  18. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

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

  19. Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies

    PubMed Central

    Tamura, Manjula Kurella; Yaffe, Kristine

    2011-01-01

    Cognitive impairment, including dementia, is a common but poorly recognized problem among patients with end-stage renal disease (ESRD), affecting 16–38% of patients. Dementia is associated with high risks of death, dialysis withdrawal, hospitalization, and disability among patients with ESRD; thus, recognizing and effectively managing cognitive impairment may improve clinical care. Dementia screening strategies should take into account patient factors, the time available, the timing of assessments relative to dialysis treatments, and the implications of a positive screen for subsequent management (for example, transplantation). Additional diagnostic testing in patients with cognitive impairment, including neuroimaging, is largely based on the clinical evaluation. There is limited data on the efficacy and safety of pharmacotherapy for dementia in the setting of ESRD; therefore, decisions about the use of these medications should be individualized. Management of behavioral symptoms, evaluation of patient safety, and advance care planning are important components of dementia management. Prevention strategies targeting vascular risk factor modification, and physical and cognitive activity have shown promise in the general population and may be reasonably extrapolated to the ESRD population. Modification of ESRD-associated factors such as anemia and dialysis dose or frequency require further study before they can be recommended for treatment or prevention of cognitive impairment. PMID:20861818

  20. Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy.

    PubMed

    Thomas, Ajit G; Wozniak, Krystyna M; Tsukamoto, Takashi; Calvin, David; Wu, Ying; Rojas, Camilo; Vornov, James; Slusher, Barbara S

    2006-01-01

    GCP II inhibition decreases extracellular excitotoxic glutamate and increases extracellular NAAG, both of which provide neuroprotection. We have demonstrated with our potent and selective GCP II inhibitors efficacy in models of stroke, ALS and neuropathic pain. GCP II inhibition may have significant potential benefits over existing glutamate-based neuroprotection strategies. The upstream mechanism seems selective for excitotoxic induced glutamate release, as GCP II inhibitors in normal animals induced no change in basal glutamate. This suggestion has recently been corroborated by Lieberman and coworkers24 who found that both NAAG release and increase in GCP II activity appear to be induced by electrical stimulation in crayfish nerve fibers and that subsequent NAAG hydrolysis to glutamate contributes, at least in part, to subsequent NMDA receptor activation. Interestingly, even at relatively high doses of compounds, GCP II inhibition did not appear to be associated with learning/memory deficits in animals. Additionally, quantitative neurophysiological testing data and visual analog scales for 'psychedelic effects' in Phase I single dose and repeat dose studies showed GCP II inhibition to be safe and well tolerated by both healthy volunteers and diabetic patients. GCP II inhibition may represent a novel glutamate regulating strategy devoid of the side effects that have hampered the development of postsynaptic glutamate receptor antagonists. PMID:16802724

  1. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

    NASA Astrophysics Data System (ADS)

    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.

    2004-08-01

    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.

  2. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

    PubMed

    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

    2004-08-17

    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. PMID:15302924

  3. Retinopathy of Prematurity: Therapeutic Strategies Based on Pathophysiology.

    PubMed

    Cayabyab, Rowena; Ramanathan, Rangasamy

    2016-01-01

    retinal detachment. Long-term complications such as refractory errors, recurrence of ROP and risk of retinal detachment require continued follow-up with an ophthalmologist through adolescence and beyond. Optimal nutrition including adequate intake of omega-3 polyunsaturated fatty acids and decreasing infection/inflammation to promote normal vascularization are important strategies. Screening guidelines for ROP based on local incidence of ROP in different regions of the world are very important. Oxygen therapy is clearly a modifiable risk factor to decrease ROP that needs further study. Understanding the two phases of ROP will help to identify appropriate therapeutic strategies and improve visual outcomes in many preterm infants globally. PMID:27251645

  4. The therapeutic efficacy of two antibabesial strategies against Babesia gibsoni.

    PubMed

    Lin, Emerald Cheng-Yi; Chueh, Ling-Ling; Lin, Chao-Nan; Hsieh, Li-En; Su, Bi-Ling

    2012-05-25

    Various combination strategies for treating Babesia gibsoni have been described. However, relapses after administering some combinations of antibabesial drugs and the presence of drug-resistant B. gibsoni still pose significant challenges to veterinarians. To compare the efficacy of a combination of clindamycin, diminazene, and imidocarb (CDI) to that of a combination of atovaquone and azithromycin (AA) for the treatment of B. gibsoni and to correlate drug efficacy with B. gibsoni mutations, 30 client-owned dogs with natural B. gibsoni infections were collected in the study. 17 dogs were treated with AA, and 13 dogs were treated with CDI combination. Hematological parameters were recorded on the day that the dogs were presented for treatment and during treatment. To detect the parasitic DNA, the B. gibsoni 18S rRNA gene was amplified, and to analyze the mutations, the cytochrome b (CYTb) gene was sequenced. The therapy duration for all of the dogs that recovered was 23.3±7.8 days in the AA group and 41.7±12.4 days in the CDI group. Nine of the 17 dogs in the AA group and 11 of the 13 dogs in the CDI group completely recovered. Seven dogs in the AA group and 2 dogs in the CDI group relapsed after treatment. The M121I mutation in the B. gibsoni CYTb gene was detected in all of the samples that were collected from AA-relapsed and AA-nonremission dogs. The dogs in the CDI group exhibited higher recovery rates and lower relapse rates during treatment for B. gibsoni infection. In addition, the detected M121I mutation was associated with AA treatment. The CDI combination is a promising alternative treatment strategy for B. gibsoni. PMID:22222008

  5. Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies.

    PubMed

    Rani, Vibha; Deep, Gagan; Singh, Rakesh K; Palle, Komaraiah; Yadav, Umesh C S

    2016-03-01

    Increased body weight and metabolic disorder including insulin resistance, type 2 diabetes and cardiovascular complications together constitute metabolic syndrome. The pathogenesis of metabolic syndrome involves multitude of factors. A number of studies however indicate, with some conformity, that oxidative stress along with chronic inflammatory condition pave the way for the development of metabolic diseases. Oxidative stress, a state of lost balance between the oxidative and anti-oxidative systems of the cells and tissues, results in the over production of oxidative free radicals and reactive oxygen species (ROS). Excessive ROS generated could attack the cellular proteins, lipids and nucleic acids leading to cellular dysfunction including loss of energy metabolism, altered cell signalling and cell cycle control, genetic mutations, altered cellular transport mechanisms and overall decreased biological activity, immune activation and inflammation. In addition, nutritional stress such as that caused by high fat high carbohydrate diet also promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation, and decreased antioxidant system and reduced glutathione (GSH) levels. These changes lead to initiation of pathogenic milieu and development of several chronic diseases. Studies suggest that in obese person oxidative stress and chronic inflammation are the important underlying factors that lead to development of pathologies such as carcinogenesis, obesity, diabetes, and cardiovascular diseases through altered cellular and nuclear mechanisms, including impaired DNA damage repair and cell cycle regulation. Here we discuss the aspects of metabolic disorders-induced oxidative stress in major pathological conditions and strategies for their prevention and therapy. PMID:26851532

  6. The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies

    PubMed Central

    Brown, Alan S.

    2014-01-01

    We discuss the rationale for a trial of a novel biologic immunotherapy in schizophrenia (SZ). Available antipsychotic treatments for SZ are often limited by partial effectiveness and significant side effects. Thus, the search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SZ postulates disturbances of cytokines and inflammatory mediators (i.e., the cytokine model), possibly originating in part from infectious exposures. Cytokines are one of the most important components of the immune system that orchestrate the response to infectious and other exogenous insults. Preclinical models of SZ support a convergence between a role for certain cytokines in the pathophysiology of SZ and major neurochemical postulates of the disorder, including the dopamine and glutamate hypotheses. Furthermore, several cytokines are elevated in plasma in SZ, and Positron Emission Tomography (PET) studies have shown active inflammation in the brains of individuals with psychosis. Treatment studies of certain anti-inflammatory agents, such as celecoxib and aspirin, in patients with SZ have provided further support for neuroinflammation in this disorder. The recent development of approved biological therapies for autoimmune diseases provides us with new opportunities to directly target cytokine signaling as a novel treatment strategy in SZ. In addition, advances in imaging, immunology, and psychopharmacology have paved the way for utilizing measures of target engagement of neuroimmune components that would facilitate the identification of patient subgroups who are most likely to benefit from cytokine modulation. PMID:24439555

  7. Passive solar addition to therapeutic pre-school. Final technical report

    SciTech Connect

    Not Available

    1983-10-01

    This project consisted of designing and constructing a passive solar system on a new classroom addition to the Peanut Butter and Jelly Therapeutic Pre-School in Albuquerque, NM. The purpose of this project was to demonstrate the applicability of solar space heating systems to large institutional buildings, and to demonstrate the energy and cost savings available through the use of such systems. Preliminary estimates indicated that the passive solar systems will provide about 90 percent of the heating and cooling needs for the new classroom addition to the school.

  8. Therapeutic Strategies to Treat Dry Eye in an Aging Population

    PubMed Central

    Ezuddin, Nisreen S.; Alawa, Karam A.; Galor, Anat

    2015-01-01

    Dry eye (DE) is a prevalent ocular disease that primarily affects the elderly. Affecting up to 30% of adults aged 50 years and older, dry eye affects both visual function and quality of life. Symptoms of dry eye which include ocular pain (aching, burning), visual disturbances, and tearing can be addressed with therapeutic agents that target dysfunction of the meibomian glands, lacrimal glands, goblet cells, ocular surface and/or neural network. This review provides an overview of the efficacy, use, and limitations of current therapeutic interventions being used to treat DE. PMID:26123947

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

    PubMed Central

    Sarkar, Sumit; Raymick, James; Imam, Syed

    2016-01-01

    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. PMID:27338353

  10. Understanding glioma stem cells: rationale, clinical relevance and therapeutic strategies

    PubMed Central

    Ahmed, Atique U; Auffinger, Brenda; Lesniak, Maciej S

    2015-01-01

    Glioblastoma multiforme is one of the most aggressive brain tumors in adults. Despite the use of the best available multimodal therapeutic approaches, the prognosis remains dismal. The identification of glioma stem cells (GSCs) has offered new hope to affected patients, since it could explain, in part, the highly heterogeneous nature of this tumor and its chemo- and radio-resistance. Although still in its infancy, GSC research has unveiled many of its complexities and the theory itself remains controversial. GSC phenotype can significantly vary between patients and a single tumor may present several distinct GSCs. New therapeutic solutions that effectively target this population are of utmost importance, since they may be able to decrease neoplastic recurrence and improve patient survival. Here, we discuss the mechanisms by which GSCs lead to glioma relapse, the main controversies in this field and the most recent treatments that could successfully target this population. PMID:23621311

  11. Understanding glioma stem cells: rationale, clinical relevance and therapeutic strategies.

    PubMed

    Ahmed, Atique U; Auffinger, Brenda; Lesniak, Maciej S

    2013-05-01

    Glioblastoma multiforme is one of the most aggressive brain tumors in adults. Despite the use of the best available multimodal therapeutic approaches, the prognosis remains dismal. The identification of glioma stem cells (GSCs) has offered new hope to affected patients, since it could explain, in part, the highly heterogeneous nature of this tumor and its chemo- and radio-resistance. Although still in its infancy, GSC research has unveiled many of its complexities and the theory itself remains controversial. GSC phenotype can significantly vary between patients and a single tumor may present several distinct GSCs. New therapeutic solutions that effectively target this population are of utmost importance, since they may be able to decrease neoplastic recurrence and improve patient survival. Here, we discuss the mechanisms by which GSCs lead to glioma relapse, the main controversies in this field and the most recent treatments that could successfully target this population. PMID:23621311

  12. Therapeutic Strategies for Treatment of Pulmonary Lymphangioleiomyomatosis (LAM)

    PubMed Central

    Krymskaya, Vera P.

    2015-01-01

    Introduction Pulmonary lymphangioleiomyomatosis (LAM) is a rare progressive lung disease affecting almost exclusively women. Neoplastic growth of atypical smooth muscle-like cells in the lung induces destruction of lung parenchyma leading to the formation of lung cysts, rupture of which results in spontaneous pneumothorax. LAM occurs sporadically or in association with inherited hamartoma syndrome tuberous sclerosis complex (TSC). Progression of LAM often results in loss of pulmonary function and death. Increasing understanding of neoplastic LAM cell growth is driving the development of therapeutic approaches targeting the disease progression. Areas covered This review provides background to understand the rationale for current treatments used in patients with LAM, to critically appraise the evidence for these treatments, and to discuss future treatment approaches. The literature review includes publications from PubMed and clinicaltrials.gov/. Expert Opinion Targeting mTOR activation with rapamycin analogs sirolimus and everolimus are awaiting approval by the FDA for treatment of LAM. A number of other treatment options have been investigated and are currently tested in clinical trials to target LAM cell survival and metastasis. Key remaining and poorly understood areas for development and validation of therapeutic targeting in LAM are destruction of lungs, pathological lymphangiogenesis, and hormonal regulation. Future will reveal whether they could be targeted therapeutically. PMID:26779398

  13. Protease inhibition as new therapeutic strategy for GI diseases

    PubMed Central

    Vergnolle, Nathalie

    2016-01-01

    The GI tract is the most exposed organ to proteases, both in physiological and pathophysiological conditions. For digestive purposes, the lumen of the upper GI tract contains large amounts of pancreatic proteases, but studies have also demonstrated increased proteolytic activity into mucosal tissues (both in the upper and lower GI tract), associated with pathological conditions. This review aims at outlining the evidences for dysregulated proteolytic homeostasis in GI diseases and the pathogenic mechanisms of increased proteolytic activity. The therapeutic potential of protease inhibition in GI diseases is discussed, with a particular focus on IBDs, functional GI disorders and colorectal cancer. PMID:27196587

  14. Protease inhibition as new therapeutic strategy for GI diseases.

    PubMed

    Vergnolle, Nathalie

    2016-07-01

    The GI tract is the most exposed organ to proteases, both in physiological and pathophysiological conditions. For digestive purposes, the lumen of the upper GI tract contains large amounts of pancreatic proteases, but studies have also demonstrated increased proteolytic activity into mucosal tissues (both in the upper and lower GI tract), associated with pathological conditions. This review aims at outlining the evidences for dysregulated proteolytic homeostasis in GI diseases and the pathogenic mechanisms of increased proteolytic activity. The therapeutic potential of protease inhibition in GI diseases is discussed, with a particular focus on IBDs, functional GI disorders and colorectal cancer. PMID:27196587

  15. Potential Therapeutic Benefits of Strategies Directed to Mitochondria

    PubMed Central

    Lesnefsky, Edward J.; Stowe, David F.

    2010-01-01

    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

  16. Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis.

    PubMed

    Geraets, Ryan D; Koh, Seung yon; Hastings, Michelle L; Kielian, Tammy; Pearce, David A; Weimer, Jill M

    2016-01-01

    The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile, late-infantile, juvenile and adult forms based on their age of onset. Though the disease phenotypes may vary in their age and order of presentation, all typically include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures. Pathological hallmarks of NCLs include the accumulation of storage material or ceroid in the lysosome, progressive neuronal degeneration and massive glial activation. Advances have been made in genetic diagnosis and counseling for families. However, comprehensive treatment programs that delay or halt disease progression have been elusive. Current disease management is primarily targeted at controlling the symptoms rather than "curing" the disease. Recognizing the growing need for transparency and synergistic efforts to move the field forward, this review will provide an overview of the therapeutic approaches currently being pursued in preclinical and clinical trials to treat different forms of NCL as well as provide insight to novel therapeutic approaches in development for the NCLs. PMID:27083890

  17. [New therapeutic strategies for remyelination in multiple sclerosis].

    PubMed

    Kremer, D; Hartung, H-P; Stangel, M; Küry, P

    2015-08-01

    Multiple sclerosis (MS) is characterized by oligodendrocyte death and myelin sheath destruction of the central nervous system (CNS) in response to autoinflammatory processes. Besides demyelination axonal degeneration constitutes the second histopathological hallmark of this disease. A large number of immunomodulatory and targeted immunosuppression treatments have been approved for relapsing remitting (RR) MS where they effectively reduce relapse rates; however, currently no treatment options exist to repair injured axonal tracts or myelin damage that accumulates over time particularly in progressive MS. In light of the growing available therapeutic repertoire of highly potent immunomodulatory medications there is an increasing interest in the development of therapies aimed at neutralizing neurodegenerative damage. Endogenous remyelination processes occur mainly as a result of oligodendrocyte precursor cell (OPC) activation, recruitment and maturation; however, this repair activity appears to be limited and increasingly fails during disease progression. Based on these observations OPCs are considered as promising targets for the regenerative treatment of all stages of MS. This article presents an overview of approved medications with a suggested role in regeneration, regenerative treatments that are currently being tested in clinical trials, as well as promising future therapeutic approaches derived from basic glial cell research aiming at the promotion of the endogenous repair activity of the brain. PMID:26122637

  18. Personalized therapeutic strategies for patients with retinitis pigmentosa

    PubMed Central

    Zheng, Andrew; Li, Yao

    2015-01-01

    Introduction Retinitis pigmentosa (RP) encompasses many different hereditary retinal degenerations that are caused by a vast array of different gene mutations and have highly variable disease presentations and severities. This heterogeneity poses a significant therapeutic challenge, although an answer may eventually be found through two recent innovations: induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genome editing. Areas covered This review discusses the wide-ranging applications of iPSCs and CRISPR–including disease modelling, diagnostics and therapeutics – with an ultimate view towards understanding how these two technologies can come together to address disease heterogeneity and orphan genes in a novel personalized medicine platform. An extensive literature search was conducted in PubMed and Google Scholar, with a particular focus on high-impact research published within the last 1 – 2 years and centered broadly on the subjects of retinal gene therapy, iPSC-derived outer retina cells, stem cell transplantation and CRISPR/Cas gene editing. Expert opinion For the retinal pigment epithelium, autologous transplantation of gene-corrected grafts derived from iPSCs may well be technically feasible in the near future. Photoreceptor transplantation faces more significant unresolved technical challenges but remains an achievable, if more distant, goal given the rapid pace of advancements in the field. PMID:25613576

  19. MicroRNA-based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer

    PubMed Central

    Sharma, Sriganesh B.; Ruppert, J. Michael

    2015-01-01

    MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using anti-sense oligonucleotide based strategies) miR activity is an area of intense research. The RAS-Extracellular signal regulated kinase (ERK) pathway represents a major miR-regulated signaling network that endows cells with some of the classical hallmarks of cancer, and is often inappropriately activated in malignancies by somatic genetic alteration through point mutation or alteration of gene copy number. In addition, recent progress indicates that many tumors may be deficient in GTPase activating proteins (GAPs) due to the collaborative action of oncogenic microRNAs. Recent studies also suggest that in tumors harboring a mutant RAS allele there is a critical role for wild type RAS proteins in determining overall RAS-ERK pathway activity. Together, these two advances comprise a new opportunity for therapeutic intervention. In this review, we evaluate miR-based therapeutic strategies for modulating RAS-ERK signaling in cancers, in particular for more direct modulation of RAS-GTP levels, with the potential to complement current strategies in order to yield more durable treatment responses. To this end, we discuss the potential for miR-based therapies focused on three prominent miRs including the pan-RAS regulator let-7 and the GAP regulator comprised of miR-206 and miR-21 (miR-206/21). PMID:26284568

  20. [Mantle cell lymphoma: Towards a personalized therapeutic strategy?].

    PubMed

    Navarro Matilla, Belén; García-Marco, José A

    2015-06-22

    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. PMID:25023849

  1. Ebola virus outbreak, updates on current therapeutic strategies.

    PubMed

    Elshabrawy, Hatem A; Erickson, Timothy B; Prabhakar, Bellur S

    2015-07-01

    Filoviruses are enveloped negative-sense single-stranded RNA viruses, which include Ebola and Marburg viruses, known to cause hemorrhagic fever in humans with a case fatality of up to 90%. There have been several Ebola virus outbreaks since the first outbreak in the Democratic Republic of Congo in 1976 of which, the recent 2013-2015 epidemic in Guinea, Liberia, and Sierra Leone is the largest in recorded history. Within a few months of the start of the outbreak in December 2013, thousands of infected cases were reported with a significant number of deaths. As of March 2015, according to the Centers for Disease Control and Prevention, there have been nearly 25,000 suspected cases, with 15,000 confirmed by laboratory testing, and over 10,000 deaths. The large number of cases and the high mortality rate, combined with the lack of effective Food and Drug Administration-approved treatments, necessitate the development of potent and safe therapeutic measures to combat the current and future outbreaks. Since the beginning of the outbreak, there have been considerable efforts to develop and characterize protective measures including vaccines and antiviral small molecules, and some have proven effective in vitro and in animal models. Most recently, a cocktail of monoclonal antibodies has been shown to be highly effective in protecting non-human primates from Ebola virus infection. In this review, we will discuss what is known about the nature of the virus, phylogenetic classification, genomic organization and replication, disease transmission, and viral entry and highlight the current approaches and efforts, in the development of therapeutics, to control the outbreak. PMID:25962887

  2. PHARMACOLOGICAL ANTIOXIDANT STRATEGIES AS THERAPEUTIC INTERVENTIONS FOR COPD

    PubMed Central

    2011-01-01

    Cigarette/tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress are intimately associated with the progression and exacerbation of chronic obstructive pulmonary disease (COPD). Therefore, targeting systemic and local oxidative stress with antioxidants/redox modulating agents, or boosting the endogenous levels of antioxidants are likely to have beneficial effects in the treatment/management of COPD. Various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine), all have been reported to modulate various cellular and biochemical aspects of COPD. These antioxidants have been found to scavenge and detoxify free radicals and oxidants, regulate of glutathione biosynthesis, control nuclear factor-kappaB (NF-kappaB) activation, and hence inhibiting inflammatory gene expression. Synthetic molecules, such as specific spin traps like α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, iNOS inhibitors, lipid peroxidation inhibitors/blockers edaravone, and lazaroids/tirilazad have also been shown to have beneficial effects by inhibiting the cigarette smoke-induced inflammatory responses and other carbonyl/oxidative stress-induced cellular alterations. A variety of oxidants, free radicals, and carbonyls/aldehydes are implicated in the pathogenesis of COPD, it is therefore, possible that therapeutic administration or supplementation of multiple antioxidants and/or boosting the endogenous levels of antioxidants will be beneficial in the treatment of COPD. This review discusses various novel pharmacological approaches adopted to enhance lung antioxidant levels, and various emerging beneficial and/or prophylactic effects of antioxidant therapeutics in halting or intervening the progression of COPD. PMID:22101076

  3. Current Diagnostic and Therapeutic Strategies in Microvascular Angina

    PubMed Central

    Mumma, Bryn; Flacke, Nathalie

    2014-01-01

    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

  4. A 3-step therapeutic strategy for severe alveolar proteinosis.

    PubMed

    Noirez, Leslie; Koutsokera, Angela; Pantet, Olivier; Duss, François-Régis; Eggimann, Philippe; Tozzi, Piergiorgio; Gonzalez, Michel; Coronado, Marcos; Nicod, Laurent P; Lovis, Alban

    2015-04-01

    Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of lipoproteinaceous material in the terminal airways. Whole lung lavage (WLL) remains the gold standard treatment but may be particularly challenging in cases of severe hypoxemia. We present a 3-step strategy that was used in a patient with PAP-associated refractory hypoxemia and that combined venovenous extracorporeal membrane oxygenation (vvECMO), double-lumen orotracheal intubation, and bilateral multisegmental sequential lavage (MSL). The procedure was well tolerated and permitted weaning from the ventilator. PMID:25841841

  5. Clinical Appearance of Oral Candida Infection and Therapeutic Strategies

    PubMed Central

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

    2015-01-01

    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. PMID:26733948

  6. Helminth products as a potential therapeutic strategy for inflammatory diseases.

    PubMed

    Soares, Maria Fernanda de Macedo; Araújo, Claudia A

    2008-06-01

    Helminths secrete several molecules that can modulate the immune responses, favoring their evasion and perpetuate their survival in the host. These molecules interfere with antigen presentation, cell proliferation and activation, antibody production, cause cell death, and stimulate regulatory responses. Here, we focus on some helminth products and address their immunomodulatory effects in the host immune system and, also, we describe some anti-inflammatory properties of an Ascaris suum-derived immunomodulatory molecule, named PAS-1. This protein is a 200-kDa molecule isolated by affinity chromatography using MAIP-1 (monoclonal antibody which recognizes PAS-1), coupled to Sepharose 4B. It suppresses the inflammatory responses in murine models of delayed-type hypersensitivity, lung allergic inflammation and LPS-induced inflammation into air pouches. PAS-1 also stimulates the secretion of regulatory cytokines such as IL-10 and TGF-beta and primes IFN-gamma-secreting CD8+ and IL-10/ TGF-beta-secreting CD4+CD25+ cell clones that avoid the lung inflammation. Thus, this protein is a potent immunomodulatory component that may be used for therapeutic interventions in inflammatory diseases. PMID:18691141

  7. Therapeutic strategies targeting B-cells in multiple sclerosis.

    PubMed

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease. PMID:26970489

  8. Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

    PubMed Central

    Chen, Xi-sha; Li, Lan-ya; Guan, Yi-di; Yang, Jin-ming; Cheng, Yan

    2016-01-01

    Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity. PMID:27374491

  9. Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect.

    PubMed

    Chen, Xi-Sha; Li, Lan-Ya; Guan, Yi-di; Yang, Jin-Ming; Cheng, Yan

    2016-08-01

    Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity. PMID:27374491

  10. Searching for additional endocrine functions of the skeleton: genetic approaches and implications for therapeutics

    PubMed Central

    Wei, Jianwen; Flaherty, Stephen; Karsenty, Gerard

    2016-01-01

    Our knowledge of whole organism physiology has greatly advanced in the past decades through mouse genetics. In particular, genetic studies have revealed that most organs interact with one another through hormones in order to maintain normal physiological functions and the homeostasis of the entire organism. Remarkably, through these studies many unexpected novel endocrine means to regulate physiological functions have been uncovered. The skeletal system is one example. In this article, we review a series of studies that over the years have identified bone as an endocrine organ. The mechanism of action, pathological relevance, and therapeutic implications of the functions of the bone-derived hormone osteocalcin are discussed. In the last part of this review we discuss the possibility that additional endocrine functions of the skeleton may exist.

  11. Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis.

    PubMed

    Xu, Suowen; Liu, Zhiping; Liu, Peiqing

    2014-03-15

    Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H2S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2S deficiency and that H2S supplementation by exogenous H2S donors (such as NaHS and GYY4137) attenuates, and H2S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523-2534) demonstrates that decreased endogenous H2S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE-/- mice, pinpointing that endogenously produced H2S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases. PMID:24491853

  12. Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review.

    PubMed

    Chibaudel, Benoist; Tournigand, Christophe; Bonnetain, Franck; Richa, Hubert; Benetkiewicz, Magdalena; André, Thierry; de Gramont, Aimery

    2015-05-01

    Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy. PMID:26673925

  13. Opportunistic yeast pathogens: reservoirs, virulence mechanisms, and therapeutic strategies.

    PubMed

    Polvi, Elizabeth J; Li, Xinliu; O'Meara, Teresa R; Leach, Michelle D; Cowen, Leah E

    2015-06-01

    Life-threatening invasive fungal infections are becoming increasingly common, at least in part due to the prevalence of medical interventions resulting in immunosuppression. Opportunistic fungal pathogens of humans exploit hosts that are immunocompromised, whether by immunosuppression or genetic predisposition, with infections originating from either commensal or environmental sources. Fungal pathogens are armed with an arsenal of traits that promote pathogenesis, including the ability to survive host physiological conditions and to switch between different morphological states. Despite the profound impact of fungal pathogens on human health worldwide, diagnostic strategies remain crude and treatment options are limited, with resistance to antifungal drugs on the rise. This review will focus on the global burden of fungal infections, the reservoirs of these pathogens, the traits of opportunistic yeast that lead to pathogenesis, host genetic susceptibilities, and the challenges that must be overcome to combat antifungal drug resistance and improve clinical outcome. PMID:25700837

  14. Treatment strategies for atopic dermatitis: optimizing the available therapeutic options.

    PubMed

    Paller, Amy S; Simpson, Eric L; Eichenfield, Lawrence F; Ellis, Charles N; Mancini, Anthony J

    2012-09-01

    Bathing and moisturization to control dryness, applications of topical anti-inflammatory agents (including corticosteroids and calcineurin inhibitors [TCIs]) to control flares, minimization of the risk for infection, and relief of pruritus are the cornerstones of effective therapy for atopic dermatitis. Education of parents and patients is crucial to enhance adherence. Strategies for reduced Staphylococcus aureus colonization may help control re-emergence of flares following cessation of antimicrobial treatment for infection; these include dilute bleach baths and minimizing the risk for contamination of topical agents. In severe, refractory cases, more aggressive therapy with systemic immunosuppressants may be considered, but appropriate laboratory testing must be included as part of patient monitoring during treatment. The value of adjuvant therapy with wet wraps to "cool down" particularly erythematous and pruritic flares is becoming increasingly recognized. PMID:23021780

  15. Protein Processing and Inflammatory Signaling in Cystic Fibrosis: Challenges and Therapeutic Strategies

    PubMed Central

    Belcher, C.N.; Vij, N.

    2010-01-01

    Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (ΔF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, ΔF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of ΔF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of ΔF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of ΔF508-CFTR with the goal of rescuing functional ΔF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially

  16. The National Literacy Strategy--Framework for Teaching: Additional Guidance.

    ERIC Educational Resources Information Center

    Department for Education and Skills, London (England).

    England's National Literacy Strategy is intended to raise standards of literacy for every student. Teachers should aim to include each student in the Literacy Hour. Evidence from the National Literacy Project (NLP), on which the national strategy is based, shows that students with widely varying needs can expect to improve their literacy skills in…

  17. Therapeutic strategies for complications secondary to hydatid cyst rupture

    PubMed Central

    Cobanoglu, Ufuk; Sayır, Fuat; Şehitoğlu, Abidin; Bilici, Salim; Melek, Mehmet

    2011-01-01

    Objective: Clinical approach and therapeutic methods are important in cases with complicated hydatid cysts of the lung. This study was designed to retrospectively investigate cases with hydatid cysts, thereby discussing diagnostic methods, treatment modalities, and rates of morbidity and mortality in line with the literature. Methods: 176 cases with perforated hydatid cysts, who presented to our clinic and underwent surgery between 2003 and 2011, were included in the study. There were 71 (40.34%) females and 105 males (59.66%) with a mean age of 27.80±14.07. The most common symptom was dyspnea (44.31%) and the most common radiological finding was the water lily sign (21.02%). 88.06% of the cases were surgically treated by Cystotomy+closure of bronchial opening+ capitonnage, 3.97% by wedge resection, 4.54% by segmentectomy and 3.40% by lobectomy. Results: The cysts exhibited multiple localization in 24 cases (13.63%), bilateral localization in 14 cases (7.95%), with the most common localization (43.75%) being the right lower lobe. While the hydatid cyst rupture occurred due to delivery in three (1.70%), trauma in 11 (6.25%), and iatrogenic causes in seven (3.97%) cases, it occurred spontaneously in the rest of the cases (88.08%). Fourteen of the cases with spontaneously occurring rupture (7.95%) were detected to have received anthelmintic treatment for hydatid cyst during the preoperative period (albendazole). The rate of morbidity was 27.27% and the rate of mortality was 1.13% in our study. Two cases recurred during a one-year follow-up (1.13%). Conclusion: Hydatid cyst rupture should be considered in the differential diagnosis of cases with pleural effusion, empyema, pneumothorax and pneumonia occurring in endemic regions. Symptoms occurring during and after perforation lead to errors in differential diagnosis. Performing the surgery without delay favorably affects postoperative morbidity and mortality. While parenchyma-preserving surgery is preferential, there

  18. Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis

    PubMed Central

    Bhise, Nupura S; Shmueli, Ron B; Sunshine, Joel C; Tzeng, Stephany Y; Green, Jordan J

    2014-01-01

    Introduction Angiogenesis is essential to human biology and of great clinical significance. Excessive or reduced angiogenesis can result in, or exacerbate, several disease states, including tumor formation, exudative age-related macular degeneration (AMD) and ischemia. Innovative drug delivery systems can increase the effectiveness of therapies used to treat angiogenesis-related diseases. Areas covered This paper reviews the basic biology of angiogenesis, including current knowledge about its disruption in diseases, with the focus on cancer and AMD. Anti- and proangiogenic drugs available for clinical use or in development are also discussed, as well as experimental drug delivery systems that can potentially improve these therapies to enhance or reduce angiogenesis in a more controlled manner. Expert opinion Laboratory and clinical results have shown pro- or antiangiogenic drug delivery strategies to be effective in drastically slowing disease progression. Further research in this area will increase the efficacy, specificity and duration of these therapies. Future directions with composite drug delivery systems may make possible targeting of multiple factors for synergistic effects. PMID:21338327

  19. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy

    PubMed Central

    Guiraud, Simon; Chen, Huijia; Burns, David T.

    2015-01-01

    New Findings 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. PMID:26140505

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

    PubMed Central

    Katoh, Hiroshi; Watanabe, Masahiko

    2015-01-01

    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. PMID:26078490

  1. Current Research Therapeutic Strategies for Alzheimer's Disease Treatment

    PubMed Central

    Folch, Jaume; Petrov, Dmitry; Ettcheto, Miren; Abad, Sonia; Sánchez-López, Elena; García, M. Luisa; Olloquequi, Jordi; Beas-Zarate, Carlos; Auladell, Carme; Camins, Antoni

    2016-01-01

    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. PMID:26881137

  2. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    PubMed

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  3. Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics

    PubMed Central

    Kim, Eunhee G.; Kim, Kristine M.

    2015-01-01

    Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris® (anti-CD30-drug conjugate) and Kadcyla® (anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed. PMID:26535074

  4. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

    PubMed Central

    Pertwee, Roger G.

    2012-01-01

    Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB2 receptors, and/or (v) adjunctive ‘multi-targeting’. PMID:23108552

  5. [Weighing use and safety of therapeutic agents and feed additives (author's transl)].

    PubMed

    van der Wal, P

    1982-02-01

    (1) The pros and cons of using feed additives and therapeutic agents may be successfully weighed in the light of carefully considered consumer requirements. (2) The socio-economic interests of the producer and the welfare of the animal will also determine the response of the production apparatus to consumer requirements. (3) Consumption of the current amounts of products of animal origin and maintenance of price and quality will only be feasible in the event of rational large-scale production in which constituents used in nutrition, prophylaxis and therapeutics are highly important factors. (4) Using these ingredients should be preceded by accurate evaluation of their use and safety. Testing facilities, conduct of studies and reporting should be such as to make the results nationally and internationally acceptable to all those concerned. (5) In deciding whether feed constituents are acceptable in view of the established use and safety, compliance will have to be sought with those standards which are accepted in other fields of society. Measures which result in raising the price of food without actually helping to reduce the risks to the safety of man, animals and environment, are likely to be rejected by any well-informed consumer who is aware of the facts. (6) For accurate weighing of use and safety at a national level, possibilities are hardly adequate in Europe. Decisions reached within the framework of the European Community, also tuned to U.S.A.- conditions are rightly encouraged. A centrally managed professionally staffed and equipped test system in the European Community would appear to be indispensable. PMID:7058519

  6. Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies

    PubMed Central

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

    2011-01-01

    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

  7. A mutational signature in gastric cancer suggests therapeutic strategies

    DOE PAGESBeta

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R.

    2015-10-29

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer andmore » demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.« less

  8. A mutational signature in gastric cancer suggests therapeutic strategies

    SciTech Connect

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R.

    2015-10-29

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Furthermore, our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors.

  9. A mutational signature in gastric cancer suggests therapeutic strategies

    PubMed Central

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Siu, Hoi Cheong; Leung, Suet Yi; Stratton, Michael R

    2015-01-01

    Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors. PMID:26511885

  10. Therapeutic strategy for small-sized lung cancer.

    PubMed

    Iwata, Hisashi

    2016-08-01

    Minimizing the volume of lung resection without diminishing curability has recently become an important issue in primary lung cancer. In this review, we will discuss the current state of the feasibility of sublobar resection and specific issues for a segmentectomy procedure. A previous randomized controlled trial showed that lobectomy must still be considered the standard surgical procedure compared with sublobar resection for T1N0 non-small cell lung cancer with a tumor less than 3 cm in size. Since then, supporting studies for segmentectomy of lung cancer with a tumor less than 2 cm in size were reported. In addition, segmentectomy seems to be feasible for clinical stage I adenocarcinoma less than 2 cm in size, in women younger than 70 years old, with a low tumor 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) from propensity-matching studies. In a meta-analysis of sublobar resection vs. lobectomy, intentionally performed sublobar resection showed equivalent outcomes to lobectomy. In the near future, two ongoing prospective, randomized trials will report results. As specific issues for the surgical procedure of segmentectomy, achieving a sufficient surgical margin is an important issue for preventing loco-regional recurrence. More studies regarding the regional lymph node dissection area for segmentectomy are needed. Sublobar resection has the potential to become the standard procedure for peripheral small-sized lung cancer less than 2 cm. However, more information is needed about the characteristics of this cancer and the surgical procedure, including nodal dissection. PMID:27300350

  11. Data Collection Strategies and Measurement Tools for Assessing Academic and Therapeutic Outcomes in Recovery Schools

    PubMed Central

    Botzet, Andria M.; McIlvaine, Patrick W.; Winters, Ken C.; Fahnhorst, Tamara; Dittel, Christine

    2014-01-01

    Accurate evaluation and documentation of the efficacy of recovery schools can be vital to the continuation and expansion of these beneficial resources. A very limited data set currently exists that examines the value of specific schools established to support adolescents and young adults in recovery; additional research is necessary. The following article outlines the methodology utilized in a current quasi-experimental study evaluating both academic and therapeutic outcomes of adolescents attending recovery high schools as compared to traditional (non-recovery-based) high schools. The developmental considerations in assessing adolescents in recovery and their parents is delineated in this article, which underscores the need for extensive knowledge of adolescent substance abuse and other mental health issues. In addition, sensitivity around privacy among adolescents, parents, schools, and health providers is highlighted, as well as the validity of assessment. Key assessment strategies, including protocol of recruitment and interviewing techniques, are also presented along with a list of parent and adolescent assessment instruments and their corresponding interpretive variables. Protocol recommendations for future research are also outlined. PMID:25018573

  12. Chronic Subdural Hematoma Associated with Spontaneous Intracranial Hypotension: Therapeutic Strategies and Outcomes of 55 Cases.

    PubMed

    Takahashi, Koichi; Mima, Tatsuo; Akiba, Yoichi

    2016-01-01

    Spontaneous intracranial hypotension (SIH) has increasingly been recognized, and it is well known that SIH is sometimes complicated by chronic subdural hematoma (SDH). In this study, 55 cases of SIH with SDH were retrospectively analyzed, focusing on therapeutic strategies and outcomes. Of 169 SIH cases (75 males, 84 females), 55 (36 males, 19 females) were complicated by SDH. SIH was diagnosed based on clinical symptoms, neuroimaging, and/or low cerebrospinal fluid pressure. Presence of orthostatic headache and diffuse meningeal enhancement on magnetic resonance imaging were regarded as the most important criteria. Among 55 SIH with SDH cases, 13 improved with conservative treatment, 25 initially received an epidural blood patch (EBP), and 17 initially underwent irrigation of the hematomas. Of the 25 initially treated with EBP, 7 (28.0%) needed SDH surgery and 18 (72.0%) recovered fully without surgery. Of 17 SDH cases initially treated with surgery, 6 (35.7%) required no EBP therapy and the other 11 (64.3%) needed EBP and/or additional SDH operations. In the latter group, 2 cases had transient severe complications during and after the procedures. One of these 2 cases developed a hoarse voice complication. Despite this single, non-severe complication, all enrolled in this study achieved good outcomes. The present study suggests that patients initially receiving SDH surgery may need additional treatments and may occasionally have complications. If conservative treatment is insufficient, EBP should be performed prior to hematoma irrigation. PMID:26489406

  13. Chronic Subdural Hematoma Associated with Spontaneous Intracranial Hypotension: Therapeutic Strategies and Outcomes of 55 Cases

    PubMed Central

    TAKAHASHI, Koichi; MIMA, Tatsuo; AKIBA, Yoichi

    2016-01-01

    Spontaneous intracranial hypotension (SIH) has increasingly been recognized, and it is well known that SIH is sometimes complicated by chronic subdural hematoma (SDH). In this study, 55 cases of SIH with SDH were retrospectively analyzed, focusing on therapeutic strategies and outcomes. Of 169 SIH cases (75 males, 84 females), 55 (36 males, 19 females) were complicated by SDH. SIH was diagnosed based on clinical symptoms, neuroimaging, and/or low cerebrospinal fluid pressure. Presence of orthostatic headache and diffuse meningeal enhancement on magnetic resonance imaging were regarded as the most important criteria. Among 55 SIH with SDH cases, 13 improved with conservative treatment, 25 initially received an epidural blood patch (EBP), and 17 initially underwent irrigation of the hematomas. Of the 25 initially treated with EBP, 7 (28.0%) needed SDH surgery and 18 (72.0%) recovered fully without surgery. Of 17 SDH cases initially treated with surgery, 6 (35.7%) required no EBP therapy and the other 11 (64.3%) needed EBP and/or additional SDH operations. In the latter group, 2 cases had transient severe complications during and after the procedures. One of these 2 cases developed a hoarse voice complication. Despite this single, non-severe complication, all enrolled in this study achieved good outcomes. The present study suggests that patients initially receiving SDH surgery may need additional treatments and may occasionally have complications. If conservative treatment is insufficient, EBP should be performed prior to hematoma irrigation. PMID:26489406

  14. Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review.

