WorldWideScience

Sample records for therapeutic strategies underpinning

  1. [Hepatitis C infection: Therapeutic strategies].

    Science.gov (United States)

    Diatta, Thierno; Chavade, Delphine; Degos, Françoise; d'Andon, Anne; Guillevin, Loïc

    2016-05-01

    The development of new direct acting antivirals has significantly modified strategies to treat chronic hepatitis C. Treatments were previously made of an interferon-based combination. This article aims to review the direct acting antivirals clinical data and to discuss the new regimens for the management of chronic hepatitis C. Direct acting antivirals combinations - with or without ribavirin - are the new chronic hepatitis C standard treatment regimen. These combinations often result in sustained viral response rate (>90%, including in patients with uncomplicated cirrhosis) after a 12-week treatment for most patients. The innovation could represent a new era for patients with unmet medical need (especially ineligible or non-responders to interferon and/or ribavirin patients). Further investigations are required to confirm the efficacy in specific population (complicated cirrhosis, pre- or post-transplantation, chronic renal failure, comorbidities, etc.) where clinical data are still limited. Other treatments are currently being developed and might lead to new perspectives, especially in terms of treatment duration or therapeutic simplification. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Therapeutic strategies in pulmonary hypertension

    Directory of Open Access Journals (Sweden)

    Leonello eFuso

    2011-04-01

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

  3. Therapeutic Strategies in Pulmonary Hypertension

    Science.gov (United States)

    Fuso, Leonello; Baldi, Fabiana; Perna, Alessandra Di

    2011-01-01

    Pulmonary hypertension (PH) is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH) whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an “ideal” therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal-oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators. PMID:21687513

  4. Mining EEG with SVM for Understanding Cognitive Underpinnings of Math Problem Solving Strategies

    Directory of Open Access Journals (Sweden)

    Paul Bosch

    2018-01-01

    Full Text Available We have developed a new methodology for examining and extracting patterns from brain electric activity by using data mining and machine learning techniques. Data was collected from experiments focused on the study of cognitive processes that might evoke different specific strategies in the resolution of math problems. A binary classification problem was constructed using correlations and phase synchronization between different electroencephalographic channels as characteristics and, as labels or classes, the math performances of individuals participating in specially designed experiments. The proposed methodology is based on using well-established procedures of feature selection, which were used to determine a suitable brain functional network size related to math problem solving strategies and also to discover the most relevant links in this network without including noisy connections or excluding significant connections.

  5. [Therapeutic strategies for systemic lupus erythematosus].

    Science.gov (United States)

    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.

  6. [Hodgkin lymphoma: Current and future therapeutic strategies].

    Science.gov (United States)

    Turpin, Anthony; Michot, Jean-Marie; Kempf, Emmanuelle; Mazeron, Renaud; Dartigues, Peggy; Terroir, Marie; Boros, Angela; Bonnetier, Serge; Castilla-Llorente, Cristina; Coman, Tereza; Danu, Alina; Ghez, David; Pilorge, Sylvain; Arfi-Rouche, Julia; Dercle, Laurent; Soria, Jean-Charles; Carde, Patrice; Ribrag, Vincent; Fermé, Christophe; Lazarovici, Julien

    2018-01-01

    Hodgkin lymphoma (HL) is a cancer that mostly affects young people, in which modern therapeutic strategies using chemotherapy and radiotherapy result in a cure rate exceeding 80%. Survivors are exposed to long-term consequences of treatments, such as secondary malignancies and cardiovascular diseases, whose mortality exceeds the one of the disease itself, with long-term follow-up. The current therapeutic strategy in HL, based on the assessment of initial risk factors, is the result of large clinical trials led by the main international cooperating groups. More recently, several groups have tried to develop treatment strategies adapted to the response to chemotherapy, evaluated by interim PET/CT scan. However to date, the combined treatment with chemotherapy followed by radiation therapy remains a standard in most of the above-diaphragmatic localized forms. Immune checkpoint inhibitors, and especially anti-PD1 antibodies, have shown dramatic results in some serious forms of relapsed or refractory HL, with limited toxicity, and may contribute in the future to reduce the toxicities of treatments. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  7. Creutzfeldt-Jakob disease: therapeutic strategies.