    PubMed

    Azevedo, Rita; Ferreira, José Alexandre; Peixoto, Andreia; Neves, Manuel; Sousa, Nuno; Lima, Aurea; Santos, Lucio Lara

    2015-09-28

    Bladder cancer is the most common malignancy of the urinary tract, presents the highest recurrence rate among solid tumors and is the second leading cause of death in genitourinary cancers. Despite recent advances in understanding of pathophysiology of the disease, the management of bladder cancer patients remains a clinically challenging problem. Particularly, bladder tumors invading the muscularis propria and disseminated disease are often not responsive to currently available therapeutic approaches, which include surgery and conventional chemotherapy. Antibody-based therapeutic strategies have become an established treatment option for over a decade in several types of cancer. However, bladder cancer has remained mostly an "orphan disease" regarding the introduction of these novel therapeutics, which has been translated in few improvements in patients overall survival. In order to shift this paradigm, several clinical studies involving antibody-based therapeutic strategies targeting the most prominent bladder cancer-related biomolecular pathways and immunological mediators are ongoing. This systematic review explores antibody-based therapeutics for bladder cancer undergoing clinical trial and discusses the future perspectives in this field, envisaging the development of more effective guided therapeutics. PMID:26196222

  15. Barriers to Effective Counseling with Blacks and Therapeutic Strategies for Overcoming Them.

    ERIC Educational Resources Information Center

    Tucker, Carolyn M.; And Others

    1981-01-01

    Presents strategies for counselors working with Black clients. Suggests awareness of potential barriers to effective counseling enables the therapist to gear the initial sessions toward overcoming these obstacles and thus make early observations of tangible therapeutic gains. Proposes such advances are important in overcoming client skepticism and…

  16. Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells.

    PubMed

    Kang, N-H; Hwang, K-A; Kim, S U; Kim, Y-B; Hyun, S-H; Jeung, E-B; Choi, K-C

    2012-08-01

    As stem cells are capable of self-renewal and can generate differentiated progenies for organ development, they are considered as potential source for regenerative medicine and tissue replacement after injury or disease. Along with this capacity, stem cells have the therapeutic potential for treating human diseases including cancers. According to the origins, stem cells are broadly classified into two types: embryonic stem cells (ESCs) and adult stem cells. In terms of differentiation potential, ESCs are pluripotent and adult stem cells are multipotent. Amnion, which is a membranous sac that contains the fetus and amniotic fluid and functions in protecting the developing embryo during gestation, is another stem cell source. Amnion-derived stem cells are classified as human amniotic membrane-derived epithelial stem cells, human amniotic membrane-derived mesenchymal stem cells and human amniotic fluid-derived stem cells. They are in an intermediate stage between pluripotent ESCs and lineage-restricted adult stem cells, non-tumorigenic, and contribute to low immunogenicity and anti-inflammation. Furthermore, they are easily available and do not cause any controversial issues in their recovery and applications. Not only are amnion-derived stem cells applicable in regenerative medicine, they have anticancer capacity. In non-engineered stem cells transplantation strategies, amnion-derived stem cells effectively target the tumor and suppressed the tumor growth by expressing cytotoxic cytokines. Additionally, they also have a potential as novel delivery vehicles transferring therapeutic genes to the cancer formation sites in gene-directed enzyme/prodrug combination therapy. Owing to their own advantageous properties, amnion-derived stem cells are emerging as a new candidate in anticancer therapy. PMID:22653384

  17. Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model

    PubMed Central

    Lineweaver, Charles H.; Davies, Paul C.W.; Vincent, Mark D.

    2014-01-01

    In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID:25043755

  18. 3D bioprinting: A new insight into the therapeutic strategy of neural tissue regeneration.

    PubMed

    Hsieh, Fu-Yu; Hsu, Shan-Hui

    2015-10-01

    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

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

    PubMed Central

    Nowara, Elżbieta

    2016-01-01

    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. PMID:27095932

  20. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies.

    PubMed

    Poulsen, Ebbe Toftgaard; Larsen, Agnete; Zollo, Alen; Jørgensen, Arne L; Sanggaard, Kristian W; Enghild, Jan J; Matrone, Carmela

    2015-01-01

    The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer's disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies. PMID:26690411

  1. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

    PubMed Central

    Pistritto, Giuseppa; Trisciuoglio, Daniela; Ceci, Claudia; Garufi, Alessia; D'Orazi, Gabriella

    2016-01-01

    Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed. PMID:27019364

  2. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies

    PubMed Central

    Ciechanover, Aaron; Kwon, Yong Tae

    2015-01-01

    Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons. PMID:25766616

  3. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC)

    PubMed Central

    Hall, Richard D.; Le, Tri M.; Haggstrom, Daniel E.

    2015-01-01

    In many cancers, including non-small cell lung cancer (NSCLC), tumor angiogenesis pathways have been identified as important therapeutic targets. Angiogenesis is essential in the process of primary tumor growth, proliferation and metastasis. One of the best characterized group of protein factors for angiogenesis include the members of the vascular endothelial growth factor (VEGF) family, consisting of VEGF-(A-D), and placenta growth factor (PIGF). Targeting tumor angiogenesis has been approached through two primary methods, monoclonal antibodies that block VEGF-vascular endothelial growth factor receptor (VEGFR) binding or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the downstream VEGFR mediated signaling. Many TKIs inhibit multiple pro-angiogenic and pro-proliferative pathways such as the mitogen activated protein (MAP) kinase pathway. Bevacizumab and ramucirumab, monoclonal antibodies targeting VEGF and the VEGFR, respectively, have each led to improvements in overall survival (OS) for NSCLC when added to standard first and second line chemotherapy, respectively. Small incremental gains seen with both bevacizumab and ramucirumab may be further improved upon by incorporating novel agents and treatment strategies, and many additional trials are ongoing. PMID:26629420

  4. Mesenchymal stem cell-based gene therapy: A promising therapeutic strategy.

    PubMed

    Mohammadian, Mozhdeh; Abasi, Elham; Akbarzadeh, Abolfazl

    2016-08-01

    Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in bone marrow, fat, and so many other tissues, and can differentiate into a variety of cell types including osteoblasts, chondrocytes, and adipocytes, as well as myocytes and neurons. Moreover, they have great capacity for self-renewal while maintaining their multipotency. Their capacity for proliferation and differentiation, in addition to their immunomodulatory activity, makes them very promising candidates for cell-based regenerative medicine. Moreover, MSCs have the ability of mobilization to the site of damage; therefore, they can automatically migrate to the site of injury via their chemokine receptors following intravenous transplantation. In this respect, they can be applied for MSC-based gene therapy. In this new therapeutic method, genes of interest are introduced into MSCs via viral and non-viral-based methods that lead to transgene expression in them. Although stem cell-based gene therapy is a relatively new strategy, it lights a new hope for the treatment of a variety of genetic disorders. In the near future, MSCs can be of use in a vast number of clinical applications, because of their uncomplicated isolation, culture, and genetic manipulation. However, full consideration is still crucial before they are utilized for clinical trials, because the number of studies that signify the advantageous effects of MSC-based gene therapy are still limited. PMID:26148175

  5. 3D bioprinting: A new insight into the therapeutic strategy of neural tissue regeneration

    PubMed Central

    Hsieh, Fu-Yu; Hsu, Shan-hui

    2015-01-01

    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

  6. Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function.

    PubMed

    Tajnik, Mojca; Rogalska, Malgorzata Ewa; Bussani, Erica; Barbon, Elena; Balestra, Dario; Pinotti, Mirko; Pagani, Franco

    2016-05-01

    Mutations that result in amino acid changes can affect both pre-mRNA splicing and protein function. Understanding the combined effect is essential for correct diagnosis and for establishing the most appropriate therapeutic strategy at the molecular level. We have identified a series of disease-causing splicing mutations in coagulation factor IX (FIX) exon 5 that are completely recovered by a modified U1snRNP particle, through an SRSF2-dependent enhancement mechanism. We discovered that synonymous mutations and missense substitutions associated to a partial FIX secretion defect represent targets for this therapy as the resulting spliced-corrected proteins maintains normal FIX coagulant specific activity. Thus, splicing and protein alterations contribute to define at the molecular level the disease-causing effect of a number of exonic mutations in coagulation FIX exon 5. In addition, our results have a significant impact in the development of splicing-switching therapies in particular for mutations that affect both splicing and protein function where increasing the amount of a correctly spliced protein can circumvent the basic functional defects. PMID:27227676

  7. Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function

    PubMed Central

    Bussani, Erica; Barbon, Elena; Pinotti, Mirko; Pagani, Franco

    2016-01-01

    Mutations that result in amino acid changes can affect both pre-mRNA splicing and protein function. Understanding the combined effect is essential for correct diagnosis and for establishing the most appropriate therapeutic strategy at the molecular level. We have identified a series of disease-causing splicing mutations in coagulation factor IX (FIX) exon 5 that are completely recovered by a modified U1snRNP particle, through an SRSF2-dependent enhancement mechanism. We discovered that synonymous mutations and missense substitutions associated to a partial FIX secretion defect represent targets for this therapy as the resulting spliced-corrected proteins maintains normal FIX coagulant specific activity. Thus, splicing and protein alterations contribute to define at the molecular level the disease-causing effect of a number of exonic mutations in coagulation FIX exon 5. In addition, our results have a significant impact in the development of splicing-switching therapies in particular for mutations that affect both splicing and protein function where increasing the amount of a correctly spliced protein can circumvent the basic functional defects. PMID:27227676

  8. The incretin system ABCs in obesity and diabetes - novel therapeutic strategies for weight loss and beyond.

    PubMed

    João, A L; Reis, F; Fernandes, R

    2016-07-01

    Incretins are gastrointestinal-derived hormones released in response to a meal playing a key role in the regulation of postprandial secretion of insulin (incretin effect) and glucagon by the pancreas. Both incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), have several other actions by peripheral and central mechanisms. GLP-1 regulates body weight by inhibiting appetite and delaying gastric, emptying actions that are dependent on central nervous system GLP-1 receptor activation. Several other hormones and gut peptides, including leptin and ghrelin, interact with GLP-1 to modulate appetite. GLP-1 is rapidly degraded by the multifunctional enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 is involved in adipose tissue inflammation, which is associated with insulin resistance and diabetes progression, being a common pathophysiological mechanism in obesity-related complications. Furthermore, the incretin system appears to provide the basis for understanding the high weight loss efficacy of bariatric surgery, a widely used treatment for obesity, often in association with diabetes. The present review brings together new insights into obesity pathogenesis, integrating GLP-1 and DPP-4 in the complex interplay between obesity and inflammation, namely, in diabetic patients. This in turn will provide the basis for novel incretin-based therapeutic strategies for obesity and diabetes with promising benefits in addition to weight loss. © 2016 World Obesity. PMID:27125902

  9. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

    PubMed Central

    Poulsen, Ebbe Toftgaard; Larsen, Agnete; Zollo, Alen; Jørgensen, Arne L.; Sanggaard, Kristian W.; Enghild, Jan J.; Matrone, Carmela

    2015-01-01

    The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies. PMID:26690411

  10. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies.

    PubMed

    Pistritto, Giuseppa; Trisciuoglio, Daniela; Ceci, Claudia; Garufi, Alessia; D'Orazi, Gabriella

    2016-04-01

    Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed. PMID:27019364

  11. Simple Addition Strategies in a First-Grade Class With Multiple Strategy Instruction

    ERIC Educational Resources Information Center

    Torbeyns, Joke; Verschaffel, Lieven; Ghesquiere, Pol

    2005-01-01

    In this study, we investigated the fluency with which first graders of different mathematical achievement levels applied multiple, school-taught strategies for finding arithmetic sums over 10. We characterized children's strategies with the 4 parameters of Lemaire and Siegler's (1995) model of strategy change (strategy repertoire, distribution,…

  12. Gender Differences in Elementary School Children's Strategy Use and Strategy Preferences on Multidigit Addition and Subtraction Story Problems

    ERIC Educational Resources Information Center

    Edwards-Omolewa, Nicola D.

    2011-01-01

    Gender differences in the strategies elementary school children use to solve multidigit addition and subtraction story problems that require regrouping are investigated in two studies. Study 1 replicates the Fennema and colleagues (1998) study by reexamining previously published data on 72 children's addition and subtraction solution strategies.…

  13. Mitigating cold flow problems of biodiesel: Strategies with additives

    NASA Astrophysics Data System (ADS)

    Mohanan, Athira

    The present thesis explores the cold flow properties of biodiesel and the effect of vegetable oil derived compounds on the crystallization path as well as the mechanisms at play at different stages and length scales. Model systems including triacylglycerol (TAG) oils and their derivatives, and a polymer were tested with biodiesel. The goal was to acquire the fundamental knowledge that would help design cold flow improver (CFI) additives that would address effectively and simultaneously the flow problems of biodiesel, particularly the cloud point (CP) and pour point (PP). The compounds were revealed to be fundamentally vegetable oil crystallization modifiers (VOCM) and the polymer was confirmed to be a pour point depressant (PPD). The results obtained with the VOCMs indicate that two cis-unsaturated moieties combined with a trans-/saturated fatty acid is a critical structural architecture for depressing the crystallization onset by a mechanism wherein while the straight chain promotes a first packing with the linear saturated FAMEs, the kinked moieties prevent further crystallization. The study of model binary systems made of a VOCM and a saturated FAME with DSC, XRD and PLM provided a complete phase diagram including the thermal transformation lines, crystal structure and microstructure that impact the phase composition along the different crystallization stages, and elicited the competing effects of molecular mass, chain length mismatch and isomerism. The liquid-solid boundary is discussed in light of a simple thermodynamic model based on the Hildebrand equation and pair interactions. In order to test for synergies, the PP and CP of a biodiesel (Soy1500) supplemented with several VOCM and PLMA binary cocktails were measured using a specially designed method inspired by ASTM standards. The results were impressive, the combination of additives depressed CP and PP better than any single additive. The PLM and DSC results suggest that the cocktail additives are most

  14. New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology.

    PubMed

    Roulston, Anne; Shore, Gordon C

    2016-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis in mammalian cells. NAMPT inhibitors represent multifunctional anticancer agents that act on NAD(+) metabolism to shut down glycolysis, nucleotide biosynthesis, and ATP generation and act indirectly as PARP and sirtuin inhibitors. The selectivity of NAMPT inhibitors preys on the increased metabolic requirements to replenish NAD(+) in cancer cells. Although initial clinical studies with NAMPT inhibitors did not achieve single-agent therapeutic levels before dose-limiting toxicities were reached, a new understanding of alternative rescue pathways and a biomarker that can be used to select patients provides new opportunities to widen the therapeutic window and achieve efficacious doses in the clinic. Recent work has also illustrated the potential for drug combination strategies to further enhance the therapeutic opportunities. This review summarizes recent discoveries in NAD(+)/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents. PMID:27308565

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

    PubMed Central

    Jung, Hun Soon; Rajasekaran, Nirmal; Ju, Woong; Shin, Young Kee

    2015-01-01

    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. PMID:26239469

  16. Crosstalk Between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

    PubMed Central

    El-Khattouti, Abdelouahid; Selimovic, Denis; Haikel, Youssef; Hassan, Mohamed

    2013-01-01

    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. PMID:25278778

  17. Therapeutic issues and intervention strategies with young adult lesbian clients: a developmental approach.

    PubMed

    Browning, C

    1987-01-01

    This paper examines the coming out process within an adult developmental context. Therapeutic issues which surface for the young adult lesbian client include separation from parents, development of social support, exploration of career/vocational goals, and the establishment of intimate relationships. Intervention strategies are suggested which facilitate the coming out process and help the client integrate her sexual orientation within her emerging adult identity. PMID:3655351

  18. Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination.

    PubMed

    Zhu, Danming; Liu, Longchao; Yang, Dan; Fu, Sherry; Bian, Yingjie; Sun, Zhichen; He, Junming; Su, Lishan; Zhang, Liguo; Peng, Hua; Fu, Yang-Xin

    2016-04-01

    Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg Ab in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4(+) T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8(+) T cells induced by the addition of a TLR agonist resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral Ag with neutralizing Abs followed by vaccination. PMID:26936879

  19. The evolution strategy--a search strategy used in individual optimization of electrical parameters for therapeutic carotid sinus nerve stimulation.

    PubMed

    Peters, T K; Koralewski, H E; Zerbst, E W

    1989-07-01

    Optimization problems, arising in the search for parameters and/or techniques of functional electrostimulation (FES), disproportionally increase when multiple electrodes, electrode configurations, electrical parameters, and stimulation modes may be applied. When computational or investigational effort precludes systematic studies in FES, we propose to apply and evaluate Rechenberg's evolution strategy, which in technical use and numerical optimization has been valid in comparison to more traditional methods. This strategy implements mutation and selection processes in analogy to biological evolution. The effect of combined multiple input variables on a quality function (Q) is experimentally evaluated. The actual computed value of Q serves as a selection criterion for those input variable combinations which lead Q to approach a target value (maximization), similar to a hill-climbing procedure. In radiofrequency controlled, therapeutic electrical carotid sinus nerve stimulation (CSNS), we varied (mutated) combinations of pulse frequency and pulse amplitude parameters, according to the evolution strategy, in individual patients. CSNS lowers blood pressure and decreases heart rate. Q was computed from blood pressure and heart rate responses to CSNS. The strategy individually optimized electrical parameters to achieve large depressor responses upon CSNS. Although, in contrast to technical usage, only two input variables were investigated, and biomedical experience with the evolution strategy is limited so far, its potential use in other fields of FES, especially when more input variables are to be optimized, is discussed and encouraged. PMID:2787277

  20. Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

    PubMed Central

    Spadi, Rosella; Brusa, Federica; Ponzetti, Agostino; Chiappino, Isabella; Birocco, Nadia; Ciuffreda, Libero; Satolli, Maria Antonietta

    2016-01-01

    Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease. PMID:26862489

  1. Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians.

    PubMed

    Spadi, Rosella; Brusa, Federica; Ponzetti, Agostino; Chiappino, Isabella; Birocco, Nadia; Ciuffreda, Libero; Satolli, Maria Antonietta

    2016-02-10

    Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease. PMID:26862489

  2. Strategy Instruction in Early Childhood Math Software: Detecting and Teaching Single-Digit Addition Strategies

    ERIC Educational Resources Information Center

    Carpenter, Kara Kilmartin

    2013-01-01

    In early childhood mathematics, strategy-use is an important indicator of children's conceptual understanding and is a strong predictor of later math performance. Strategy instruction is common in many national curricula, yet is virtually absent from most math software. The current study describes the design of one software activity teaching…

  3. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

    PubMed Central

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R.; Choy, Meng S.; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D.; Tonks, Nicholas K.

    2015-01-01

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG–binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2–/y) mice and improved behavior in female heterozygous (Mecp2–/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs. PMID:26214522

  4. [Recent advances in pathogenic concepts and therapeutic strategies in Rasmussen's encephalitis].

    PubMed

    Bahi-Buisson, N; Nabbout, R; Plouin, P; Bulteau, C; Delalande, O; Hertz Pannier, L; Dulac, O; Chiron, C

    2005-04-01

    Rasmussen's encephalitis (RE) is a rare inflammatory brain disease mainly affecting children and characterised by intractable epilepsy involving a single hemisphere that undergoes progressive atrophy. RE is characterized by refractory focal seizures, often associated with epilepsia partialis continua, progressive unilateral motor defect, slow EEG activity over the entire contralateral hemisphere, with focal white matter hyperintensity and insular cortical atrophy on neuroimaging. Surgical exclusion of the affected hemisphere is the only treatment that interrupts progression of the disease. Pathogenic concepts have considered viruses, autoimmune antibodies and autoimmune cytotoxic T lymphocytes that might contribute to the initiating or perpetuating events in the central nervous system. Based on these concepts, different therapeutic strategies have been pursued, such as antiviral agents, plasmapheresis, immuno-adsorption, immunosuppression or immunomodulation with intravenous immunoglobulins. However, due to the lack of large studies, to date there is no established therapeutic strategy for this devastating condition. In this review, we give an overview of the current state of immunopathogenic concepts for Rasmussen's encephalitis and discuss the different therapeutic options for future perspectives. PMID:15924075

  5. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome.

    PubMed

    Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R; Choy, Meng S; Page, Rebecca; Peti, Wolfgang; Van Aelst, Linda; Shea, Stephen D; Tonks, Nicholas K

    2015-08-01

    The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2-/y) mice and improved behavior in female heterozygous (Mecp2-/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs. PMID:26214522

  6. Potential Therapeutic Strategies for Alzheimer's Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials

    PubMed Central

    Jia, Qiutian; Qing, Hong

    2014-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer's disease. PMID:25136630

  7. The arsenal of pathogens and antivirulence therapeutic strategies for disarming them

    PubMed Central

    Brannon, John R; Hadjifrangiskou, Maria

    2016-01-01

    Pathogens deploy an arsenal of virulence factors (VFs) to establish themselves within their infectious niche. The discovery of antimicrobial compounds and their development into therapeutics has made a monumental impact on human and microbial populations. Although humans have used antimicrobials for medicinal and agricultural purposes, microorganism populations have developed and shared resistance mechanisms to persevere in the face of classical antimicrobials. However, a positive substitute is antivirulence therapy; antivirulence therapeutics prevent or interrupt an infection by counteracting a pathogen’s VFs. Their application can reduce the use of broad-spectrum antimicrobials and dampen the frequency with which resistant strains emerge. Here, we summarize the contribution of VFs to various acute and chronic infections. In correspondence with this, we provide an overview of the research and development of antivirulence strategies. PMID:27313446

  8. Therapeutic strategy for hair regeneration: Hair cycle activation, niche environment modulation, wound-induced follicle neogenesis and stem cell engineering

    PubMed Central

    Chueh, Shan-Chang; Lin, Sung-Jan; Chen, Chih-Chiang; Lei, Mingxing; Wang, Ling Mei; Widelitz, Randall B.; Hughes, Michael W.; Jiang, Ting-Xing; Chuong, Cheng Ming

    2013-01-01

    Introduction There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate and apply these findings to tissue engineering and regenerative medicine. Readers will learn about new progress in cellular and molecular aspects of hair follicle development, regeneration and potential therapeutic opportunities these advances may offer. Areas covered Here we use hair follicle formation to illustrate this progress and to identify targets for potential strategies in therapeutics. Hair regeneration is discussed in four different categories. (1) Intra-follicle regeneration (or renewal) is the basic production of hair fibers from hair stem cells and dermal papillae in existing follicles. (2) Chimeric follicles via epithelial-mesenchymal recombination to identify stem cells and signaling centers. (3) Extra-follicular factors including local dermal and systemic factors can modulate the regenerative behavior of hair follicles, and may be relatively easy therapeutic targets. (4) Follicular neogenesis means the de novo formation of new follicles. In addition, scientists are working to engineer hair follicles, which require hair forming competent epidermal cells and hair inducing dermal cells. Expert opinion Ideally self-organizing processes similar to those occurring during embryonic development should be elicited with some help from biomaterials. PMID:23289545

  9. Radioimmunotherapy: potential as a therapeutic strategy in non-Hodgkin's lymphoma.

    PubMed

    Wun, T; Kwon, D S; Tuscano, J M

    2001-01-01

    Lymphomas are the fifth most common malignancy in the United States and are increasing in incidence. Despite being among the most responsive malignancies to radiation and chemotherapy, the majority of patients relapse or have progressive disease. Monoclonal antibodies (MAbs) directed at cell-specific surface antigens have been useful in the diagnosis of lymphomas and, more recently, the therapeutic mouse-human chimeric MAb rituximab has demonstrated effectiveness in B cell lymphomas. Conjugating MAbs to radionuclides is a strategy for improving the efficacy of MAb lymphoma therapy by delivering radiation in close proximity to the tumour (radioimmunotherapy or RIT). In addition, the low dose rate of the delivered radiation may exert a greater antitumour activity than an equivalent dose of conventional external beam radiation. The antigenic targets for MAb therapy have included CD20, CD22, HLA-DR, and B cell idiotype. Radionuclides that have been used include iodine-131, yttrium-90, and copper-67; there are relative merits and disadvantages to each source of radiation. Clinical studies to date have focused on relapsed and refractory patients with both indolent and aggressive lymphomas, although more recent studies have included previously untreated patients with indolent lymphoma. Radioimmunoconjugate has been delivered as either single or multiple doses. Response rates have varied widely, dependent on the patient population and the response criteria. Of note, complete responses can be achieved in this typically refractory patient group. Toxicities have generally consisted of mild infusion-related nausea, fever, chills, and asthenia. Neutropenia and thrombocytopenia are the dose-limiting toxicities and have prompted the incorporation of autologous stem cell support as a means of achieving dose escalation. To date, RIT has been delivered to highly selected patients in relatively few centres with requisite equipment and specialised personnel. In addition to these

  10. Young children's use of derived fact strategies for addition and subtraction

    PubMed Central

    Dowker, Ann

    2014-01-01

    Forty-four children between 6;0 and 7;11 took part in a study of derived fact strategy use. They were assigned to addition and subtraction levels on the basis of calculation pretests. They were then given Dowker's (1998) test of derived fact strategies in addition, involving strategies based on the Identity, Commutativity, Addend +1, Addend −1, and addition/subtraction Inverse principles; and test of derived fact strategies in subtraction, involving strategies based on the Identity, Minuend +1, Minuend −1, Subtrahend +1, Subtrahend −1, Complement and addition/subtraction Inverse principles. The exact arithmetic problems given varied according to the child's previously assessed calculation level and were selected to be just a little too difficult for the child to solve unaided. Children were given the answer to a problem and then asked to solve another problem that could be solved quickly by using this answer, together with the principle being assessed. The children also took the WISC Arithmetic subtest. Strategies differed greatly in difficulty, with Identity being the easiest, and the Inverse and Complement principles being most difficult. The Subtrahend +1 and Subtrahend −1 problems often elicited incorrect strategies based on an overextension of the principles of addition to subtraction. It was concluded that children may have difficulty with understanding and applying the relationships between addition and subtraction. Derived fact strategy use was significantly related to both calculation level and to WISC Arithmetic scaled score. PMID:24431996

  11. Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics.

    PubMed

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

    2016-04-01

    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. PMID:27079260

  12. Molecular basis and current strategies of therapeutic arginine depletion for cancer.

    PubMed

    Fultang, Livingstone; Vardon, Ashley; De Santo, Carmela; Mussai, Francis

    2016-08-01

    Renewed interest in the use of therapeutic enzymes combined with an improved knowledge of cancer cell metabolism, has led to the translation of several arginine depletion strategies into early phase clinical trials. Arginine auxotrophic tumors are reliant on extracellular arginine, due to the downregulation of arginosuccinate synthetase or ornithine transcarbamylase-key enzymes for intracellular arginine recycling. Engineered arginine catabolic enzymes such as recombinant human arginase (rh-Arg1-PEG) and arginine deiminase (ADI-PEG) have demonstrated cytotoxicity against arginine auxotrophic tumors. In this review, we discuss the molecular events triggered by extracellular arginine depletion that contribute to tumor cell death. PMID:26913960

  13. HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies

    PubMed Central

    Battistini, Angela; Sgarbanti, Marco

    2014-01-01

    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. PMID:24736215

  14. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

    PubMed

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

    2016-07-01

    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. PMID:26841308

  15. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer.

    PubMed

    Kirk, Jason S; Schaarschuch, Kevin; Dalimov, Zafardjan; Lasorsa, Elena; Ku, ShengYu; Ramakrishnan, Swathi; Hu, Qiang; Azabdaftari, Gissou; Wang, Jianmin; Pili, Roberto; Ellis, Leigh

    2015-02-20

    Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development. PMID:25605014

  16. Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer

    PubMed Central

    Lasorsa, Elena; Ku, ShengYu; Ramakrishnan, Swathi; Hu, Qiang; Azabdaftari, Gissou; Wang, Jianmin; Pili, Roberto; Ellis, Leigh

    2015-01-01

    Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development. PMID:25605014

  17. Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine.

    PubMed

    Nguyen, Minh Khanh; Alsberg, Eben

    2014-07-01

    Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years. PMID:25242831

  18. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

    PubMed Central

    Mangiafico, Sarah; Costello-Boerrigter, Lisa C.; Andersen, Ingrid A.; Cataliotti, Alessandro; Burnett, John C.

    2013-01-01

    Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension. PMID:22942338

  19. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies

    PubMed Central

    Passaro, Antonio; Gori, Bruno; Del Signore, Ester; Migliorino, Maria Rita; Ricciardi, Serena; Fulvi, Alberto; de Marinis, Filippo

    2014-01-01

    Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor κB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer. PMID:24790650

  20. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies

    PubMed Central

    Ju, Cynthia; Tacke, Frank

    2016-01-01

    Macrophages represent a major cell type of innate immunity and have emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. Hepatic macrophages play a central role in maintaining homeostasis of the liver and in the pathogenesis of liver injury, making them an attractive therapeutic target for liver diseases. However, the various populations of hepatic macrophages display different phenotypes and exert distinct functions. Thus, more research is required to better understand these cells to guide the development of macrophage-based therapeutic interventions. This review article will summarize the current knowledge on the origins and composition of hepatic macrophages, their functions in maintaining hepatic homeostasis, and their involvement in both promoting and resolving liver inflammation, injury, and fibrosis. Finally, the current strategies being developed to target hepatic macrophages for the treatment of liver diseases will be reviewed. PMID:26908374

  1. miRNAs in pancreatic cancer: therapeutic potential, delivery challenges and strategies.

    PubMed

    Chitkara, Deepak; Mittal, Anupama; Mahato, Ram I

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a severe pancreatic malignancy and is predicted to victimize 1.5% of men and women during their lifetime (Cancer statistics: SEER stat fact sheet, National Cancer Institute, 2014). miRNAs have emerged as a promising prognostic, diagnostic and therapeutic tool to fight against pancreatic cancer. miRNAs could modulate gene expression by imperfect base-pairing with target mRNA and hence provide means to fine-tune multiple genes simultaneously and alter various signaling pathways associated with the disease. This exceptional miRNA feature has provided a paradigm shift from the conventional one drug one target concept to one drug multiple target theory. However, in vivo miRNA delivery is not fully realized due to challenges posed by this special class of therapeutic molecules, which involves thorough understanding of the biogenesis and physicochemical properties of miRNA and delivery carriers along with the pathophysiology of the PDAC. This review highlights the delivery strategies of miRNA modulators (mimic/inhibitor) in cancer with special emphasis on PDAC since successful delivery of miRNA in vivo constitutes the major challenge in clinical translation of this promising class of therapeutics. PMID:25252098

  2. Mechanisms of drug resistance in colon cancer and its therapeutic strategies

    PubMed Central

    Hu, Tao; Li, Zhen; Gao, Chun-Ying; Cho, Chi Hin

    2016-01-01

    Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics. PMID:27570424

  3. New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology

    PubMed Central

    Roulston, Anne; Shore, Gordon C.

    2016-01-01

    ABSTRACT Nicotinamide phosphoribosyltransferase (NAMPT) is crucial for nicotinamide adenine dinucleotide (NAD+) biosynthesis in mammalian cells. NAMPT inhibitors represent multifunctional anticancer agents that act on NAD+ metabolism to shut down glycolysis, nucleotide biosynthesis, and ATP generation and act indirectly as PARP and sirtuin inhibitors. The selectivity of NAMPT inhibitors preys on the increased metabolic requirements to replenish NAD+ in cancer cells. Although initial clinical studies with NAMPT inhibitors did not achieve single-agent therapeutic levels before dose-limiting toxicities were reached, a new understanding of alternative rescue pathways and a biomarker that can be used to select patients provides new opportunities to widen the therapeutic window and achieve efficacious doses in the clinic. Recent work has also illustrated the potential for drug combination strategies to further enhance the therapeutic opportunities. This review summarizes recent discoveries in NAD+/NAMPT inhibitor biology in the context of exploiting this new knowledge to optimize the clinical outcomes for this promising new class of agents. PMID:27308565

  4. Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

    PubMed Central

    Nguyen, Minh Khanh; Alsberg, Eben

    2014-01-01

    Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years. PMID:25242831

  5. Strategies for Implementing and Sustaining Therapeutic Lifestyle Changes as Part of Hypertension Management in African Americans

    PubMed Central

    Scisney-Matlock, Margaret; Bosworth, Hayden B.; Giger, Joyce Newman; Strickland, Ora L.; Van Harrison, R.; Coverson, Dorothy; Shah, Nirav R.; Dennison, Cheryl R.; Dunbar-Jacob, Jacqueline M.; Jones, Loretta; Ogedegbe, Gbenga; Batts-Turner, Marian L.; Jamerson, Kenneth A.

    2009-01-01

    African Americans with high blood pressure (BP) can benefit greatly from therapeutic lifestyle changes (TLC) such as diet modification, physical activity, and weight management. However, they and their health care providers face many barriers in modifying health behaviors. A multidisciplinary panel synthesized the scientific data on TLC in African Americans for efficacy in improving BP control, barriers to behavioral change, and strategies to overcome those barriers. Therapeutic lifestyle change interventions should emphasize patient self-management, supported by providers, family, and the community. Interventions should be tailored to an individual’s cultural heritage, beliefs, and behavioral norms. Simultaneously targeting multiple factors that impede BP control will maximize the likelihood of success. The panel cited limited progress with integrating the Dietary Approaches to Stop Hypertension (DASH) eating plan into the African American diet as an example of the need for more strategically developed interventions. Culturally sensitive instruments to assess impact will help guide improved provision of TLC in special populations. The challenge of improving BP control in African Americans and delivery of hypertension care requires changes at the health system and public policy levels. At the patient level, culturally sensitive interventions that apply the strategies described and optimize community involvement will advance TLC in African Americans with high BP. PMID:19491553

  6. Physical and Chemical Strategies for Therapeutic Delivery by Using Polymeric Nanoparticles

    PubMed Central

    Morachis, José M.; Mahmoud, Enas A.

    2012-01-01

    A significant challenge that most therapeutic agents face is their inability to be delivered effectively. Nanotechnology offers a solution to allow for safe, high-dose, specific delivery of pharmaceuticals to the target tissue. Nanoparticles composed of biodegradable polymers can be designed and engineered with various layers of complexity to achieve drug targeting that was unimaginable years ago by offering multiple mechanisms to encapsulate and strategically deliver drugs, proteins, nucleic acids, or vaccines while improving their therapeutic index. Targeting of nanoparticles to diseased tissue and cells assumes two strategies: physical and chemical targeting. Physical targeting is a strategy enabled by nanoparticle fabrication techniques. It includes using size, shape, charge, and stiffness among other parameters to influence tissue accumulation, adhesion, and cell uptake. New methods to measure size, shape, and polydispersity will enable this field to grow and more thorough comparisons to be made. Physical targeting can be more economically viable when certain fabrication techniques are used. Chemical targeting can employ molecular recognition units to decorate the surface of particles or molecular units responsive to diseased environments or remote stimuli. In this review, we describe sophisticated nanoparticles designed for tissue-specific chemical targeting that use conjugation chemistry to attach targeting moieties. Furthermore, we describe chemical targeting using stimuli responsive nanoparticles that can respond to changes in pH, heat, and light. PMID:22544864

  7. Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies

    PubMed Central

    Mileo, Anna Maria; Miccadei, Stefania

    2016-01-01

    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

  8. Image-Guided Local Delivery Strategies Enhance Therapeutic Nanoparticle Uptake in Solid Tumors

    PubMed Central

    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.

    2013-01-01

    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 nano-ablation and nano-embolization. Nano-ablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nano-embolization 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 intra-tumoral 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. PMID:23952712

  9. Strategies for Delivery of Therapeutics into the Central Nervous System for Treatment of Lysosomal Storage Disorders

    PubMed Central

    Muro, Silvia

    2014-01-01

    Lysosomal storage disorders (LSDs) are a group of about fifty life-threatening conditions caused by genetic defects affecting lysosomal components. The underscoring molecular deficiency leads to widespread cellular dysfunction through most tissues in the body, including peripheral organs and the central nervous system (CNS). Efforts during the last few decades have rendered a remarkable advance regarding our knowledge, medical awareness, and early detection of these genetic defects, as well as development of several treatment modalities. Clinical and experimental strategies encompassing enzyme replacement, gene and cell therapies, substrate reduction, and chemical chaperones are showing considerable potential in attenuating the peripheral pathology. However, a major drawback has been encountered regarding the suboptimal impact of these approaches on the CNS pathology. Particular anatomical and biochemical constraints of this tissue pose a major obstacle to the delivery of therapeutics into the CNS. Approaches to overcome these obstacles include modalities of local administration, strategies to enhance the blood-CNS permeability, intranasal delivery, use of exosomes, and those exploiting targeting of transporters and transcytosis pathways in the endothelial lining. The later two approaches are being pursued at the time by coupling therapeutic agents to affinity moieties and drug delivery systems capable of targeting these natural transport routes. This approach is particularly promising, as using paths naturally active at this interface may render safe and effective delivery of LSD therapies into the CNS. PMID:24688886

  10. No-reflow: a heterogeneous clinical phenomenon with multiple therapeutic strategies.

    PubMed

    Galiuto, Leonarda; Crea, Filippo

    2006-01-01

    Previously defined as the failure to achieve uniform intramyocardial reperfusion after prolonged but reversible coronary occlusion, only recently has no-reflow phenomenon been characterized as a heterogeneous clinical condition. In fact, in about half of post-infarct patients that show no-reflow after 24 hours from coronary recanalization by either thrombolysis or PTCA, no-reflow phenomenon is spontaneously reversible. Reversible no-reflow is associated with favorable left ventricular remodeling even in the absence of significant improvement in regional contractile function. Thus, it may be a clinical marker of yet unknown mechanisms, which may favorably affect myocardial response to necrosis. Based on the pathogenesis and on the time-course of no-reflow, the phenomenon may be associated with lack of patency or with loss of anatomic integrity of microvessels, with the former being potentially reversible while the latter associated with definitive tissue damage. As a consequence, possible therapeutic strategies of no-reflow have to be designed according to not only the main target [microvessel patency or integrity], but also taking into account the timing of development of the damage. This "mini review" is focused on recent advances on the pathogenesis and clinical presentation on no-reflow. These data will give the opportunity to formulate novel interpretation and classification of the phenomenon and consequently, to propose adequate therapeutic strategies. PMID:17073679

  11. Efficiency and Adaptiveness of Multiple School-Taught Strategies in the Domain of Simple Addition

    ERIC Educational Resources Information Center

    Torbeyns, Joke; Verschaffel, Lieven; Ghesquiere, Pol

    2004-01-01

    This study investigated the fluency with which first-graders with strong, moderate, or weak mathematical abilities apply the decomposition-to-10 and tie strategy on almost-tie sums with bridge over 10. It also assessed children's memorized knowledge of additions up to 20. Children's strategies were analysed in terms of Lemaire and Siegler's model…

  12. Strategies of Pre-Service Primary School Teachers for Solving Addition Problems with Negative Numbers

    ERIC Educational Resources Information Center

    Almeida, Rut; Bruno, Alicia

    2014-01-01

    This paper analyses the strategies used by pre-service primary school teachers for solving simple addition problems involving negative numbers. The findings reveal six different strategies that depend on the difficulty of the problem and, in particular, on the unknown quantity. We note that students use negative numbers in those problems they find…

  13. Synthesis of Nanodiamond Drug Carriers to Overcome Multidrug Chemoresistance in Leukemia and Other Nanodiamond-based Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Man, Han Bin

    Nanodiamonds (NDs) are remarkable nanoscale materials uniting key properties necessary for clinical applications. The Ho group has focused on developing ND platforms for cancer therapy, specifically as delivery vehicles able to protect and enhance the efficacy of therapeutic payloads. This thesis will highlight progress made towards bringing nanodiamonds from the bench to the bedside in several critical therapeutic strategies. We have synthesized ND vectors capable of chemotherapeutic loading and delivery to treat chemoresistant leukemia. Daunorubicin (DNR) loading, a novel therapeutic payload for NDs, was optimized by adjusting reaction parameters. A K562 leukemia line, with multidrug resistance conferred by incremental DNR exposure, was used to demonstrate the efficacy enhancement resulting from ND-based delivery. While resistant K562 cells were able to overcome treatment from DNR alone, as compared with non-resistant K562 cells, NDs were able to improve DNR delivery into resistant K562 cells. By overcoming efflux mechanisms, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains. NDs functionalized with polyethylenimine (PEI) can transfect siRNAs in vitro with high efficiency and low cytotoxicity. A modeling framework has been developed to accurately guide the design of ND-PEI gene platforms and elucidate binding mechanisms between ND, PEI, and siRNA. This is among the first ND simulations to comprehensively account for size, charge distribution, surface functionalization, and graphitization. Simulations were compared with experiments for PEI loading onto NDs and siRNA (C-myc) loading onto ND-PEI for various mixing ratios. Remarkably, the model was able to predict PEI/siRNA loading trends and saturation limits, while confirming the essential role of surface functionalization. These results demonstrate that this robust framework can be a powerful tool in ND platform development. Hybrid

  14. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  15. Memory focused interventions (MFI) as a therapeutic strategy in hypnotic psychotherapy.

    PubMed

    Meyerson, Joseph

    2010-01-01

    The prospect of utilizing memory plasticity (the constructive and transitory nature of memory) for therapeutic purposes has not been widely recognized. However, a number of theoretical and clinical venues throughout the last century have shown its potential application. Intensive research conducted during these last decades, pointed out the possibility of influencing human memory in relation to new memories and their specific components. Moreover, the research showed the feasibility of planting alternative early childhood memories and thus altering memories of personal history. Additionally, researchers found that memory is naturally very fallible due to everyday phenomena of forgetfulness, distortion and intrusion of past and present information. Throughout the course of this paper, the integrative overview of these empirical findings with the aforementioned clinical and theoretical foundations serves as a substratum in an attempt to present an integrative therapeutic approach, named Memory Focused Interventions (MFI). PMID:20187338

  16. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia.

    PubMed

    Peirs, Sofie; Matthijssens, Filip; Goossens, Steven; Van de Walle, Inge; Ruggero, Katia; de Bock, Charles E; Degryse, Sandrine; Canté-Barrett, Kirsten; Briot, Delphine; Clappier, Emmanuelle; Lammens, Tim; De Moerloose, Barbara; Benoit, Yves; Poppe, Bruce; Meijerink, Jules P; Cools, Jan; Soulier, Jean; Rabbitts, Terence H; Taghon, Tom; Speleman, Frank; Van Vlierberghe, Pieter

    2014-12-11

    T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, therapy-resistant or refractory T-ALL remains a major clinical challenge. Here, we evaluated B-cell lymphoma (BCL)-2 inhibition by the BH3 mimetic ABT-199 as a new therapeutic strategy in human T-ALL. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3- or HOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T-cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL. In conclusion, our study highlights BCL-2 as an attractive molecular target in specific subtypes of human T-ALL that could be exploited by ABT-199. PMID:25301704

  17. Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies

    PubMed Central

    Medina, Miguel; Garrido, Juan Jose; Wandosell, Francisco G.

    2011-01-01

    Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed and unusually active in resting, non-stimulated cells. In mammals, at least three proteins (α, β1, and β2), generated from two different genes, gsk-3α and gsk-3β, are widely expressed at both the RNA and protein levels although some tissues show preferential expression of some of the three proteins. Control of GSK-3 activity occurs by complex mechanisms that depend on specific signaling pathways, often controlling the inhibition of the kinase activity. GSK-3 appears to integrate different signaling pathways from a wide selection of cellular stimuli. The unique position of GSK-3 in modulating the function of a diverse series of proteins and its association with a wide variety of human disorders has attracted significant attention as a therapeutic target and as a means to understand the molecular basis of brain disorders. Different neurodegenerative diseases including frontotemporal dementia, progressive supranuclear palsy, and Alzheimer’s disease, present prominent tau pathology such as tau hyperphosphorylation and aggregation and are collectively referred to as tauopathies. GSK-3 has also been associated to different neuropsychiatric disorders, like schizophrenia and bipolar disorder. GSK-3β is the major kinase to phosphorylate tau both in vitro and in vivo and has been proposed as a target for therapeutic intervention. The first therapeutic strategy to modulate GSK-3 activity was the direct inhibition of its kinase activity. This review will focus on the signaling pathways involved in the control of GSK-3 activity and its pathological deregulation. We will highlight different alternatives of GSK-3 modulation including the direct pharmacological inhibition as compared to the modulation by upstream regulators. PMID:22007157

  18. The potential utilizations of hydrogen as a promising therapeutic strategy against ocular diseases

    PubMed Central

    Tao, Ye; Geng, Lei; Xu, Wei-Wei; Qin, Li-Min; Peng, Guang-Hua; Huang, Yi-Fei

    2016-01-01

    Hydrogen, one of the most well-known natural molecules, has been used in numerous medical applications owing to its ability to selectively neutralize cytotoxic reactive oxygen species and ameliorate hazardous inflammations. Hydrogen can exert protective effects on various reactive oxygen species-related diseases, including the transplantation-induced intestinal graft injury, chronic inflammation, ischemia–reperfusion injuries, and so on. Especially in the eye, hydrogen has been used to counteract multiple ocular pathologies in the ophthalmological models. Herein, the ophthalmological utilizations of hydrogen are systematically reviewed and the underlying mechanisms of hydrogen-induced beneficial effects are discussed. It is our hope that the protective effects of hydrogen, as evidenced by these pioneering studies, would enrich our pharmacological knowledge about this natural element and cast light into the discovery of a novel therapeutic strategy against ocular diseases. PMID:27279745

  19. Pharmacological induction of mitochondrial biogenesis as a therapeutic strategy for the treatment of type 2 diabetes.

    PubMed

    Zamora, Mònica; Pardo, Rosario; Villena, Josep A

    2015-11-01

    Defects in mitochondrial oxidative function have been associated with the onset of type 2 diabetes. Although the causal relationship between mitochondrial dysfunction and diabetes has not been fully established, numerous studies indicate that improved glucose homeostasis achieved via lifestyle interventions, such as exercise or calorie restriction, is tightly associated with increased mitochondrial biogenesis and oxidative function. Therefore, it is conceivable that potentiating mitochondrial biogenesis by pharmacological means could constitute an efficacious therapeutic strategy that would particularly benefit those diabetic patients who cannot adhere to comprehensive programs based on changes in lifestyle or that require a relatively rapid improvement in their diabetic status. In this review, we discuss several pharmacological targets and drugs that modulate mitochondrial biogenesis as well as their potential use as treatments for insulin resistance and diabetes. PMID:26212547

  20. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies

    PubMed Central

    Cheng, Gang; Kong, Rong-hua; Zhang, Lei-ming; Zhang, Jian-ning

    2012-01-01

    Traumatic brain injury (TBI) is a major health and socioeconomic problem throughout the world. It is a complicated pathological process that consists of primary insults and a secondary insult characterized by a set of biochemical cascades. The imbalance between a higher energy demand for repair of cell damage and decreased energy production led by mitochondrial dysfunction aggravates cell damage. At the cellular level, the main cause of the secondary deleterious cascades is cell damage that is centred in the mitochondria. Excitotoxicity, Ca2+ overload, reactive oxygen species (ROS), Bcl-2 family, caspases and apoptosis inducing factor (AIF) are the main participants in mitochondria-centred cell damage following TBI. Some preclinical and clinical results of mitochondria-targeted therapy show promise. Mitochondria- targeted multipotential therapeutic strategies offer new hope for the successful treatment of TBI and other acute brain injuries. PMID:23003569

  1. Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer's Disease Treatment: Rethinking the Current Strategy

    PubMed Central

    Mondragón-Rodríguez, Siddhartha; Perry, George; Zhu, Xiongwei; Boehm, Jannic

    2012-01-01

    Alzheimer's disease (AD) is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ) and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβ and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment. PMID:22482074

  2. Molecular, genetic and stem cell-mediated therapeutic strategies for spinal muscular atrophy (SMA)

    PubMed Central

    Zanetta, Chiara; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Faravelli, Irene; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease. It is the first genetic cause of infant mortality. It is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The most striking component is the loss of alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment other than supportive care, although the past decade has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials. In this review, we would like to outline the most interesting therapeutic strategies that are currently developing, which are represented by molecular, gene and stem cell-mediated approaches for the treatment of SMA. PMID:24400925

  3. Retromandibular vein diverticulum: unique imaging findings with a novel therapeutic strategy.

    PubMed

    Mondel, Prabath Kumar; Udare, Ashlesha Satish; Saraf, Rashmi; Limaye, Uday S

    2014-10-01

    Diverticula of the vascular system are rare. A diverticulum involving the retromandibular vein has not been described to date. We describe the imaging findings and a novel therapeutic strategy for the management of this rare diverticulum. A 25-year-old male presented with complaints of swelling behind the angle of mandible that enlarged on straining. On imaging, a retromandibular vein diverticulum was seen. The diverticulum was punctured percutaneously with the patient performing Valsalva maneuver and injected with sclerosant microfoam. There was no sclerosant reflux into the normal neck veins. At 6-month follow-up, the patient had complete resolution of his symptoms. We also have done a review of literature for patients with venous diverticula in the head and neck region treated by endovascular techniques. PMID:24556831

  4. Effects on bone metabolism of new therapeutic strategies with standard chemotherapy and biologic drugs

    PubMed Central

    Ciolli, Stefania

    2013-01-01

    Summary Recent biological advances have provided the framework for novel therapeutic strategies in oncology. Many new treatments are now based on standard cytotoxic drugs plus biologic agents. In Multiple Myeloma, a plasma cell neoplasm characterized by a severe bone disease, biologic drugs such as proteasome inhibitors and immunomodulatory agents, above their antineoplastic efficacy have a beneficial effects on bone disease. Bortezomib, a clinically available proteasome inhibitor active against myeloma, induces the differentiation of mesenchymal stem/progenitor cells into osteoblasts, resulting in new bone formation. Immunomodulatory drugs (e.g., thalidomide and lenalidomide), which are active against myeloma, also block the activity of bone-resorbing osteoclasts. These data reflect the utility of targeting endogenous mesenchymal stem/progenitor cells for the purpose of tissue repair and suggest that combining different classes of agents that are antineoplastic and also inhibit bone destruction and increase bone formation should be very beneficial for myeloma patients suffering from severe bone disease. PMID:24554928

  5. Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back.

    PubMed

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

    2015-07-01

    Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNA-binding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders. PMID:25986746

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

    PubMed

    Lee, Gum Hwa; Kim, Sang Seong

    2016-01-01

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

  7. Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock.

    PubMed

    Kim, Ye-Ram; Koh, Hyun-Jung; Kim, Jae-Sung; Yun, Jin-Seung; Jang, Kiseok; Lee, Joo-Youn; Jung, Jae U; Yang, Chul-Su

    2016-09-01

    Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS. PMID:27267627

  8. Future therapeutical strategies dictated by pre-clinical evidence in ALS.

    PubMed

    Fornai, Francesco; Meininger, Vincent; Silani, Vincent

    2011-03-01

    Classic concepts on amyotrophic lateral sclerosis led to define the disease as a selective degeneration of upper and lower motor neurons. At present such selectivity is questioned by novel findings. For instance, the occurrence of frontotemporal dementia is now increasingly recognized in the course of ALS. Again, areas outside the central nervous system are targeted in ALS. In keeping with motor areas other cell types surrounding motor neurons such as glia and interneurons are key in the pathogenesis of ALS. This multiple cell involvement may be due to a prion-like diffusion of specific misfolded proteins which are altered in ALS. This is the case of FUS and TDP-43 which harbor a prion domain prone to pathological misfolding. These misfolded proteins are metabolized by the autophagy, but in ALS there is evidence for a specific deficit of autophagy which impedes the clearance of these proteins. These concepts lead to re-analyze the potential therapeutics of ALS. In fact, mere cell substitution (stem cell) therapy appears insufficient to contrast all the alterations in the various pathways affected by ALS. Although preclinical data speed the application of stem cells in human clinical trials, several hurdles limit their translation into new therapies. Future treatments are expected to consider the need to target both motor neurons and neighboring cells which may contribute to the diffusion and persistence of the disease. On this basis the present manuscript describes which future strategies need to be pursued in order to design optimal therapeutic trial in ALS. PMID:21412723

  9. MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer

    PubMed Central

    Passadouro, Marta; Pedroso de Lima, Maria C; Faneca, Henrique

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and mortal cancer, characterized by a set of known mutations, invasive features, and aberrant microRNA expression that have been associated with hallmark malignant properties of PDAC. The lack of effective PDAC treatment options prompted us to investigate whether microRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. In this work, we show that the developed human serum albumin–1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine:cholesterol/anti-microRNA oligonucleotides (+/−) (4/1) nanosystem exhibits the ability to efficiently deliver anti-microRNA oligonucleotides targeting the overexpressed microRNAs miR-21, miR-221, miR-222, and miR-10 in PDCA cells, promoting an almost complete abolishment of microRNA expression. Silencing of these microRNAs resulted in a significant increase in the levels of their targets. Moreover, the combination of microRNA silencing, namely miR-21, with low amounts of the chemotherapeutic drug sunitinib resulted in a strong and synergistic antitumor effect, showing that this combined strategy could be of great importance for therapeutic application in PDAC. PMID:25061297

  10. Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases.

    PubMed

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

    2016-06-01

    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

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

    PubMed Central

    Lee, Gum Hwa; Kim, Sang Seong

    2016-01-01

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

  12. Initiating therapeutic relaxation in Britain: a twentieth-century strategy for health and wellbeing

    PubMed Central

    Nathoo, Ayesha

    2016-01-01

    In 1972, a British charity, Relaxation for Living, was established “to promote the teaching of physical relaxation, to combat stress, strain, anxiety and the tension of modern life, and to reduce fatigue”. This article explores the origins and development of “physical relaxation” techniques and ideologies, starting in the interwar period, and the development of practical, therapeutic, social and cultural frameworks necessary for such an organization to come into being in 1970s Britain. It traces how relaxation was reconstituted as a scientifically-based skill that could be learnt and taught, imbued with therapeutic value for combating and preventing specific physical ailments and enhancing individual health and wellbeing. The article explores how relaxation techniques gained currency among particular demographic and clinical groups, ranging from middle-class, child-bearing women to middle-aged, “coronary-prone” men. This analysis highlights the role that relaxation practitioners played in both creating and responding to demand for individualistic health-management strategies, many of which have shaped contemporary health and wellbeing agendas. This article is published as part of a collection entitled “On balance: lifestyle, mental health and wellbeing”. PMID:27563437

  13. Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer

    PubMed Central

    Hasima, N; Ozpolat, B

    2014-01-01

    Autophagy, a lysosomal degradation pathway for cellular constituents and organelles, is an adaptive and essential process required for cellular homeostasis. Although autophagy functions as a survival mechanism in response to cellular stressors such as nutrient or growth factor deprivation, it can also lead to a non-apoptotic form of programmed cell death (PCD) called autophagy-induced cell death or autophagy-associated cell death (type II PCD). Current evidence suggests that cell death through autophagy can be induced as an alternative to apoptosis (type I PCD), with therapeutic purpose in cancer cells that are resistant to apoptosis. Thus, modulating autophagy is of great interest in cancer research and therapy. Natural polyphenolic compounds that are present in our diet, such as rottlerin, genistein, quercetin, curcumin, and resveratrol, can trigger type II PCD via various mechanisms through the canonical (Beclin-1 dependent) and non-canonical (Beclin-1 independent) routes of autophagy. The capacity of these compounds to provide a means of cancer cell death that enhances the effects of standard therapies should be taken into consideration for designing novel therapeutic strategies. This review focuses on the autophagy- and cell death-inducing effects of these polyphenolic compounds in cancer. PMID:25375374

  14. Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy.

    PubMed

    Nabavi, Seyed Fazel; Barber, Alistair J; Spagnuolo, Carmela; Russo, Gian Luigi; Daglia, Maria; Nabavi, Seyed Mohammad; Sobarzo-Sánchez, Eduardo

    2016-10-01

    Diabetic retinopathy is a microvascular complication of diabetes that is considered one of the leading causes of blindness among adults. More than 4.4 million people suffer from this disorder throughout the world. Growing evidence suggests that oxidative stress plays a crucial role in the pathophysiology of diabetic retinopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, plays an essential protective role in regulating the physiological response to oxidative and electrophilic stress via regulation of multiple genes encoding antioxidant proteins and phase II detoxifying enzymes. Many studies suggest that dozens of natural compounds, including polyphenols, can supress oxidative stress and inflammation through targeting Nrf2 and consequently activating the antioxidant response element-related cytoprotective genes. Therefore, Nrf2 may provide a new therapeutic target for treatment of diabetic retinopathy. In the present article, we will focus on the role of Nrf2 in diabetic retinopathy and the ability of polyphenols to target Nrf2 as a therapeutic strategy. PMID:26926494

  15. A test strategy for the assessment of additive attributed toxicity of tobacco products.

    PubMed

    Kienhuis, Anne S; Staal, Yvonne C M; Soeteman-Hernández, Lya G; van de Nobelen, Suzanne; Talhout, Reinskje

    2016-08-01

    The new EU Tobacco Product Directive (TPD) prohibits tobacco products containing additives that are toxic in unburnt form or that increase overall toxicity of the product. This paper proposes a strategy to assess additive attributed toxicity in the context of the TPD. Literature was searched on toxicity testing strategies for regulatory purposes from tobacco industry and governmental institutes. Although mainly traditional in vivo testing strategies have been applied to assess toxicity of unburnt additives and increases in overall toxicity of tobacco products due to additives, in vitro tests combined with toxicogenomics and validated using biomarkers of exposure and disease are most promising in this respect. As such, tests are needed that are sensitive enough to assess additive attributed toxicity above the overall toxicity of tobacco products, which can associate assay outcomes to human risk and exposure. In conclusion, new, sensitive in vitro assays are needed to conclude whether comparable testing allows for assessment of small changes in overall toxicity attributed to additives. A more pragmatic approach for implementation on a short-term is mandated lowering of toxic emission components. Combined with risk assessment, this approach allows assessment of effectiveness of harm reduction strategies, including banning or reducing of additives. PMID:27155068

  16. Targeting inflammation as a therapeutic strategy for drug-resistant epilepsies

    PubMed Central

    Vitaliti, Giovanna; Pavone, Piero; Mahmood, Fahad; Nunnari, Giuseppe; Falsaperla, Raffaele

    2014-01-01

    An increasing body of literature data suggests that inflammation, and in particular neuroinflammation, is involved in the pathophysiology of particular forms of epilepsy and convulsive disorders. Animal models have been used to identify inflammatory triggers in epileptogenesis and inflammation has recently been shown to enhance seizures. For example, pharmacological blockade of the IL-1beta/IL-1 receptor type 1 axis during epileptogenesis has been demonstrated to provide neuroprotection in temporal lobe epilepsy. Furthermore, experimental models have suggested that neural damage and the onset of spontaneous recurrent seizures are modulated via complex interactions between innate and adaptive immunity. However, it has also been suggested that inflammation can occur as a result of epilepsy, since animal models have also shown that seizure activity can induce neuroinflammation, and that recurrent seizures maintain chronic inflammation, thereby perpetuating seizures. On the basis of these observations, it has been suggested that immune-mediated therapeutic strategies may be beneficial for treating some drug resistant epilepsies with an underlying demonstrable inflammatory process. Although the potential mechanisms of immunotherapeutic strategies in drug-resistant seizures have been extensively discussed, evidence on the efficacy of such therapy is limited. However, recent research efforts have been directed toward utilizing the potential therapeutic benefits of anti-inflammatory agents in neurological disease and these are now considered prime candidates in the ongoing search for novel anti-epileptic drugs. The objective of our review is to highlight the immunological features of the pathogenesis of seizures and to analyze possible immunotherapeutic approaches for drug resistant epilepsies that can alter the immune-mediated pathogenesis. PMID:24609096

  17. New therapeutic strategies for the treatment of male lower urinary tract symptoms

    PubMed Central

    Dimitropoulos, Konstantinos; Gravas, Stavros

    2016-01-01

    Male lower urinary tract symptoms (LUTS) are prevalent in the general population, especially in those of advanced age, and are characterized by notable diversity in etiology and presentation, and have been proven to cause various degrees of impairment on quality of life. The prostate has traditionally been regarded as the core cause of male LUTS. As a result, medical treatment aims to provide symptomatic relief and effective management of progression of male LUTS due to benign prostatic enlargement. In this context, α1-blockers, phosphodiesterase-5 inhibitors, and 5α-reductase inhibitors have long been used as monotherapies or in combination treatment to control voiding LUTS. There is accumulating evidence, however, that highlights the role of the bladder in the pathogenesis of male LUTS. Current research interests have shifted to bladder disorders, and medical management is aimed at the bladder. Muscarinic receptor antagonists and the newly approved β3-adrenergic agonist mirabegron aim to alleviate the most bothersome storage LUTS and thus improve quality of life. As voiding and storage LUTS frequently coexist, combination therapeutic strategies with α1-blockers and antimuscarinics or β3-agonists have been introduced to manage symptoms effectively. Anti-inflammatory agents, vitamin D3-receptor analogs, and cannabinoids represent treatment modalities currently under investigation for use in LUTS patients. Furthermore, luteinizing hormone-releasing hormone antagonists, transient receptor-potential channel blockers, purinergic neurotransmission antagonists, Rho-kinase inhibitors, and inhibitors of endothelin-converting enzymes could have therapeutic potential in LUTS management, but still remain in the experimental setting. This article reviews new strategies for the medical treatment of male LUTS, which are dictated by the potential role of the bladder and the risk of benign prostatic hyperplasia progression. Moreover, combination treatments and therapies

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

    PubMed

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

    2016-01-01

    Mesenchymal stem cells have emerged as promising therapeutic candidates in regenerative medicine. The mechanisms underlying mesenchymal stem cells regenerative properties were initially attributed to their engraftment in injured tissues and their subsequent transdifferentiation to repair and replace damaged cells. However, studies in animal models and patients indicated that the low number of transplanted mesenchymal stem cells localize to the target tissue and transdifferentiate to appropriate cell lineage. Instead the regenerative potential of mesenchymal stem cells has been found - at least in part - to be mediated via their paracrine actions. Recently, a secreted group of vesicles, called "exosome" has been identified as major mediator of mesenchymal stem cells therapeutic efficacy. In this review, we will summarize the current literature on administration of exosomes released by mesenchymal stem cells in regenerative medicine and suggest how they could help to improve tissue regeneration following injury. PMID:27453276

  19. Progress in new diagnosis and therapeutic strategy for gastrointestinal malignancy: focus on new molecular-targeted treatments.

    PubMed

    Sugiyama, Toshiro

    2015-01-01

    The core symposiums of the Japanese Gastroenterological Association (JGA) annual scientific meetings focus on similar topics from year to year. The main topics of these symposiums for the last 3 years were centered on progress in new diagnostics and therapeutic strategies for gastrointestinal malignancy, with a special focus on new molecular-targeted treatments for gastrointestinal stromal tumors (GIST), neuroendocrine tumors (NET) and other gastrointestinal (GI) cancers, including malignant lymphoma, for which new molecular-targeted treatments are now being commonly used. The 8th annual meeting of the JGA was held in 2012 and 8 excellent papers were presented on progress in new diagnostics and therapy for GIST. The 9th annual meeting of the JGA was held in 2013 and 7 excellent papers were presented on new molecular-targeted treatments for colorectal carcinomas and GI lymphoma. At the 10th annual meeting of the JGA, which was held in 2014, novel concepts of and therapeutic strategies for GI cancers, NET and GIST were discussed. In 2010, the WHO proposed a new classification system in which NET was classified into three categories - NET-G1, NET-G2 and NEC - dependent on proliferative activity, and the term 'carcinoid' was deleted. Regarding GIST, several management guidelines have already been published: by NCCN in 2004, by ESMO in 2005, and in Japan in 2006. The Japanese guidelines have recently been revised. In addition to the summaries of the annual meetings from 2012 to 2014, the major points of the recently revised Japanese guidelines for the diagnosis and management of GIST are described in this review. PMID:25632910

  20. Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

    PubMed Central

    Talmadge, James E.; Singh, Rakesh K.; Fidler, Isaiah J.; Raz, Avraham

    2007-01-01

    Animal models, by definition, are an approximation of reality, and their use in developing anti-cancer drugs is controversial. Positive retrospective clinical correlations have been identified with several animal models, in addition to limitations and a need for improvement. Model inadequacies include experimental designs that do not incorporate biological concepts, drug pharmacology, or toxicity. Ascites models have been found to identify drugs active against rapidly dividing tumors; however, neither ascitic nor transplantable subcutaneous tumors are predictive of activity for solid tumors. In contrast, primary human tumor xenografts have identified responsive tumor histiotypes if relevant pharmacodynamic and toxicological parameters were considered. Murine toxicology studies are also fundamental because they identify safe starting doses for phase I protocols. We recommend that future studies incorporate orthotopic and spontaneous metastasis models (syngeneic and xenogenic) because they incorporate microenvironmental interactions, in addition to confirmatory autochthonous models and/or genetically engineered models, for molecular therapeutics. Collectively, murine models are critical in drug development, but require a rational and hierarchical approach beginning with toxicology and pharmacology studies, progressing to human primary tumors to identify therapeutic targets and models of metastatic disease from resected orthotopic, primary tumors to compare drugs using rigorous, clinically relevant outcome parameters. PMID:17322365

  1. Therapeutic strategies to improve drug delivery across the blood-brain barrier

    PubMed Central

    Azad, Tej D.; Pan, James; Connolly, Ian D.; Remington, Austin; Wilson, Christy M.; Grant, Gerald A.

    2015-01-01

    Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB’s physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it. PMID:25727231

  2. Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis

    PubMed Central

    Sloane, Peter A.; Rowe, Steven M.

    2013-01-01

    Purpose of review Recent progress in understanding the production, processing, and function of the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), has revealed new therapeutic targets to repair the mutant protein. Classification of CFTR mutations and new treatment strategies to address each will be described here. Recent findings High-throughput screening and other drug discovery efforts have identified small molecules that restore activity to mutant CFTR. Compounds such as VX-770 that potentiate CFTR have demonstrated exciting results in recent clinical trials and demonstrate robust effects across several CFTR mutation classes in the laboratory. A number of novel F508del CFTR processing correctors restore protein to the cell surface and improve ion channel function in vitro and are augmented by coadministration of CFTR potentiators. Ongoing discovery efforts that target protein folding, CFTR trafficking, and cell stress have also indicated promising results. Aminoglycosides and the novel small molecule ataluren induce translational readthrough of nonsense mutations in CFTR and other genetic diseases in vitro and in vivo and have shown activity in proof of concept trials, and ataluren is now being studied in confirmatory trials. Summary An improved understanding of the molecular mechanisms underlying the basic genetic defect in cystic fibrosis have led to new treatment strategies to repair the mutant protein. PMID:20829696

  3. You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia.

    PubMed

    Sehgal, A R; Konig, H; Johnson, D E; Tang, D; Amaravadi, R K; Boyiadzis, M; Lotze, M T

    2015-03-01

    A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia. PMID:25541151

  4. Therapeutic strategies for anchored kinases and phosphatases: exploiting short linear motifs and intrinsic disorder

    PubMed Central

    Nygren, Patrick J.; Scott, John D.

    2015-01-01

    Phosphorylation events that occur in response to the second messenger cAMP are controlled spatially and temporally by protein kinase A (PKA) interacting with A-kinase anchoring proteins (AKAPs). Recent advances in understanding the structural basis for this interaction have reinforced the hypothesis that AKAPs create spatially constrained signaling microdomains. This has led to the realization that the PKA/AKAP interface is a potential drug target for modulating a plethora of cell-signaling events. Pharmacological disruption of kinase–AKAP interactions has previously been explored for disease treatment and remains an interesting area of research. However, disrupting or enhancing the association of phosphatases with AKAPs is a therapeutic concept of equal promise, particularly since they oppose the actions of many anchored kinases. Accordingly, numerous AKAPs bind phosphatases such as protein phosphatase 1 (PP1), calcineurin (PP2B), and PP2A. These multimodal signaling hubs are equally able to control the addition of phosphate groups onto target substrates, as well as the removal of these phosphate groups. In this review, we describe recent advances in structural analysis of kinase and phosphatase interactions with AKAPs, and suggest future possibilities for targeting these interactions for therapeutic benefit. PMID:26283967

  5. Preventing antiblastic drug-related cardiomyopathy: old and new therapeutic strategies.

    PubMed

    Cadeddu, Christian; Mercurio, Valentina; Spallarossa, Paolo; Nodari, Savina; Triggiani, Marco; Monte, Ines; Piras, Roberta; Madonna, Rosalinda; Pagliaro, Pasquale; Tocchetti, Carlo G; Mercuro, Giuseppe

    2016-05-01

    Because of the recent advances in chemotherapeutic protocols, cancer survival has improved significantly, although cardiovascular disease has become a major cause of morbidity and mortality among cancer survivors: in addition to the well-known cardiotoxicity (CTX) from anthracyclines, biologic drugs that target molecules that are active in cancer biology also interfere with cardiovascular homeostasis.Pharmacological and non-pharmacological strategies to protect the cardiovascular structure and function are the best approaches to reducing the prevalence of cardiomyopathy linked to anticancer drugs. Extensive efforts have been devoted to identifying and testing strategies to achieve this end, but little consensus has been reached on a common and shared operability.Timing, dose and mode of chemotherapy administration play a crucial role in the development of acute or late myocardial dysfunction. Primary prevention initiatives cover a wide area that ranges from conventional heart failure drugs, such as β-blockers and renin-angiotensin-aldosterone system antagonists to nutritional supplementation and physical training. Additional studies on the pathophysiology and cellular mechanisms of anticancer-drug-related CTX will enable the introduction of novel therapies.We present various typologies of prevention strategies, describing the approaches that have already been used and those that could be effective on the basis of a better understanding of pharmacokinetic and pharmacodynamic CTX mechanisms. PMID:27183527

  6. Facing Facts: Can the Face-Name Mnemonic Strategy Accommodate Additional Factual Information?

    ERIC Educational Resources Information Center

    Carney, Russell N.; Levin, Joel R.

    2012-01-01

    In 3 experiments, undergraduates used their own best method (control) or an "imposed" face-name mnemonic strategy to associate 18 caricatured faces, names, and additional facts. On all immediate tests (prompted by the faces), and on the delayed tests of Experiments 2a and 2b combined, mnemonic students statistically outperformed control students…

  7. Strategies and Performance in Elementary Students' Three-Digit Mental Addition

    ERIC Educational Resources Information Center

    Csíkos, Csaba

    2016-01-01

    The focus of this study is the relationship between students' performance in mental calculation and the strategies they use when solving three-digit mental addition problems. The sample comprises 78 4th grade students (40 boys and 38 girls). Their mean age was 10 years and 4 months. The main novelties of the current research include (1)…

  8. Haptic Exploratory Strategies and Children Who Are Blind and Have Additional Disabilities

    ERIC Educational Resources Information Center

    McLinden, Mike

    2004-01-01

    This study of the haptic exploratory strategies used by nine children with visual impairments and additional disabilities when interacting with portable and freely manipulable objects found that a broader approach to assessment and analysis is required than is used with typically developing children. An "adaptive-tasks" approach is proposed as a…

  9. Similarities and Differences in Addition Strategies of Children with and without Mental Retardation

    ERIC Educational Resources Information Center

    Huffman, Lisa F.; Fletcher, Kathryn, L.; Bray, Norman W.; Grupe, Lisa A.

    2004-01-01

    This microgenetic study investigated similarities and differences in use and discovery of addition strategies in children with and without mild mental retardation across 24 sessions. Nine children with mild mental retardation in third through fifth grade classrooms and 14 children without mental retardation in kindergarten classrooms were tested…

  10. Teaching Young Children Decomposition Strategies to Solve Addition Problems: An Experimental Study

    ERIC Educational Resources Information Center

    Cheng, Zi-Juan

    2012-01-01

    The ability to count has traditionally been considered an important milestone in children's development of number sense. However, using counting (e.g., counting on, counting all) strategies to solve addition problems is not the best way for children to achieve their full mathematical potential and to prepare them to develop more complex and…

  11. Laser Ablation as Treatment Strategy for Medically Refractory Dominant Insular Epilepsy – Therapeutic and Functional Considerations

    PubMed Central

    Hawasli, Ammar H.; Bandt, S. Kathleen; Hogan, R. Edward; Werner, Nicole; Leuthardt, Eric C.

    2014-01-01

    Since its introduction to neurosurgery in 2008, laser ablative techniques have been largely confined to the management of unresectable tumors. Application of this technology for the management of focal epilepsy in the adult population has not been fully explored. Given that nearly 1,000,000 Americans live with medically refractory epilepsy and current surgical techniques only address a fraction of epileptic pathologies, additional therapeutic options are needed. We report the successful treatment of dominant insular epilepsy in a 53 year-old male with minimally-invasive laser ablation complicated by mild verbal and memory deficits. We also report neuropsychological test data on this patient before surgery and at 8-months after the ablation procedure. This account represents the first reported successful patient outcome of laser ablation as an effective treatment option for medically refractory post-stroke epilepsy in an adult. PMID:25359500

  12. Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for "vertical" and "lateral" combination strategies.

    PubMed

    Ricciardi, Maria Rosaria; Scerpa, Maria Cristina; Bergamo, Paola; Ciuffreda, Ludovica; Petrucci, Maria Teresa; Chiaretti, Sabina; Tavolaro, Simona; Mascolo, Maria Grazia; Abrams, Stephen L; Steelman, Linda S; Tsao, Twee; Marchetti, Antonio; Konopleva, Marina; Del Bufalo, Donatella; Cognetti, Francesco; Foà, Robin; Andreeff, Michael; McCubrey, James A; Tafuri, Agostino; Milella, Michele

    2012-10-01

    In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacological MEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G(1)-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70( S6K ) kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of AML. PMID:22399013

  13. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

    PubMed Central

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

    2014-01-01

    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

  14. NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

    PubMed Central

    2013-01-01

    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. PMID:23786653

  15. Protein Homeostasis Defects of Alanine-Glyoxylate Aminotransferase: New Therapeutic Strategies in Primary Hyperoxaluria Type I

    PubMed Central

    Pey, Angel L.; Albert, Armando; Salido, Eduardo

    2013-01-01

    Alanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5′-phosphate (PLP) as cofactor. Human alanine-glyoxylate aminotransferase is a peroxisomal enzyme expressed in the hepatocytes, the main site of glyoxylate detoxification. Its deficit causes primary hyperoxaluria type I, a rare but severe inborn error of metabolism. Single amino acid changes are the main type of mutation causing this disease, and considerable effort has been dedicated to the understanding of the molecular consequences of such missense mutations. In this review, we summarize the role of protein homeostasis in the basic mechanisms of primary hyperoxaluria. Intrinsic physicochemical properties of polypeptide chains such as thermodynamic stability, folding, unfolding, and misfolding rates as well as the interaction of different folding states with protein homeostasis networks are essential to understand this disease. The view presented has important implications for the development of new therapeutic strategies based on targeting specific elements of alanine-glyoxylate aminotransferase homeostasis. PMID:23956997

  16. Targeting survivin with YM155 (Sepantronium Bromide): a novel therapeutic strategy for paediatric acute myeloid leukaemia.

    PubMed

    Smith, Amanda M; Little, Erica B; Zivanovic, Andjelija; Hong, Priscilla; Liu, Alfred K S; Burow, Rachel; Stinson, Caedyn; Hallahan, Andrew R; Moore, Andrew S

    2015-04-01

    Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 μM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation. PMID:25659731

  17. Essential oils loaded in nanosystems: a developing strategy for a successful therapeutic approach.

    PubMed

    Bilia, Anna Rita; Guccione, Clizia; Isacchi, Benedetta; Righeschi, Chiara; Firenzuoli, Fabio; Bergonzi, Maria Camilla

    2014-01-01

    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. PMID:24971152

  18. Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility

    PubMed Central

    Nicholas, Cory R.; Haston, Kelly M.; Grewall, Amarjeet K.; Longacre, Teri A.; Reijo Pera, Renee A.

    2009-01-01

    Ten to 15% of couples are infertile, with the most common causes being linked to the production of few or no oocytes or sperm. Yet, our understanding of human germ cell development is poor, at least in part due to the inaccessibility of early stages to genetic and developmental studies. Embryonic stem cells (ESCs) provide an in vitro system to study oocyte development and potentially treat female infertility. However, most studies of ESC differentiation to oocytes have not documented fundamental properties of endogenous development, making it difficult to determine the physiologic relevance of differentiated germ cells. Here, we sought to establish fundamental parameters of oocyte development during ESC differentiation to explore suitability for basic developmental genetic applications using the mouse as a model prior to translating to the human system. We demonstrate a timeline of definitive germ cell differentiation from ESCs in vitro that initially parallels endogenous oocyte development in vivo by single-cell expression profiling and analysis of functional milestones including responsiveness to defined maturation media, shared genetic requirement of Dazl, and entry into meiosis. However, ESC-derived oocyte maturation ultimately fails in vitro. To overcome this obstacle, we transplant ESC-derived oocytes into an ovarian niche to direct their functional maturation and, thereby, present rigorous evidence of oocyte physiologic relevance and a potential therapeutic strategy for infertility. PMID:19696121

  19. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy.

    PubMed

    Pobbati, Ajaybabu V; Han, Xiao; Hung, Alvin W; Weiguang, Seetoh; Huda, Nur; Chen, Guo-Ying; Kang, CongBao; Chia, Cheng San Brian; Luo, Xuelian; Hong, Wanjin; Poulsen, Anders

    2015-11-01

    The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers. PMID:26592798

  20. Sulphonamides as anti-inflammatory agents: old drugs for new therapeutic strategies in neutrophilic inflammation?

    PubMed

    Ottonello, L; Dapino, P; Scirocco, M C; Balbi, A; Bevilacqua, M; Dallegri, F

    1995-03-01

    1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (alpha 1-antitrypsin), thereby favouring digestion of the connective matrix. 2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of alpha 1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent alpha 1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the alpha 1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation. PMID:7736703

  1. Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma.

    PubMed

    Kang, Zhigang; Sun, Shi-Yong; Cao, Liang

    2012-01-01

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors with p53 mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5. PMID:22577581

  2. Bone-cartilage interface crosstalk in osteoarthritis: potential pathways and future therapeutic strategies.

    PubMed

    Yuan, X L; Meng, H Y; Wang, Y C; Peng, J; Guo, Q Y; Wang, A Y; Lu, S B

    2014-08-01

    Currently, osteoarthritis (OA) is considered a disease of the entire joint, which is not simply a process of wear and tear but rather abnormal remodelling and joint failure of an organ. The bone-cartilage interface is therefore a functioning synergistic unit, with a close physical association between subchondral bone and cartilage suggesting the existence of biochemical and molecular crosstalk across the OA interface. The crosstalk at the bone-cartilage interface may be elevated in OA in vivo and in vitro. Increased vascularisation and formation of microcracks associated with abnormal bone remodelling in joints during OA facilitate molecular transport from cartilage to bone and vice versa. Recent reports suggest that several critical signalling pathways and biological factors are key regulators and activate cellular and molecular processes in crosstalk among joint compartments. Therapeutic interventions including angiogenesis inhibitors, agonists/antagonists of molecules and drugs targeting bone remodelling are potential candidates for this interaction. This review summarised the premise for the presence of crosstalk in bone-cartilage interface as well as the current knowledge of the major signalling pathways and molecular interactions that regulate OA progression. A better understanding of crosstalk in bone-cartilage interface may lead to development of more effective strategies for treating OA patients. PMID:24928319

  3. Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities.

    PubMed

    O'Reilly, Ciaran; Doroudian, Mohammad; Mawhinney, Leona; Donnelly, Seamas C

    2016-04-01

    Strong evidence has been presented linking chronic inflammation to the onset and pathogenesis of cancer. The multifunctional pro-inflammatory protein macrophage migration inhibitory factor (MIF) occupies a central role in the inflammatory pathway and has been implicated in the tumorigenesis, angiogenesis, and metastasis of many cancer phenotypes. This review highlights the current state of the art, which presents MIF, and the second member of the MIF structural superfamily, d-DT (MIF2), as significant mediators in the inflammatory-cancer axis. Although the mechanism by which MIF asserts its biological activity has yet to be fully understood, it has become clear in recent years that for certain phenotypes of cancer, MIF represents a valid therapeutic target. Current research efforts have focused on small molecule approaches that target MIF's unique tautomerase active site and neutralization of MIF with anti-MIF antibodies. These approaches have yielded promising results in a number of preclinical murine cancer models and have helped to increase our understanding of MIF biological activity. More recently, MIF's involvement in a number of key protein-protein interactions, such as with CD74 and HSP90, has been highlighted and provides a novel platform for the development of anti-MIF chemotherapeutic strategies in the future. PMID:26777977

  4. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets.

    PubMed

    Safi, Sher Zaman; Qvist, Rajes; Kumar, Selva; Batumalaie, Kalaivani; Ismail, Ikram Shah Bin

    2014-01-01

    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

  5. Nanocarriers for spleen targeting: anatomo-physiological considerations, formulation strategies and therapeutic potential.

    PubMed

    Jindal, Anil B

    2016-10-01

    There are several clinical advantages of spleen targeting of nanocarriers. For example, enhanced splenic concentration of active agents could provide therapeutic benefits in spleen resident infections and hematological disorders including malaria, hairy cell leukemia, idiopathic thrombocytopenic purpura, and autoimmune hemolytic anemia. Furthermore, spleen delivery of immunosuppressant agents using splenotropic carriers may reduce the chances of allograft rejection in organ transplantation. Enhanced concentration of radiopharmaceuticals in the spleen may improve visualization of the organ, which could provide benefit in the diagnosis of splenic disorders. Unique anatomical features of the spleen including specialized microvasculature environment and slow blood circulation rate enable it an ideal drug delivery site. Because there is a difference in blood flow between spleen and liver, splenic delivery is inversely proportional to the hepatic uptake. It is therefore desirable engineering of nanocarriers, which, upon intravenous administration, can avoid uptake by hepatic Kupffer cells to enhance splenic localization. Stealth and non-spherical nanocarriers have shown enhanced splenic delivery of active agents by avoiding hepatic uptake. The present review details the research in the field of splenotropy. Formulation strategies to design splenotropic drug delivery systems are discussed. The review also highlights the clinical relevance of spleen targeting of nanocarriers and application in diagnostics. PMID:27334277

  6. Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension

    PubMed Central

    Fisher, James P.; Fadel, Paul J.

    2010-01-01

    The pathogenesis of hypertension and its mode of progression are complex, multifactoral and incompletely understood. However, there is accumulating evidence from humans and animal models of hypertension indicating that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in triggering and sustaining the essential hypertensive state (the so-called “neuroadrenergic hypothesis”). Importantly, augmented central sympathetic outflow has also been implicated in the initiation and progression of a plethora of pathophysiological processes independent of any increase in blood pressure, such as left ventricular hypertrophy and cardiac arrhythmias. Thus, the sympathetic nervous system constitutes an important putative drug target in hypertension. However, traditional pharmacological approaches for the management of essential hypertension appear ineffective in reducing central sympathetic outflow. Recently, several new and promising therapeutic strategies targeting neurogenic hypertension have been developed. The present report will provide a brief update of this topic with a particular emphasis on human studies examining the efficacy of novel pharmacological approaches (central sympatholytics, statins), lifestyle modification (aerobic exercise training, weight loss, stress reduction) and surgical intervention (renal denervation, chronic carotid baroreflex stimulation, deep brain stimulation) in reducing excessive central sympathetic activation in hypertension. PMID:20304932

  7. [Therapeutic readthrough strategy for suppression of nonsense mutations in duchenne muscular dystrophy].

    PubMed

    Shiozuka, Masataka; Matsuda, Ryoichi

    2011-11-01

    Effective treatment for Duchenne muscular dystrophy (DMD) is currently unavailable. Readthrough of disease-causing premature termination codons might alleviate the symptoms of genetic diseases caused by nonsense mutations. Several ribosome-binding compounds, including selective antibiotics and synthetic novel small molecules, induce translational readthrough, restoring full-length functional proteins. Here in this innovative therapeutic strategy has been summarized with a focus on DMD. We have previously reported that negamycin restored dystrophin expression with less toxicity than gentamicin in mdx mice. To explore more potent readthrough inducers, we established the transgenic mouse called READ (readthrough evaluation and assessment by dural receptor) for readthrough-specific detection. Using READ mice, we discovered drug candidates, including sterically negamycin-like small molecules and aminoglycoside derivatives. The newly developed small molecules induced dose-dependent readthrough with greater potency than ataluren in vitro and promoted the expression of dystrophin and reduction in serum creatine kinase activity in mdx mice. Moreover, the aminoglycoside derivative restored both dystrophin protein and contractile function of mdx skeletal muscles with appreciably higher readthrough activity and lower toxicity than that of gentamicin. Furthermore, we confirmed the efficacy of a thioglycolate-based depilatory agent to enhance the topical delivery of skin-impermeable drugs, including aminoglycosides. These promising new chemotherapeutic agents with beneficial effects on readthrough action, lower toxicity, and transdermal delivery may have significant value in treating or preventing genetic diseases caused by nonsense mutations. PMID:22068478

  8. New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances.

    PubMed

    Flaherty, Keith T; Fisher, David E

    2011-08-01

    The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. PMID:21670085

  9. New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape.

    PubMed

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

    2016-03-01

    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. PMID:26933174

  10. Retroviral restriction factors TRIM5α: therapeutic strategy to inhibit HIV-1 replication.

    PubMed

    Zhang, Jing; Ge, Weiying; Zhan, Peng; De Clercq, Erik; Liu, Xinyong

    2011-01-01

    Tripartite motif protein 5-alpha (TRIM5α) is a cytoplasmic protein that efficiently recognizes the incoming capsid (CA) protein of retroviruses and potently inhibits virus infection in a species-specific manner. Through directly recognizing and interacting with HIV CA, TRIM5α is capable of disrupting the ordered process of viral uncoating, eventually interfering with HIV-1 reverse transcription and virus replication. TRIM5α protein contains four domains: RING domain, B-box 2 domain, coiled-coil domain, and B30.2 domain (SPRY) domain. All of the domains are necessary for efficient retrovirus restriction and the B30.2 domain has been shown to be the determinant of the specificity of restriction. Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. Various mutants of TRIM5α have been described which differently affect the HIV-1 reverse transcription process. This makes the establishment of new and improved models for HIV replication and AIDS pathogenesis by monitoring endogenous TRIM5α an attractive approach. TRIM5α-mediated restriction is modulated by the host protein Cyclophilin A (Cyp A) which could effectively interact with the CA of HIV-1. Here we will review the structure and roles of TRIM5α protein, the interaction between Cyp A and TRIM5α, as well as gene therapy strategies associated with TRIM5α to inhibit HIV-1 infection. PMID:21568899

  11. Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria.