    Science.gov (United States)

    Beringue, V; Deslys, J P; Adjou, K T; Dormont, D

    1997-04-01

    Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative illness which belongs to the group of transmissible subacute spongiform encephalopathies (TSSE). Today, no treatment is available for TSSE. The appearance of a new variant of CJD, which affects young people and could be linked to so-called ;mad cow disease', has stimulated researchers to develop new therapies against CJD. A few drugs have already been shown to delay the onset of experimental TSSE. They could contribute to the understanding of the pathogenic mechanisms involved in TSSE and, therefore, could be the basis for therapeutic strategies against CJD.

  8. Mustard Gas Inhalation Injury: Therapeutic Strategy.

    Science.gov (United States)

    Keyser, Brian M; Andres, Devon K; Holmes, Wesley W; Paradiso, Danielle; Appell, Ashley; Letukas, Valerie A; Benton, Betty; Clark, Offie E; Gao, Xiugong; Ray, Prabhati; Anderson, Dana R; Ray, Radharaman

    2014-07-01

    Mustard gas (sulfur mustard [SM], bis-[2-chloroethyl] sulfide) is a vesicating chemical warfare agent and a potential chemical terrorism agent. Exposure of SM causes debilitating skin blisters (vesication) and injury to the eyes and the respiratory tract; of these, the respiratory injury, if severe, may even be fatal. Therefore, developing an effective therapeutic strategy to protect against SM-induced respiratory injury is an urgent priority of not only the US military but also the civilian antiterrorism agencies, for example, the Homeland Security. Toward developing a respiratory medical countermeasure for SM, four different classes of therapeutic compounds have been evaluated in the past: anti-inflammatory compounds, antioxidants, protease inhibitors and antiapoptotic compounds. This review examines all of these different options; however, it suggests that preventing cell death by inhibiting apoptosis seems to be a compelling strategy but possibly dependent on adjunct therapies using the other drugs, that is, anti-inflammatory, antioxidant, and protease inhibitor compounds. © The Author(s) 2014.

  9. The effects of explicit teaching of strategies, second-order concepts, and epistemological underpinnings on students’ ability to reason causally in history

    NARCIS (Netherlands)

    Stoel, G.L.; van Drie, J.P.; van Boxtel, C.A.M.

    This article reports an experimental study on the effects of explicit teaching on 11th grade students’ ability to reason causally in history. Underpinned by the model of domain learning, explicit teaching is conceptualized as multidimensional, focusing on strategies and second-order concepts to

  10. Colorectal cancer: diagnostic and therapeutic strategies

    International Nuclear Information System (INIS)

    Vaillant, J.C.

    1996-01-01

    Technical advances that has been achieved during the past two decades have not dramatically improved the 35 % five-year rate observed in patients with colorectal cancer. These tumours remain one of the most challenging problems in public health policies in western countries. Screening applies to some subgroups of high-risk individuals and the general population aged over 50. In order to improve their efficacy, such screening programs imply large-scale information campaigns and a strong cooperation with the general physicians. The diagnosis is strongly suggested by any recent modification of bowel habits ad by rectal bleeding. It has to be confirmed by rectal examination and by colonoscopy which allows sampling to the tumour. Loco-regional and distant metastatic tumour spread must be assessed precisely before any therapeutic strategy is decided. Surgery, which resects the tumour en bloc with the corresponding lymphatic territories, is the only treatment that can achieve long term cure. In localized tumours, surgery alone can provide patients with 5-years survival rates close to 95 %. On the other hand, surgery alone is not sufficient to cure patients with advances cancers. In recent years, several adjuvant therapeutic modalities have been shown to improve the results of surgery in these cases (rectal cancer: pre-operative radiotherapy or post-operative radio-chemotherapy, colon cancer with nodal metastases: post-operative chemotherapy). There is a hope that a better use of our diagnostic and therapeutic armementarium would be able to avoid or to cure up to 75 % of the colorectal cancers we are dealing with. (author)

  11. Hydrogels for central nervous system therapeutic strategies.

    Science.gov (United States)

    Russo, Teresa; Tunesi, Marta; Giordano, Carmen; Gloria, Antonio; Ambrosio, Luigi

    2015-12-01

    The central nervous system shows a limited regenerative capacity, and injuries or diseases, such as those in the spinal, brain and retina, are a great problem since current therapies seem to be unable to achieve good results in terms of significant functional recovery. Different promising therapies have been suggested, the aim being to restore at least some of the lost functions. The current review deals with the use of hydrogels in developing advanced devices for central nervous system therapeutic strategies. Several approaches, involving cell-based therapy, delivery of bioactive molecules and nanoparticle-based drug delivery, will be first reviewed. Finally, some examples of injectable hydrogels for the delivery of bioactive molecules in central nervous system will be reported, and the key features as well as the basic principles in designing multifunctional devices will be described. © IMechE 2015.