    PubMed

    Bassetti, Matteo; De Waele, Jan J; Eggimann, Philippe; Garnacho-Montero, Josè; Kahlmeter, Gunnar; Menichetti, Francesco; Nicolau, David P; Paiva, Jose Arturo; Tumbarello, Mario; Welte, Tobias; Wilcox, Mark; Zahar, Jean Ralph; Poulakou, Garyphallia

    2015-05-01

    The antibiotic pipeline continues to diminish and the majority of the public remains unaware of this critical situation. The cause of the decline of antibiotic development is multifactorial and currently most ICUs are confronted with the challenge of multidrug-resistant organisms. Antimicrobial multidrug resistance is expanding all over the world, with extreme and pandrug resistance being increasingly encountered, especially in healthcare-associated infections in large highly specialized hospitals. Antibiotic stewardship for critically ill patients translated into the implementation of specific guidelines, largely promoted by the Surviving Sepsis Campaign, targeted at education to optimize choice, dosage, and duration of antibiotics in order to improve outcomes and reduce the development of resistance. Inappropriate antimicrobial therapy, meaning the selection of an antibiotic to which the causative pathogen is resistant, is a consistent predictor of poor outcomes in septic patients. Therefore, pharmacokinetically/pharmacodynamically optimized dosing regimens should be given to all patients empirically and, once the pathogen and susceptibility are known, local stewardship practices may be employed on the basis of clinical response to redefine an appropriate regimen for the patient. This review will focus on the most severely ill patients, for whom substantial progress in organ support along with diagnostic and therapeutic strategies markedly increased the risk of nosocomial infections. PMID:25792203

  12. Selection of chemotherapy for non-small cell lung cancer is facilitated by new therapeutic strategies

    PubMed Central

    Wang, Zhehai

    2014-01-01

    Nowadays, advanced non-small cell lung cancer is still an incurable disease. Recent researches have led to considerable progress in the treatment of non-small cell lung cancer. This article reviews the main studies on chemotherapy on non-small cell lung cancer and discusses the new therapeutic strategies available to date. Stable disease (SD) is necessary in chemotherapy for tumor. The proportion of population with responders or SD basically maintained similar regardless of regimens. The overall survival after chemotherapy for patients with SD was lower than patients with responders, and higher than patients with progressive disease. Greater benefits could be achieved in patients with effective induction chemotherapy using chemotherapeutic agents for maintenance therapy, whereas the benefits were relatively small for patients with SD. It has been found that epidermal growth factor receptor (EGFR) mutation status had certain correlation with the efficacy of chemotherapy. First-line chemotherapy has shown advantages in effective rate and progression free survival on EGFR mutant. EGFR mutation produced significant effects on the efficacy of postoperative adjuvant chemotherapy. Patients with EGFR mutation had a higher effective rate than wild-type EGFR patients, and patients with responders had a greater benefit in progression free survival from maintenance therapy. However, it is still necessary to carry out more careful and deeper studies and analyses on traditional cytotoxic chemotherapy, to further optimize cytotoxic chemotherapy and to use molecular targeted agents with different mechanisms. PMID:25550891

  13. Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer

    PubMed Central

    Baylot, Virginie; Katsogiannou, Maria; Andrieu, Claudia; Taieb, David; Acunzo, Julie; Giusiano, Sophie; Fazli, Ladan; Gleave, Martin; Garrido, Carmen; Rocchi, Palma

    2012-01-01

    Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression. Collectively, these findings provide a new Hsp27 cytoprotection mechanism in CRPC, and preclinical proof-of-concept that combining ASO-mediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells. PMID:22893039

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

    PubMed Central

    Bilia, Anna Rita; Guccione, Clizia; Isacchi, Benedetta; Righeschi, Chiara; Firenzuoli, Fabio; Bergonzi, Maria Camilla

    2014-01-01

    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. PMID:24971152

  15. Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.

    PubMed

    Mo, Charlie Y; Manning, Sara A; Roggiani, Manuela; Culyba, Matthew J; Samuels, Amanda N; Sniegowski, Paul D; Goulian, Mark; Kohli, Rahul M

    2016-01-01

    The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in

  16. Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

    PubMed Central

    Mo, Charlie Y.; Manning, Sara A.; Roggiani, Manuela; Culyba, Matthew J.; Samuels, Amanda N.; Sniegowski, Paul D.; Goulian, Mark

    2016-01-01

    ABSTRACT The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role

  17. Novel Therapeutic Targets for Preserving a Healthy Endothelium: Strategies for Reducing the Risk of Vascular and Cardiovascular Disease

    PubMed Central

    Ramli, Joseph; CalderonArtero, Pedro; Block, Robert C.; Mousa, Shaker A.

    2012-01-01

    The endothelium lies in a strategic anatomical position between the circulating blood and vascular smooth-muscle cells as a source of vasodilators such as nitric oxide, prostacyclin, and hyperpolarizing factor as well as heparin-like substances as well as other molecules with anti-proliferative properties. These effects of endothelial cells may explain why platelets and monocytes usually do not adhere at the blood vessel wall. However, under pathological conditions, endothelial dysfunction occurs and significantly contributes to the increase of platelet-vessel wall interaction, vasoconstriction, pro-inflammation, and proliferation. Under these conditions, endothelium-dependent vasodilation is reduced and endothelium-dependent constrictor responses are augmented. Upon vessel wall injury platelets rapidly adhere to the exposed sub-endothelial matrix which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates forming a stable platelet plug. Therapeutic strategies aimed at improving or preserving endothelial function therefore may be promising in the prevention and treatment of coronary artery disease. Diagnostic modalities for assessment of endothelial function should allow for the early detection of vascular endothelial dysfunction before the manifestation of serious adverse vascular disorders. PMID:21769815

  18. ATR-Chk1 signaling inhibition as a therapeutic strategy to enhance cisplatin chemosensitivity in urothelial bladder cancer

    PubMed Central

    Lu, Mei-Chin; Lee, Chia-Lin; Peng, Chieh-Yu; Hsu, Wei-Yu; Dai, Yun-Hao; Chang, Fang-Rong; Zhang, Da-Yong; Wu, Wen-Jeng; Wu, Yang-Chang

    2016-01-01

    DNA damage responses contribute to cisplatin resistance; however, therapeutic strategies to overcome cisplatin resistance have not yet been established. Here, we demonstrate that inhibition of ATR-Chk1 pathway with the potent inhibitor WYC0209 sensitizes bladder cancer cells to cisplatin. In the clinical microarray profile, high ATR expression is associated with poor prognosis in bladder cancer patients who receive chemotherapy. We show that pharmacological and genetic suppressing of ATR sensitized cells to cisplatin. Treatment with WYC0209 or siATR increased levels of cisplatin-DNA adducts, concomitant with decreased levels of p-glycoprotein expression. Additionally, Combinations of cisplatin and WYC0209 show synergistic activity against bladder cancer. Ultimately, WYC0209 enhanced the anti-tumor effects of cisplatin and suppressed p-glycoprotein expression in bladder cancer xenografts. These results indicate that inhibiting ATR-Chk1 activation with WYC0209 suppresses p-glycoprotein expression and increases cisplatin activity in bladder cancer. Our findings collectively suggest that ATR-Chk1 is a target for improving the efficacy of cisplatin in bladder cancer. PMID:26657501

  19. Synthetic protocol toward fused pyrazolone derivatives via a Michael addition and reductive ring closing strategy.

    PubMed

    Parekh, Nikita; Thomas, Joice; John, Jubi; Kusurkar, Radhika; De Borggraeve, Wim M; Dehaen, Wim

    2014-06-01

    A new class of pyrazolo[3,4-c]pyridine-3,7-dione and pyrazolo[3,4-d]azepine-3,7-dione scaffolds was synthesized via a Michael addition and reductive cyclization strategy. These fused heterocycles were accessed from simple starting materials such as nitroolefins and 3-ethoxycarbonyl(methylene)pyrazoline-5-one. The pyrazolo-fused heterocycles were obtained in good overall yields. PMID:24797239

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

    PubMed Central

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

    2012-01-01

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

  1. Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies

    PubMed Central

    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

    2015-01-01

    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. PMID:25629685

  2. Exploiting endogenous anti-apoptotic proteins for novel therapeutic strategies in cerebral ischemia.

    PubMed

    Rami, Abdelhaq; Bechmann, Ingo; Stehle, Jörg H

    2008-07-01

    The acute neuronal degeneration in the ischemic core upon stroke is followed by a second wave of cell demise in the ischemic penumbra and neuroanatomically connected sites. This temporally delayed deleterious event of programmed cell death ('secondary degeneration') often exceeds the initial damage of stroke and, thus, contributes pivotally to significant losses in neurological functions. In fact, it is the injured neurons in these regions around the ischemic core zone that neuropharmacological prevention is targeting to preserve. Clinical and pre-clinical studies have focussed on neuroprotective interventions with caspase inhibitors, but it remains ambiguous whether diminishing or even silencing these aspartate-specific cysteine proteases are in sum beneficial for the clinical outcome. It is often ignored that caspase inhibitors are able to antagonize calpain and cathepsins, thereby protecting the cytoskeleton from damage. Moreover, there is a point of no return, beyond which interfering with caspases cannot rescue the cell, but spoil the obligate and necessary suicide program such that the cellular environment suffers from by-products of necrosis and secondary inflammation. Here we discuss novel alternative strategies to abrogate the death cascade at the level of the genomic response (transcription factors, NF-kappaB, CREB, ICER, HIF), of mitochondrial effectors (cytochrome c, Bcl-2, Smac/DIABLO, HtrA2), and of inhibitor of apoptosis proteins (IAPs). IAPs are the only known endogenous proteins that inhibit specifically and with high affinity the activity of both initiator and effector caspases. Based on compelling biochemical evidence, we argue that patronizing the neuronal endogenous anti-apoptotic machinery could be superior to the pharmacological inhibition of caspases at various levels, with regard to specificity, side effects, and the 'therapeutic window of opportunity'. PMID:18511172

  3. Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

    PubMed Central

    Luan, Deyan; Zai, Michael; Varner, Jeffrey D

    2007-01-01

    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 fragility of human

  4. Inflammatory mechanisms and oxidative stress in Peyronie's disease: therapeutic "rationale" and related emerging treatment strategies.

    PubMed

    Paulis, Gianni; Brancato, Tommaso

    2012-02-01

    fibroblasts and myo-fibroblasts and excessive production of collagen between the layers of the tunica albuginea (penile plaque). Referring to the current knowledge of inflammatory and oxidative mechanisms of PD, a possible therapeutic strategy is then analyzed. PMID:22309083

  5. Spermine metabolism and radiation-derived reactive oxygen species for future therapeutic implications in cancer: an additive or adaptive response.

    PubMed

    Amendola, Roberto; Cervelli, Manuela; Tempera, Giampiero; Fratini, Emiliano; Varesio, Luigi; Mariottini, Paolo; Agostinelli, Enzo

    2014-03-01

    Destruction of cells by irradiation-induced radical formation is one of the most frequent interventions in cancer therapy. An alternative to irradiation-induced radical formation is in principle drug-induced formation of radicals, and the formation of toxic metabolites by enzyme catalyzed reactions. Thus, combination therapy targeting polyamine metabolism could represent a promising strategy to fight hyper-proliferative disease. The aim of this work is to discuss and evaluate whether the presence of a DNA damage provoked by enzymatic ROS overproduction may act as an additive or adaptive response upon radiation and combination of hyperthermia with lysosomotropic compounds may improve the cytocidal effect of polyamines oxidation metabolites. Low level of X-irradiations delivers challenging dose of damage and an additive or adaptive response with the chronic damage induced by spermine oxidase overexpression depending on the deficiency of the DNA repair mechanisms. Since reactive oxygen species lead to membrane destabilization and cell death, we discuss the effects of BSAO and spermine association in multidrug resistant cells that resulted more sensitive to spermine metabolites than their wild-type counterparts, due to an increased mitochondrial activity. Since mammal spermine oxidase is differentially activated in a tissue specific manner, and cancer cells can differ in term of DNA repair capability, it could be of interest to open a scientific debate to use combinatory treatments to alter spermine metabolism and deliver differential response. PMID:23999645

  6. Recent Progress in Therapeutic Treatments and Screening Strategies for the Prevention and Treatment of HPV-Associated Head and Neck Cancer

    PubMed Central

    Whang, Sonia N.; Filippova, Maria; Duerksen-Hughes, Penelope

    2015-01-01

    The rise in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has elicited significant interest in the role of high-risk HPV in tumorigenesis. Because patients with HPV-positive HNSCC have better prognoses than do their HPV-negative counterparts, current therapeutic strategies for HPV+ HNSCC are increasingly considered to be overly aggressive, highlighting a need for customized treatment guidelines for this cohort. Additional issues include the unmet need for a reliable screening strategy for HNSCC, as well as the ongoing assessment of the efficacy of prophylactic vaccines for the prevention of HPV infections in the head and neck regions. This review also outlines a number of emerging prospects for therapeutic vaccines, as well as for targeted, molecular-based therapies for HPV-associated head and neck cancers. Overall, the future for developing novel and effective therapeutic agents for HPV-associated head and neck tumors is promising; continued progress is critical in order to meet the challenges posed by the growing epidemic. PMID:26393639

  7. Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding

    PubMed Central

    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

    2016-01-01

    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. PMID:26877782

  8. Early Treatment with Addition of Low Dose Prednisolone to Methotrexate Improves Therapeutic Outcome in Severe Psoriatic Arthritis

    PubMed Central

    Mahajan, Vikram K; Sharma, Anju Lath; Chauhan, Pushpinder S; Mehta, Karaninder S; Sharma, Nand Lal

    2013-01-01

    Psoriatic arthritis (PsA) is increasingly being recognized to cause progressive joint damage and disability. PsA unresponsive to non-steroidal anti-inflammatory drugs (NSAIDs), the conventional first-line choice of treatment, is usually managed with disease-modifying antirheumatic drugs (DMARDs) especially methotrexate. An 18-year-old HIV-negative male had progressively severe PsA of 4-month duration that was nearly confining him to a wheel chair. He did not respond to multiple NSAIDs, alone or in combination with methotrexate (15 mg/week), given for 4 weeks. Addition of prednisolone (10 mg on alternate days) controlled his symptoms within a week. The NSAIDs could be withdrawn after 4 weeks as the treatment progressed. The doses were tapered for methotrexate (5 mg/week) and prednisolone (2.5 mg on alternate days) every 8 weekly subsequently during 15 months of follow-up without recurrence/deformities or drug toxicity. For years, the use of corticosteroids in psoriasis has been criticized for their propensity to exacerbate the skin disease on withdrawal. However, monitored use of corticosteroids, even in low doses, combined with DMARDs may be a good therapeutic option in early stage of the PsA rather than ‘steroid rescue’ later. This will help in early control of joint inflammation, prevent joint damage and maintain long-term good functional capacity and quality of life. This may be useful when the cost or availability of biologics precludes their use. However, we discourage the use of corticosteroids as monotherapy. PMID:23723489

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

    PubMed Central

    Youn, Sung Won; Park, Kwan-Kyu

    2015-01-01

    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. PMID:26006249

  10. [Modulating the survival and maturation system of B lymphocytes: Current and future new therapeutic strategies in systemic lupus erythematosus].

    PubMed

    Valor, Lara; López-Longo, Francisco Javier

    2015-09-01

    Systemic lupus erythematosus is an autoimmune disease associated with an aberrant production of autoantibodies by self-reactive B lymphocytes. The study of the phenotypic characteristics of B lymphocytes and the identification of their surface receptors such as BAFF-R, TACI and BCMA, which are responsible of their survival and maturation, have contributed to the development of new therapeutic strategies in recent years. PMID:25433780

  11. Ten-year-old children strategies in mental addition: A counting model account.

    PubMed

    Thevenot, Catherine; Barrouillet, Pierre; Castel, Caroline; Uittenhove, Kim

    2016-01-01

    For more than 30 years, it has been admitted that individuals from the age of 10 mainly retrieve the answer of simple additions from long-term memory, at least when the sum does not exceed 10. Nevertheless, recent studies challenge this assumption and suggest that expert adults use fast, compacted and unconscious procedures in order to solve very simple problems such as 3+2. If this is true, automated procedures should be rooted in earlier strategies and therefore observable in their non-compacted form in children. Thus, contrary to the dominant theoretical position, children's behaviors should not reflect retrieval. This is precisely what we observed in analyzing the responses times of a sample of 42 10-year-old children who solved additions with operands from 1 to 9. Our results converge towards the conclusion that 10-year-old children still use counting procedures in order to solve non-tie problems involving operands from 2 to 4. Moreover, these counting procedures are revealed whatever the expertise of children, who differ only in their speed of execution. Therefore and contrary to the dominant position in the literature according to which children's strategies evolve from counting to retrieval, the key change in development of mental addition solving appears to be a shift from slow to quick counting procedures. PMID:26402647

  12. Human organ-on-a-chip BioMEMS devices for testing new diagnostic and therapeutic strategies

    NASA Astrophysics Data System (ADS)

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

    2013-03-01

    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.

  13. Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases

    PubMed Central

    Oh, Doo-Byoung

    2015-01-01

    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. [BMB Reports 2015; 48(8): 438-444] PMID:25999178

  14. Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases.

    PubMed

    Oh, Doo-Byoung

    2015-08-01

    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. PMID:25999178

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

    PubMed

    Thode, Adam R; Latkany, Robert A

    2015-07-01

    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. PMID:26130187

  16. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies.

    PubMed

    Manna, Prasenjit; Jain, Sushil K

    2015-12-01

    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

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

    PubMed Central

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

    2012-01-01

    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

  18. Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies.

    PubMed

    Geszke-Moritz, Małgorzata; Moritz, Michał

    2016-11-01

    This work briefly reviews up-to-date developments in solid lipid nanoparticles (SLNs) as effective nanocolloidal system for drug delivery. It summarizes SLNs in terms of their preparation, surface modification and properties. The application of SLNs as a carrier system enables to improve the therapeutic efficacy of drugs from various therapeutic groups. Present uses of SLNs include cancer therapy, dermatology, bacterial infections, brain targeting and eye disorders among others. The usage of SLNs provides enhanced pharmacokinetic properties and modulated release of drugs. SLN ubiquitous application results from their specific features such as possibility of surface modification, increased permeation through biological barriers, resistance to chemical degradation, possibility of co-delivery of various therapeutic agents or stimuli-responsiveness. This paper will be useful to the scientists working in the domain of SLN-based drug delivery systems. PMID:27524099

  19. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies.

    PubMed

    Adibhatla, Rao Muralikrishna; Hatcher, James F

    2008-06-01

    Today there exists only one FDA-approved treatment for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA). In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? Is the animal research truly translational in identifying new agents for stroke treatment? This review summarizes the current state of affairs with plasminogen activators in thrombolytic therapy. In addition to therapeutic value, potential side effects of tPA also exist that aggravate stroke injury and offset the benefits provided by reperfusion of the occluded artery. Thus, combinational options (ultrasound alone or with microspheres/nanobubbles, mechanical dissociation of clot, activated protein C (APC), plasminogen activator inhibitor-1 (PAI-1), neuroserpin and CDP-choline) that could offset tPA toxic side effects and improve efficacy are also discussed here. Desmoteplase, a plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, antagonizes vascular tPA-induced neurotoxicity by competitively binding to low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) interface, minimizing the tPA uptake into brain parenchyma. tPA can also activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised of 24 mammalian enzymes that primarily catalyze the turnover and degradation of the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and neuronal injury in the early times after stroke, but also contribute to vascular remodeling, angiogenesis, neurogenesis and axonal regeneration during the later repair phase after stroke. tPA, directly or by activation of MMP-9, could have beneficial effects on recovery after stroke by promoting neurovascular repair through vascular endothelial growth factor (VEGF). However, any treatment regimen directed at MMPs must consider their

  20. Aerosol Droplet Delivery of Mesoporous Silica Nanoparticles: A Strategy for Respiratory-Based Therapeutics

    PubMed Central

    Li, Xueting; Xue, Min; Raabe, Otto G.; Aaron, Holly L.; Eisen, Ellen A.; Evans, James E.; Hayes, Fred A.; Inaga, Sumire; Tagmout, Abderrahmane; Takeuchi, Minoru; Vulpe, Chris; Zink, Jeffrey I.; Risbud, Subhash H.; Pinkerton, Kent E.

    2015-01-01

    A highly versatile nanoplatform that couples mesoporous silica nanoparticles (MSN) with an aerosol technology to achieve direct nanoscale delivery to the respiratory tract is described. This novel method can deposit MSN nanoparticles throughout the entire respiratory tract, including nasal, tracheobronchial and pulmonary regions using a water-based aerosol. This delivery method was successfully tested in mice by inhalation. The MSN nanoparticles used have the potential for carrying and delivering therapeutic agents to highly specific target sites of the respiratory tract. The approach provides a critical foundation for developing therapeutic treatment protocols for a wide range of diseases where aerosol delivery to the respiratory system would be desirable. PMID:25819886

  1. Combination therapy of angiotensin II receptor blocker and calcium channel blocker exerts pleiotropic therapeutic effects in addition to blood pressure lowering: amlodipine and candesartan trial in Yokohama (ACTY).

    PubMed

    Maeda, Akinobu; Tamura, Kouichi; Kanaoka, Tomohiko; Ohsawa, Masato; Haku, Sona; Azushima, Kengo; Dejima, Toru; Wakui, Hiromichi; Yanagi, Mai; Okano, Yasuko; Fujikawa, Tetsuya; Toya, Yoshiyuki; Mizushima, Shunsaku; Tochikubo, Osamu; Umemura, Satoshi

    2012-01-01

    Recent guidelines recommend combination antihypertensive therapy to achieve the target blood pressure (BP) and to suppress target organ damage. This study aimed to examine the beneficial effects of combination therapy with candesartan and amlodipine on BP control and markers of target organ function in Japanese essential hypertensive patients (N = 20) who did not achieve the target BP level during the monotherapy period with either candesartan or amlodipine. After the monotherapy period, for patients already being treated with amlodipine, a once-daily 8 mg dose of candesartan was added on during the combination therapy period (angiotensin II receptor blocker [ARB] add-on group, N = 10), and a once-daily 5 mg dose of amlodipine was added on for those already being treated with candesartan (calcium channel blocker [CCB] add-on group, N = 10). Combination therapy with candesartan and amlodipine for 12 weeks significantly decreased clinic and home systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, the combination therapy was able to significantly reduce urine albumin excretion without decrease in estimated glomerular filtration ratio and resulted in significant improvements in brachial-ankle pulse wave velocity, central SBP, and insulin sensitivity. Furthermore, the CCB add-on group showed a significantly greater decrease in clinic and home DBP than the ARB add-on group. The calcium channel blocker add-on group also exhibited better improvements in vascular functional parameters than the ARB add-on group. These results suggest that combination therapy with candesartan and amlodipine is an efficient therapeutic strategy for hypertension with pleiotropic benefits. PMID:22571446

  2. [Preparation of epitope imprinted particles for transferrin recognition by reversible addition fragmentation chain transfer strategy].

    PubMed

    Li, Qinran; Yang, Kaiguang; Li, Senwu; Liu, Jianxi; Zhang, Lihua; Liang, Zhen; Zhang, Yukui

    2014-10-01

    A kind of novel epitope surface imprinted particles was prepared by the reversible addition fragmentation chain transfer (RAFT) strategy. The epitope of transferrin, N-terminal peptide of the protein with nine amino acid residues, was chosen as the template and immobi- lized with covalent interaction on the surface of silica particles through the truss arm glutaraldehyde. The living/controlled polymerization was initialed by 2,2'-azobisisobutyronitrile (AIBN) at 70 °C in the solution of N,N-dimethylformamide, with the regulation by triothioester agent 2-(dodecylthiocarbonothioylthio)-2-methylpropanoic acid. Methacrylic acid and 2-hydroxyethyl methacrylate were chosen as the functional monomers and N, N-methylenebisacrylamide was chosen as the cross-linker in this polymerization. For this material, the binding capacity of the nine residue peptide could reach 2.36 mg/g with the imprinting factor (IF) of 1.89, while that for transferrin could reach 4.98 mg/g with IF of 1.61. The equilibrium could be achieved in 120 min for the transferrin recognition. In multi-protein competitive recognition, the imprinted factor of transferrin was the highest in the mixture of transferrin and other competitive proteins, such as cytochrome C and β-lactoglobulin. The results indicated that these epitope surface imprinted particles with RAFT strategy could recognize not only the nine residue peptide but also the transferrin with good selectivity, high binding capacity and fast mass transfer. PMID:25739262

  3. State of the art of Ready-to-Use Therapeutic Food: a tool for nutraceuticals addition to foodstuff.

    PubMed

    Santini, Antonello; Novellino, Ettore; Armini, Vincenzo; Ritieni, Alberto

    2013-10-15

    Therapeutic foodstuff are a challenge for the use of food and functional food ingredients in the therapy of different pathologies. Ready-to-Use Therapeutic Food (RUTF) are a mixture of nutrients designed and primarily addressed to the therapy of the severe acute malnutrition. The main ingredients of the formulation are powdered milk, peanuts butter, vegetal oil, sugar, and a mix of vitamins, salts, and minerals. The potential of this food are the low percentage of free water and the high energy and nutritional density. The high cost of the powdered milk, and the food safety problems connected to the onset of toxigenic moulds on the peanuts butter, slowed down considerably the widespread and homogenous diffusion of this product. This paper presents the state of the art of RUTF, reviews the different proposed recipes, suggests some possible new formulations as an alternative of novel recipes for this promising food. PMID:23692774

  4. Therapeutic Hypothermia as a Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Brain Injury and Traumatic Brain Injury

    PubMed Central

    Ma, H.; Sinha, B.; Pandya, R.S.; Lin, N.; Popp, A.J.; Li, J.; Yao, J.; Wang, X.

    2014-01-01

    Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury. PMID:22834830

  5. Therapeutic strategies and mechanisms of tumorigenesis of HER2-overexpressing breast cancer.

    PubMed

    Emde, Anna; Köstler, Wolfgang J; Yarden, Yosef

    2012-12-01

    The receptor tyrosine kinase HER2 is overexpressed in approximately 25% of breast cancers. HER2 acts as a signal amplifier for its siblings, namely three different transmembrane receptors that collectively bind with 11 distinct growth factors of the EGF family. Thus, overexpression of HER2 confers aggressive invasive growth in preclinical models and in patients. Specific therapies targeting HER2 include monoclonal antibodies, antibody-drug conjugates, small molecule tyrosine kinase inhibitors, as well as heat shock protein and sheddase inhibitors. Two of these drugs have shown impressive - yet mostly transient - efficacy in patients with HER2 overexpressing breast cancer. We highlight the biological roles of HER2 in breast cancer progression, and overview the available therapeutic armamentarium directed against this receptor-kinase molecule. Focusing on the mechanisms that confer resistance to individual HER2 targeting agents, we envisage therapeutic approaches to delay or overcome the evolvement of resistance in patients. PMID:20951604

  6. Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation

    PubMed Central

    Hermanson, Daniel J.; Gamble-George, Joyonna C.; Marnett, Lawrence J.; Patel, Sachin

    2014-01-01

    Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of canonical eCB inactivation pathways, fatty acid amide hydrolase for anandamide and monoacylglycerol lipase for 2-arachidonoylglycerol. Here we review experimental evidence that cyclooxygenase-2-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of “substrate-selective” COX-2 inhibitors that prevent eCB inactivation by COX-2 without affecting the prostaglandin generation from arachidonic acid. Lastly, we review recent data on the potential therapeutic applications of substrate-selective COX-2 inhibitors with a focus on neuropsychiatric disorders. PMID:24845457

  7. Therapeutic strategies for treatment of CF based on knowledge of CFTR.

    PubMed

    Riordan, J R

    1999-01-01

    CF is one of the first diseases where it is now possible to take an entirely "bottom-up" approach and attempt to develop molecular therapeutics based on fundamental properties of the gene and gene product which cause the disease. As I have tried to illustrate this is a task of enormous magnitude and although significant progress is being made, it is reasonable to expect that considerable time may be required for a satisfactory outcome to be achieved. PMID:10093106

  8. [Therapeutic strategies. Evolution and current status of the European Guidelines on Cardiovascular disease prevention].

    PubMed

    Guijarro, Carlos; García-Díaz, Juan de Dios

    2013-01-01

    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. PMID:23769961

  9. Use of Hydrogen as a Novel Therapeutic Strategy Against Photoreceptor Degeneration in Retinitis Pigmentosa Patients

    PubMed Central

    Tao, Ye; Geng, Lei; Wang, Liqiang; Xu, Weiwei; Qin, Limin; Peng, Guanghua; Huang, Yi Fei; Yang, Ji xue

    2016-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor apoptosis. Reactive oxygen species (ROS) have been recognized as critical initiators of the photoreceptor apoptosis in RP. Photoreceptor survival in RP mutants will not only require the inhibition of effectors of apoptotic machinery, but also the elimination of the initiating upstream signals, such as ROS. These cytotoxic ROS should be neutralized by the antioxidant defense system, otherwise they would interact with the macromolecules essential for photoreceptor survival. Hydrogen is a promising gaseous agent that has come to the forefront of therapeutic research over the last few years. It has been verified that hydrogen is capable of neutralizing the cytotoxic ROS selectively, rectifying abnormities in the apoptotic cascades, and attenuating the related inflammatory response. Hydrogen is so mild that it does not disturb the metabolic oxidation-reduction reactions or disrupt the physiologic ROS involved in cell signaling. Based on these findings, we hypothesize that hydrogen might be an effective therapeutic agent to slow or prevent photoreceptor degeneration in RP retinas. It is a logical step to test hydrogen for therapeutic use in multiple RP animal models, and ultimately in human RP patients. PMID:26952558

  10. Molecular and Cellular Pathobiology of Ehrlichia Infection: Targets for New Therapeutics and Immunomodulation Strategies

    PubMed Central

    McBride, Jere W.; Walker, David H.

    2013-01-01

    Ehrlichia are small gram-negative obligately intracellular bacteria in the order Rickettsiales that are transmitted by ticks and associated with emerging life-threatening human zoonoses. Vaccines are not available for human ehrlichiosis, and therapeutic options are limited to a single antibiotic class. Ehrlichia are able to subvert both innate and adaptive host defenses, and advances in understanding molecular Ehrlichia-eukaryotic host cell interactions and the cellular and immunologic basis of disease are important for developing effective next generation therapies. New technologies for exploring host-pathogen interactions have yielded recent advances in understanding the molecular interactions between these intracellular pathogens and host cell components and identified new targets for therapeutic and vaccine development including those that target pathogen virulence mechanisms or disrupt the processes associated with ehrlichial effector proteins. Animal models have also provided insight into immunopathologic mechanisms that contribute significantly to understanding severe disease manifestations that will lead to the development of immunomodulatory approaches for treating patients nearing or experiencing severe disease states. In this review, we discuss the recent advances in our understanding of molecular and cellular pathobiology and the immunobiology of Ehrlichia infection. We identify new molecular host-pathogen interactions that can be targets of new therapeutics and prospects for treating immunologic dysregulation that occurs during acute infection leading to life-threatening complications. PMID:21276277

  11. Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: New trends in the development of miRNA therapeutic strategies in oncology (Review)

    PubMed Central

    GAMBARI, ROBERTO; BROGNARA, ELEONORA; SPANDIDOS, DEMETRIOS A.; FABBRI, ENRICA

    2016-01-01

    MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects. PMID:27175518

  12. Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review).

    PubMed

    Gambari, Roberto; Brognara, Eleonora; Spandidos, Demetrios A; Fabbri, Enrica

    2016-07-01

    MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects. PMID:27175518

  13. Current Status of Therapeutic Strategies for Patent Ductus Arteriosus in Very-Low-Birth-Weight Infants in Korea

    PubMed Central

    Lee, Jin A; Kim, Myo-Jing; Oh, Sohee

    2015-01-01

    This study aimed to investigate current therapeutic strategies for patent ductus arteriosus (PDA) in very-low-birth-weight (VLBW) infants in Korea. A total of 2,254 VLBW infants among 2,386 from Korean Neonatal Network cohort born from January 2013 to June 2014 were included. No PDA was seen for 1,206 infants (53.5%) and the infants diagnosed or treated for PDA were 1,048 infants (46.5%). The proportion of infants with PDA was decreased according to the increase in gestational age (GA) and birthweight. Infants with PDA were divided into groups according to the therapeutic strategies of PDA: prophylactic treatment (PT, n = 69, 3.1%), pre-symptomatic treatment (PST, n = 212, 9.4%), symptomatic treatment (ST, n = 596, 26.4%), and conservative treatment (CT, n = 171, 7.6%). ST was the most preferred treatment modality for preterm PDA and the proportion of the patients was decreased in the order of PST, CT, and PT. Although ST was still the most favored treatment in GA < 24 weeks group, CT was more preferred than PST or ST when compared with GA ≥ 32 weeks group [CT vs. PST, OR 5.3, 95% CI 1.56-18.18; CT vs. ST, OR 2.9, 95% CI 1.03-8.13]. A total of 877 infants (38.9%) received pharmacological or surgical treatment about PDA, and 35.5% (801 infants) received pharmacological treatment, mostly with ibuprofen. Seventy-six infants (3.4%) received primary ligation and 8.9% (201 infants) received secondary ligation. Diverse treatment strategies are currently used for preterm PDA in Korea. Further analyses of neonatal outcomes according to the treatment strategies are necessary to obtain a standardized treatment guideline for preterm PDA. PMID:26566359

  14. Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

    PubMed Central

    Kaplan, Jason B.; Stein, Brady L.; McMahon, Brandon; Giles, Francis J.; Platanias, Leonidas C.

    2016-01-01

    Despite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs. PMID:26870834

  15. A strategy for reaching therapeutic salicylate levels in patients with rheumatoid arthritis using standardized dosing regimens.

    PubMed

    Furst, D E; Blocka, K; Cassell, S; Dromgoole, S; Harris, E R; Hirschberg, J M; Josephson, N; Rupp, P A; Paulus, H E; Trimble, R B

    1987-04-01

    After one to 2 weeks of 45 mg/kg/day choline magnesium trisalicylate (CMT) in 2 divided doses, 51 of 71 patients with rheumatoid arthritis (72%) had observed steady state serum salicylate concentrations between 150 and 300 mg/l (mean salicylate: 213 +/- 10 mg/l), although 17 later required dose adjustment. CMT dosing was changed in 37 cases by using the formula: dosing rate = total clearance X concentration. The expected and observed concentrations were not different (p = 0.31); thus, this formula can help calculate salicylate dosing changes to bring the serum salicylate level to within the therapeutic range. PMID:3599003

  16. How genetic errors in GPCRs affect their function: Possible therapeutic strategies

    PubMed Central

    Stoy, Henriette; Gurevich, Vsevolod V.

    2015-01-01

    Activating and inactivating mutations in numerous human G protein-coupled receptors (GPCRs) are associated with a wide range of disease phenotypes. Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations, many of which were biochemically characterized, along with known GPCR structures and current models of GPCR activation, to understand the molecular mechanisms yielding pathological phenotypes. Based on this mechanistic understanding we also propose different therapeutic approaches, both conventional, using small molecule ligands, and novel, involving gene therapy. PMID:26229975

  17. Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing’s sarcoma

    PubMed Central

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

    2011-01-01

    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

  18. Adults' Strategies for Simple Addition and Multiplication: Verbal Self-Reports and the Operand Recognition Paradigm

    ERIC Educational Resources Information Center

    Metcalfe, Arron W. S.; Campbell, Jamie I. D.

    2011-01-01

    Accurate measurement of cognitive strategies is important in diverse areas of psychological research. Strategy self-reports are a common measure, but C. Thevenot, M. Fanget, and M. Fayol (2007) proposed a more objective method to distinguish different strategies in the context of mental arithmetic. In their operand recognition paradigm, speed of…

  19. MIF-CD74 GUIDED THERAPEUTIC STRATEGY FOR THE UPFRONT TREATMENT OF GBM PATIENTS WITH AN UNMETHYLATED MGMT PROMOTER

    PubMed Central

    McDonald, Kerrie L; Ha, Wendy; Sevim, Hatice

    2014-01-01

    BACKGROUND: Promoter methylation of the DNA repair gene, MGMT is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. Currently, there are no universally effective systemic treatments available for patients with an unmethylated MGMT promoter or treatments for patients whose tumor recurs after primary treatment, irrespective of MGMT methylation status. We used SELDI-TOF MS to identify low molecular weight proteins associated with poor survival. We report a new therapeutic strategy with potential to overcome the drug resistance conferred by MGMT when applied as an adjunct therapy to the standard chemoradiation for patients. METHODS: We screened the low molecular weight proteome of patients' tumors, which were non-responsive to chemoradiotherapy (survival <12 months). Proteins of significant abundance in the non-responsive patients were purified, identified and validated in a larger cohort of GBM (n = 230). Inhibitors were sourced and efficacy of the drug was tested in patient derived tumor models. RESULTS: High expression of the inflammatory related protein Macrophage Inhibitory Factor (MIF) and its receptor, CD74 were found in patients who were non-responsive to chemoradiation. Heightened expression of both MIF and CD74 were identified in 57% of GBM (n = 230) and co-segregated with poor prognosis. CD74 forms a complex with CD44 at the cell surface. After MIF binds to the CD74/44 complex, Src is recruited. Src recruitment then initiates the activation of multiple pathways including Ras/MAPK and Akt resulting in tumor proliferation. Pro-angiogenic effects have also been attributed to this complex. Because of its involvement in tumorigenesis, inhibition of the MIF/CD74/CD44 complex with specific inhibitors in combination with chemoradiotherapy will likely abate the resistance to standard treatment and result in longer survival. Ibudilast (AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a] pyridine) is an

  20. Impact of Comorbidity and Age on Determinants Therapeutic Strategies in Advanced Pancreatic Head Cancer Patients With Obstructive Jaundices

    PubMed Central

    Chen, Yu-Guang; Pan, Hsueh-Hsing; Dai, Ming-Shen; Lin, Chin; Lu, Chieh-Sheng; Su, Sui-Lung; Chang, Ping-Ying; Huang, Tzu-Chuan; Chen, Jia-Hong; Wu, Yi-Ying; Chen, Yeu-Chin; Ho, Ching Liang

    2015-01-01

    Abstract The current retrospective study aimed to investigate the relationship between prognostic factors and overall survival (OS) in patients with advanced pancreatic head cancers who initially presented with obstructive jaundice. Furthermore, the impact of age and comorbidities on therapeutic strategies in such patients was evaluated. A total of 79 advanced pancreatic head cancer patients who were treated at our institution between January 2006 and November 2013 were reviewed. We analyzed OS risk factors including sex, age, laboratory characteristics, Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index Scores (CCIS), and therapeutic strategies using Cox proportional hazards regression models. There was no difference in the OS of patients according to the type biliary drainage procedure they underwent. Other related factors, such as better performance status, lower CCIS, and receiving chemotherapy significantly correlated with survival in multivariate analyses. There was a significant survival benefit in systemic chemotherapy compared to best supportive care (BSC) or local radiotherapy. However, no survival benefit was found in elderly patients (age >70 years) undergoing systemic therapy compared to younger patients, except in those elderly patients with CCIS ≤ 1. In advanced pancreatic head cancer patients with obstructive jaundice, systemic therapy and adequate biliary drainage were still the most effective procedures for improving OS in the general population. However, in elderly patients with relatively higher CCIS, BSC with adequate biliary drainage was palliative and no less effective than systemic/local therapies. PMID:26252308

  1. Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques.

    PubMed

    Yang, Hao; Liu, Cui-Cui; Wang, Chun-Yu; Zhang, Qian; An, Jiang; Zhang, Lingling; Hao, Ding-Jun

    2016-07-01

    Spinal cord injury (SCI) is a traumatic event resulting in disturbances to normal sensory, motor, or autonomic functions, which ultimately impacts a patient's physical, psychological, and social well-being. Until now, no available therapy for SCI can effectively slow down or halt the disease progression. Compared to traditional treatments, e.g., medication, surgery, and functional electrical stimulation, stem cell replacement therapy shows high potential for repair and functional plasticity. Thus, stem cell therapy may provide a promising strategy in curative treatment of SCI, specifically when considering the requirement of neuron replenishment in the spinal cord after distinct acute injuries. However, the therapeutic application of neural stem cells (NSCs) still faces enormous challenges, such as ethical issues, possible inflammatory reactions, graft rejection, and tumor formation. Therefore, it is of vital interest to identify more suitable sources of cells with stem cell potential, which might potentially be harnessed for local neural repair. Due to abovementioned possible drawbacks, these cells should be autologous. Reprogramming of astrocytes to generate the desired neuronal cell types would open the door to autologous cell transplantation and treatment of SCI without possible severe side effects. In this paper, we review the relevant therapeutic strategies for SCI, and conversion of astrocyte into NSCs, suggesting this procedure as a possible treatment option. PMID:25863960

  2. Age-related deficits in voluntary control over saccadic eye movements: consideration of electrical brain stimulation as a therapeutic strategy.

    PubMed

    Chen, Po Ling; Machado, Liana

    2016-05-01

    Sudden changes in our visual environment trigger reflexive eye movements, so automatically they often go unnoticed. Consequently, voluntary control over reflexive eye movements entails considerable effort. In relation to frontal-lobe deterioration, adult aging adversely impacts voluntary saccadic eye movement control in particular, which compromises effective performance of daily activities. Here, we review the nature of age-related changes in saccadic control, focusing primarily on the antisaccade task because of its assessment of 2 key age-sensitive control functions: reflexive saccade inhibition and voluntary saccade generation. With an ultimate view toward facilitating development of therapeutic strategies, we systematically review the neuroanatomy underpinning voluntary control over saccadic eye movements and natural mechanisms that kick in to compensate for age-related declines. We then explore the potential of noninvasive electrical brain stimulation to counteract aging deficits. Based on evidence that anodal transcranial direct current stimulation can confer a range of benefits specifically relevant to aging brains, we put forward this neuromodulation technique as a therapeutic strategy for improving voluntary saccadic eye movement control in older adults. PMID:27103518

  3. Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer's Disease

    PubMed Central

    Agis-Torres, Angel; Sölhuber, Monica; Fernandez, Maria; Sanchez-Montero, J.M.

    2014-01-01

    The lack of an adequate therapy for Alzheimer's Disease (AD) contributes greatly to the continuous growing amount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD is the most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, which contrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or even unknown. This review offers a view of the current state of knowledge about AD which includes more relevant findings and processes that take part in the disease; it also shows more relevant past, present and future research on therapeutic drugs taking into account the new paradigm “Multi-Target-Directed Ligands” (MTDLs). In our opinion, this paradigm will lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD but also in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targets that should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goes from the pathology and the processes involved in AD to the strategies to consider in on-going and future researches. PMID:24533013

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

    PubMed

    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

    2013-01-01

    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

  5. [Stage I seminoma: therapeutic strategy: surveillance, radiotherapy, chemotherapy. A case-report].

    PubMed

    Bigot, P; Droupy, S; Houlgatte, A; De Crevoisier, R; Fléchon, A

    2011-03-01

    The management guide-lines about stage I seminoma (pT1 à pT4, No, Mo) recommend to perform a surveillance, an adjuvant chemotherapy based on carboplatine, or a radiotherapy. However, these options are not equivalent for side effects and relapse risk. Debates are in progress in order to simplify the surveillance protocols which remain essential because of the tumoral relapses for 15% of the patients. The occurrence of a tumoral relapse during the follow-up does not decrease the specific survival. The para-aortic 20 Gy radiotherapy is efficient on the seminoma and decreases the relapse risk. Its main side-effect is a long-term risk of secondary cancer. Carboplatine chemotherapy is also an efficient option which provides good results on the specific survival and the survival without progression. Very few studies assess the long-term side effects of chemotherapy. In the end, the therapeutic decision must be taken with the patient after informing him about all the therapeutic options. PMID:21397830

  6. Novel therapeutic strategies in human malignancy: combining immunotherapy and oncolytic virotherapy

    PubMed Central

    Sampath, Padma; Thorne, Steve H

    2015-01-01

    Results from randomized clinical trials over the last several years have finally begun to demonstrate the potential of oncolytic viral therapies to treat a variety of cancers. One reason for these successes has been the realization that this platform is most effective when considered primarily as an immunotherapy. Cancer immunotherapy has also made dramatic strides recently with antibodies capable of blocking immune checkpoint inhibitors and adoptive T-cell therapies, notably CAR T-cells, leading a panel of novel and highly clinically effective therapies. It is clear therefore that an understanding of how and when these complementary approaches can most effectively be combined offers the real hope of moving beyond simply treating the disease and toward starting to talk about curative therapies. In this review we discuss approaches to combining these therapeutic platforms, both through engineering the viral vectors to more beneficially interact with the host immune response during therapy, as well as through the direct combinations of different therapeutics. This primarily, but not exclusively focuses on strains of oncolytic vaccinia virus. Some of the results reported to date, primarily in pre-clinical models but also in early clinical trials, are dramatic and hold great promise for the future development of similar therapies and their translation into cancer therapies.

  7. Self-Microemulsifying Drug Delivery Systems: An Attractive Strategy for Enhanced Therapeutic Profile

    PubMed Central

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

    2014-01-01

    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. PMID:27382619

  8. Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis.

    PubMed

    Royce, Simon G; Moodley, Yuben; Samuel, Chrishan S

    2014-03-01

    Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial-mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments. PMID:24513131

  9. Stem cells for cell replacement therapy: a therapeutic strategy for HD?

    PubMed

    Rosser, Anne; Svendsen, Clive N

    2014-09-15

    Much interest has been expressed over the last couple of decades in the potential application of stem cells to medicine, both for research and diagnostic tools and as a source of donor cells for therapeutic purposes. Potential therapeutic applications include replacement of cells in many body organs where the capacity for intrinsic repair is limited, including the pancreas, heart, and brain. A key challenge is to generate the relevant donor cell types, and this is particularly challenging in the brain where the number of different neuronal subtypes is so great. Although dopamine neuron replacement in Parkinson's disease has been the focus of most clinical studies, great interest has been shown in this approach for other disorders, including Huntington's disease. Replacing complete neural circuits in the adult brain is clearly challenging, and there are many other complexities with regard to both donor cells and host. This article presents the pros and cons of taking a cell therapy approach in Huntington's disease. It considers the implantation both of cells that are already of the same neural subtype as those lost in the disease process (ie, primary fetal cells derived from the developing striatum) and those derived from stem cells, which require "directing" toward that phenotype. PMID:25216372

  10. mTOR inhibition as a Therapeutic Strategy in the Management of Urologic Malignancies

    PubMed Central

    Garcia, Jorge A.; Danielpour, David

    2008-01-01

    The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth and apoptosis. Recently, there has been an enormous increase in our understanding on molecular mechanisms underlying the therapeutics of rapamycin in cancer. Alterations in the pathway regulating mTOR occur in many solid malignancies including prostate, bladder and kidney cancer; and in-vitro and in-vivo models of prostate and bladder cancer have established the importance of the mTOR pathway in control of cancer progression and metastasis. Temsirolimus (Torisel™) and everolimus (RAD-001), two ester analogues of rapamycin, as well as rapamycin itself have clear antitumor activity in in-vitro and in-vivo models, and are under clinical trial investigations for prostate and bladder cancer. Phase II and III trials have already established the clinical efficacy of temsirolimus in renal cancer, and current renal trials are evaluating the combined effects of VEGF and mTOR inhibition. Ongoing studies in prostate and bladder cancer will soon define the activity and safety profiles of everolimus and temsirolimus. Recent molecular advances have uncovered a startling complexity in the macromolecular function of mTOR complexes, with the identification of new mTOR partners (raptor, rictor, FKBP38, PRAS40 and mSIN1), putative cancer therapeutic/prognostic targets for future clinical trials. PMID:18566209

  11. Vemurafenib resistance signature by proteome analysis offers new strategies and rational therapeutic concepts.

    PubMed

    Paulitschke, Verena; Berger, Walter; Paulitschke, Philipp; Hofstätter, Elisabeth; Knapp, Bernhard; Dingelmaier-Hovorka, Ruth; Födinger, Dagmar; Jäger, Walter; Szekeres, Thomas; Meshcheryakova, Anastasia; Bileck, Andrea; Pirker, Christine; Pehamberger, Hubert; Gerner, Christopher; Kunstfeld, Rainer

    2015-03-01

    The FDA-approved BRAF inhibitor vemurafenib achieves outstanding clinical response rates in patients with melanoma, but early resistance is common. Understanding the pathologic mechanisms of drug resistance and identification of effective therapeutic alternatives are key scientific challenges in the melanoma setting. Using proteomic techniques, including shotgun analysis and 2D-gel electrophoresis, we identified a comprehensive signature of the vemurafenib-resistant M24met in comparison with the vemurafenib-sensitive A375 melanoma cell line. The resistant cells were characterized by loss of differentiation, induction of transformation, enhanced expression of the lysosomal compartment, increased potential for metastasis, migration, adherence and Ca2(+) ion binding, enhanced expression of the MAPK pathway and extracellular matrix proteins, and epithelial-mesenchymal transformation. The main features were verified by shotgun analysis with QEXACTIVE orbitrap MS, electron microscopy, lysosomal staining, Western blotting, and adherence assay in a VM-1 melanoma cell line with acquired vemurafenib resistance. On the basis of the resistance profile, we were able to successfully predict that a novel resveratrol-derived COX-2 inhibitor, M8, would be active against the vemurafenib-resistant but not the vemurafenib-sensitive melanoma cells. Using high-throughput methods for cell line and drug characterization may thus offer a new way to identify key features of vemurafenib resistance, facilitating the design of effective rational therapeutic alternatives. PMID:25612618

  12. Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases

    PubMed Central

    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.

    2013-01-01

    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

  13. Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter.

    PubMed

    Bakiri, Yamina; Hamilton, Nicola B; Káradóttir, Ragnhildur; Attwell, David

    2008-01-15

    Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors. PMID:18046734

  14. Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis.

    PubMed

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

    2016-06-01

    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. PMID:27018006

  15. Dilution standard addition calibration: A practical calibration strategy for multiresidue organic compounds determination.

    PubMed

    Martins, Manoel L; Rizzetti, Tiele M; Kemmerich, Magali; Saibt, Nathália; Prestes, Osmar D; Adaime, Martha B; Zanella, Renato

    2016-08-19

    Among calibration approaches for organic compounds determination in complex matrices, external calibration, based in solutions of the analytes in solvent or in blank matrix extracts, is the most applied approach. Although matrix matched calibration (MMC) can compensates the matrix effects, it does not compensate low recovery results. In this way, standard addition (SA) and procedural standard calibration (PSC) are usual alternatives, despite they generate more sample and/or matrix blanks consumption need, extra sample preparations and higher time and costs. Thus, the goal of this work was to establish a fast and efficient calibration approach, the diluted standard addition calibration (DSAC), based on successive dilutions of a spiked blank sample. In order to evaluate the proposed approach, solvent calibration (SC), MMC, PSC and DSAC were applied to evaluate recovery results of grape blank samples spiked with 66 pesticides. Samples were extracted with the acetate QuEChERS method and the compounds determined by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Results indicated that low recovery results for some pesticides were compensated by both PSC and DSAC approaches. Considering recoveries from 70 to 120% with RSD <20% as adequate, DSAC presented 83%, 98% and 100% of compounds meeting this criteria for the spiking levels 10, 50 and 100μgkg(-1), respectively. PSC presented same results (83%, 98% and 100%), better than those obtained by MMC (79%, 95% and 97%) and by SC (62%, 70% and 79%). The DSAC strategy showed to be suitable for calibration of multiresidue determination methods, producing adequate results in terms of trueness and is easier and faster to perform than other approaches. PMID:27432791

  16. The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)

    PubMed Central

    Xu, Meng; Xie, Yiqun; Ni, Songshi

    2015-01-01

    First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, produce reliable responses and survival benefits in selected patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who initially respond to first-line therapy with EGFR TKIs will experience disease progression in 1-2 years. To overcome the resistance of EGFR TKIs, the potent resistance mechanisms and novel therapeutic strategies have been developed. T790M mutation and activation of bypass signaling pathway are identified the predominant mechanisms of acquired resistance to TKIs. Several approaches have shown promise, such as next-generation EGFR TKIs, immunotherapy, and combinational therapies. And the limited clinical data suggest that all drugs are acceptable safe. Additionally, this review will also focus on the increasingly importance of re-biopsy at the time of disease progression, and the matching effective therapies is related to the identification of specific molecular types of tumors. PMID:26015938

  17. Optimizing therapeutic efficacy of chemopreventive agents: A critical review of delivery strategies in oral cancer chemoprevention clinical trials

    PubMed Central

    Holpuch, Andrew S.; Desai, Kashappa-Goud H.; Schwendeman, Steven P.; Mallery, Susan R.

    2011-01-01

    Due to its characterized progression from recognized premalignant oral epithelial changes (i.e., oral epithelial dysplasia) to invasive cancer, oral squamous cell carcinoma represents an optimal disease for chemopreventive intervention prior to malignant transformation. The primary goal of oral cancer chemoprevention is to reverse, suppress, or inhibit the progression of premalignant lesions to cancer. Over the last several decades, numerous oral cancer chemoprevention clinical trials have assessed the therapeutic efficacy of diverse chemopreventive agents. The standard of care for more advanced oral dysplastic lesions entails surgical excision and close clinical follow-up due to the potential (~33%) for local recurrence at a similar or more advanced histological stage. The purpose of this review was to identify prominent oral cancer chemoprevention clinical trials, assess their overall therapeutic efficacy, and delineate effects of local versus systemic drug administration. In addition, these compiled clinical trial data present concepts for consideration in the design and conduction of future clinical trials. PMID:22013393

  18. Cell penetrating peptides as a therapeutic strategy in chronic lymphocytic leukemia.

    PubMed

    Arrouss, Issam; Decaudin, Didier; Choquet, Sylvain; Azar, Nabih; Parizot, Christophe; Zini, Jean M; Nemati, Fariba; Rebollo, Angelita

    2015-01-01

    PP2A is a serine/threonine phosphatase critical to a number of physiological and developmental processes. In this manuscript, we show that a peptide, specifically blocking the caspase- 9/PP2A interaction, DPT-C9h, induces apoptosis in primary tumour B cells isolated from peripheral blood mononuclear cells or bone marrow of chronic lymphocytic leukemia (CLL) patients, but not on B cells obtained from healthy donors (HD). Moreover, in both CLL patients and HD, DPT-C9h does not induce apoptosis on T- and NKcells and monocytes. Our results strongly suggest that DPT-C9h peptide has tumour specificity and that caspase-9/PP2Ac interaction constitutes a novel therapeutic approach for the treatment in CLL patients. PMID:25687226

  19. Characteristics, diagnosis and therapeutic strategies for IgG4-related orbital disease.

    PubMed

    Oles, Krzysztof; Sładzień, Jacek; Bartuś, Krzysztof; Leszczyńska, Joanna; Bojanowska, Emila; Krakowczyk, Łukasz; Mika, Joanna

    2016-06-01

    Thanks to detailed studies conducted in recent years, a new disease syndrome was identified in 2001. It is known as a IgG4-related disease and its differentiation is based on the analysis of IgG4 levels in the affected tissues. The IgG4-related disease is considered to be a generalized pathological process involving a wide spectrum of various disorders that may affect distant organs. Orbital IgG4-related disease is a recently reported issue that may prove important for the elucidation of the etiology of idiopathic, lymphoplasmacytic or fibrotic disorders of various organs, including the orbits. In this article, we are describing epidemiology and differential diagnostics of IgG4-related orbital disease with particular focus on pseudotumors, MALT lymphomas and lymphocyte/plasma cell infiltrations of the orbit. We are also discussing therapeutic possibilities currently available in the management of the disease. PMID:27116895

  20. Vasopressin receptors and pharmacological chaperones: from functional rescue to promising therapeutic strategies.

    PubMed

    Mouillac, Bernard; Mendre, Christiane

    2014-05-01

    Conformational diseases result from protein misfolding and/or aggregation and constitute a major public health problem. Congenital Nephrogenic Diabetes Insipidus is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor gene leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of specific ligands such as antagonists (vaptans), agonists as well as biased agonists of the V2 receptor have proven their usefulness as efficient pharmacochaperones. These compounds represent a potential therapeutic treatment of this X-linked genetic pathology. PMID:24239889

  1. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    PubMed Central

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  2. Current developments in therapeutic and diagnostic strategies for Q fever: glimpses of patent analysis.

    PubMed

    Chauhan, Rashi; Wadhwa, Gulshan; Sharma, Sanjeev K; Jain, Chakresh K

    2014-01-01

    Coxiella burnetii is an infectious and etiological agent responsible for causing Q fever. There are mainly two forms of the Q fever that are chronic and acute. Though the acute type is usually linked with symptoms like pneumonia and hepatitis, the chronic form is shown to have mortality rate of 5%. Percentage of mortality rate might increases from 5% to 25% if left untreated. The present treatments of disease include the recommended dose of drugs and vaccine. Presently, extensive attempt is in progress to find novel therapies to combat the disease. This review is projected to provide a brief introduction of C. burnetii and Q fever while emphasizing therapeutics, prophylactic measures and diagnostic applications based on recent patents prospects. PMID:25409874

  3. Trans-synaptic (GABA-dopamine) modulation of cocaine induced dopamine release: A potential therapeutic strategy for cocaine abuse

    SciTech Connect

    Dewey, S.L.; Straughter-Moore, R.; Chen, R.

    1995-05-01

    We recently developed a new experimental strategy for measuring interactions between functionally-linked neurotransmitter systems in the primate and human brain with PET. As part of this research, we demonstrated that increases in endogenous GABA concentrations significantly reduced striatal dopamine concentrations in the primate brain. We report here the application of the neurotransmitter interaction paradigm with PET and with microdialysis to the investigation of a novel therapeutic strategy for treating cocaine abuse based on the ability of GABA to inhibit cocaine induced increases in striatal dopamine. Using gamma-vinyl GABA (GVG, a suicide inhibitor of GABA transaminase), we performed a series of PET studies where animals received a baseline PET scan with labeled raclopride injection, animals received cocaine (2.0 mg/kg). Normally, a cocaine challenge significantly reduces the striatal binding of {sup 11}C-raclopride. However, in animals pretreated with GVG, {sup 11}C-raclopride binding was less affected by a cocaine challenge compared to control studies. Furthermore, microdialysis studies in freely moving rats demonstrate that GVG (300 mg/kg) significantly inhibited cocaine-induced increases in extracellular dopamine release. GVG also attenuated cocaine-induced increases in locomotor activity. However, at a dose of 100 mg/kg, GVG had no effect. Similar findings were obtained with alcohol. Alcohol pretreatment dose dependantly (1-4 g/kg) inhibited cocaine-induced increases in extracellular dopamine concentrations in freely moving rats. Taken together, these studies suggest that therapeutic strategies targeted at increasing central GABA concentrations may be beneficial for the treatment of cocaine abuse.

  4. Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers.

    PubMed

    Modugno, Michele; Banfi, Patrizia; Gasparri, Fabio; Borzilleri, Robert; Carter, Percy; Cornelius, Lyndon; Gottardis, Marco; Lee, Ving; Mapelli, Claudio; Naglich, Joseph G; Tebben, Andrew; Vite, Gregory; Pastori, Wilma; Albanese, Clara; Corti, Emiliana; Ballinari, Dario; Galvani, Arturo

    2015-03-15

    Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein. PMID:25486070

  5. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies

    PubMed Central

    Loane, David J.; Faden, Alan I.

    2010-01-01

    Traumatic brain injury (TBI) causes secondary biochemical changes that contribute to subsequent tissue damage and associated neuronal cell death. Neuroprotective treatments that limit secondary tissue loss and/or improve behavioral outcome have been well established in multiple animal models of TBI. However, translation of such neuroprotective strategies to human injury have been disappointing, with more than thirty controlled clinical trials having failed. Both conceptual issues and methodological differences between preclinical and clinical injury have undoubtedly contributed to these translational difficulties. More recently, changes in experimental approach, as well as altered clinical trial methodologies, have raised cautious optimism regarding outcomes of future clinical trials. Here, we critically review developing experimental neuroprotective strategies that show promise and propose criteria for improving the probability of successful clinical translation. PMID:21035878

  6. Multi-target siRNA: Therapeutic Strategy for Hepatocellular Carcinoma

    PubMed Central

    Li, Tiejun; Xue, Yuwen; Wang, Guilan; Gu, Tingting; Li, Yunlong; Zhu, York Yuanyuan; Chen, Li

    2016-01-01

    Multiple targets RNAi strategy is a preferred way to treat multigenic diseases, especially cancers. In the study, multi-target siRNAs were designed to inhibit NET-1, EMS1 and VEGF genes in hepatocellular carcinoma (HCC) cells. And multi-target siRNAs showed better silencing effects on NET-1, EMS1 and VEGF, compared with single target siRNA. Moreover, multi-target siRNA showed greater suppression effects on proliferation, migration, invasion, angiogenesis and induced apoptosis in HCC cells. The results suggested that multi-target siRNA might be a preferred strategy for cancer therapy and NET-1, EMS1 and VEGF could be effective targets for HCC treatments. PMID:27390607

  7. Multiple plaque rupture and intracoronary thrombosis: two successful therapeutic strategies in the same patient.

    PubMed

    Tigen, Kursat; Mutlu, Bulent; Cevik, Cihan; Karavelioglu, Yusuf; Basaran, Yelda

    2008-01-01

    Interventionalists have many tools at their disposal for percutaneous revascularization and they all use every modality to restore flow. Sometimes they face challenging situations in the setting of acute coronary syndromes in which more than one strategy has to be used urgently. We are presenting a young male patient with myocardial infarction having two simultaneous occluding fresh coronary thrombi in his left anterior descending coronary artery and its diagonal side branch. Clot extraction catheter is used for aspiration of left anterior descending coronary artery thrombus and he received lytic therapy for the thrombus in the large diagonal side branch. PMID:18486083

  8. Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes

    PubMed Central

    Zou, Jixue; Zhou, Zhigang; Wan, Liping; Tong, Yin; Qin, Youwen; Wang, Chun; Zhou, Kun

    2015-01-01

    The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2'-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS. PMID:26317501

  9. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease

    PubMed Central

    Quetglas, Emilio G; Mujagic, Zlatan; Wigge, Simone; Keszthelyi, Daniel; Wachten, Sebastian; Masclee, Ad; Reinisch, Walter

    2015-01-01

    The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients. PMID:26640330

  10. Drug Repositioning for Gynecologic Tumors: A New Therapeutic Strategy for Cancer

    PubMed Central

    Banno, Kouji; Yanokura, Megumi; Irie, Haruko; Masuda, Kenta; Kobayashi, Yusuke; Tominaga, Eiichiro; Aoki, Daisuke

    2015-01-01

    The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery. PMID:25734181

  11. Surgical strategies and modern therapeutic options in the treatment of craniopharyngiomas.

    PubMed

    Mortini, Pietro; Gagliardi, Filippo; Boari, Nicola; Losa, Marco

    2013-12-01

    The optimal treatment of patients with craniopharyngioma remains controversial. In particular, the role of aggressive treatment compared to less aggressive therapeutic options is poorly understood. Radical resection is the therapy of choice at any age, because it is associated with the best outcome in terms of survival. Nevertheless, aggressive behaviour, location, involvement of critical structures, tumour size, calcifications, and patient age may limit the extent of resection. Surgery can also carry significant morbidity in terms of visual, hypothalamic, and endocrinological disturbances. Long term sequelae reduce the quality of life in 50% of long-term survivors, notably obesity and neurobehavioral impairment due to hypthalamic involvement and iatrogenic induced lesions. The quality of life should be considered as a clinically important endpoint in patients, who currently experience good overall survival rates, regardless of the degree of surgical resection. Tendency to recur despite negative postoperative imaging led many authors to advocate a less aggressive surgical treatment followed by radiation therapy. We review the data reported in the literature, especially early outcome after surgical treatment and factors affecting the risk of tumour recurrence, to elucidate the role of attempted radical resection in the treatment of craniopharyngioma and to identify the clinical and morphological characteristics predictive for the best surgical prognosis. PMID:23932582

  12. The Third Therapeutic System: Faith Healing Strategies in the Context of a Generalized AIDS Epidemic

    PubMed Central

    Manglos, Nicolette D.; Trinitapoli, Jenny

    2014-01-01

    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

  13. mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis.

    PubMed

    Citraro, Rita; Leo, Antonio; Constanti, Andrew; Russo, Emilio; De Sarro, Giovambattista

    2016-05-01

    Several preclinical and some clinical studies have revealed that the mammalian target of rapamycin (mTOR) signaling pathway is involved in both genetic and acquired epilepsy syndromes. Excessive activation of mTOR signaling, as a consequence of loss-of-function of genes encoding for tuberous sclerosis complex (TSC) 1 and 2, is linked to the development of cortical malformations and epilepsy. This mTOR hyperactivation is associated with different epileptogenic conditions under the term of 'mTORopathies' such as tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly and ganglioglioma. mTOR overactivation produces brain abnormalities that include dysplastic neurons, abnormal cortical organization and astrogliosis. mTOR inhibitors (e.g. rapamycin) have consistent protective effects in various genetic (e.g. TSC models and WAG/Rij rats) and acquired (e.g. kainate or pilocarpine post-status epilepticus) epilepsy animal models. Furthermore, clinical studies in patients with TSC and cortical dysplasia (CD) have confirmed the effectiveness of mTOR inhibitors also in epileptic patients. Therefore, mTOR is currently a very good candidate as a target for epilepsy and epileptogenesis. This review describes the relevance of the mTOR pathway to epileptogenesis and its potential as a therapeutic target in epilepsy treatment by presenting the most recent findings on mTOR inhibitors. PMID:27049136

  14. New therapeutic strategies targeting transmembrane signal transduction in the immune system

    PubMed Central

    2010-01-01

    Single-chain receptors and multi-chain immune recognition receptors (SRs and MIRRs, respectively) represent families of structurally related but functionally different surface receptors expressed on different cells. In contrast to SRs, a distinctive and common structural characteristic of MIRR family members is that the extracellular recognition domains and intracellular signaling domains are located on separate subunits. How extracellular ligand binding triggers MIRRs and initiates intracellular signal transduction processes is not clear. A novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, suggests that the homooligomerization of receptor intracellular signaling domains represents a necessary and sufficient condition for receptor triggering. In this review, I demonstrate striking similarities between a consensus model of SR signaling and the SCHOOL model of MIRR signaling and show how these models, together with the lessons learned from viral pathogenesis, provide a molecular basis for novel pharmacological approaches targeting inter- and intrareceptor transmembrane interactions as universal therapeutic targets for a diverse variety of immune and other disorders. PMID:20519929

  15. Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway

    PubMed Central

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

    2016-01-01

    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

  16. Inhibiting NF-κB Activation by Small Molecules As a Therapeutic Strategy

    PubMed Central

    Gupta, Subash C; Sundaram, Chitra; Reuter, Simone; Aggarwal, Bharat B

    2010-01-01

    Because nuclear factor-κB (NF-κB) is a ubiquitously expressed proinflammatory transcription factor that regulates the expression of over 500 genes involved in cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and inflammation, the NF-κB signaling pathway has become a potential target for pharmacological intervention. A wide variety of agents can activate NF-κB through canonical and noncanonical pathways. Canonical pathway involves various steps including the phosphorylation, ubiquitnation, and degradation of the inhibitor of NF-κB (IκBα), which leads to the nuclear translocation of the p50- p65 subunits of NF-κB followed by p65 phosphorylation, acetylation and methylation, DNA binding, and gene transcription. Thus, agents that can inhibit protein kinases, protein phosphatases, proteasomes, ubiquitnation, acetylation, methylation, and DNA binding steps have been identified as NF-κB inhibitors. Here, we review the small molecules that suppress NF-κB activation and thus may have therapeutic potential. PMID:20493977

  17. Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

    PubMed Central

    2010-01-01

    Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects. PMID:20540720

  18. ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies.

    PubMed

    Rinaldi, Mariagrazia; Caffo, Maria; Minutoli, Letteria; Marini, Herbert; Abbritti, Rosaria Viola; Squadrito, Francesco; Trichilo, Vincenzo; Valenti, Andrea; Barresi, Valeria; Altavilla, Domenica; Passalacqua, Marcello; Caruso, Gerardo

    2016-01-01

    Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas. PMID:27338365

  19. ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies

    PubMed Central

    Rinaldi, Mariagrazia; Caffo, Maria; Minutoli, Letteria; Marini, Herbert; Abbritti, Rosaria Viola; Squadrito, Francesco; Trichilo, Vincenzo; Valenti, Andrea; Barresi, Valeria; Altavilla, Domenica; Passalacqua, Marcello; Caruso, Gerardo

    2016-01-01

    Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas. PMID:27338365

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

    PubMed

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

    2016-03-01

    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. PMID:27011200

  1. Blockade of Apoptosis as a Rational Therapeutic Strategy for the Treatment of Sepsis

    PubMed Central

    Ayala, Alfred; Wesche-Soldato, Doreen E.; Perl, Mario; Lomas-Neira, Joanne L.; Swan, Ryan; Chung, Chun-Shiang

    2006-01-01

    Over time it has become clear, that much like other organ systems, the function and responsiveness of the immune system is impaired during the course of sepsis and that this is a precipitous event in the decline of the critically ill patient/animal. One hypothesis put forward to explain the development of septic immune dysfunction is that it is a pathological result of increased immune cell apoptosis. Alternatively, it has been proposed that the clearance of increased numbers of apoptotic cells may actively drive immune suppression through the cells that handle them. Here we will review the data from studies involving septic animals and patients, which indicate that loss of immune cells, as well as non-immune cells, in some cases, is a result of dysregulated apoptosis. Subsequently, we will consider the cell death pathways, i.e., ‘extrinsic’ and/or ‘intrinsic’, which are activated and what cell populations may orchestrate this dysfunctional apoptotic process, immune and/or non-immune. Finally, we will discuss potentially novel therapeutic targets, such as caspases, death receptor family members [e.g., TNF, Fas], pro-/anti-apoptotic Bcl-family members, etc., and approaches, such as caspase inhibitors, use of fusion proteins, peptidomimetics, siRNA, etc., which might be considered for the treatment of the septic patient. PMID:17380787

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

    PubMed Central

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

    2016-01-01

    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. PMID:27011200

  3. Stenotrophomonas, Achromobacter, and nonmelioid Burkholderia species: antimicrobial resistance and therapeutic strategies.

    PubMed

    Abbott, Iain J; Peleg, Anton Y

    2015-02-01

    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. PMID:25643274

  4. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    PubMed

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. PMID:27449595

  5. Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?

    PubMed Central

    De Silva, T. Michael; Miller, Alyson A.

    2016-01-01

    Cerebral small vessel disease (SVD) is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the arteriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy) forms of cerebral SVD and its most important risk factors (hypertension and aging), as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors. PMID:27014073

  6. Glucose Lowering Therapeutic Strategies for Type 2 Diabetic Patients with Chronic Kidney Disease in Primary Care Setting in France: A Cross-Sectional Study

    PubMed Central

    Grandfils, N.; Detournay, B.; Attali, C.; Joly, D.; Simon, D.; Vergès, B.; Toussi, M.; Briand, Y.; Delaitre, O.

    2013-01-01

    Aim. To understand glucose lowering therapeutic strategies of French general practitioners (GPs) in the management of type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD). Methods. A multicenter cross-sectional study was conducted from March to June 2011 among a sample of French GPs who contribute to the IMS Lifelink Disease Analyzer database. Eligible patients were those with T2DM and moderate-to-severe CKD who visited their GPs at least once during the study period. Data were collected through electronic medical records and an additional questionnaire. Results. 116 GPs included 297 patients: 86 with stage 3a (Group 1, GFR = 45–60 mL/min/1.73 m2) and 211 with stages 3b, 4, or 5 (Group 2, GFR < 45 mL/min/1.73 m2). Patients' mean age was approximately 75 years. Insulin was used in 19% of patients, and was predominant in those with severe CKD. More than two-thirds of patients were treated with glucose lowering agents which were either contraindicated or not recommended for CKD. Conclusion Physicians most commonly considered the severity of diabetes and not CKD in their therapeutic decision making, exposing patients to potential iatrogenic risks. The recent patient oriented approach and individualization of glycemic objectives according to patient profile rather than standard HbA1c would improve this situation. PMID:23653644

  7. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy?

    PubMed

    Rösler, Barbara; Herold, Susanne

    2016-12-01

    Influenza viruses (IVs) circulate seasonally and are a common cause of respiratory infections in pediatric and adult patients. Additionally, recurrent pandemics cause massive morbidity and mortality worldwide. Infection may result in rapid progressive viral pneumonia with fatal outcome. Since accurate treatment strategies are still missing, research refocuses attention to lung pathology and cellular crosstalk to develop new therapeutic options.Alveolar epithelial cells (AECs) play an important role in orchestrating the pulmonary antiviral host response. After IV infection they release a cascade of immune mediators, one of which is granulocyte and macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to promote differentiation, activation and mobilization of myeloid cells. In the lung, GM-CSF drives immune functions of alveolar macrophages and dendritic cells (DCs) and also improves epithelial repair processes through direct interaction with AECs. During IV infection, AEC-derived GM-CSF shows a lung-protective effect that is also present after local GM-CSF application. This mini-review provides an overview on GM-CSF-modulated immune responses to IV pneumonia and its therapeutic potential in severe IV pneumonia. PMID:27480877

  8. Genomic Characterization of High-Grade Serous Ovarian Cancer: Dissecting Its Molecular Heterogeneity as a Road Towards Effective Therapeutic Strategies.

    PubMed

    Mittempergher, Lorenza

    2016-07-01

    High-grade serous ovarian carcinoma (HGSOC) accounts for the majority of the ovarian cancer deaths, but over the last years little improvement in overall survival has been achieved. HGSOC is a molecularly and clinically heterogeneous disease. At genomic level, it represents a C-class malignancy having frequent gene losses (NF1, RB1, PTEN) and gains (CCNE1, MYC). HGSOC shows a simple mutational profile with TP53 nearly always mutated and with other genes mutated at low frequency. Importantly, 50 % of all HGSOCs have genetic features indicating a homologous recombination (HR) deficiency. HR deficient tumors are highly sensitive to PARP inhibitor anticancer agents, which exhibit synthetic lethality with a defective HR pathway. Transcriptionally, HGSOCs can be grouped into different molecular subtypes with distinct biology and prognosis. Molecular stratification of HGSOC based on these genomic features may result in improved therapeutic strategies. PMID:27241520

  9. Data Collection Strategies and Measurement Tools for Assessing Academic and Therapeutic Outcomes in Recovery Schools

    ERIC Educational Resources Information Center

    Botzet, Andria M.; McIlvaine, Patrick W.; Winters, Ken C.; Fahnhorst, Tamara; Dittel, Christine

    2014-01-01

    Accurate evaluation and documentation of the efficacy of recovery schools can be vital to the continuation and expansion of these beneficial resources. A very limited data set currently exists that examines the value of specific schools established to support adolescents and young adults in recovery; additional research is necessary. The following…

  10. In situ eNOS/NO up-regulation—a simple and effective therapeutic strategy for diabetic skin ulcer

    PubMed Central

    Yang, Ye; Yin, Dengke; Wang, Fei; Hou, Ziyan; Fang, Zhaohui

    2016-01-01

    Decreased nitric oxide (NO) synthesis and increased NO consumption in diabetes induces the inadequate blood flow to tissues that is primarily responsible for the pathogenesis and refractoriness of diabetic skin ulcers. The present study proposed a simple and effective therapeutic strategy for diabetic skin ulcers—in situ up-regulation of endothelial nitric oxide synthase (eNOS) expression and NO synthesis by statin-loaded tissue engineering scaffold (TES). In vitro experiments on human umbilical vein endothelial cells indicated that the statin-loaded TES relieved the high-glucose induced decrease in cell viability and promoted NO synthesis under high-glucose conditions. In a rat model of diabetes, the statin-loaded TES promoted eNOS expression and NO synthesis in/around the regenerated tissues. Subsequently, accelerated vascularization and elevated blood supply were observed, followed by rapid wound healing. These findings suggest that the in situ up-regulation of eNOS/NO by a statin-loaded TES may be a useful therapeutic method for intractable diabetic skin wounds. PMID:27453476

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

    PubMed Central

    Cristóbal, Ion; González-Alonso, Paula; Daoud, Lina; Solano, Esther; Torrejón, Blanca; Manso, Rebeca; Madoz-Gúrpide, Juan; Rojo, Federico; García-Foncillas, Jesús

    2015-01-01

    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. PMID:26023836

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

    PubMed Central

    Khazaei, Mohamad; Siddiqui, Ahad M.; Fehlings, Michael G.

    2014-01-01

    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. PMID:26237017

  13. Advances in peripheral nervous system regenerative therapeutic strategies: A biomaterials approach.

    PubMed

    Dalamagkas, Kyriakos; Tsintou, Magdalini; Seifalian, Alexander

    2016-08-01

    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. PMID:27157770

  14. Skeletal Muscle Homeostasis in Duchenne Muscular Dystrophy: Modulating Autophagy as a Promising Therapeutic Strategy

    PubMed Central

    De Palma, Clara; Perrotta, Cristiana; Pellegrino, Paolo; Clementi, Emilio; Cervia, Davide

    2014-01-01

    Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized 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 myofibers by connective and adipose tissue. DMD patients suffer from 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. 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 level, the Akt axis is one of the key dysregulated 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 signaling 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. PMID:25104934

  15. Sphingosine 1-phosphate signaling pathway in inner ear biology. New therapeutic strategies for hearing loss?

    PubMed Central

    Romero-Guevara, Ricardo; Cencetti, Francesca; Donati, Chiara; Bruni, Paola

    2015-01-01

    Hearing loss is one of the most prevalent conditions around the world, in particular among people over 60 years old. Thus, an increase of this affection is predicted as result of the aging process in our population. In this context, it is important to further explore the function of molecular targets involved in the biology of inner ear sensory cells to better individuate new candidates for therapeutic application. One of the main causes of deafness resides into the premature death of hair cells and auditory neurons. In this regard, neurotrophins and growth factors such as insulin like growth factor are known to be beneficial by favoring the survival of these cells. An elevated number of published data in the last 20 years have individuated sphingolipids not only as structural components of biological membranes but also as critical regulators of key biological processes, including cell survival. Ceramide, formed by catabolism of sphingomyelin (SM) and other complex sphingolipids, is a strong inducer of apoptotic pathway, whereas sphingosine 1-phosphate (S1P), generated by cleavage of ceramide to sphingosine and phosphorylation catalyzed by two distinct sphingosine kinase (SK) enzymes, stimulates cell survival. Interestingly S1P, by acting as intracellular mediator or as ligand of a family of five distinct S1P receptors (S1P1–S1P5), is a very powerful bioactive sphingolipid, capable of triggering also other diverse cellular responses such as cell migration, proliferation and differentiation, and is critically involved in the development and homeostasis of several organs and tissues. Although new interesting data have become available, the information on S1P pathway and other sphingolipids in the biology of the inner ear is limited. Nonetheless, there are several lines of evidence implicating these signaling molecules during neurogenesis in other cell populations. In this review, we discuss the role of S1P during inner ear development, also as guidance for future

  16. CRISPR-Cas9 systems: versatile cancer modelling platforms and promising therapeutic strategies.

    PubMed

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

    2016-03-15

    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. PMID:26044706

  17. Understanding Host-Adherent-Invasive Escherichia coli Interaction in Crohn's Disease: Opening Up New Therapeutic Strategies

    PubMed Central

    Massier, Sébastien; Darfeuille-Michaud, Arlette; Billard, Elisabeth; Barnich, Nicolas

    2014-01-01

    A trillion of microorganisms colonize the mammalian intestine. Most of them have coevolved with the host in a symbiotic relationship and some of them have developed strategies to promote their replication in the presence of competing microbiota. Recent evidence suggests that perturbation of the microbial community favors the emergence of opportunistic pathogens, in particular adherent-invasive Escherichia coli (AIEC) that can increase incidence and severity of gut inflammation in the context of Crohn's disease (CD). This review will report the importance of AIEC as triggers of intestinal inflammation, focusing on their impact on epithelial barrier function and stimulation of mucosal inflammation. Beyond manipulation of immune response, restoration of gut microbiota as a new treatment option for CD patients will be discussed. PMID:25580435

  18. [The diagnostic and therapeutic strategies in neoplasms of the adrenal cortex: the authors' own experience].

    PubMed

    Giordano, G; Angelelli, G; Losacco, T; Mustacchio, N; Macarini, L; Grimaldi, F; Cannone, G; Colelli, P; Spada, I S

    1993-01-01

    The Authors report their limited series of neoplasms of the adrenal cortex, and underline the decisive role of the modern diagnostics based on imaging techniques (US--TC--NMR). These, in fact, often allow a good definition also in the non-functioning adrenal masses incidentally discovered (incidentalomas). The authors emphasize the high quality of such diagnostic methods offering a good reliability in discriminating the nature of the adrenal mass. These undeniable diagnostic advantages have a positive impact on the surgical strategy, allowing together with a careful morphological study of the lesion, to program in detail possible demolitive operations. The authors finally underline the importance of the surgical access: they are persuaded the best is the bilateral under-rib incision. This surgical approach assures a complete exploration of the abdominal and pelvic cavity; moreover, it allows to face every complication. PMID:8481276

  19. Natural History, Diagnostic Approaches, and Therapeutic Strategies for Patients With Asymptomatic Severe Aortic Stenosis.

    PubMed

    Généreux, Philippe; Stone, Gregg W; O'Gara, Patrick T; Marquis-Gravel, Guillaume; Redfors, Björn; Giustino, Gennaro; Pibarot, Philippe; Bax, Jeroen J; Bonow, Robert O; Leon, Martin B

    2016-05-17

    Aortic stenosis (AS) is one of the most common valvular diseases encountered in clinical practice. Current guidelines recommend aortic valve replacement (AVR) when the aortic valve is severely stenotic and the patient is symptomatic; however, a substantial proportion of patients with severe AS are asymptomatic at the time of first diagnosis. Although specific morphological valve features, exercise testing, stress imaging, and biomarkers can help to identify patients with asymptomatic severe AS who may benefit from early AVR, the optimal management of these patients remains uncertain and controversial. The current report presents a comprehensive review of the natural history and the diagnostic evaluation of asymptomatic patients with severe AS, and is followed by a meta-analysis from reported studies comparing an early AVR strategy to active surveillance, with an emphasis on the level of evidence substantiating the current guideline recommendations. Finally, perspectives on directions for future investigation are discussed. PMID:27049682

  20. Challenging chemoresistant metastatic colorectal cancer: therapeutic strategies from the clinic and from the laboratory.