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

    Science.gov (United States)

    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

  13. [Therapeutic strategies in the first psychotic episode].

    Science.gov (United States)

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

    1999-11-01

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

  14. The therapeutic strategies against Naegleria fowleri.

    Science.gov (United States)

    Bellini, Natália Karla; Santos, Thomás Michelena; da Silva, Marco Túlio Alves; Thiemann, Otavio Henrique

    2018-04-01

    Naegleria fowleri is a pathogenic amoeboflagellate most prominently known for its role as the etiological agent of the Primary Amoebic Meningoencephalitis (PAM), a disease that afflicts the central nervous system and is fatal in more than 95% of the reported cases. Although being fatal and with potential risks for an increase in the occurrence of the pathogen in populated areas, the organism receives little public health attention. A great underestimation in the number of PAM cases reported is assumed, taking into account the difficulty in obtaining an accurate diagnosis. In this review, we summarize different techniques and methods used in the identification of the protozoan in clinical and environmental samples. Since it remains unclear whether the protozoan infection can be successfully treated with the currently available drugs, we proceed to discuss the current PAM therapeutic strategies and its effectiveness. Finally, novel compounds for potential treatments are discussed as well as research on vaccine development against PAM. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Sterile Neuroinflammation and Strategies for Therapeutic Intervention

    Directory of Open Access Journals (Sweden)

    Manoj Banjara

    2017-01-01

    Full Text Available Sterile neuroinflammation is essential for the proper brain development and tissue repair. However, uncontrolled neuroinflammation plays a major role in the pathogenesis of various disease processes. The endogenous intracellular molecules so called damage-associated molecular patterns or alarmins or damage signals that are released by activated or necrotic cells are thought to play a crucial role in initiating an immune response. Sterile inflammatory response that occurs in Alzheimer’s disease (AD, Parkinson’s disease (PD, stroke, hemorrhage, epilepsy, or traumatic brain injury (TBI creates a vicious cycle of unrestrained inflammation, driving progressive neurodegeneration. Neuroinflammation is a key mechanism in the progression (e.g., AD and PD or secondary injury development (e.g., stroke, hemorrhage, stress, and TBI of multiple brain conditions. Hence, it provides an opportunity for the therapeutic intervention to prevent progressive tissue damage and loss of function. The key for developing anti-neuroinflammatory treatment is to minimize the detrimental and neurotoxic effects of inflammation while promoting the beneficial and neurotropic effects, thereby creating ideal conditions for regeneration and repair. This review outlines how inflammation is involved in the pathogenesis of major nonpathogenic neuroinflammatory conditions and discusses the complex response of glial cells to damage signals. In addition, emerging experimental anti-neuroinflammatory drug treatment strategies are discussed.

  16. Therapeutic vaccination strategies to treat nasopharyngeal carcinoma.

    Science.gov (United States)

    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.

  17. Therapeutic Strategy for Chronic Headache in Children

    Directory of Open Access Journals (Sweden)

    H.O. Lezhenko

    2016-05-01

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

  18. Inflammatory bowel disease: potential therapeutic strategies

    DEFF Research Database (Denmark)

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

    1997-01-01

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

  19. Therapeutic Strategies for Hereditary Kidney Cancer.

    Science.gov (United States)

    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.

  20. New therapeutic strategies for malignant pleural mesothelioma.

    Science.gov (United States)

    Bonelli, Mara A; Fumarola, Claudia; La Monica, Silvia; Alfieri, Roberta

    2017-01-01

    Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. Therapeutic actions are limited due to the late stage at which most patients are diagnosed and the intrinsic chemo-resistance of the tumor. The recommended systemic therapy for MPM is cisplatin/pemetrexed regimen with a mean overall survival of about 12months and a median progression free survival of less than 6months. Considering that the incidence of this tumor is expected to increase in the next decade and that its prognosis is poor, novel therapeutic approaches are urgently needed. For some tumors, such as lung cancer and breast cancer, druggable oncogenic alterations have been identified and targeted therapy is an important option for these patients. For MPM, clinical guidelines do not recommend biological targeted therapy, mainly because of poor target definition or inappropriate trial design. Further studies are required for a full comprehension of the molecular pathogenesis of MPM and for the development of new target agents. This review updates pre-clinical and clinical data on the efficacy of targeted therapy and immune checkpoint inhibition in the treatment of mesothelioma. Finally, future perspectives in this deadly disease are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Myasthenia gravis: subgroup classification and therapeutic strategies.

    Science.gov (United States)

    Gilhus, Nils Erik; Verschuuren, Jan J

    2015-10-01

    Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Biliary parasites: diagnostic and therapeutic strategies.

    Science.gov (United States)

    Khandelwal, Niraj; Shaw, Joanna; Jain, Mamta K

    2008-04-01

    Parasitic infections of the biliary tract are a common cause of biliary obstruction in endemic areas. This article focuses on primary biliary parasites: Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Dicrocoelium dendriticum, Fasciola hepatica, and Fasciola gigantica. Tropical and subtropical countries have the highest incidence and prevalence of these infections. Diagnosis is made primarily through direct microscopic examination of eggs in the stool, duodenal, or bile contents. Radiologic imaging may show intrahepatic ductal dilatation, whereas endoscopic retrograde cholangiopancreatography can be used diagnostically and therapeutically. However, oral treatment is inexpensive and effective for most of these parasites and can prevent untoward consequences. Primary and alternative treatments are available and are reviewed in this article.

  3. Therapeutic strategies in the treatment of periodontitis

    Directory of Open Access Journals (Sweden)

    Liljana Bogdanovska

    2012-04-01

    Full Text Available Periodontitis is a chronic inflammatory process which affects the tooth - supporting structures of the teeth. The disease is initiated by subgingival periopathogenic bacteria in susceptible periodontal sites. The host immune response towards periodontal pathogens helps to sustain periodontal disease and eventual alveolar bone loss. Although scaling and root planing is the standard treatment modality for periodontitis, it suffers from several drawbacks such as the inability to reach the base of deep pockets and doesn’t arrest migration of periodontal pathogens from other sites in the oral cavity. In order to overcome the limitations of scaling and root planning, adjunctive chemotherapeutics and host modulatory agents to the treatment are used. These therapeutic agents show substantial beneficial effects when compared to scaling and root planning alone. This review will cover an update on chemotherapeutic and past and future host immune modulatory agents used adjunctively to treat and manage periodontal diseases.

  4. Therapeutic Strategies and Intellectualism in On Anger by Seneca

    Directory of Open Access Journals (Sweden)

    Rodrigo Sebastián Braicovich

    2015-08-01

    Full Text Available I try to show that a the treatise On Anger by Seneca includes not one but two therapeutic strategies designed to avoid anger and that b the second of these strategies –which has been neglected in the secondary literature– presents unsolvable problems when we contrast it with the Stoic theory of action, which is rooted in intellectualist premises.

  5. Search strategy selection in the Morris water maze indicates allocentric map formation during learning that underpins spatial memory formation.

    Science.gov (United States)