    PubMed

    Sartore-Bianchi, A; Loupakis, F; Argilés, G; Prager, G W

    2016-08-01

    As survival has improved for patients with metastatic colorectal cancer (mCRC), there is an increasing need for effective and well-tolerated third-line and subsequent-lines of treatment. Despite recent advances with the development of new-targeted therapies in this setting, there remains an unmet need to exploit oncogenic drivers of colorectal cancer and overcome acquired resistance. Potential treatment strategies include revisiting old targets such as human epidermal growth factor receptor 2, RAS, and BRAF and investigating new targets such as c-MET, the PI3 kinase, and Wnt pathways, and also the use of immune-checkpoint inhibitors. Here, we review recent phase III trials exploring approved agents, early trials investigating new drugs for chemorefractory mCRC, and the potential of capturing tumour dynamics during its evolution by liquid biopsy analysis. PMID:27154421

  1. Advances in biosensing strategies for HIV-1 detection, diagnosis, and therapeutic monitoring.

    PubMed

    Lifson, Mark A; Ozen, Mehmet Ozgun; Inci, Fatih; Wang, ShuQi; Inan, Hakan; Baday, Murat; Henrich, Timothy J; Demirci, Utkan

    2016-08-01

    HIV-1 is a major global epidemic that requires sophisticated clinical management. There have been remarkable efforts to develop new strategies for detecting and treating HIV-1, as it has been challenging to translate them into resource-limited settings. Significant research efforts have been recently devoted to developing point-of-care (POC) diagnostics that can monitor HIV-1 viral load with high sensitivity by leveraging micro- and nano-scale technologies. These POC devices can be applied to monitoring of antiretroviral therapy, during mother-to-child transmission, and identification of latent HIV-1 reservoirs. In this review, we discuss current challenges in HIV-1 diagnosis and therapy in resource-limited settings and present emerging technologies that aim to address these challenges using innovative solutions. PMID:27262924

  2. Inhibition of ileal bile acid transporter: An emerging therapeutic strategy for chronic idiopathic constipation

    PubMed Central

    Mosińska, Paula; Fichna, Jakub; Storr, Martin

    2015-01-01

    Chronic idiopathic constipation is a common disorder of the gastrointestinal tract that encompasses a wide profile of symptoms. Current treatment options for chronic idiopathic constipation are of limited value; therefore, a novel strategy is necessary with an increased effectiveness and safety. Recently, the inhibition of the ileal bile acid transporter has become a promising target for constipation-associated diseases. Enhanced delivery of bile acids into the colon achieves an accelerated colonic transit, increased stool frequency, and relief of constipation-related symptoms. This article provides insight into the mechanism of action of ileal bile acid transporter inhibitors and discusses their potential clinical use for pharmacotherapy of constipation in chronic idiopathic constipation. PMID:26139989

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

    PubMed Central

    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

    2011-01-01

    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

  4. [Recurrent cystitis and vaginitis: role of biofilms and persister cells. From pathophysiology to new therapeutic strategies].

    PubMed

    Graziottin, A; Zanello, P P; D'Errico, G

    2014-10-01

    Recurrent vaginitis and cystitis are a daily challenge for the woman and the physician. The recurrence worsens the symptoms' severity, increases comorbidities, both pelvic (provoked vestibulodynia, bladder pain syndrome, levator ani hyperactivity, introital dyspareunia, obstructive constipation, chronic pelvic pain) and cerebral (neuroinflammation and depression), increases health costs, worsens the quality of life. Antibiotics increase the risk of bacterial resistences and devastate the ecosystems: intestinal, vaginal and mucocutaneous. Pathogenic biofilms are the (still) neglected etiology of recurrences. Biofilms are structured communities of bacteria and yeasts, protected by a self-produced polymeric matrix adherent to a living or inert structures, such as medical devices. Biofims can be intra or extracellular. Pathogens live in a resting state in the deep biofilm layers as "persister cells", resistant to antibiotics and host defences and ready to re-attack the host. The paper updates the evidence on biofilms and introduces new non-antibiotic strategies of preventing and modulating recurrent vaginitis and cystitis. PMID:25245998

  5. Bacterial Biofilms: Development, Dispersal, and Therapeutic Strategies in the Dawn of the Postantibiotic Era

    PubMed Central

    Kostakioti, Maria; Hadjifrangiskou, Maria

    2013-01-01

    Biofilm formation constitutes an alternative lifestyle in which microorganisms adopt a multicellular behavior that facilitates and/or prolongs survival in diverse environmental niches. Biofilms form on biotic and abiotic surfaces both in the environment and in the healthcare setting. In hospital wards, the formation of biofilms on vents and medical equipment enables pathogens to persist as reservoirs that can readily spread to patients. Inside the host, biofilms allow pathogens to subvert innate immune defenses and are thus associated with long-term persistence. Here we provide a general review of the steps leading to biofilm formation on surfaces and within eukaryotic cells, highlighting several medically important pathogens, and discuss recent advances on novel strategies aimed at biofilm prevention and/or dissolution. PMID:23545571

  6. Preventive and therapeutic strategies for bovine leukemia virus: lessons for HTLV.

    PubMed

    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

    2011-07-01

    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

  7. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery

    PubMed Central

    Li, Jing-jing; Huang, Jian; Ouyang, Liang; Zhang, Yonghui; Liu, Bo

    2015-01-01

    As a conserved protein interaction module that recognizes and binds to acetylated lysine, bromodomain (BRD) contains a deep, largely hydrophobic acetyl lysine binding site. Proteins that share the feature of containing two BRDs and an extra-terminal domain belong to BET family, including BRD2, BRD3, BRD4 and BRDT. BET family proteins perform transcription regulatory function under normal conditions, while in cancer, they regulate transcription of several oncogenes, such as c-Myc and Bcl-2. Thus, targeting BET proteins may be a promising strategy, and intense interest of BET proteins has fueled the development of structure-based bromodomain inhibitors in cancer. In this review, we focus on summarizing several small-molecule BET inhibitors and their relevant anti-tumor mechanisms, which would provide a clue for exploiting new targeted BET inhibitors in the future cancer therapy. PMID:25849938

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

    PubMed Central

    Maiese, Kenneth

    2016-01-01

    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. PMID:27127460

  9. Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies.

    PubMed

    Lettre, Guillaume; Bauer, Daniel E

    2016-06-18

    Sickle-cell disease affects millions of individuals worldwide, but the global incidence is concentrated in Africa. The burden of sickle-cell disease is expected to continue to rise over the coming decades, adding to stress on the health infrastructures of many countries. Although the molecular cause of sickle-cell disease has been known for more than half a century, treatment options remain greatly limited. Allogeneic haemopoietic stem-cell transplantation is the only existing cure but is limited to specialised clinical centres and remains inaccessible for most patients. Induction of fetal haemoglobin production is a promising strategy for the treatment of sickle-cell disease. In this Series paper, we review scientific breakthroughs in epidemiology, genetics, and molecular biology that have brought reactivation of fetal haemoglobin to the forefront of sickle-cell disease research. Improved knowledge of the regulation of fetal haemoglobin production in human beings and the development of genome editing technology now support the design of innovative therapies for sickle-cell disease that are based on fetal haemoglobin. PMID:27353686

  10. The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies

    PubMed Central

    Modi, Meera E.; Young, Larry J.

    2012-01-01

    Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID:22206823

  11. Pharmacological approaches to manage persistent symptoms of major depressive disorder: rationale and therapeutic strategies.

    PubMed

    Epstein, Irvin; Szpindel, Isaac; Katzman, Martin A

    2014-12-01

    Major depressive disorder (MDD) is a highly prevalent chronic psychiatric illness associated with significant morbidity, mortality, loss of productivity, and diminished quality of life. Typically, only a minority of patients responds to treatment and meet criteria for remission as residual symptoms may persist, the result of an inadequate course of treatment and/or the presence of persistent side effects. The foremost goal of treatment should be to restore patients to full functioning and eliminate or relieve all MDD symptoms, while being virtually free of troublesome side effects. The current available pharmacological options to manage persistent depressive symptoms include augmentation or adjunctive combination strategies, both of which target selected psychobiological systems and specific mood and somatic symptoms experienced by the patient. As well, non-pharmacological interventions including psychotherapies may be used in either first-line or adjunctive approaches. However, the evidence to date with respect to available adjunct therapies is limited by few studies and those published have utilized only a small number of subjects and lack enough data to allow for a consensus of expert opinion. This underlines the need for further longer term, large population-based studies and those that include comorbid populations, all of which are seen in real world community psychiatry. PMID:25539871

  12. Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy

    PubMed Central

    Gramlich, Michael; Pane, Luna Simona; Zhou, Qifeng; Chen, Zhifen; Murgia, Marta; Schötterl, Sonja; Goedel, Alexander; Metzger, Katja; Brade, Thomas; Parrotta, Elvira; Schaller, Martin; Gerull, Brenda; Thierfelder, Ludwig; Aartsma-Rus, Annemieke; Labeit, Siegfried; Atherton, John J; McGaughran, Julie; Harvey, Richard P; Sinnecker, Daniel; Mann, Matthias; Laugwitz, Karl-Ludwig; Gawaz, Meinrad Paul; Moretti, Alessandra

    2015-01-01

    Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)-mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal-dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient-specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock-in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA-based strategies as a potential treatment option for DCM. PMID:25759365

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

    PubMed

    Maiese, Kenneth

    2016-03-01

    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. PMID:27127460

  14. The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies.

    PubMed

    Modi, Meera E; Young, Larry J

    2012-03-01

    Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID:22206823

  15. Plasma jet-induced tissue oxygenation: potentialities for new therapeutic strategies

    NASA Astrophysics Data System (ADS)

    Collet, G.; Robert, E.; Lenoir, A.; Vandamme, M.; Darny, T.; Dozias, S.; Kieda, C.; Pouvesle, J. M.

    2014-02-01

    The lack of oxygen is a major reason for the resistance of tumor cells to treatments such as radiotherapies. A large number of recent publications on non-thermal plasma applications in medicine report cell behavior modifications and modulation of soluble factors. This in vivo study tested whether such modifications can lead to vascular changes in response to plasma application. Two in situ optical-based methods were used simultaneously, in real time, to assess the effect of non-thermal plasma on tissue vasculature. Tissue oxygen partial pressure (pO2) was measured using a time-resolved luminescence-based optical probe, and the microvascular erythrocyte flow was determined by laser Doppler flowmetry. When plasma treatment was applied on mouse skin, a rapid pO2 increase (up to 4 times) was subcutaneously measured and correlated with blood flow improvement. Such short duration, i.e. 5 min, plasma-induced effects were shown to be locally restricted to the treated area and lasted over 120 min. Further investigations should elucidate the molecular mechanisms of these processes. However, improvement of oxygenation and perfusion open new opportunities for tumor treatments in combination with radiotherapy, and for tumor blood vessel normalization based strategies.

  16. Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans.

    PubMed

    Blevins, James E; Baskin, Denis G

    2015-12-01

    The fact that more than 78 million adults in the US are considered overweight or obese highlights the need to develop new, effective strategies to treat obesity and its associated complications, including type 2 diabetes, kidney disease and cardiovascular disease. While the neurohypophyseal peptide oxytocin (OT) is well recognized for its peripheral effects to stimulate uterine contraction during parturition and milk ejection during lactation, release of OT within the brain is implicated in prosocial behaviors and in the regulation of energy balance. Previous findings indicate that chronic administration of OT decreases food intake and weight gain or elicits weight loss in diet-induced obese (DIO) mice and rats. Furthermore, chronic systemic treatment with OT largely reproduces the effects of central administration to reduce weight gain in DIO and genetically obese rodents at doses that do not appear to result in tolerance. These findings have now been recently extended to more translational models of obesity showing that chronic subcutaneous or intranasal OT treatment is sufficient to elicit body weight loss in DIO nonhuman primates and pre-diabetic obese humans. This review assesses the potential use of OT as a therapeutic strategy for treatment of obesity in rodents, nonhuman primates, and humans, and identifies potential mechanisms that mediate this effect. PMID:26013577

  17. Enrofloxacin-based therapeutic strategy for the prevention of endometritis in susceptible mares.

    PubMed

    González, C; Moreno, L; Fumuso, E; García, J; Rivulgo, M; Confalonieri, A; Sparo, M; Sánchez Bruni, S

    2010-06-01

    Enrofloxacin (EFX) is often used empirically to prevent uterine infections in mares in order to improve efficiency on Commercial Embryo Transfer Farms. This study investigated the uterine distribution of EFX and its metabolite ciprofloxacin (CFX) in mares and assessed the minimal inhibitory concentrations (MIC) of EFX against various common pathogens as a basis for establishing a rational dosing schedule. Plasma and uterine pharmacokinetic (PK) studies were performed in two groups (n = 5) of healthy mares following intravenous (i.v.) administration of EFX at either 2.5 and at 5 mg/kg bodyweight. Plasma and endometrial tissue samples, taken before for up to 48 h after treatment were analysed by Reverse Phase HPLC. MIC values for wild strains of Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (beta-haemolytic streptococci) ranged from 0.25-2 and 1.5-3.0 microg/mL respectively. In terms of tissue distribution, the sum of the endometrial concentrations of the parent drug (EFX) and its active metabolite (CFX) (in terms of AUC), exceeded those in plasma by 249% and 941% following administration of EFX at 2.5 and 5 mg/kg respectively. After i.v. treatment with EFX at 5 mg/kg, endometrial concentrations of EFX and CFX above the MIC value were detected for 36-48 and 22-43 h posttreatment for Gram-negative and -positive isolates respectively. Concentrations above MIC were maintained for much shorter periods at the lower (2.5 mg/kg) treatment dose. Based on these results, a conventional dose (5 mg/kg) of EFX given prebreeding followed by two further doses at 36-48 h postbreeding are proposed as a rational strategy for using of EFX as a preventative therapy against a variety of common bacterial strains associated with equine endometritis. PMID:20557446

  18. Deciphering the therapeutic stem cell strategies of large and midsize pharmaceutical firms.

    PubMed

    Vertès, Alain A

    2014-01-01

    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. PMID:25159065

  19. New therapeutic strategies for systemic sclerosis--a critical analysis of the literature.

    PubMed

    Zandman-Goddard, Gisele; Tweezer-Zaks, Nurit; Shoenfeld, Yehuda

    2005-09-01

    Systemic sclerosis (SSc) is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted. Methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, and IVIg may be beneficial in improving the skin tightness in SSc. Calcium channel blockers, the angiotensin II receptor type 1 antagonist losartan, prazocin, the prostacyclin analogue iloprost, N-acetylcysteine and the dual endothelin-receptor antagonist bosentan may be beneficial for Raynaud's phenomenon. Epoprostenol and bosentan are approved for therapy of pulmonary hypertension (PAH). Other options under investigation include intravenous or aerolized iloprost. Cyclophosphamide (CYC) pulse therapy is effective in suppressing active alveolitis. Stem cell and lung transplantation is a viable option for carefully selected patients. Renal crisis can be effectively managed when hypertension is aggressively controlled with angiotensin converting enzyme (ACE) inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hope of discontinuing dialysis. Antithymocyte globulin and mycophenolate mofetil appear safe in SSc. The improvement in skin score and the apparent stability of systemic disease during the treatment period suggest that controlled studies of these agents are justified. Stem cell transplantation is under

  20. New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature

    PubMed Central

    Zandman-Goddard, Gisele; Tweezer-Zaks, Nurit; Shoenfeld, Yehuda

    2005-01-01

    Systemic sclerosis (SSc) is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted. Methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, and IVIg may be beneficial in improving the skin tightness in SSc. Calcium channel blockers, the angiotensin II receptor type 1 antagonist losartan, prazocin, the prostacyclin analogue iloprost, N-acetylcysteine and the dual endothelin-receptor antagonist bosentan may be beneficial for Raynaud's phenomenon. Epoprostenol and bosentan are approved for therapy of pulmonary hypertension (PAH). Other options under investigation include intravenous or aerolized iloprost. Cyclophosphamide (CYC) pulse therapy is effective in suppressing active alveolitis. Stem cell and lung transplantation is a viable option for carefully selected patients. Renal crisis can be effectively managed when hypertension is aggressively controlled with angiotensin converting enzyme (ACE) inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hope of discontinuing dialysis. Anti-thymocyte globulin and mycophenolate mofetil appear safe in SSc. The improvement in skin score and the apparent stability of systemic disease during the treatment period suggest that controlled studies of these agents are justified. Stem cell transplantation is under

  1. Education for Homeless Adults: Strategies for Implementation. Volume II - Resources and Additional Lessons.

    ERIC Educational Resources Information Center

    Hudson River Center for Program Development, Glenmont, NY.

    This document, the second in a series of guidebooks that were developed for educators of homeless adults in New York, offers strategies and plans for sample lessons in which a holistic approach is used to help homeless adults and families improve their lives through education. The guidebook begins with lists of print and nonprint resources,…

  2. Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.

    PubMed

    Greene, Stephen J; Sabbah, Hani N; Butler, Javed; Voors, Adriaan A; Albrecht-Küpper, Barbara E; Düngen, Hans-Dirk; Dinh, Wilfried; Gheorghiade, Mihai

    2016-01-01

    Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF. PMID:26701329

  3. Relapsed and refractory Hodgkin lymphoma: transplantation strategies and novel therapeutic options.

    PubMed

    David, Kevin A; Mauro, Lauren; Evens, Andrew M

    2007-10-01

    Many patients with Hodgkin lymphoma are cured with initial therapy, although a portion of patients will experience primary induction failure or disease relapse. Pathologic confirmation of refractory or relapsed Hodgkin lymphoma is important. Following two to four cycles of non-cross-resistant salvage chemotherapy, the standard of care is high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT), which is associated with long-term event-free survival rates of 45-68%. Of note, survival rates for studies integrating total lymphoid irradiation into the autologous HSCT-conditioning regimen are among the highest reported for relapsed/refractory Hodgkin lymphoma. Further treatment options are available for patients not fit to proceed to HSCT, for relapsed disease after autologous HSCT, and for 'high-risk' Hodgkin lymphoma including chemotherapy-resistant disease. Allogeneic HSCT is a valid treatment option, as a graft-vs.-Hodgkin-lymphoma effect has been demonstrated. In addition, novel targeted treatments are being investigated such as receptor-specific antibodies, radiolabeled antibodies, antiapoptotic agents including inhibitors of the nuclear factor-kappaB complex or X-linked inhibitor of apoptosis proteins, transcription pathway modulators such as histone deacetylase and mTOR inhibitors, and Epstein-Barr virus-directed therapy. Continued translational and collaborative prospective clinical research efforts are needed in order to continue to increase the survival rates for Hodgkin lymphoma and to lessen the toxicities associated with lymphoma-related therapy. PMID:18214690

  4. Phosphorylation of Single Stranded RNA Virus Proteins and Potential for Novel Therapeutic Strategies

    PubMed Central

    Keck, Forrest; Ataey, Pouya; Amaya, Moushimi; Bailey, Charles; Narayanan, Aarthi

    2015-01-01

    Post translational modification of proteins is a critical requirement that regulates function. Among the diverse kinds of protein post translational modifications, phosphorylation plays essential roles in protein folding, protein:protein interactions, signal transduction, intracellular localization, transcription regulation, cell cycle progression, survival and apoptosis. Protein phosphorylation is also essential for many intracellular pathogens to establish a productive infection cycle. Preservation of protein phosphorylation moieties in pathogens in a manner that mirrors the host components underscores the co-evolutionary trajectory of pathogens and hosts, and sheds light on how successful pathogens have usurped, either in part or as a whole, the host enzymatic machinery. Phosphorylation of viral proteins for many acute RNA viruses including Flaviviruses and Alphaviruses has been demonstrated to be critical for protein functionality. This review focuses on phosphorylation modifications that have been documented to occur on viral proteins with emphasis on acutely infectious, single stranded RNA viruses. The review additionally explores the possibility of repurposing Food and Drug Administration (FDA) approved inhibitors as antivirals for the treatment of acute RNA viral infections. PMID:26473910

  5. Identification of Students' Intuitive Mental Computational Strategies for 1, 2 and 3 Digits Addition and Subtraction: Pedagogical and Curricular Implications

    ERIC Educational Resources Information Center

    Ghazali, Munirah; Alias, Rohana; Ariffin, Noor Asrul Anuar; Ayub, Ayminsyadora

    2010-01-01

    This paper reports on a study to examine mental computation strategies used by Year 1, Year 2, and Year 3 students to solve addition and subtraction problems. The participants in this study were twenty five 7 to 9 year-old students identified as excellent, good and satisfactory in their mathematics performance from a school in Penang, Malaysia.…

  6. Ten-Structure as Strategy of Addition 1-20 by Involving Spatial Structuring Ability for First Grade Students

    ERIC Educational Resources Information Center

    Salmah, Ummy; Putri, Ratu Ilma Indra; Somakim

    2015-01-01

    The aim of this study is to design learning activities that can support students to develop strategies for the addition of number 1 to 20 in the first grade by involving students' spatial structuring ability. This study was conducted in Indonesia by involving 27 students. In this paper, one of three activities is discussed namely ten-box activity.…

  7. Early multi-system organ failure associated with acute pancreatitis: a plea for a conservative therapeutic strategy.

    PubMed

    Dugernier, T; Reynaert, M; Laterre, P F

    2003-01-01

    The mortality of severe acute pancreatitis still ranges between 10 and 20%. Nowadays, infected pancreatic necrosis is the leading cause of death. Despite advances in intensive care therapy, however, early and worsening multi-system organ failure remains a source of substantial morbidity and still accounts for 20 to 50% of the deaths. In recent years, the systemic inflammatory response syndrome and the relevant cascades of inflammatory mediators have been implicated as the key factor in the emergence of remote tissue damage. Early multi-system organ failure that supervenes in the first week is typically associated with a sterile necrotizing process. There are no pathophysiological, clinical or economical data to support the practice of debridement of sterile necrosis to prevent or to control early multi-system organ failure. This issue has never been addressed in a controlled study. Besides intensive care support, non-surgical therapeutic modalities including urgent endoscopic sphincterotomy for impacted stones, antibiotic prophylaxis for the prevention of pancreatic infection and early jejunal nutrition have been specifically developed hopefully to attenuate multiple organ failure, to obviate the need of surgical drainage and to improve survival. Fine needle aspiration of necrotic areas must be incorporated in any conservative therapeutic strategy in order to identify and not to jeopardize those with infected necrosis that remains an absolute indication for drainage. A specific treatment of acute pancreatitis is still lacking, so far. However, there is ample experimental and pathophysiological evidence in favour of immunomodulatory therapy in severe acute pancreatitis. The administration of one or several antagonists of inflammatory mediators possibly combined with a protease inhibitor may at last provide the opportunity to interfere with the two major determinants of prognosis: the severity of multiple organ failure and the extent of necrotic areas that creates

  8. Control strategies against Campylobacter at the poultry production level: biosecurity measures, feed additives and vaccination.

    PubMed

    Meunier, M; Guyard-Nicodème, M; Dory, D; Chemaly, M

    2016-05-01

    Campylobacteriosis is the most prevalent bacterial foodborne gastroenteritis affecting humans in the European Union, and ranks second in the United States only behind salmonellosis. In Europe, there are about nine million cases of campylobacteriosis every year, making the disease a major public health issue. Human cases are mainly caused by the zoonotic pathogen Campylobacter jejuni. The main source of contamination is handling or consumption of poultry meat. Poultry constitutes the main reservoir of Campylobacter, substantial quantities of which are found in the intestines following rapid, intense colonization. Reducing Campylobacter levels in the poultry chain would decrease the incidence of human campylobacteriosis. As primary production is a crucial step in Campylobacter poultry contamination, controlling the infection at this level could impact the following links along the food chain (slaughter, retail and consumption). This review describes the control strategies implemented during the past few decades in primary poultry production, including the most recent studies. In fact, the implementation of biosecurity and hygiene measures is described, as well as the immune strategy with passive immunization and vaccination trials and the nutritional strategy with the administration of organic and fatty acids, essential oil and plant-derived compound, probiotics, bacteriocins and bacteriophages. PMID:26541243

  9. Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine.

    PubMed

    Friestad, Gregory K; Ji, An; Korapala, Chandra Sekhar; Qin, Jun

    2011-06-01

    Stereocontrolled Mn-mediated radical addition of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond disconnection of chiral amines. This strategy was examined in the context of a total synthesis of quinine, generating new findings of functional group compatibility leading to a revised strategy. Completion of a formal synthesis of quinine is presented, validating the application of Mn-mediated radical addition as a useful new C-C bond construction method for alkaloid synthesis. The Mn-mediated addition generates the chiral amine substructure of quinine with complete stereocontrol. Subsequent elaboration includes two successive ring closures to forge the azabicyclo[2.2.2]octane ring system of quincorine, linked to quinine through two known reactions. PMID:21537510

  10. Strategies for recruiting additional African Americans into the NASA JSC summer faculty fellows program

    NASA Technical Reports Server (NTRS)

    Hyman, Ladelle M.

    1993-01-01

    African Americans have participated sporadically in the NASA JSC Summer Faculty Fellows Program--none in 1992 and four in 1993. There is a pool of African Americans who are both qualified to provide services and willing to participate in initiatives which support technologies required for future JSC programs. They can provide human support and handle mission operations, spacecraft systems, planet surface systems, and management tools. Most of these faculty teach at historically black colleges and universities (HBCU's). This research will document the current recruitment system, critique it, and develop a strategy which will facilitate the diversification of the NASA JSC Summer Faculty Fellows Program. While NASA currently mails notices to HBCU's, such notices have generated few applications from, and fewer selections of, targeted faculty. To increase the participation of African Americans in the NASA JSC Summer Faculty Fellows Program, this participant will prepare a strategy which includes a document which identifies HBCU-targeted faculty and enumerates more formally extensive and intensive communication procedures. A fifteen-minute panel discussion, which will include a video, will be delivered during the annual meeting of the American Society for Engineering Education (ASEE) to be held in Edmonton, Alberta, Canada, June 26-29, 1994. An announcement letter will be mailed to targeted faculty; follow-up telephone calls and personal visits will be made and a checklist flowchart will be completed by key NASA personnel or designee. Although initially limited to NASA JSC's recruitment of African Americans, this strategy may be broadened to include other NASA sites and other targeted minority groups.

  11. Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: a promising strategy for discovering new antiviral therapeutics.

    PubMed

    Wang, Chao; Lu, Lu; Na, Heya; Li, Xiangpeng; Wang, Qian; Jiang, Xifeng; Xu, Xiaoyu; Yu, Fei; Zhang, Tianhong; Li, Jinglai; Zhang, Zhenqing; Zheng, Baohua; Liang, Guodong; Cai, Lifeng; Jiang, Shibo; Liu, Keliang

    2014-09-11

    Triterpene saponins are a major group of active components in natural products with nonspecific antiviral activities, while T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD), is a gp41-specific HIV-1 fusion inhibitor. In this paper, we report the design, synthesis, and structure-activity relationship (SAR) of a group of hybrid molecules in which bioactive triterpene sapogenins were covalently attached to the HBD-containing peptides via click chemistry. We found that either the triterpenes or peptide part alone showed weak activity against HIV-1 Env-mediated cell-cell fusion, while the hybrids generated a strong cooperative effect. Among them, P26-BApc exhibited anti-HIV-1 activity against both T20-sensitive and -resistant HIV-1 strains and improved pharmacokinetic properties. These results suggest that this scaffold design is a promising strategy for developing new HIV-1 fusion inhibitors and possibly novel antiviral therapeutics against other viruses with class I fusion proteins. PMID:25156906

  12. [Hypertriglyceridemia: therapeutic strategy].

    PubMed

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

    2011-10-01

    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. PMID:22135979

  13. New Cardiovascular and Pulmonary Therapeutic Strategies Based on the Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas Receptor Axis

    PubMed Central

    Ferreira, Anderson J.; Murça, Tatiane M.; Fraga-Silva, Rodrigo A.; Castro, Carlos Henrique; Raizada, Mohan K.; Santos, Robson A. S.

    2012-01-01

    Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1–7). The axis formed by ACE2/Ang-(1–7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT1 receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis. PMID:22319643

  14. Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple negative breast cancer

    PubMed Central

    Kwon, Yeon-Jin; Petrie, Kevin; Leibovitch, Boris A.; Zeng, Lei; Mezei, Mihaly; Howell, Louise; Gil, Veronica; Christova, Rossitza; Bansal, Nidhi; Yang, Shuai; Sharma, Rajal; Ariztia, Edgardo V.; Frankum, Jessica; Brough, Rachel; Sbirkov, Yordan; Ashworth, Alan; Lord, Christopher J.; Zelent, Arthur; Farias, Eduardo; Zhou, Ming-Ming; Waxman, Samuel

    2015-01-01

    Triple negative breast cancers (TNBC) lacking estrogen, progesterone and HER2 receptors account for 10–20% of breast cancer and are indicative of poor prognosis. The development of effective treatment strategies therefore represents a pressing unmet clinical need. We previously identified a molecularly-targeted approach to target aberrant epigenetics of TNBC using a peptide corresponding to the SIN3 interaction domain (SID) of MAD. SID peptide selectively blocked binding of SID-containing proteins to the paired α-helix (PAH2) domain of SIN3, resulting in epigenetic and transcriptional modulation of genes associated with epithelial-mesenchymal transition (EMT). To find small molecule inhibitor (SMI) mimetics of SID peptide we performed an in silico screen for PAH2 domain-binding compounds. This led to the identification of the avermectin macrocyclic lactone derivatives selamectin and ivermectin (Mectizan) as candidate compounds. Both selamectin and ivermectin phenocopied the effects of SID peptide to block SIN3-PAH2 interaction with MAD, induce expression of CDH1 and ESR1 and restore tamoxifen sensitivity in MDA-MB-231 human and MMTV-Myc mouse TNBC cells in vitro. Treatment with selamectin or ivermectin led to transcriptional modulation of genes associated with EMT and maintenance of a cancer stem cell phenotype in TNBC cells. This resulted in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo. Underlining the potential of avermectins in TNBC, pathway analysis revealed that selamectin also modulated the expression of therapeutically-targetable genes. Consistent with this, an unbiased drug screen in TNBC cells identified selamectin-induced sensitization to a number of drugs, including those targeting modulated genes. PMID:26078298

  15. Mitochondrial protection impairs BET bromodomain inhibitor-mediated cell death and provides rationale for combination therapeutic strategies

    PubMed Central

    Lasorsa, E; Smonksey, M; Kirk, J S; Rosario, S; Hernandez-Ilizaliturri, F J; Ellis, L

    2015-01-01

    Inhibitors of the bromodomain and extraterminal domain family (BETI) have recently entered phase I clinical trials. In patients with advanced leukemia's, potent antileukemia activity was displayed with minimum dose-limiting toxicity. In preclinical models of hematological malignancies, including aggressive B-cell lymphomas, BETI induced cell-cycle arrest and apoptosis. However, the underlying cell death mechanisms are still not well understood. Dissecting the mechanisms required by BETI to mediate cell death would provide strong direction on how to best utilize BETI to treat patients with aggressive hematological malignancies. Herein, we provide understanding of the molecular mechanisms underlying BETI-mediated cell death using I-BET762. Induction of cell death occurred in primary murine and human B-cell lymphomas through apoptosis. Genetic dissection using Eμ-myc B-cell lymphoma compound mutants demonstrated that I-BET762-induced apoptosis does not require the p53 pathway. Furthermore, deletion of Apaf1, and thus the absence of a functional apoptosome, is associated with a delayed drug response but do not provide long-term resistance. Prolonged treatment of this model in fact fails to suppress the therapeutic efficacy of the drug and is associated with biochemical features of autophagy. However, lack of mitochondrial permeability completely inhibited I-BET762-mediated tumor cell death, indicating mitochondrial damage as key events for its activity. Combination of I-BET762 with BH3-only mimetics ABT-263 or obatoclax, restored sensitivity to I-BET762 lymphoma killing; however, success was determined by expression of Bcl-2 family antiapoptotic proteins. Our study provides critical insight for clinical decisions regarding the appropriate strategy for using BETI as a single agent or in combination to treat patients with aggressive B-cell lymphomas. PMID:26658189

  16. Enhancing Specific Energy and Power in Asymmetric Supercapacitors - A Synergetic Strategy based on the Use of Redox Additive Electrolytes.

    PubMed

    Singh, Arvinder; Chandra, Amreesh

    2016-01-01

    The strategy of using redox additive electrolyte in combination with multiwall carbon nanotubes/metal oxide composites leads to a substantial improvements in the specific energy and power of asymmetric supercapacitors (ASCs). When the pure electrolyte is optimally modified with a redox additive viz., KI, ~105% increase in the specific energy is obtained with good cyclic stability over 3,000 charge-discharge cycles and ~14.7% capacitance fade. This increase is a direct consequence of the iodine/iodide redox pairs that strongly modifies the faradaic and non-faradaic type reactions occurring on the surface of the electrodes. Contrary to what is shown in few earlier reports, it is established that indiscriminate increase in the concentration of redox additives will leads to performance loss. Suitable explanations are given based on theoretical laws. The specific energy or power values being reported in the fabricated ASCs are comparable or higher than those reported in ASCs based on toxic acetonitrile or expensive ionic liquids. The paper shows that the use of redox additive is economically favorable strategy for obtaining cost effective and environmentally friendly ASCs. PMID:27184260

  17. Enhancing Specific Energy and Power in Asymmetric Supercapacitors - A Synergetic Strategy based on the Use of Redox Additive Electrolytes

    NASA Astrophysics Data System (ADS)

    Singh, Arvinder; Chandra, Amreesh

    2016-05-01

    The strategy of using redox additive electrolyte in combination with multiwall carbon nanotubes/metal oxide composites leads to a substantial improvements in the specific energy and power of asymmetric supercapacitors (ASCs). When the pure electrolyte is optimally modified with a redox additive viz., KI, ~105% increase in the specific energy is obtained with good cyclic stability over 3,000 charge-discharge cycles and ~14.7% capacitance fade. This increase is a direct consequence of the iodine/iodide redox pairs that strongly modifies the faradaic and non-faradaic type reactions occurring on the surface of the electrodes. Contrary to what is shown in few earlier reports, it is established that indiscriminate increase in the concentration of redox additives will leads to performance loss. Suitable explanations are given based on theoretical laws. The specific energy or power values being reported in the fabricated ASCs are comparable or higher than those reported in ASCs based on toxic acetonitrile or expensive ionic liquids. The paper shows that the use of redox additive is economically favorable strategy for obtaining cost effective and environmentally friendly ASCs.

  18. Enhancing Specific Energy and Power in Asymmetric Supercapacitors - A Synergetic Strategy based on the Use of Redox Additive Electrolytes

    PubMed Central

    Singh, Arvinder; Chandra, Amreesh

    2016-01-01

    The strategy of using redox additive electrolyte in combination with multiwall carbon nanotubes/metal oxide composites leads to a substantial improvements in the specific energy and power of asymmetric supercapacitors (ASCs). When the pure electrolyte is optimally modified with a redox additive viz., KI, ~105% increase in the specific energy is obtained with good cyclic stability over 3,000 charge-discharge cycles and ~14.7% capacitance fade. This increase is a direct consequence of the iodine/iodide redox pairs that strongly modifies the faradaic and non-faradaic type reactions occurring on the surface of the electrodes. Contrary to what is shown in few earlier reports, it is established that indiscriminate increase in the concentration of redox additives will leads to performance loss. Suitable explanations are given based on theoretical laws. The specific energy or power values being reported in the fabricated ASCs are comparable or higher than those reported in ASCs based on toxic acetonitrile or expensive ionic liquids. The paper shows that the use of redox additive is economically favorable strategy for obtaining cost effective and environmentally friendly ASCs. PMID:27184260

  19. Oxidative stress in sickle cell disease: an overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies.

    PubMed

    Silva, Danilo Grunig Humberto; Belini Junior, Edis; de Almeida, Eduardo Alves; Bonini-Domingos, Claudia Regina

    2013-12-01

    Erythrocytes have an environment of continuous pro-oxidant generation due to the presence of hemoglobin (Hb), which represents an additional and quantitatively significant source of superoxide (O2(-)) generation in biological systems. To counteract oxidative stress, erythrocytes have a self-sustaining antioxidant defense system. Thus, red blood cells uniquely function to protect Hb via a selective barrier allowing gaseous and other ligand transport as well as providing antioxidant protection not only to themselves but also to other tissues and organs in the body. Sickle hemoglobin molecules suffer repeated polymerization/depolymerization generating greater amounts of reactive oxygen species, which can lead to a cyclic cascade characterized by blood cell adhesion, hemolysis, vaso-occlusion, and ischemia-reperfusion injury. In other words, sickle cell disease is intimately linked to a pathophysiologic condition of multiple sources of pro-oxidant processes with consequent chronic and systemic oxidative stress. For this reason, newer therapeutic agents that can target oxidative stress may constitute a valuable means for preventing or delaying the development of organ complications. PMID:24002011

  20. Backtracking behaviour in lost ants: an additional strategy in their navigational toolkit.

    PubMed

    Wystrach, Antoine; Schwarz, Sebastian; Baniel, Alice; Cheng, Ken

    2013-10-22

    Ants use multiple sources of information to navigate, but do not integrate all this information into a unified representation of the world. Rather, the available information appears to serve three distinct main navigational systems: path integration, systematic search and the use of learnt information--mainly via vision. Here, we report on an additional behaviour that suggests a supplemental system in the ant's navigational toolkit: 'backtracking'. Homing ants, having almost reached their nest but, suddenly displaced to unfamiliar areas, did not show the characteristic undirected headings of systematic searches. Instead, these ants backtracked in the compass direction opposite to the path that they had just travelled. The ecological function of this behaviour is clear as we show it increases the chances of returning to familiar terrain. Importantly, the mechanistic implications of this behaviour stress an extra level of cognitive complexity in ant navigation. Our results imply: (i) the presence of a type of 'memory of the current trip' allowing lost ants to take into account the familiar view recently experienced, and (ii) direct sharing of information across different navigational systems. We propose a revised architecture of the ant's navigational toolkit illustrating how the different systems may interact to produce adaptive behaviours. PMID:23966644

  1. Backtracking behaviour in lost ants: an additional strategy in their navigational toolkit

    PubMed Central

    Wystrach, Antoine; Schwarz, Sebastian; Baniel, Alice; Cheng, Ken

    2013-01-01

    Ants use multiple sources of information to navigate, but do not integrate all this information into a unified representation of the world. Rather, the available information appears to serve three distinct main navigational systems: path integration, systematic search and the use of learnt information—mainly via vision. Here, we report on an additional behaviour that suggests a supplemental system in the ant's navigational toolkit: ‘backtracking’. Homing ants, having almost reached their nest but, suddenly displaced to unfamiliar areas, did not show the characteristic undirected headings of systematic searches. Instead, these ants backtracked in the compass direction opposite to the path that they had just travelled. The ecological function of this behaviour is clear as we show it increases the chances of returning to familiar terrain. Importantly, the mechanistic implications of this behaviour stress an extra level of cognitive complexity in ant navigation. Our results imply: (i) the presence of a type of ‘memory of the current trip’ allowing lost ants to take into account the familiar view recently experienced, and (ii) direct sharing of information across different navigational systems. We propose a revised architecture of the ant's navigational toolkit illustrating how the different systems may interact to produce adaptive behaviours. PMID:23966644

  2. Angiogenesis as a novel therapeutic strategy for Duchenne muscular dystrophy through decreased ischemia and increased satellite cells

    PubMed Central

    Shimizu-Motohashi, Yuko; Asakura, Atsushi

    2014-01-01

    Duchenne muscular dystrophy (DMD) is the most common hereditary muscular dystrophy caused by mutation in dystrophin, and there is no curative therapy. Dystrophin is a protein which forms the dystrophin-associated glycoprotein complex (DGC) at the sarcolemma linking the muscle cytoskeleton to the extracellular matrix. When dystrophin is absent, muscle fibers become vulnerable to mechanical stretch. In addition to this, accumulating evidence indicates DMD muscle having vascular abnormalities and that the muscles are under an ischemic condition. More recent studies demonstrate decreased vascular densities and impaired angiogenesis in the muscles of murine model of DMD. Therefore, generation of new vasculature can be considered a potentially effective strategy for DMD therapy. The pro-angiogenic approaches also seem to be pro-myogenic and could induce muscle regeneration capacity through expansion of the satellite cell juxtavascular niche in the mouse model. Here, we will focus on angiogenesis, reviewing the background, vascular endothelial growth factor (VEGF)/VEGF receptor-pathway, effect, and concerns of this strategy in DMD. PMID:24600399

  3. Nanolipodendrosome-loaded glatiramer acetate and myogenic differentiation 1 as augmentation therapeutic strategy approaches in muscular dystrophy

    PubMed Central

    Afzal, Ehsan; Zakeri, Saba; Keyhanvar, Peyman; Bagheri, Meisam; Mahjoubi, Parvin; Asadian, Mahtab; Omoomi, Nogol; Dehqanian, Mohammad; Ghalandarlaki, Negar; Darvishmohammadi, Tahmineh; Farjadian, Fatemeh; Golvajoee, Mohammad Sadegh; Afzal, Shadi; Ghaffari, Maryam; Cohan, Reza Ahangari; Gravand, Amin; Ardestani, Mehdi Shafiee

    2013-01-01

    Backgrond Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion – like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 [MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. Methods In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. Results The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation. PMID:23966782

  4. Therapeutic perspectives

    PubMed Central

    Fiore, Carmelo E.; Pennisi, Pietra; Tinè, Marianna

    2008-01-01

    Osteoporosis and atherosclerosis are linked by biological association. This encourages the search for therapeutic strategies having both cardiovascular and skeletal beneficial effects. Among drugs that may concordantly enhance bone density and reduce the progression of atherosclerosis we can include bisphosphonates (BP), statins, β -blockers, and possibly anti-RANKL antibodies. Available data come from experimental animals and human studies. All these treatments however lack controlled clinical studies designed to demonstrate dual-action effects. PMID:22460845

  5. Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

    PubMed

    Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

    2016-04-15

    Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. PMID:26787513

  6. Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

    PubMed

    Bianchi, Enrica; Taurone, Samanta; Bardella, Lia; Signore, Alberto; Pompili, Elena; Sessa, Vincenzo; Chiappetta, Caterina; Fumagalli, Lorenzo; Di Gioia, Cira; Pastore, Francesco S; Scarpa, Susanna; Artico, Marco

    2015-10-01

    Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD). PMID:26201022

  7. The Use of Empirically Supported Strategies for Building a Therapeutic Relationship with an Adolescent with Oppositional-Defiant Disorder

    ERIC Educational Resources Information Center

    Karver, Marc S.; Caporino, Nicole

    2010-01-01

    Manualized evidence-based treatments, particularly behavioral and cognitive-behavioral interventions, have been found efficacious for the treatment of adolescents with oppositional-defiant disorder (ODD). However, despite research that underscores the importance of the therapeutic relationship for the success of treatment, manuals do not…

  8. Identifying and Evaluating the Therapeutic Strategies Used During a Manualized Self- Advocacy Intervention for Transition-Age Youth.

    PubMed

    Kramer, Jessica M

    2015-01-01

    Prior to undertaking randomized control trials, pilot research should ensure that an intervention's active ingredients are operationalized in manuals or protocols. This study identified the strategies facilitators reported to use during the implementation of a problem-solving self-advocacy intervention, Project "Teens making Environment and Activity Modifications" (TEAM), with transition-age youth with developmental disabilities, and evaluated the alignment of strategies with the intervention's hypothesized mechanisms of change. An iterative process was used to conduct a content analysis of 106 field notes completed by six facilitators. Facilitators used 19 strategies. Findings suggest that facilitators used strategies simultaneously to ensure universal design for learning, maximize relevance for individual trainees, and maintain a safe and encouraging environment. Facilitators can individualize Project TEAM in a way that operationalizes the mechanisms of change underlying Project TEAM. The quality of the intervention may improve by explicitly incorporating these strategies into the intervention protocol. The strategies may also be applicable to therapists implementing interventions informed, by similar theoretical propositions. PMID:26069464

  9. Identifying and Evaluating the Therapeutic Strategies Used During a Manualized Self-Advocacy Intervention for Transition-Age Youth

    PubMed Central

    Kramer, Jessica M.