    Rogers, Jake; Churilov, Leonid; Hannan, Anthony J; Renoir, Thibault

    2017-03-01

    Using a Matlab classification algorithm, we demonstrate that a highly salient distal cue array is required for significantly increased likelihoods of spatial search strategy selection during Morris water maze spatial learning. We hypothesized that increased spatial search strategy selection during spatial learning would be the key measure demonstrating the formation of an allocentric map to the escape location. Spatial memory, as indicated by quadrant preference for the area of the pool formally containing the hidden platform, was assessed as the main measure that this allocentric map had formed during spatial learning. Our C57BL/6J wild-type (WT) mice exhibit quadrant preference in the highly salient cue paradigm but not the low, corresponding with a 120% increase in the odds of a spatial search strategy selection during learning. In contrast, quadrant preference remains absent in serotonin 1A receptor (5-HT 1A R) knockout (KO) mice, who exhibit impaired search strategy selection during spatial learning. Additionally, we also aimed to assess the impact of the quality of the distal cue array on the spatial learning curves of both latency to platform and path length using mixed-effect regression models and found no significant associations or interactions. In contrast, we demonstrated that the spatial learning curve for search strategy selection was absent during training in the low saliency paradigm. Therefore, we propose that allocentric search strategy selection during spatial learning is the learning parameter in mice that robustly indicates the formation of a cognitive map for the escape goal location. These results also suggest that both latency to platform and path length spatial learning curves do not discriminate between allocentric and egocentric spatial learning and do not reliably predict spatial memory formation. We also show that spatial memory, as indicated by the absolute time in the quadrant formerly containing the hidden platform alone (without

  6. Novel therapeutic strategies against AIDS progression based on the ...

    African Journals Online (AJOL)

    Novel therapeutic strategies against AIDS progression based on the pathogenic effects of HIV-1 and V pr Proteins. Ahmed A Azad. Abstract. No Abstract. Discovery and Innovation Vol. 17, 2005: 52-60. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Article Metrics.

  7. Russian Gas for Europe. Creating Access and Choice. Underpinning Russia's gas export strategy with Gazprom's infrastructure investments

    International Nuclear Information System (INIS)

    Smeenk, T.

    2010-07-01

    This study deals with Gazprom's investment strategy regarding Russia's gas exports and export market behaviour, with a focus on European infrastructure projects, in a the geopolitical context. Because of its large gas reserves, Russia is well-positioned to take advantage of gas exports even as it faces possible competition from other gas suppliers and uncertain gas demand. Gas export earnings are an important source of income for Russia. As a government-controlled firm, Gazprom depends to a large extent on Europe for its hard-currency income. For Russia and Gazprom, the stream of income from gas exports and its expansion are economically vital. In this regard, gas export infrastructures such as Nord and South Stream could act as important instruments to expand Gazprom's market share in current markets and in growth markets. This study uses a real-option game model to assess the overall value of gas infrastructures in the face of demand uncertainties and potential competition. The result of this approach illustrates the strategic-economic character of Gazprom's infrastructure investments in possibly creating a first-mover's advantage. Yet, the model is of a highly stylised nature. Therefore, other aspects should be taken into account in assessing gas infrastructure investments. Besides the goal of possibly expanding Gazprom's market share, infrastructure investments could serve to mitigate overall transit risks. However, Gazprom's organisational constraints in realising gas infrastructures could put into question the rationale of such investments. In addition, Gazprom's position as well as that of Russian gas may be pressured by European (regulatory) policy in favour of alternative gas and other energy sources. The desired market outcomes for Gazprom have an impact on the prioritisation of Russian investments in the gas value chain.

  8. Biofilms in chronic rhinosinusitis: Pathophysiology and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Judd H. Fastenberg

    2016-12-01

    Full Text Available Background: There is increasing evidence that biofilms are critical to the pathophysiology of chronic infections including chronic rhinosinusitis (CRS. Until relatively recently, our understanding of biofilms was limited. Recent advances in methods for biofilm identification and molecular biology have offered new insights into the role of biofilms in CRS. With these insights, investigators have begun to investigate novel therapeutic strategies that may disrupt or eradicate biofilms in CRS. Objective: This review seeks to explore the evidence implicating biofilms in CRS, discuss potential anti-biofilm therapeutic strategies, and suggest future directions for research. Results: The existing evidence strongly supports the role of biofilms in the pathogenesis of CRS. Several anti-biofilm therapies have been investigated for use in CRS and these are at variable stages of development. Generally, these strategies: 1 neutralize biofilm microbes; 2 disperse existing biofilms; or 3 disrupt quorum sensing. Several of the most promising anti-biofilm therapeutic strategies are reviewed. Conclusions: A better understanding of biofilm function and their contribution to the CRS disease process will be pivotal to the development of novel treatments that may augment and, potentially, redefine the CRS treatment paradigm. There is tremendous potential for future research. Keywords: Sinusitis, Biofilms, Anti-bacterial agents, Quorum sensing, Surface-active agents, Active immune response, Innate immune response

  9. Therapeutic and prevention strategies against human enterovirus 71 infection

    Science.gov (United States)

    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

  10. Therapeutic strategies based on glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F

    2004-01-01

    of its antihyperglycemic effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short......-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite. Strategies for harnessing GLP-1's therapeutic potential, based on an understanding...... of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation...