    2015-01-01

    Prior to undertaking randomized control trials, pilot research should ensure that an intervention’s active ingredients are operationalized in manuals or protocols. This study identified the strategies facilitators reported to use during the implementation of a problem-solving self-advocacy intervention, Project “Teens making Environment and Activity Modifications” (TEAM), with transition-age youth with developmental disabilities, and evaluated the alignment of strategies with the intervention’s hypothesized mechanisms of change. An iterative process was used to conduct a content analysis of 106 field notes completed by six facilitators. Facilitators used 19 strategies. Findings suggest that facilitators used strategies simultaneously to ensure universal design for learning, maximize relevance for individual trainees, and maintain a safe and encouraging environment. Facilitators can individualize Project TEAM in a way that operationalizes the mechanisms of change underlying Project TEAM. The quality of the intervention may improve by explicitly incorporating these strategies into the intervention protocol. The strategies may also be applicable to therapists implementing interventions informed by similar theoretical propositions. PMID:26069464

  10. The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson’s Disease

    PubMed Central

    D’Ostilio, Kevin; Garraux, Gaëtan

    2016-01-01

    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

  11. HDL cholesterol: all hope is not lost after the torcetrapib setback--emerging therapeutic strategies on the horizon.

    PubMed

    Verma, Nitin; Figueredo, Vincent M

    2014-01-01

    Lowering low-density lipoprotein cholesterol (LDL) has been definitely shown to reduce cardiovascular events and improve clinical outcomes in the literature. As a result, LDL lowering has become the cornerstone of therapeutic approaches to cardiovascular disease prevention. Recently, there has been a focus on targeting other lipid fractions to improve the clinical risk profile of patients. Raising high-density lipoprotein (HDL) has received considerable attention. Low HDL levels are often seen in combination with elevated triglyceride levels. New therapeutic modalities are being developed to increase HDL levels. Recent failure of agents such as cholesteryl ester transferase protein inhibitor torcetrapib has highlighted the importance of measuring functionality of HDL particles and not just focus quantitatively on HDL-C levels. The heterogeneity of HDL within the systemic circulation results from constant remodeling of particles in response to several factors. Established dyslipidemia therapies such as stains, fibrates, and niacin have already been well known in the literature to have a substantial benefit. Lifestyle changes such as smoking cessation and moderate alcohol consumption have also shown to have some benefit. Several novel HDL therapies are currently being developed, but only the cholesteryl ester transferase protein inhibitors have received considerable attention. Although torcetrapib has received some negative attention due to adverse effects, this overall class of therapeutic agents still holds a lot of promise. Newer agents without the concerned toxicities are currently being developed. ApoA-1-related peptides, peroxisome proliferator-activated receptor agonists, endothelial lipase inhibitors, and liver X receptor agonists are some of the other novel agents currently in various stages of development. PMID:22967983

  12. CRISPRi and CRISPRa: New Functional Genomics Tools Provide Complementary Insights into Cancer Biology and Therapeutic Strategies | Office of Cancer Genomics

    Cancer.gov

    A central goal of research for targeted cancer therapy, or precision oncology, is to reveal the intrinsic vulnerabilities of cancer cells and exploit them as therapeutic targets. Examples of cancer cell vulnerabilities include driver oncogenes that are essential for the initiation and progression of cancer, or non-oncogene addictions resulting from the cancerous state of the cell. To identify vulnerabilities, scientists perform genetic “loss-of-function” and “gain-of-function” studies to better understand the roles of specific genes in cancer cells.

  13. Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies.

    PubMed

    Pinkas, Adi; Aschner, Michael

    2016-05-16

    Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies. PMID:27054356

  14. The Rag2⁻Il2rb⁻Dmd⁻ mouse: a novel dystrophic and immunodeficient model to assess innovating therapeutic strategies for muscular dystrophies.

    PubMed

    Vallese, Denis; Negroni, Elisa; Duguez, Stéphanie; Ferry, Arnaud; Trollet, Capucine; Aamiri, Ahmed; Vosshenrich, Christian A J; Füchtbauer, Ernst-Martin; Di Santo, James P; Vitiello, Libero; Butler-Browne, Gillian; Mouly, Vincent

    2013-10-01

    The development of innovative therapeutic strategies for muscular dystrophies, particularly cell-based approaches, is still a developing field. Although positive results have been obtained in animal models, they have rarely been confirmed in patients and resulted in very limited clinical improvements, suggesting some specificity in humans. These findings emphasized the need for an appropriate animal model (i.e., immunodeficient and dystrophic) to investigate in vivo the behavior of transplanted human myogenic stem cells. We report a new model, the Rag2(-)Il2rb(-)Dmd(-) mouse, which lacks T, B, and NK cells, and also carries a mutant Dmd allele that prevents the production of any dystrophin isoform. The dystrophic features of this new model are comparable with those of the classically used mdx mouse, but with the total absence of any revertant dystrophin positive fiber. We show that Rag2(-)Il2rb(-)Dmd(-) mice allow long-term xenografts of human myogenic cells. Altogether, our findings indicate that the Rag2(-)Il2rb(-)Dmd(-) mouse represents an ideal model to gain further insights into the behavior of human myogenic stem cells in a dystrophic context, and can be used to assess innovative therapeutic strategies for muscular dystrophies. PMID:23975040

  15. Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance.

    PubMed

    Ganai, Shabir Ahmad

    2016-09-01

    Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown encouraging results in haematological malignancies, but the poor pharmacokinetic of these inhibitors leads to insufficient tumour concentration limiting their application against solid malignancies. Objective This article deals with novel HDAC inhibitor pracinostat (SB939) and delineates its therapeutic role in solid and haematological malignancies. The article provides rigorous details about the underlying molecular mechanisms modulated by pracinostat to exert cytotoxic effect. The article further highlights the doublet therapy that may be used to tackle monotonous cancer chemoresistance. Methods Both old and the latest literature on pracinostat was retrieved from diverse sources, such as PubMed, Science Direct, Springer Link, general Google search using both pracinostat and SB939 keywords in various ways: after thorough evaluation the topic which can fulfil the current gap was chosen. Results Pracinostat shows potent anticancer activity against both solid and haematological malignancies compared to the FDA-approved drug vorinostat. This marvellous inhibitor has better physicochemical, pharmaceutical and pharmacokinetic properties than the defined inhibitor vorinostat. Pracinostat has  >100-fold more affinity towards HDACs compared to other zinc-dependent metalloenzymes and shows maximum efficacy when used in doublet therapy. Conclusion Pracinostat shows potent anticancer activity even against therapeutically challenging cancers when used in doublet therapy. However, the triplet combination studies of the defined inhibitor that may prove even more beneficial are still undone, emphasizing the desperate need of further research in the defined gap. PMID:26853619

  16. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma.

    PubMed

    Ambrogio, Chiara; Gómez-López, Gonzalo; Falcone, Mattia; Vidal, August; Nadal, Ernest; Crosetto, Nicola; Blasco, Rafael B; Fernández-Marcos, Pablo J; Sánchez-Céspedes, Montserrat; Ren, Xiaomei; Wang, Zhen; Ding, Ke; Hidalgo, Manuel; Serrano, Manuel; Villanueva, Alberto; Santamaría, David; Barbacid, Mariano

    2016-03-01

    Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma. PMID:26855149

  17. Effectiveness of nitrate addition and increased oil content as methane mitigation strategies for beef cattle fed two contrasting basal diets.

    PubMed

    Troy, S M; Duthie, C-A; Hyslop, J J; Roehe, R; Ross, D W; Wallace, R J; Waterhouse, A; Rooke, J A

    2015-04-01

    The objectives of this study were to investigate the effects of (1) the addition of nitrate and (2) an increase in dietary oil on methane (CH4) and hydrogen (H2) emissions from 2 breeds (cross-bred Charolais and purebred Luing) of finishing beef cattle receiving 2 contrasting basal diets consisting (grams per kilogram DM) of 500:500 (Mixed) and 80:920 (Concentrate) forage to concentrate ratios. Within each basal diet there were 3 treatments: (i) control treatments (mixed-CTL and concentrate-CTL) contained rapeseed meal as the protein source, which was replaced with either (ii) calcium nitrate (mixed-NIT and concentrate-NIT) supplying 21.5 g nitrate/kg DM, or (iii) rapeseed cake (mixed-RSC and concentrate-RSC) to increase dietary oil from 27 (CTL) to 53 g/kg DM (RSC). Following adaption to diets, CH4 and H2 emissions were measured on 1 occasion from each of the 76 steers over a 13-wk period. Dry matter intakes tended (P = 0.051) to be greater for the concentrate diet than the mixed diet; however, when expressed as grams DMI per kilogram BW, there was no difference between diets (P = 0.41). Dry matter intakes for NIT or RSC did not differ from CTL. Steers fed a concentrate diet produced less CH4 and H2 than those fed a mixed diet (P < 0.001). Molar proportions of acetate (P < 0.001) and butyrate (P < 0.01) were lower and propionate (P < 0.001) and valerate (P < 0.05) higher in the rumen fluid from steers fed the concentrate diet. For the mixed diet, CH4 yield (grams per kilogram DMI) was decreased by 17% when nitrate was added (P < 0.01), while H2 yield increased by 160% (P < 0.001). The addition of RSC to the mixed diet decreased CH4 yield by 7.5% (P = 0.18). However, for the concentrate diet neither addition of nitrate (P = 0.65) nor increasing dietary oil content (P = 0.46) decreased CH4 yield compared to concentrate-CTL. Molar proportions of acetate were higher (P < 0.001) and those of propionate lower (P < 0.01) in rumen fluid from NIT treatments compared to

  18. The pathogenesis of rheumatoid arthritis and the development of therapeutic strategies for the clinical investigation of biologics.

    PubMed

    Panayi, G S

    1995-01-01

    This review discusses current concepts of the pathogenesis of rheumatoid arthritis. It is proposed that RA is a T cell mediated disease following which a large number of subsequent inflammatory events are unleashed. Many of the pathogenetic steps are targets for new therapies including biologics. Laboratory, clinical and radiological methods of assessing disease activity are sufficiently sensitive and reproducible to permit their use in multicentre studies capable of detecting a biologic with disease modifying activity. The clinical assessment of the efficacy and toxicity of biologics poses unique problems. These have been illustrated by the example of 3 monoclonal antibodies directed against ICAM-1, CD4 and TNF alpha. The main role of most biologics may be to pinpoint important therapeutic targets which can be attacked by more easily administered and less costly xenobiotic drugs. PMID:7785487

  19. A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy

    PubMed Central

    Maruani, Antoine; Smith, Mark E.B.; Miranda, Enrique; Chester, Kerry A.; Chudasama, Vijay; Caddick, Stephen

    2015-01-01

    Although recent methods for the engineering of antibody–drug conjugates (ADCs) have gone some way to addressing the challenging issues of ADC construction, significant hurdles still remain. There is clear demand for the construction of novel ADC platforms that offer greater stability, homogeneity and flexibility. Here we describe a significant step towards a platform for next-generation antibody-based therapeutics by providing constructs that combine site-specific modification, exceptional versatility and high stability, with retention of antibody binding and structure post-modification. The relevance of the work in a biological context is also demonstrated in a cytotoxicity assay and a cell internalization study with HER2-positive and -negative breast cancer cell lines. PMID:25824906

  20. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation.

    PubMed

    Addolorato, Giovanni; Leggio, Lorenzo; Hopf, F Woodward; Diana, Marco; Bonci, Antonello

    2012-01-01

    Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism. PMID:22030714

  1. Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

    PubMed Central

    Addolorato, Giovanni; Leggio, Lorenzo; Hopf, F Woodward; Diana, Marco; Bonci, Antonello

    2012-01-01

    Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism. PMID:22030714

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

    PubMed Central

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

    2015-01-01

    expected by The Cochrane Collaboration. Main results We identified seven RCTs that compared 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

  3. Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma.

    PubMed

    Soares, Ana S; Costa, Vera M; Diniz, Carmen; Fresco, Paula

    2013-10-01

    Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48 h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10 ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma. PMID:24035253

  4. A Heterologous Prime/Boost Vaccination Strategy Enhances the Immunogenicity of Therapeutic Vaccines for Hepatitis C Virus

    PubMed Central

    Fournillier, Anne; Frelin, Lars; Jacquier, Emilie; Ahlén, Gustaf; Brass, Anette; Gerossier, Estelle; Holmström, Fredrik; Broderick, Kate E.; Sardesai, Niranjan Y.; Bonnefoy, Jean-Yves; Inchauspé, Geneviève; Sällberg, Matti

    2013-01-01

    Background. We explored the concept of heterologous prime/boost vaccination using 2 therapeutic vaccines currently in clinical development aimed at treating chronically infected hepatitis C virus (HCV) patients: prime with a DNA-based vaccine expressing HCV genotype 1a NS3/4A proteins (ChronVac-C) and boost with a modified vaccinia virus Ankara vaccine expressing genotype 1b NS3/4/5B proteins (MVATG16643). Methods. Two ChronVac-C immunizations 4 weeks apart were delivered intramuscularly in combination with in vivo electroporation and subsequently 5 or 12 weeks later boosted by 3 weekly subcutaneous injections of MVATG16643. Two mouse strains were used, and we evaluated quality, magnitude, and functionality of the T cells induced. Results. DNA prime/MVA boost regimen induced significantly higher levels of interferon γ (IFN-γ) or interleukin 2 (IL-2) ELISpot responses compared with each vaccine alone, independent of the time of analysis and the time interval between vaccinations. Both CD8+ and CD4+ T-cell responses as well as the spectrum of epitopes recognized was improved. A significant increase in polyfunctional IFN-γ/tumor necrosis factor α (TNF-α)/CD107a+ CD8+ T cells was detected following ChronVac-C/MVATG16643 vaccination (from 3% to 25%), and prime/boost was the only regimen that activated quadrifunctional T cells (IFN-γ/TNF-α/CD107a/IL-2). In vivo functional protective capacity of DNA prime/MVA boost was demonstrated in a Listeria-NS3-1a challenge model. Conclusions. We provide a proof-of-concept that immunogenicity of 2 HCV therapeutic vaccines can be improved using their combination, which merits further clinical development. PMID:23776192

  5. Additional evidence for a dual-strategy model of reasoning: Probabilistic reasoning is more invariant than reasoning about logical validity.

    PubMed

    Markovits, Henry; Brisson, Janie; de Chantal, Pier-Luc

    2015-11-01

    One of the major debates concerning the nature of inferential reasoning is between counterexample-based strategies such as mental model theory and the statistical strategies underlying probabilistic models. The dual-strategy model proposed by Verschueren, Schaeken, and d'Ydewalle (2005a, 2005b) suggests that people might have access to both kinds of strategies. One of the postulates of this approach is that statistical strategies correspond to low-cost, intuitive modes of evaluation, whereas counterexample strategies are higher-cost and more variable in use. We examined this hypothesis by using a deductive-updating paradigm. The results of Study 1 showed that individual differences in strategy use predict different levels of deductive updating on inferences about logical validity. Study 2 demonstrated no such variation when explicitly probabilistic inferences were examined. Study 3 showed that presenting updating problems with probabilistic inferences modified performance on subsequent problems using logical validity, whereas the opposite was not true. These results provide clear evidence that the processes used to make probabilistic inferences are less subject to variation than those used to make inferences of logical validity. PMID:26148720

  6. New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK

    PubMed Central

    Di Paolo, Daniela; Yang, D.; Pastorino, Fabio; Emionite, Laura; Cilli, Michele; Daga, Antonio; Destefanis, Elisa; Di Fiore, Annarita; Piaggio, Francesca; Brignole, Chiara; Xu, Xiaobao; Liang, Chris; Gibbons, James

    2015-01-01

    Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors. PMID:26299615

  7. Genetic strategies to study TDP-43 in rodents and to develop preclinical therapeutics for amyotrophic lateral sclerosis.

    PubMed

    Wang, David B; Gitcho, Michael A; Kraemer, Brian C; Klein, Ronald L

    2011-10-01

    The neuropathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) and a class of frontotemporal lobar degeneration is ubiquitinated cytoplasmic aggregates composed of transactive response DNA binding protein 43 kDa (TDP-43). Genetic manipulation of TDP-43 in animal models has been used to study the protein's role in pathogenesis. Transgenic rodents for TDP-43 have recapitulated key aspects of ALS such as paralysis, loss of spinal motor neurons and muscle atrophy. Viral vectors are an alternate approach to express pathological proteins in animals. Use of the recombinant adeno-associated virus vector serotype 9 has permitted widespread transgene expression throughout the central nervous system after intravenous administration. Expressing TDP-43 in rats with this method produced a phenotype that was consistent with and similar to TDP-43 transgenic lines. Increased levels of TDP-43 in the nucleus are toxic to neurons and sufficient to produce ALS-like symptoms. Animal models based on TDP-43 will address the relationships between TDP-43 expression levels, pathology, neuronal loss, muscle atrophy, motor function and causative mechanisms of disease. New targets that modify TDP-43 function, or targets from previous ALS models and other models of spinal cord diseases, could be tested for efficacy in the recent rodent models of ALS based on TDP-43. The vector approach could be an important therapeutic channel because the entire spinal cord can be affected from a one-time peripheral administration. PMID:21777407

  8. Contribution of reactive oxygen species to cartilage degradation in rheumatic diseases: molecular pathways, diagnosis and potential therapeutic strategies.

    PubMed

    Schiller, J; Fuchs, B; Arnhold, J; Arnold, K

    2003-10-01

    Inflammatory joint diseases are of considerable socio-economic significance. However, mechanisms of cartilage destruction are so far only poorly understood. This review is dedicated to reactive oxygen species (ROS) like superoxide anion radicals, hydrogen peroxide, singlet oxygen, hypochlorous acid, hydroxyl radicals and nitric oxide that are generated under inflammatory conditions and also to their potential contribution to cartilage degradation. First, the relevance of rheumatic diseases and potential mechanisms of cartilage degradation are discussed in this review, followed by the description of the chemical constituents and the molecular architecture of articular cartilage as well as the different cell types that play a role in inflammation and cartilage destruction. Methods of the assessment of cartilage degeneration are also shortly discussed. In the main chapter of this review the characteristics of individual ROS, their generation under in vivo conditions as well as their reactivities with individual cartilage components are discussed. Because of the low selectivity of ROS, useful "markers" of cartilage degradation allowing the differentiation of effects induced by individual ROS are also discussed. In the last chapter current therapeutic concepts of the treatment of rheumatic diseases are reviewed. The recently developed "anti-TNF-alpha" therapy that is primarily directed against neutrophilic granulocytes that are powerful sources of ROS and, therefore, important mediators of joint degeneration are emphasised. PMID:12871089

  9. [Beta-blockers in cardiac insufficiency: should they always be considered in the therapeutic strategy? Arguments against].

    PubMed

    Ortigosa Aso, J; Silva Melchor, L; García, A; de Artaza Andrade, M

    1997-05-01

    The evidence supporting the use of beta-adrenergic blockers in the treatment of heart failure secondary to systolic dysfunction is reviewed. Up to date, seven controlled trials of carvedilol in patients with heart failure have been published. It has been concluded that the use of the non-selective, third generation beta-adrenergic blockers, with alpha-adrenergic (vasodilator) and antioxidant properties, carvedilol, is only justified in patients with mild or moderate heart failure without contraindications to beta-adrenergic blockers. There are not data to support the use of carvedilol in patients with severe or unstable heart failure. It seems logical to wait for the results of the ongoing trials (BEST Trial, CIBIS II Trial, COMET Trial, and MERIT Trial) to more precisely define the role that beta-adrenergic blockers should play in the treatment of patients with heart failure. The information presently available suggests that carvedilol should be considered a therapeutic agent for the prevention of progressive clinical heart failure rather than for the treatment of refractory heart failure. PMID:9281008

  10. Haemophilia at various stages of life: design of new therapeutic strategies through an interactive course - the Kogeniale project

    PubMed Central

    Santagostino, Elena; Messina, Maria; Tagliaferri, Annarita; Iorio, Alfonso; Morfini, Massimo

    2013-01-01

    Background High-quality evidence is lacking in several areas of haemophilia treatment, in part because little time is allocated to the treatment and care of haemophilia in university education in Italy. Physicians caring for patients with haemophilia must, therefore, rely on their information on background pathophysiology and more experienced colleagues. This makes diagnostic and therapeutic choices difficult, especially when the patient has concomitant disorders or psychological issues. Material and methods This article describes a course to educate young physicians who were already engaged in the management of haemophilia on the emerging and unmet issues of haemophilia care and to implement existing guidelines. Physicians (n=53) already caring for patients with haemophilia in their haematology, internal medicine, or paediatric practices in Italy attended the course. Problem-solving group activity and open discussion were the methods chosen to formulate consensus statements. During the specifically designed interactive course, three clinical cases were simulated: a young child with congenital dislocation of the hip, an adolescent refusing prophylactic treatment, and an elderly man with cardiovascular disorders. The physicians were asked questions during the course and, through a Wi-Fi console, were able to answer and discuss each case interactively. Results Following discussion of each case, agreement was reached regarding general statements on the management of patients with severe haemophilia A in the three different age ranges considered. Discussion This project helped to outline useful decision-making tools for handling diagnostic and treatment issues in the field of haemophilia. PMID:23399360

  11. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

    PubMed Central

    Chang, Betty Y.; Kong, Sun-Young; Fulciniti, Mariateresa; Yang, Guang; Calle, Yolanda; Hu, Yiguo; Lin, Jianhong; Zhao, Jian-Jun; Cagnetta, Antonia; Cea, Michele; Sellitto, Michael A.; Zhong, Mike Y.; Wang, Qiuju; Acharya, Chirag; Carrasco, Daniel R.; Buggy, Joseph J.; Elias, Laurence; Treon, Steven P.; Matsui, William; Richardson, Paul; Munshi, Nikhil C.; Anderson, Kenneth C.

    2012-01-01

    Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF–induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5nM) and MM patients. It decreased SDF-1–induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell–induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM. PMID:22689860

  12. Fc Receptor-Mediated Phagocytosis in Tissues as a Potent Mechanism for Preventive and Therapeutic HIV Vaccine Strategies

    PubMed Central

    Sips, Magdalena; Krykbaeva, Marina; Diefenbach, Thomas J.; Ghebremichael, Musie; Bowman, Brittany A.; Dugast, Anne-Sophie; Boesch, Austin W.; Streeck, Hendrik; Kwon, Douglas S.; Ackerman, Margaret E.; Suscovich, Todd J.; Brouckaert, Peter; Schacker, Timothy W.; Alter, Galit

    2016-01-01

    While the development of a protective HIV vaccine is the ultimate goal of HIV research, to date only one HIV vaccine trial, the RV144, has successfully induced a protective response. The 31% protection from infection achieved in the RV144 trial was linked to the induction of non-neutralizing antibodies, able to mediate ADCC, suggestive of an important role of Fc-mediated functions in protection. Likewise, Fc-mediated antiviral activity was recently shown to play a critical role in actively suppressing the viral reservoir, however, the Fc-effector mechanisms within tissues that provide protection from or after infection are largely unknown. Here we aimed to define the landscape of effector cells and Fc-receptors present within vulnerable tissues. We found negligible Fc-receptor expressing NK cells in the female reproductive and gastrointestinal mucosa. Conversely, Fc-receptor expressing macrophages were highly enriched in most tissues, but neutrophils mediated superior antibody-mediated phagocytosis. Modifications in Fc domain of VRC01 antibody increased phagocytic responses in both phagocytes. These data suggest that non-ADCC mediated mechanisms, such as phagocytosis and neutrophil activation, are more likely to play a role in preventative vaccine or reservoir-eliminating therapeutic approaches. PMID:26883728

  13. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma.

    PubMed

    Tai, Yu-Tzu; Chang, Betty Y; Kong, Sun-Young; Fulciniti, Mariateresa; Yang, Guang; Calle, Yolanda; Hu, Yiguo; Lin, Jianhong; Zhao, Jian-Jun; Cagnetta, Antonia; Cea, Michele; Sellitto, Michael A; Zhong, Mike Y; Wang, Qiuju; Acharya, Chirag; Carrasco, Daniel R; Buggy, Joseph J; Elias, Laurence; Treon, Steven P; Matsui, William; Richardson, Paul; Munshi, Nikhil C; Anderson, Kenneth C

    2012-08-30

    Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17 nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5 nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM. PMID:22689860

  14. In Vivo Hepatic Reprogramming of Myofibroblasts with AAV Vectors as a Therapeutic Strategy for Liver Fibrosis.

    PubMed

    Rezvani, Milad; Español-Suñer, Regina; Malato, Yann; Dumont, Laure; Grimm, Andrew A; Kienle, Eike; Bindman, Julia G; Wiedtke, Ellen; Hsu, Bernadette Y; Naqvi, Syed J; Schwabe, Robert F; Corvera, Carlos U; Grimm, Dirk; Willenbring, Holger

    2016-06-01

    Liver fibrosis, a form of scarring, develops in chronic liver diseases when hepatocyte regeneration cannot compensate for hepatocyte death. Initially, collagen produced by myofibroblasts (MFs) functions to maintain the integrity of the liver, but excessive collagen accumulation suppresses residual hepatocyte function, leading to liver failure. As a strategy to generate new hepatocytes and limit collagen deposition in the chronically injured liver, we developed in vivo reprogramming of MFs into hepatocytes using adeno-associated virus (AAV) vectors expressing hepatic transcription factors. We first identified the AAV6 capsid as effective in transducing MFs in a mouse model of liver fibrosis. We then showed in lineage-tracing mice that AAV6 vector-mediated in vivo hepatic reprogramming of MFs generates hepatocytes that replicate function and proliferation of primary hepatocytes, and reduces liver fibrosis. Because AAV vectors are already used for liver-directed human gene therapy, our strategy has potential for clinical translation into a therapy for liver fibrosis. PMID:27257763

  15. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment

    PubMed Central

    Lee, Youjin; Auh, Sogyong L.; Wang, Yugang; Burnette, Byron; Wang, Yang; Meng, Yuru; Beckett, Michael; Sharma, Rohit; Chin, Robert; Tu, Tony

    2009-01-01

    Patients with locally advanced cancer or distant metastasis frequently receive prolonged treatment with chemotherapy and/or fractionated radiotherapy (RT). Despite the initial clinical response, treatment resistance frequently develops and cure in these patients is uncommon. Developments in RT technology allow for the use of high-dose (or ablative) RT to target local tumors, with limited damage to the surrounding normal tissue. We report that reduction of tumor burden after ablative RT depends largely on T-cell responses. Ablative RT dramatically increases T-cell priming in draining lymphoid tissues, leading to reduction/eradication of the primary tumor or distant metastasis in a CD8+ T cell–dependent fashion. We further demonstrate that ablative RT-initiated immune responses and tumor reduction are abrogated by conventional fractionated RT or adjuvant chemotherapy but greatly amplified by local immunotherapy. Our study challenges the rationale for current RT/chemotherapy strategies and highlights the importance of immune activation in preventing tumor relapse. Our findings emphasize the need for new strategies that not only reduce tumor burden but also enhance the role of antitumor immunity. PMID:19349616

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

    PubMed Central

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

    2015-01-01

    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

  17. A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host

    PubMed Central

    Rai, Pradeep K; Chodisetti, Sathi Babu; Nadeem, Sajid; Maurya, Sudeep K; Gowthaman, Uthaman; Zeng, Weiguang; Janmeja, Ashok K; Jackson, David C; Agrewala, Javed N

    2016-01-01

    Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ+TNF-α+ polyfunctional Th1 cells and IL-17A+IFN-γ+ Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime. PMID:27052185

  18. Beyond evidence-based data: scientific rationale and tumor behavior to drive sequential and personalized therapeutic strategies for the treatment of metastatic renal cell carcinoma

    PubMed Central

    Badalamenti, Giuseppe; Rizzo, Sergio; Pantuso, Gianni; Natoli, Clara; Russo, Antonio

    2016-01-01

    The recent advances in identification of the molecular mechanisms related to tumorigenesis and angiogenesis, along with the understanding of molecular alterations involved in renal cell carcinoma (RCC) pathogenesis, has allowed the development of several new drugs which have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). This process has resulted in clinically significant improvements in median overall survival and an increasing number of patients undergoes two or even three lines of therapy. Therefore, it is necessary a long-term perspective of the treatment: planning a sequential and personalized therapeutic strategy to improve clinical outcome, the potential to achieve long-term response, and to preserve quality of life (QOL), minimizing treatment-related toxicity and transforming mRCC into a chronically treatable condition. Because of the challenges still encountered to draw an optimal therapeutic sequence, the main focus of this article will be to propose the optimal sequencing of existing, approved, oral targeted agents for the treatment of mRCC using evidence-based data along with the knowledge available on the tumor behavior and mechanisms of resistance to anti-angiogenic treatment to provide complementary information and to help the clinicians to maximize the effectiveness of targeted agents in the treatment of mRCC. PMID:26872372

  19. 5-hydroxytryptamine1A (5-HT1A) receptor agonists: A decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma.

    PubMed

    Cheng, Jeffrey P; Leary, Jacob B; Sembhi, Aerin; Edwards, Clarice M; Bondi, Corina O; Kline, Anthony E

    2016-06-01

    Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led to enhanced motor and/or cognitive performance, the benefits of these treatments have not translated to the clinic. One plausible explanation is that the therapies may not have been rigorously evaluated, thus rendering the bench-to-bedside leap premature and subsequently unsuccessful. An approach that has undergone considerable empirical research after TBI is pharmacological targeting of 5-HT1A receptors with agonists such as repinotan HCl, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and buspirone. The goal of this review is to integrate and interpret the findings from a series of studies that evaluated the efficacy of 5-HT1A receptor agonists on functional, histological, and molecular outcome after acquired brain injury. The overwhelming consensus of this exhaustive review is that a decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID:26612522

  20. New insights into therapeutic strategies for the treatment of peritoneal fibrosis: learning from histochemical analyses of animal models.

    PubMed

    Kitamura, Mineaki; Nishino, Tomoya; Obata, Yoko; Ozono, Yoshiyuki; Koji, Takehiko; Kohno, Shigeru

    2014-08-29

    Encapsulating peritoneal sclerosis (EPS) is a fatal complication that can occur in patients undergoing long-term peritoneal dialysis. It is characterized by bowel obstruction and marked sclerotic thickening of the peritoneal membrane. Although the mechanisms underlying the development of EPS are complex, angiogenesis, inflammation, and peritoneal fibrosis are known to be essential factors. Now, several animal models that exhibit EPS have pathophysiology similar to that of human EPS and have been proposed for use in research to provide insights into it. Recent histochemical methods also help us to understand the pathophysiology of EPS. Advances in basic research based on the findings in those animal models have enabled the development of several strategies for the prevention and treatment of EPS. We describe here interventional studies in some animal models for peritoneal fibrosis, one of the histological disorders findings characteristic to EPS, and we highlight the need for a sophisticated animal model that closely resembles human conditions. PMID:25392567

  1. New Insights into Therapeutic Strategies for the Treatment of Peritoneal Fibrosis: Learning from Histochemical Analyses of Animal Models

    PubMed Central

    Kitamura, Mineaki; Nishino, Tomoya; Obata, Yoko; Ozono, Yoshiyuki; Koji, Takehiko; Kohno, Shigeru

    2014-01-01

    Encapsulating peritoneal sclerosis (EPS) is a fatal complication that can occur in patients undergoing long-term peritoneal dialysis. It is characterized by bowel obstruction and marked sclerotic thickening of the peritoneal membrane. Although the mechanisms underlying the development of EPS are complex, angiogenesis, inflammation, and peritoneal fibrosis are known to be essential factors. Now, several animal models that exhibit EPS have pathophysiology similar to that of human EPS and have been proposed for use in research to provide insights into it. Recent histochemical methods also help us to understand the pathophysiology of EPS. Advances in basic research based on the findings in those animal models have enabled the development of several strategies for the prevention and treatment of EPS. We describe here interventional studies in some animal models for peritoneal fibrosis, one of the histological disorders findings characteristic to EPS, and we highlight the need for a sophisticated animal model that closely resembles human conditions. PMID:25392567

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

    PubMed Central

    Tan, Teik Hin; Boey, Ching Yeen; Lee, Boon Nang

    2016-01-01

    Objective(s): The present study aimed to evaluate the role of pre-therapeutic 18fluorine-fluorodeoxyglucose positron emission tomography-computed 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 the patients. 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-CT staging 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 26 (65.0%) cases, with upstaging and downstaging reported in 10 (25.0%) and 16 (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 the 18F-FDG PET-CT scan alone, the median survival of patients in the palliative group was 4.0 (95% CI 3.0-5.0) months, whereas the median survival in the curative group has not been reached, based on the 12-month follow-up. 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=0.03). On the basis of 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

  3. Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin

    PubMed Central

    Laughney, Ashley M.; Kim, Eunha; Sprachman, Melissa M.; Miller, Miles A.; Kohler, Rainer H.; Yang, Katy S.; Orth, James D.; Mitchison, Timothy J.; Weissleder, Ralph

    2015-01-01

    Eribulin mesylate was developed as a potent microtubule-targeting cytotoxic agent to treat taxane-resistant cancers, but recent clinical trials have shown that it eventually fails in many patient sub-populations for unclear reasons. To investigate its resistance mechanisms, we developed a fluorescent analog of eribulin with pharmacokinetic (PK) properties and cytotoxic activity across a human cell line panel that are sufficiently similar to the parent drug to study its cellular PK and tissue distribution. Using intravital imaging and automated tracking of cellular dynamics, we found that resistance to eribulin and the fluorescent analog depended directly on the multidrug resistance protein 1 (MDR1). Intravital imaging allowed for real-time analysis of in vivo pharmacokinetics in tumors that were engineered to be spatially heterogeneous for taxane resistance, whereby an MDR1-mApple fusion protein distinguished resistant cells fluorescently. In vivo, MDR1-mediated drug efflux and the three-dimensional tumor vascular architecture were discovered to be critical determinants of drug accumulation in tumor cells. We furthermore show that standard intravenous administration of a third-generation MDR1 inhibitor, HM30181, failed to rescue drug accumulation; however, the same MDR1 inhibitor encapsulated within a nanoparticle delivery system reversed the multidrug-resistant phenotype and potentiated the eribulin effect in vitro and in vivo in mice. Our work demonstrates that in vivo assessment of cellular PK of an anticancer drug is a powerful strategy for elucidating mechanisms of drug resistance in heterogeneous tumors and evaluating strategies to overcome this resistance. PMID:25378644

  4. Deferoxamine Preconditioning of Neural-Like Cells Derived from Human Wharton's Jelly Mesenchymal Stem Cells as a Strategy to Promote Their Tolerance and Therapeutic Potential: An In Vitro Study.

    PubMed

    Nouri, Fatemeh; Salehinejad, Parvin; Nematollahi-Mahani, Seyed Noureddin; Kamarul, Tunku; Zarrindast, Mohammad Reza; Sharifi, Ali Mohammad

    2016-07-01

    Transplantation of neural-like cells is considered as a promising therapeutic strategy developed for neurodegenerative disease in particular for ischemic stroke. Since cell survival is a major concern following cell implantation, a number of studies have underlined the protective effects of preconditioning with hypoxia or hypoxia mimetic pharmacological agents such as deferoxamine (DFO), induced by activation of hypoxia inducible factor-1 (HIF-1) and its target genes. The present study has investigated the effects of DFO preconditioning on some factors involved in cell survival, angiogenesis, and neurogenesis of neural-like cells derived from human Wharton's jelly mesenchymal stem cells (HWJ-MSCs) in presence of hydrogen peroxide (H2O2). HWJ-MSCs were differentiated toward neural-like cells for 14 days and neural cell markers were identified using immunocytochemistry. HWJ-MSC-derived neural-like cells were then treated with 100 µM DFO, as a known hypoxia mimetic agent for 48 h. mRNA and protein expression of HIF-1 target genes including brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) significantly increased using RT-PCR and Western blotting which were reversed by HIF-1α inhibitor, while, gene expression of Akt-1, Bcl-2, and Bax did not change significantly but pAkt-1 was up-regulated as compared to poor DFO group. However, addition of H2O2 to DFO-treated cells resulted in higher resistance to H2O2-induced cell death. Western blotting analysis also showed significant up-regulation of HIF-1α, BDNF, VEGF, and pAkt-1, and decrease of Bax/Bcl-2 ratio as compared to poor DFO. These results may suggest that DFO preconditioning of HWJ-MSC-derived neural-like cells improves their tolerance and therapeutic potential and might be considered as a valuable strategy to improve cell therapy. PMID:26242172

  5. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    PubMed

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  6. Dry eye disease treatment: a systematic review of published trials and a critical appraisal of therapeutic strategies.

    PubMed

    Alves, Monica; Fonseca, Ellen Carrara; Alves, Milena Freitas; Malki, Leonardo Tannus; Arruda, Gustavo Viani; Reinach, Peter S; Rocha, Eduardo Melani

    2013-07-01

    Dry eye disease (DED) treatment is an area of increasing complexity, with the emergence of several new treatment agents in recent years. Evaluation of the efficacy of these agents is limited by heterogeneity in outcomes definition and the small number of comparative studies. We provide a systematic review of clinical trials (CTs) related to DED treatment and a critical appraisal of CT public databases. CT reports obtained from eight databases were reviewed, as well as public free-access electronic databases for CT registration. Data evaluation was based on endpoints such as symptoms, Schirmer test, ocular surface staining scores, recruitment of patients, type and efficacy of the drug, and the design and site of performance of the study. Forty-nine CTs were evaluated involving 5,189 patients receiving DED treatment. Heterogeneity in study design prevented meta-analysis from yielding meaningful results, and a descriptive analysis of these studies was conducted. The most frequent categories of drugs for DED in these studies were artificial tears, followed by anti-inflammatory drugs and secretagogues. Although 116 studies have been completed, according to the registration database for clinical trials, only 17 of them (15.5%) were published. Out of 185 registered CTs related to DED, 72% were performed in the USA. The pharmaceutical industry sponsored 78% of them. The identification of effective DED treatment strategies is hindered by the lack of an accepted set of definitive criteria for evaluating disease severity. PMID:23838019

  7. Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies.

    PubMed

    Aleksic, Milos; Liddy, Nathaniel; Molloy, Peter E; Pumphrey, Nick; Vuidepot, Annelise; Chang, Kyong-Mi; Jakobsen, Bent K

    2012-12-01

    T-cell destiny during thymic selection depends on the affinity of the TCR for autologous peptide ligands presented in the context of MHC molecules. This is a delicately balanced process; robust binding leads to negative selection, yet some affinity for the antigen complex is required for positive selection. All TCRs of the resulting repertoire thus have some intrinsic affinity for an MHC type presenting an assortment of peptides. Generally, TCR affinities of peripheral T cells will be low toward self-derived peptides, as these would have been presented during thymic selection, whereas, by serendipity, binding to pathogen-derived peptides that are encountered de novo could be stronger. A crucial question in assessing immunotherapeutic strategies for cancer is whether natural TCR repertoires have the capacity for efficiently recognizing tumor-associated peptide antigens. Here, we report a comprehensive comparison of TCR affinities to a range of HLA-A2 presented antigens. TCRs that bind viral antigens fall within a strikingly higher affinity range than those that bind cancer-related antigens. This difference may be one of the key explanations for tumor immune escape and for the deficiencies of T-cell vaccines against cancer. PMID:22949370

  8. A therapeutic strategy for spinal cord defect: human dental follicle cells combined with aligned PCL/PLGA electrospun material.

    PubMed

    Li, Xinghan; Yang, Chao; Li, Lei; Xiong, Jie; Xie, Li; Yang, Bo; Yu, Mei; Feng, Lian; Jiang, Zongting; Guo, Weihua; Tian, Weidong

    2015-01-01

    Stem cell implantation has been utilized for the repair of spinal cord injury; however, it shows unsatisfactory performance in repairing large scale lesion of an organ. We hypothesized that dental follicle cells (DFCs), which possess multipotential capability, could reconstruct spinal cord defect (SCD) in combination with biomaterials. In the present study, mesenchymal and neurogenic lineage characteristics of human DFCs (hDFCs) were identified. Aligned electrospun PCL/PLGA material (AEM) was fabricated and it would not lead to cytotoxic reaction; furthermore, hDFCs could stretch along the oriented fibers and proliferate efficiently on AEM. Subsequently, hDFCs seeded AEM was transplanted to restore the defect in rat spinal cord. Functional observation was performed but results showed no statistical significance. The following histologic analyses proved that AEM allowed nerve fibers to pass through, and implanted hDFCs could express oligodendrogenic lineage maker Olig2 in vivo which was able to contribute to remyelination. Therefore, we concluded that hDFCs can be a candidate resource in neural regeneration. Aligned electrospun fibers can support spinal cord structure and induce cell/tissue polarity. This strategy can be considered as alternative proposals for the SCD regeneration studies. PMID:25695050

  9. A Therapeutic Strategy for Spinal Cord Defect: Human Dental Follicle Cells Combined with Aligned PCL/PLGA Electrospun Material

    PubMed Central

    Yang, Chao; Li, Lei; Xiong, Jie; Xie, Li; Yang, Bo; Yu, Mei; Feng, Lian; Jiang, Zongting; Guo, Weihua; Tian, Weidong

    2015-01-01

    Stem cell implantation has been utilized for the repair of spinal cord injury; however, it shows unsatisfactory performance in repairing large scale lesion of an organ. We hypothesized that dental follicle cells (DFCs), which possess multipotential capability, could reconstruct spinal cord defect (SCD) in combination with biomaterials. In the present study, mesenchymal and neurogenic lineage characteristics of human DFCs (hDFCs) were identified. Aligned electrospun PCL/PLGA material (AEM) was fabricated and it would not lead to cytotoxic reaction; furthermore, hDFCs could stretch along the oriented fibers and proliferate efficiently on AEM. Subsequently, hDFCs seeded AEM was transplanted to restore the defect in rat spinal cord. Functional observation was performed but results showed no statistical significance. The following histologic analyses proved that AEM allowed nerve fibers to pass through, and implanted hDFCs could express oligodendrogenic lineage maker Olig2 in vivo which was able to contribute to remyelination. Therefore, we concluded that hDFCs can be a candidate resource in neural regeneration. Aligned electrospun fibers can support spinal cord structure and induce cell/tissue polarity. This strategy can be considered as alternative proposals for the SCD regeneration studies. PMID:25695050

  10. Blocking Aβ seeding-mediated aggregation and toxicity in an animal model of Alzheimer's Disease: A novel therapeutic strategy for neurodegeneration

    PubMed Central

    Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward; Mante, Mike; Adame, Antony; Trejo, Margarita; Wrasidlo, Wolf; Wu, Fang; Fraering, Patrick C.; Masliah, Eliezer; Lashuel, Hilal A.

    2014-01-01

    Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represent an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD. PMID:25173807

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

    PubMed

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

    2002-01-01

    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. PMID:12422553

  12. Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

    PubMed Central

    Conery, Andrew R; Centore, Richard C; Neiss, Adrianne; Keller, Patricia J; Joshi, Shivangi; Spillane, Kerry L; Sandy, Peter; Hatton, Charlie; Pardo, Eneida; Zawadzke, Laura; Bommi-Reddy, Archana; Gascoigne, Karen E; Bryant, Barbara M; Mertz, Jennifer A; Sims, Robert J

    2016-01-01

    Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. DOI: http://dx.doi.org/10.7554/eLife.10483.001 PMID:26731516

  13. Funding for Higher Education in Asia and the Pacific. Strategies To Increase Cost Efficiency and Attract Additional Financial Support.

    ERIC Educational Resources Information Center

    Harman, Grant, Ed.; Selim, M., Ed.

    This book presents articles that document the serious funding problems faced by higher education institutions and systems in the Asian and Pacific region, and explores possible strategies to address these problems. It presents an overview of the financial situation faced by higher education in the region, and then discusses two main strategies…

  14. Can the Isolated-Elements Strategy Be Improved by Targeting Points of High Cognitive Load for Additional Practice?

    ERIC Educational Resources Information Center

    Ayres, Paul

    2013-01-01

    Reducing problem complexity by isolating elements has been shown to be an effective instructional strategy. Novices, in particular, benefit from learning from worked examples that contain partially interacting elements rather than worked examples that provide full interacting elements. This study investigated whether the isolating-elements…

  15. [Acute therapeutic measures for limb salvage Part 2 : Debridement, lavage techniques and anti-infectious strategies].

    PubMed

    Willy, C; Stichling, M; Müller, M; Gatzer, R; Kramer, A; Back, D A; Vogt, D

    2016-05-01

    The quality of the primary care of Gustilo-Anderson (GA) type IIIB and IIIC extremity injuries is crucial to the success of the limb salvage procedure. This article provides a compilation of consistent, but often controversially discussed aspects of initial debridement, modern techniques of lavage and wound closure, in addition to current issues on the application of antibiotics and antiseptics, based on our own experiences and the latest literature. The following points should be stressed. Severe extremity injuries with gross contamination (GA IIIA, B, and C) will still be associated with an infection rate of up to 60 %. The initial debridement should be performed as soon as an experienced trauma surgeon is available. Tissue that is definitely avital will have to be removed, whereas traumatized but potentially surviving tissue will have to be re-evaluated during a second-look operation after 36-48 h. Given a high enough level of contamination, biofilms will form after as few as 6 h. The perioperative antibiotic prophylaxis has to be initiated early and should be continued for at least 24 h (GA I/II) or up to 5 days (GA III). In cases of bacterial contamination, wound irrigation will be useful with additives such as polyhexanide, octenidine or superoxidized water. Rinsing of the wound should be performed with 3-9 L and only slight manual pressure (no jet lavage). The definitive primary closure of a wound should be achieved in the initial operation, but only in the case of certain "decontamination" and overall vitality of the wound (GA I and II). In the presence of high-grade injuries, a temporary vacuum sealing technique can be used until the earliest possible definitive plastic surgical wound closure. PMID:27160730

  16. Heart Failure and Mitochondrial Dysfunction: The Role of Mitochondrial Fission/Fusion Abnormalities and New Therapeutic Strategies

    PubMed Central

    Knowlton, A. A.; Chen, Le; Malik, Zulfiqar A.

    2013-01-01

    The treatment of heart failure has evolved during the last thirty years with recognition of neurohormonal activation and the effectiveness of its inhibition in improving quality of life and survival. Over the last twenty years there has been a revolution in the investigation of the mitochondrion with the development of new techniques and the finding that mitochondria are connected in networks and undergo constant division (fission) and fusion, even in cardiac myocytes. This has led to new molecular and cellular discoveries in heart failure, which offer the potential for the development of new molecular-based therapies. Reactive oxygen species (ROS) are an important cause of mitochondrial and cellular injury in heart failure, but there are other abnormalities, such as depressed mitochondrial fusion, that may eventually become targets of at least episodic treatment. The overall need for mitochondrial fission/fusion balance may preclude sustained change in either fission or fusion. In this review we will discuss current heart failure therapy and its impact on the mitochondria. In addition we will review some of the new drug targets under development. There is potential for effective, novel therapies for heart failure to arise from new molecular understanding. PMID:23884159

  17. The Additive Inflammatory In Vivo and In Vitro Effects of IL-7 and TSLP in Arthritis Underscore the Therapeutic Rationale for Dual Blockade

    PubMed Central

    Hillen, Maarten R.; Hartgring, Sarita A. Y.; Willis, Cynthia R.; Radstake, Timothy R. D. J.; Hack, Cornelis E.; Lafeber, Floris P. J. G.; van Roon, Joel A. G

    2015-01-01

    Introduction The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied. Methods Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed. Results Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors. Conclusion TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA. PMID:26110994

  18. Radiation Therapy in the Management of Head-and-Neck Cancer of Unknown Primary Origin: How Does the Addition of Concurrent Chemotherapy Affect the Therapeutic Ratio?

    SciTech Connect

    Chen, Allen M.; Farwell, D. Gregory; Lau, Derick H.; Li Baoqing; Luu, Quang; Donald, Paul J.

    2011-10-01

    Purpose: To determine how the addition of cisplatin-based concurrent chemotherapy to radiation therapy influences outcomes among a cohort of patients treated for head-and-neck cancer of unknown primary origin. Methods and Materials: The medical records of 60 consecutive patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Thirty-two patients (53%) were treated by concurrent chemoradiation, and 28 patients (47%) were treated by radiation therapy alone. Forty-five patients (75%) received radiation therapy after surgical resection, and 15 patients (25%) received primary radiation therapy. Thirty-five patients (58%) were treated by intensity-modulated radiotherapy. Results: The 2-year estimates of overall survival, local-regional control, and progression-free survival were 89%, 89%, and 79%, respectively, among patients treated by chemoradiation, compared to 90%, 92%, and 83%, respectively, among patients treated by radiation therapy alone (p > 0.05, for all). Exploratory analysis failed to identify any subset of patients who benefited from the addition of concurrent chemotherapy to radiation therapy. The use of concurrent chemotherapy was associated with a significantly increased incidence of Grade 3+ acute and late toxicity (p < 0.001, for both). Conclusions: Concurrent chemoradiation is associated with significant toxicity without a clear advantage to overall survival, local-regional control, and progression-free survival in the treatment of head-and-neck cancer of unknown primary origin. Although selection bias cannot be ignored, prospective data are needed to further address this question.

  19. In vivo cartilage regeneration induced by a double-network hydrogel: Evaluation of a novel therapeutic strategy for femoral articular cartilage defects in a sheep model.

    PubMed

    Kitamura, Nobuto; Yokota, Masashi; Kurokawa, Takayuki; Gong, Jian Ping; Yasuda, Kazunori

    2016-09-01

    The purpose of this study was to establish the efficacy of a therapeutic strategy for an articular cartilage defect using a poly-(2-acrylamido-2-methylpropanesulfonic acid)/poly-(N,N'-dimethyl acrylamide) DN gel in a sheep model. Seventeen mature sheep were used in this study. We created a 6.0-mm osteochondral defect in the femoral trochlea of the patellofemoral (PF) joint and the medial condyle of the tibiofemoral (TF) joint. A cylindrical DN gel plug was implanted into the defect of the right knee so that a vacant space of the planned depths of 2.0 mm in group I, 3.0 mm in group II, and 4.0 mm in group III were left. In the left knee, we created a defect with the same depth as the right knee. The regenerated tissues were evaluated with the O'Driscoll score and real-time PCR analysis of the cartilage marker genes at 12 weeks. The DN gel implanted defect of group II in the PF and TF joints was completely filled with a sufficient volume of the proteoglycan-rich tissue stained with Safranin-O. The score showed that group II was significantly greater than groups I and III when treated with DN gel in the PF joint (p = 0.0441, p = 0.0174, respectively) and in the TF joint (p = 0.0019, p = 0.0006, respectively). This study has clarified the short-term efficacy of the cartilage regeneration strategy using the DN gel in a sheep model. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2159-2165, 2016. PMID:27087198

  20. Therapeutic Strategies for Patients With Metastatic Renal Cell Carcinoma in Whom First-Line Vascular Endothelial Growth Factor Receptor-Directed Therapies Fail.

    PubMed

    Malouf, Gabriel G; Flippot, Ronan; Khayat, David

    2016-05-01

    Metastases are present in one third of renal cell carcinomas at diagnosis. The overall survival duration in metastatic renal cell carcinoma is approximately 22 months, which underlines the need for more effective systemic treatments. Therapies on the basis of antiangiogenic agents and inhibitors of the mammalian target of rapamycin have been approved for treatment of metastatic renal cell carcinoma, but only benefits for progression-free survival were demonstrated in the second-line setting. Fortunately, promising treatments are emerging, from new antiangiogenic agents to immune checkpoint inhibitors. For the first time, both an immune checkpoint inhibitor (nivolumab) and a dual inhibitor of the tyrosine kinases c-Met and vascular endothelial growth factor receptor-2 (cabozantinib) have demonstrated improvements in overall survival in the second-line setting. Finding the best sequence for these novel agents will be crucial to improving outcomes in patients with metastatic renal cell carcinoma. This article comprises both a systematic review of the literature and recommendations for second-line therapeutic strategies for patients with metastatic clear cell renal cell carcinoma in whom inhibitors of vascular endothelial growth factor have failed. PMID:27170687

  1. Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision-like Proteins?

    PubMed

    Talman, Virpi; Pascale, Alessia; Jäntti, Maria; Amadio, Marialaura; Tuominen, Raimo K

    2016-08-01

    Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterized by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the embryonic lethal abnormal vision (ELAV)-like RNA-binding proteins that modulate the stability and the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD. PMID:27001133

  2. Therapeutic strategies for allergic diseases

    NASA Astrophysics Data System (ADS)

    Barnes, Peter J.

    1999-11-01

    Many drugs are now in development for the treatment of atopic diseases, including asthma, allergic rhinitis and atopic dermatitis. These treatments are based on improvements in existing therapies or on a better understanding of the cellular and molecular mechanisms involved in atopic diseases. Although most attention has been focused on asthma, treatments that inhibit the atopic disease process would have application to all atopic diseases, as they often coincide. Most of the many new therapies in development are aimed at inhibiting components of the allergic inflammatory response, but in the future there are real possibilities for the development of preventative and even curative treatments.

  3. Therapeutic strategies for autoimmune hepatitis.

    PubMed

    Manns, Michael P; Strassburg, Christian P

    2011-01-01

    Autoimmune hepatitis (AIH) is a disease of unknown etiology. However, a loss of tolerance against the patient's own liver is regarded as the main pathogenetic mechanism. Immunosuppressive therapy prolongs survival in patients with severe AIH. Two phases of therapy have to be distinguished. In newly diagnosed AIH, induction of remission is the main goal. Here predniso(lo)ne alone or in combination with azathioprine has been shown to induce remission in the majority of patients. In the past, reduction of aminotransferase levels below two times the upper limit of normal was the aim of therapy. Nowadays, normalization of aminotransferase levels should be achieved. The majority of patients usually respond to therapy within 6-12 months. A significant reduction in aminotransferase levels is achieved within a few weeks of therapy. Improvement in clinical symptoms is followed by improvement in biochemical parameters of disease activity and then by significant improvement in histological disease activity. Around 20-40% of patients do not achieve remission. In these patients, alternative therapies should be evaluated for the individual patient. Prospective controlled trials with a larger number of patients are missing in this population. At the moment, mycophenolate mofetil at a dose of 2 × 1 g daily, either given alone or in combination with predniso(lo)ne, is able to achieve remission in a significant proportion of patients. Based on recent retrospective observations, mycophenolate mofetil is beneficial in patients who were previously azathioprine intolerant rather than azathioprine failure patients. Again, prospective trials are missing. Alternative drugs include cyclophosphamide, cyclosporin A, tacrolimus and others. Women in particular suffer from steroid-specific side effects, including weight gain, moon face, diabetes, glaucoma and bone disease. Recently, a topical steroid, budesonide, was shown to induce disease remission in combination with azathioprine. The second phase of therapy is maintenance of remission with the lowest possible dose in order to maintain remission while preventing significant side effects. Careful evaluation of the individual patients should lead to the decision whether predniso(lo)ne, budesonide, azathioprine or a combination of one of the steroids with azathioprine is to be used to maintain remission. Recently, a study has shown that after 6 months of induction therapy with prednisone plus azathioprine, a switch to budesonide in combination with azathioprine reduced steroid-specific side effects while maintaining remission of liver disease. Therefore, the application of the topical steroids may be helpful in maintaining remission while reducing steroid-specific side effects. Patients with liver cirrhosis should not be treated with budesonide since the benefit of budesonide with its 90% pass effect in the liver is lost if the patient has already developed portal hypertension with significant portosystemic shunting. Furthermore, there are safety concerns regarding budesonide use in cirrhotic patients derived from studies in primary biliary cirrhosis. If the diagnosis is correct and the appropriate therapy is chosen, liver transplantation should be avoidable in patients with AIH. PMID:21894012

  4. Examination of nanoformulated crosslinked polymers complexed with copper/zinc superoxide dismutase as a therapeutic strategy for angiotensin II-mediated hypertension

    NASA Astrophysics Data System (ADS)

    Savalia, Krupa

    . While these physiologic data are promising, it was essential to determine the biological distribution of our nanozymes. The experimental data provided herein implicate the proximal tubules in the kidney cortex as a primary target for CuZnSOD nanozyme following IV administration. Collectively, these studies support the further development of PLL50 -PEG CuZnSOD nanozyme as an antioxidant-based therapeutic option for the improved treatment of hypertension. Furthermore, the therapeutic impact of CuZnSOD nanozyme could be investigated in additional pathologies in which there are excessive levels of O2·- present in the kidney.

  5. Enhanced production of recombinant Escherichia coli glutamate decarboxylase through optimization of induction strategy and addition of pyridoxine.

    PubMed

    Su, Lingqia; Huang, Yan; Wu, Jing

    2015-12-01

    This report describes the optimization of recombinant Escherichia coli glutamate decarboxylase (GAD) production from engineered E. coli BL21(DE3) in a 3-L fermentor. Investigation of different induction strategies revealed that induction was optimal when the temperature was maintained at 30°C, the inducer (lactose) was fed at a rate of 0.2 g L(-1)h(-1), and protein expression was induced when the cell density (OD600) reached 50. Under these conditions, the GAD activity of 1273.8 U mL(-1) was achieved. Because GAD is a pyridoxal 5'-phosphate (PLP)-dependent enzyme, the effect of supplementing the medium with pyridoxine hydrochloride (PN), a cheap and stable PLP precursor, on GAD production was also investigated. When the culture medium was supplemented with PN to a concentration of 2mM at the initiation of protein expression, and then again 10h later, the GAD activity reached 3193.4 U mL(-1), which represented the highest GAD production ever reported. PMID:26364229

  6. [Additional administration of dutasteride in patients with benign prostatic hyperplasia who did not respond sufficiently to α1-adrenoceptor antagonist : investigation of clinical factors affecting the therapeutic effect of dutasteride].

    PubMed

    Masuda, Mitsunobu; Murai, Tetsuo; Osada, Yutaka; Kawai, Masaki; Kasuga, Jun; Yokomizo, Yumiko; Kuroda, Shinnosuke; Nakamura, Mami; Noguchi, Go

    2014-02-01

    We performed additional administration of dutasteride in patients who did not respond sufficiently to α1-adrenoceptor antagonist treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) (LUTS/BPH). Among 76 registered patients, efficacy was analyzed in 58 patients. International Prostate Symptom Score (IPSS), subscores for voiding and storage symptoms and quality of life (QOL) on the IPSS, and Overactive Bladder Symptom Score (OABSS) were all significantly improved from the third month of administration compared to the time of initiating additional administration of dutasteride. Additional administration of dutasteride also significantly reduced prostate volume, and residual urine with the exception of the sixth month after administration. Age at initiation of administration and voiding symptom subscore on the IPSS were clinical factors affecting the therapeutic effects of dutasteride. The rate of improvement with treatment decreased with increasing age at initiation of dutasteride administration, and increased as voiding symptom subscore on the IPSS increased. Therefore, additional administration of dutasteride appears useful for cases of LUTS/BPH in which a sufficient response is not achieved with α1-adrenoceptor antagonist treatment. Because patients who have severe voiding symptoms or begin dutasteride at an early age may be expected to respond particularly well to dutasteride in terms of clinical efficacy, they were considered to be suitable targets for additional administration. PMID:24755815

  7. Blockage of Src by Specific siRNA as a Novel Therapeutic Strategy to Prevent Destructive Repair in Steroid-Associated Osteonecrosis in Rabbits.

    PubMed

    Zheng, Li-zhen; Cao, Hui-juan; Chen, Shi-hui; Tang, Tao; Fu, Wei-min; Huang, Le; Chow, Dick Ho Kiu; Wang, Yi-xiang; Griffith, James Francis; He, Wei; Zhou, Hong; Zhao, De-wei; Zhang, Ge; Wang, Xin-luan; Qin, Ling

    2015-11-01

    Vascular hyperpermeability and highly upregulated bone resorption in the destructive repair progress of steroid-associated osteonecrosis (SAON) are associated with a high expression of VEGF and high Src activity (Src is encoded by the cellular sarcoma [c-src] gene). This study was designed to prove our hypothesis that blocking the VEGF-Src signaling pathway by specific Src siRNA is able to prevent destructive repair in a SAON rabbit model. Destructive repair in SAON was induced in rabbits. At 2, 4, and 6 weeks after SAON induction, VEGF, anti-VEGF, Src siRNA, Src siRNA+VEGF, control siRNA, and saline were introduced via intramedullary injection into proximal femora for each group, respectively. Vascularization and permeability were quantified by dynamic contrast-enhanced (DCE) MRI. At week 6 after SAON induction, proximal femurs were dissected for micro-computed tomography (μCT)-based trabecular architecture with finite element analysis (FEA), μCT-based angiography, and histological analysis. Histological evaluation revealed that VEGF enhanced destructive repair, whereas anti-VEGF prevented destructive repair and Src siRNA and Src siRNA+VEGF prevented destructive repair and enhanced reparative osteogenesis. Findings of angiography and histomorphometry were consistent with those determined by DCE MRI. Src siRNA inhibited VEGF-mediated vascular hyperpermeability but preserved VEGF-induced neovascularization. Bone resorption was enhanced in the VEGF group and inhibited in the anti-VEGF, Src siRNA, Src siRNA+VEGF groups as determined by both 3D μCT and 2D histomorphometry. FEA showed higher estimated failure load in the Src siRNA and Src siRNA+VEGF groups when compared to the vehicle control group. Blockage of VEGF-Src signaling pathway by specific Src siRNA was able to prevent steroid-associated destructive repair while improving reconstructive repair in SAON, which might become a novel therapeutic strategy. PMID:25917347

  8. MiR675-5p Acts on HIF-1α to Sustain Hypoxic Responses: A New Therapeutic Strategy for Glioma

    PubMed Central

    Lo Dico, Alessia; Costa, Viviana; Martelli, Cristina; Diceglie, Cecilia; Rajata, Francesca; Rizzo, Aroldo; Mancone, Carmine; Tripodi, Marco; Ottobrini, Luisa; Alessandro, Riccardo; Conigliaro, Alice

    2016-01-01

    Hypoxia is a common feature in solid tumours. In glioma, it is considered the major driving force for tumour angiogenesis and correlates with enhanced resistance to conventional therapies, increased invasiveness and a poor prognosis for patients. Here we describe, for the first time, that miR675-5p, embedded in hypoxia-induced long non-coding RNA H19, plays a mandatory role in establishing a hypoxic response and in promoting hypoxia-mediated angiogenesis. We demonstrated, in vitro and in vivo, that miR675-5p over expression in normoxia is sufficient to induce a hypoxic moreover, miR675-5p depletion in low oxygen conditions, drastically abolishes hypoxic responses including angiogenesis. In addition, our data indicate an interaction of miR675-5p, HIF-1α mRNA and the RNA Binding Protein HuR in hypoxia-induced responses. We suggest the modulation of miR675-5p as a new therapeutic option to promote or abolish hypoxia induced angiogenesis. PMID:27279905

  9. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

    PubMed

    Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

    2016-09-01

    Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function. PMID:27288727

  10. Recent Progress in Nanomedicine: Therapeutic, Diagnostic and Theranostic Applications

    PubMed Central

    Rizzo, Larissa Y.; Theek, Benjamin; Storm, Gert; Kiessling, Fabian; Lammers, Twan

    2013-01-01

    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-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions. PMID:23578464

  11. Effects of nutrient and lime additions in mine site rehabilitation strategies on the accumulation of antimony and arsenic by native Australian plants.

    PubMed

    Wilson, Susan C; Leech, Calvin D; Butler, Leo; Lisle, Leanne; Ashley, Paul M; Lockwood, Peter V

    2013-10-15

    The effects of nutrient and lime additions on antimony (Sb) and arsenic (As) accumulation by native Australian and naturalised plants growing in two contaminated mine site soils (2,735 mg kg(-1) and 4,517 mg kg(-1) Sb; 826 mg kg(-1) and 1606 As mgkg(-1)) was investigated using a glasshouse pot experiment. The results indicated an increase in soil solution concentrations with nutrient addition in both soils and also with nutrient+lime addition for Sb in one soil. Metalloid concentrations in plant roots were significantly greater than concentrations in above ground plant parts. The metalloid transfer to above ground plant parts from the roots and from the soil was, however, low (ratio of leaf concentration/soil concentration≪1) for all species studied. Eucalyptus michaeliana was the most successful at colonisation with lowest metalloid transfer to above ground plant parts. Addition of nutrients and nutrients+lime to soils, in general, increased plant metalloid accumulation. Relative As accumulation was greater than that of Sb. All the plant species studied were suitable for consideration in the mine soil phytostabilisation strategies but lime additions should be limited and longer term trials also recommended. PMID:23433572

  12. New Therapeutic Approaches for Advanced Gastrointestinal Stromal Tumors (GISTs)

    PubMed Central

    Somaiah, Neeta

    2010-01-01

    Synopsis The management of advanced GIST is increasingly complex due to imatinib refractory disease. Primary resistance to imatinib is uncommon, and most patients progress after development of additional genetic changes. This article reviews management strategies including surgical approaches, local modalities for progressive liver metastases, as well as novel therapeutic agents. PMID:19248977

  13. Independent Contributions of the Central Executive, Intelligence, and In-Class Attentive Behavior to Developmental Change in the Strategies Used to Solve Addition Problems

    PubMed Central

    Geary, David C.; Hoard, Mary K.; Nugent, Lara

    2012-01-01

    Children’s (n = 275) use of retrieval, decomposition (e.g., 7 = 4+3, and thus 6+7=6+4+3), and counting to solve additional problems was longitudinally assessed from first to fourth grade, and intelligence, working memory, and in-class attentive behavior was assessed in one or several grades. The goal was to assess the relation between capacity of the central executive component of working memory, controlling for intelligence and in-class attentive behavior, and grade-related changes in children’s use of these strategies. The predictor on intercept effects from multilevel models revealed that children with higher central executive capacity correctly retrieved more facts and used the most sophisticated counting procedure more frequently and accurately than did their lower capacity peers at the beginning of first grade, but the predictor on slope effects indicated that this advantage disappeared (retrieval) or declined in importance (counting) from first to fourth grade. The predictor on slope effects also revealed that from first through fourth grade, children with higher capacity adopted the decomposition strategy more quickly than did other children. The results remained robust with controls for children’s sex, race, school site, speed of encoding Arabic numerals and articulating number words, and mathematics achievement in kindergarten. The results also revealed that intelligence and in-class attentive behavior independently contributed to children’s strategy development. PMID:22698947

  14. Surface protein imprinted core-shell particles for high selective lysozyme recognition prepared by reversible addition-fragmentation chain transfer strategy.

    PubMed

    Li, Qinran; Yang, Kaiguang; Liang, Yu; Jiang, Bo; Liu, Jianxi; Zhang, Lihua; Liang, Zhen; Zhang, Yukui

    2014-12-24

    A novel kind of lysozyme (Lys) surface imprinted core-shell particles was synthesized by reversible addition-fragmentation chain transfer (RAFT) strategy. With controllable polymer shell chain length, such particles showed obviously improved selectivity for protein recognition. After the RAFT initial agent and template protein was absorbed on silica particles, the prepolymerization solution, with methacrylic acid and 2-hydroxyethyl methacrylate as the monomers, and N,N'-methylenebis(acrylamide) as the cross-linker, was mixed with the silica particles, and the polymerization was performed at 40 °C in aqueous phase through the oxidation-reduction initiation. Ater polymerization, with the template protein removal and destroying dithioester groups with hexylamine, the surface Lyz imprinted particles were obtained with controllable polymer chain length. The binding capacity of the Lys imprinted particles could reach 5.6 mg protein/g material, with the imprinting factor (IF) as 3.7, whereas the IF of the control material prepared without RAFT strategy was only 1.6. The absorption equilibrium could be achieved within 60 min. Moreover, Lys could be selectively recognized by the imprinted particles from both a four-proteins mixture and egg white sample. All these results demonstrated that these particles prepared by RAFT strategy are promising to achieve the protein recognition with high selectivity. PMID:25434676

  15. A New Era of Therapeutic Strategies for Chronic Thromboembolic Pulmonary Hypertension by Two Different Interventional Therapies; Pulmonary Endarterectomy and Percutaneous Transluminal Pulmonary Angioplasty

    PubMed Central

    Ando, Motomi; Fukuda, Keiichi; Yoshino, Hideaki; Satoh, Toru

    2014-01-01

    -based interventional therapies leads us to expect the dawn of a new era of therapeutic strategies for CTEPH. PMID:24728482

  16. Control of Granule Cell Dispersion by Natural Materials Such as Eugenol and Naringin: A Potential Therapeutic Strategy Against Temporal Lobe Epilepsy.

    PubMed

    Kim, Sang Ryong

    2016-08-01

    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. PMID:27404051

  17. Alzheimer's disease & metals: therapeutic opportunities

    PubMed Central

    Kenche, Vijaya B; Barnham, Kevin J

    2011-01-01

    Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called ‘metal protein attenuating compound’ approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD. PMID:21232050

  18. Biomimetic Particles as Therapeutics

    PubMed Central

    Green, Jordan J.

    2015-01-01

    In recent years, there have been major advances in the development of novel nanoparticle and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health. PMID:26277289

  19. Strategy to enhance the therapeutic effect of doxorubicin in human hepatocellular carcinoma by selenocystine, a synergistic agent that regulates the ROS-mediated signaling

    PubMed Central

    Fan, Cundong; Zheng, Wenjie; Fu, Xiaoyan; Li, Xiaoling; Wong, Yum-Shing; Chen, Tianfeng

    2014-01-01

    Doxorubicin-based chemotherapy represents one of the most effective ways in combating human cancers. However, its clinical use is limited by severe side effects. Selenocystine (SeC) is a natural available selenoamino acid with novel anticancer efficacy. In this study, we used SeC to sensitize HepG2 human hepatocellular carcinoma (HCC) cells to DOX, and to achieve anticancer synergism in vitro and in vivo. Treatment with DOX dose-dependently reduced HepG2 cell viability through initiating cell apoptosis and strong G2/M phase cell cycle arrest. Mechanistic studies indicated that this sensitization of SeC to DOX was achieved by triggering inactivation of ERK and AKT and DNA damage through reactive oxygen species (ROS) overproduction. Pretreatment with inhibitors of ERK and AKT markedly enhanced combined treatment-induced cell killing, indicating that combined treatment-induced HCC cell killing with ERK- and AKT-dependent manner. Furthermore, inhibition of ROS effectively attenuated combined treatment-induced DNA damage and inactivation of ERK and AKT. Additionally, xenograft hepatocellular carcinoma growth was also effectively inhibited by combined treatment through induction of cell apoptosis in vivo. Taken together, our results suggest that the strategy to use SeC and DOX in combination could be a highly efficient way to achieve anticancer synergism against HCC. PMID:24797310

  20. Preliminary evaluation of a microwave-assisted metal-labeling strategy for quantification of peptides via RPLC-ICP-MS and the method of standard additions.

    PubMed

    Christopher, Steven J; Kilpatrick, Eric L; Yu, Lee L; Davis, W Clay; Adair, Blakely M

    2012-01-15

    NIST has performed preliminary research on applying a calibration methodology based on the method of standard additions to the quantification of peptides via reverse-phase liquid chromatography coupled to inductively coupled plasma mass spectrometry (RPLC-ICP-MS). A microwave-assisted lanthanide labeling procedure was developed and applied to derivatize peptides using the macrocyclic bifunctional chemical chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), which significantly improved the lanthanide labeling yield and reduced reaction times compared to benchtop labeling procedures. Biomolecular MS technologies of matrix-assisted laser desorption ionization (MALDI)-MS and electrospray ionization (ESI)-MS/MS were used in concert with ICP-MS to confirm the results of microwave labeling, sample cleanup and standard additions experiments for several test peptides. The calibration scheme is outlined in detail and contextualized against complementary high accuracy calibration strategies currently employed for ICP-MS detection of biomolecules. Standard additions experiments using native, non-isotopic peptide calibrants confirm the simplicity of the scheme and the potential of applying a blending (recombined sample and spike) procedure, facilitating calibration via co-elution of lanthanide labeled peptides. Ways to improve and fully leverage the analytical methodology are highlighted. PMID:22265570

  1. DELIVERY OF THERAPEUTIC PROTEINS

    PubMed Central

    Pisal, Dipak S.; Kosloski, Matthew P.; Balu-Iyer, Sathy V.

    2009-01-01

    The safety and efficacy of protein therapeutics are limited by three interrelated pharmaceutical issues, in vitro and in vivo instability, immunogenicity and shorter half-lives. Novel drug modifications for overcoming these issues are under investigation and include covalent attachment of poly(ethylene glycol) (PEG), polysialic acid, or glycolic acid, as well as developing new formulations containing nanoparticulate or colloidal systems (e.g. liposomes, polymeric microspheres, polymeric nanoparticles). Such strategies have the potential to develop as next generation protein therapeutics. This review includes a general discussion on these delivery approaches. PMID:20049941

  2. Evaluation of Relaxin Blood Profiles of Horses as A Means of Assessing Placental Function in High-Risk Pregnancies And Responsiveness to Therapeutic Strategies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Placental insufficiency is regarded as the primary factor contributing to late-term abortion and perinatal death of foals. Often when problems associated with late-term pregnancy in the horse are manifest the condition is well-advanced and therapeutic intervention may not be effective in rescuing th...

  3. Too Much Fun for Therapy: Therapeutic Recreation as an Intervention Tool with At-Risk Youth. A Series of Solutions and Strategies.

    ERIC Educational Resources Information Center

    Brooks, Katherine Walker

    This publication introduces the concept of therapeutic recreation (TR), illustrating its natural fit into the educational process and its use with at-risk students, and providing resources for further use. Section 1 examines what places a child at risk, focusing on educational goals, student behaviors, and home life. Section 2 defines TR as a…

  4. Evaluation of Systemic Relaxin Blood Profiles in Horses as A Means of Assessing Placental Function in High-Risk Pregnancies and Responsiveness to Therapeutic Strategies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Placental insufficiency is regarded as the primary factor contributing to late-term abortion and perinatal death of foals. Often when problems associated with late-term pregnancy in the horse are manifest the condition is well-advanced and therapeutic intervention may not be effective in rescuing th...

  5. Therapeutic cloning: The ethical limits

    SciTech Connect

    Whittaker, Peter A. . E-mail: p.whittaker@lancaster.ac.uk

    2005-09-01

    A brief outline of stem cells, stem cell therapy and therapeutic cloning is given. The position of therapeutic cloning with regard to other embryonic manipulations - IVF-based reproduction, embryonic stem formation from IVF embryos and reproductive cloning - is indicated. The main ethically challenging stages in therapeutic cloning are considered to be the nuclear transfer process including the source of eggs for this and the destruction of an embryo to provide stem cells for therapeutic use. The extremely polarised nature of the debate regarding the status of an early human embryo is noted, and some potential alternative strategies for preparing immunocompatible pluripotent stem cells are indicated.

  6. MACROMOLECULAR THERAPEUTICS

    PubMed Central

    Yang, Jiyuan; Kopeček, Jindřich

    2014-01-01

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

  7. A new strategy for co-composting dairy manure with rice straw: Addition of different inocula at three stages of composting.

    PubMed

    Zhou, Cheng; Liu, Zhang; Huang, Zhao-Lin; Dong, Ming; Yu, Xiao-Long; Ning, Ping

    2015-06-01

    In considering the impact of inoculation time and the characteristics of composting material and inoculants on the usefulness of inoculation, a new composting strategy has been proposed and studied, in which three inocula were inoculated at three stages of composting process respectively: inoculum A (Thermoactinomyces sp. GF1 and GF2) was inoculated before fermentation to increase or maintain high temperature of pile, inoculum B (Coprinus cinerea and Coprinus comatus) was inoculated after thermophilic phase to promote degradation of lignin, and inoculum C (Trichoderma harzianum and Rhizopus oryzae) was inoculated after 30-day fermentation to promote degradation of cellulose. The results showed that the inoculations could significantly enhance the temperature of pile and the degradation of lignocelluloses. When inocula A, B, and C were inoculated into pile, temperature increased from 25°C to 65°C, from 33°C to 39°C and from 33°C to 38°C respectively and 35% lignin and 43% cellulose had been degraded in inoculated pile compared to the degradation of 15% lignin and 25% cellulose in control pile. As a result, the C/N ratio dropped more rapidly degraded in the inoculated pile (reached 20 after 33-day fermentation) than that in the control pile (reached 21.7 after 45-day fermentation). In addition, the volume loss in inoculated pile (76.5%) was higher than that in control pile (53.2%). The study, therefore, indicated that inoculating proper microorganisms at appropriate time improved the composting process and our new composting strategy would be propitious to the co-composting dairy manure with rice straw. PMID:25837785

  8. Homocystinuria: Therapeutic approach.

    PubMed

    Kumar, Tarun; Sharma, Gurumayum Suraj; Singh, Laishram Rajendrakumar

    2016-07-01

    Homocystinuria is a disorder of sulfur metabolism pathway caused by deficiency of cystathionine β-synthase (CBS). It is characterized by increased accumulation of homocysteine (Hcy) in the cells and plasma. Increased homocysteine results in various vascular and neurological complications. Present strategies to lower cellular and plasma homocysteine levels include vitamin B6 intake, dietary methionine restriction, betaine supplementation, folate and vitamin B12 administration. However, these strategies are inefficient for treatment of homocystinuria. In recent years, advances have been made towards developing new strategies to treat homocystinuria. These mainly include functional restoration to mutant CBS, enhanced clearance of Hcy from the body, prevention of N-homocysteinylation-induced toxicity and inhibition of homocysteine-induced oxidative stress. In this review, we have exclusively discussed the recent advances that have been achieved towards the treatment of homocystinuria. The review is an attempt to help clinicians in developing effective therapeutic strategies and designing novel drugs against homocystinuria. PMID:27059523

  9. A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation

    PubMed Central

    Estcourt, Lise J; Crighton, Gemma L; Wood, Erica M; Stanworth, Simon; Trivella, Marialena; Doree, Carolyn; Tinmouth, Alan; Murphy, Michael F

    2014-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether a therapeutic-only platelet transfusion policy (platelet transfusions given when patient bleeds) is as effective and safe as a prophylactic platelet transfusion policy (platelet transfusions given to prevent bleeding usually when the platelet count falls below a given trigger level) in patients with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation. PMID:25722649

  10. Pigeon therapeutics.

    PubMed

    Harlin, R W

    2000-01-01

    This article examines therapeutics for pigeons, discussing their physiology and reproduction, housing, and nutrition. The author also looks at ways to prevent infection, while discussing treatments for various viral diseases, such as paramyxovirus and pigeon herpesvirus, bacterial infections, such as paratyphoid, and parasitic diseases. Drug dosages are listed for antibiotics, antifungals, antiparasitics, and vaccines. PMID:11228828

  11. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

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

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

  12. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

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

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

  13. Feedlot therapeutics.

    PubMed

    Apley, M D; Fajt, V R

    1998-07-01

    This article discusses therapeutic approaches to conditions commonly encountered in feedlots. Challenges discussed include bovine respiratory complex, tracheal edema, atypical interstitial pneumonia, footrot, toe abscesses, mycoplasma arthritis, cardiovascular disease, lactic acidosis, bloat, coccidiosis, central nervous system diseases, abscesses and cellulitis, pregnancy management and abortion, and ocular disease. PMID:9704416

  14. gp130 receptor ligands as potential therapeutic targets for obesity

    PubMed Central

    Febbraio, Mark A.

    2007-01-01

    Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world’s population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity. PMID:17404609

  15. [Multiple sclerosis: potential therapeutic options and update of ongoing studies].

    PubMed

    Wiendl, H; Lehmann, H C; Hohlfeld, R; Hartung, H-P; Kieseier, B C

    2004-06-01

    The therapeutic options for the treatment of multiple sclerosis (MS) have experienced enormous progress over recent years. Despite these encouraging developments, available therapies are only partially effective, and the ultimate goal of curing MS is still far from being attained. The improved understanding of the cellular and molecular mechanisms of MS (immune) pathogenesis together with recent shifts in paradigms led to a variety of new therapeutic targets and approaches. In addition to modulation of the inflammatory process, therapeutic approaches focussing on active neuroprotection, remyelinization, and regeneration have become increasingly important. Based on current concepts of the MS pathogenesis, this article summarizes new therapeutic approaches. Substances and strategies currently tested in clinical trials are reviewed. PMID:15257377

  16. Synthesis of magnetic molecularly imprinted polymers by reversible addition fragmentation chain transfer strategy and its application in the Sudan dyes residue analysis.

    PubMed

    Xie, Xiaoyu; Chen, Liang; Pan, Xiaoyan; Wang, Sicen

    2015-07-31

    Magnetic molecularly imprinted polymers (MMIPs) have become a hotspot owing to the dual functions of target recognition and magnetic separation. In this study, the MMIPs were obtained by the surface-initiated reversible addition fragmentation chain transfer (RAFT) polymerization using Sudan I as the template. The resultant MMIPs were characterized by transmission electron microscope, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, vibrating sample magnetometer, and X-ray diffraction. Benefiting from the controlled/living property of the RAFT strategy, the uniform MIP layer was successfully grafted on the surface of RAFT agent-modified Fe3O4@SiO2 nanoparticles, favoring the fast mass transfer and rapid binding kinetics. The developed MMIPs were used as the solid-phase extraction sorbents to selectively extract four Sudan dyes (Sudan I, II, III, and IV) from chili powder samples. The recoveries of the spiked samples in chili powder samples ranged from 74.1 to 93.3% with RSD lower than 6.4% and the relative standard uncertainty lower than 0.029. This work provided a good platform for the extraction and removal of Sudan dyes in complicated matrixes and demonstrated a bright future for the application of the well-constructed MMIPs in the field of solid-phase extraction. PMID:26077971

  17. Therapeutic Strategies for Human IgM Antibodies Directed at Tumor-Associated Ganglioside Antigens: Discoveries Made During the Morton Era and Future Directions.

    PubMed

    Jones, Peter C; Irie, Reiko F

    2016-01-01

    Tumor-associated gangliosides have been investigated for their potential as antigenic targets for more than 35 years, culminating in the recent Food and Drug Administration approval of dinutuximab (Unituxin), an IgG antibody targeted against GD2, for the treatment of neuroblastoma in children. This review is focused on discoveries and development of therapeutic approaches involving human IgM antibodies directed against gangliosides, which occurred over the past 40 years at University of California-Los Angeles and the John Wayne Cancer Institute, where Dr. Donald Morton led the surgical oncology department until his death. PMID:27481004

  18. Therapeutic Strategy for the Prevention of Pseudorabies Virus Infection in C57BL/6 Mice by 3D8 scFv with Intrinsic Nuclease Activity

    PubMed Central

    Lee, Gunsup; Cho, SeungChan; Hoang, Phuong Mai; Kim, Dongjun; Lee, Yongjun; Kil, Eui-Joon; Byun, Sung-June; Lee, Taek-Kyun; Kim, Dae-Hyun; Kim, Sunghan; Lee, Sukchan

    2015-01-01

    3D8 single chain variable fragment (scFv) is a recombinant monoclonal antibody with nuclease activity that was originally isolated from autoimmune-prone MRL mice. In a previous study, we analyzed the nuclease activity of 3D8 scFv and determined that a HeLa cell line expressing 3D8 scFv conferred resistance to herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV). In this study, we demonstrate that 3D8 scFv could be delivered to target tissues and cells where it exerted a therapeutic effect against PRV. PRV was inoculated via intramuscular injection, and 3D8 scFv was injected intraperitoneally. The observed therapeutic effect of 3D8 scFv against PRV was also supported by results from quantitative reverse transcription polymerase chain reaction, southern hybridization, and immunohistochemical assays. Intraperitoneal injection of 5 and 10 μg 3D8 scFv resulted in no detectable toxicity. The survival rate in C57BL/6 mice was 9% after intramuscular injection of 10 LD50 PRV. In contrast, the 3D8 scFv-injected C57BL/6 mice showed survival rates of 57% (5 μg) and 47% (10 μg). The results indicate that 3D8 scFv could be utilized as an effective antiviral agent in several animal models. PMID:26255831

  19. The transcorneal electrical stimulation as a novel therapeutic strategy against retinal and optic neuropathy: a review of experimental and clinical trials

    PubMed Central

    Tao, Ye; Chen, Tao; Liu, Bei; Wang, Li-Qiang; Peng, Guang-Hua; Qin, Li-Min; Yan, Zhong-Jun; Huang, Yi-Fei

    2016-01-01

    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. PMID:27366697

  20. The transcorneal electrical stimulation as a novel therapeutic strategy against retinal and optic neuropathy: a review of experimental and clinical trials.

    PubMed

    Tao, Ye; Chen, Tao; Liu, Bei; Wang, Li-Qiang; Peng, Guang-Hua; Qin, Li-Min; Yan, Zhong-Jun; Huang, Yi-Fei

    2016-01-01

    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 mecha