  11. Which therapeutic strategy will achieve a cure for HIV-1?

    Science.gov (United States)

    Cillo, Anthony R; Mellors, John W

    2016-06-01

    Strategies to achieve a cure for HIV-1 infection can be broadly classified into three categories: eradication cure (elimination of all viral reservoirs), functional cure (immune control without reservoir eradication), or a hybrid cure (reservoir reduction with improved immune control). The many HIV-1 cure strategies being investigated include modification of host cells to resist HIV-1, engineered T cells to eliminate HIV-infected cells, broadly HIV-1 neutralizing monoclonal antibodies, and therapeutic vaccination, but the 'kick and kill' strategy to expose latent HIV-1 with latency reversing agents (LRAs) and kill the exposed cells through immune effector functions is currently the most actively pursued. It is unknown, however, whether LRAs can deplete viral reservoirs in vivo or whether current LRAs are sufficiently safe for clinical use. Copyright © 2016. Published by Elsevier B.V.

  12. Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Chang Youn Lee

    2016-01-01

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

  13. Future-Focused Therapeutic Strategies for Integrative Health.

    Science.gov (United States)

    Torem, Moshe S

    2017-01-01

    For many years, the therapy field was dominated by a focus on the past. In this context, many clinicians were trained to use hypnosis as a tool to explore the past, and there is a rich literature documenting the use of hypnosis as a tool to induce age regression and the uncovering of traumatic memories. This article presents a therapeutic paradigm that focuses on the future. Hypnosis is used to induce creativity, flexibility, and openness to the future. In the context of health care, hypnosis is used to explore the best possible treatment outcome, which may be pharmacological, surgical, or a combination of both as well as other nonsurgical interventions. This article elaborates on the effective use of a therapeutic hypnosis strategy and technique focused on the future.

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

    Directory of Open Access Journals (Sweden)

    Roszkowski Jeffrey J

    2005-09-01

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

  15. Therapeutic strategies of urinary disorders in MS. Practice and algorithms.

    Science.gov (United States)

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

    2014-07-01

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

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. TNF biology, pathogenic mechanisms and emerging therapeutic strategies

    Science.gov (United States)

    Kalliolias, George D.; Ivashkiv, Lionel B.

    2016-01-01

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

  18. Current therapeutic strategies for anal squamous cell carcinoma in Japan

    International Nuclear Information System (INIS)

    Takashima, Atsuo; Shimada, Yasuhiro; Hamaguchi, Tetsuya

    2009-01-01

    In Western countries, chemoradiotherapy (CRT) is well established as the standard therapy for stages II/III anal squamous cell carcinoma (ASCC). In Japan, the therapeutic modalities for and outcomes of this disease have not been clarified because ASCC is quite rare. The Colorectal Cancer Study Group of the Japan Clinical Oncology Group (JCOG-CCSG) conducted a survey to determine the current therapeutic strategies for ASCC in Japan. In July 2006, a questionnaire was sent to 49 institutions affiliated with the JCOG-CCSG to gather information on numbers of cases, therapeutic modalities, and outcomes. The target subjects were patients with stages II/III ASCC, diagnosed from January 2000 to December 2004, who were 20-80 years of age with normal major organ function and no severe complications. Replies were received from 40 institutions. A total of 59 patients satisfied the subject criteria. Detailed information was obtained for 55 subjects; 25 (45%) had stage II ASCC and 30 (55%) had stage III ASCC. CRT was performed in 25 patients (45%); surgery in 17 (31%); surgery combined with radiotherapy (RT), chemotherapy, or CRT in 8 (15%); and RT in 5 (9%). Complete response rate in CRT was 80% (20/25). The 3-year progression-free survival rates for all subjects and for CRT-only subjects were 67% and 77%, respectively. From 2000 to 2004, only 59 patients with ASCC were identified in the JCOG-CCSG survey and about half of them underwent CRT. (author)

  19. Therapeutic targeting strategies using endogenous cells and proteins.

    Science.gov (United States)

    Parayath, Neha N; Amiji, Mansoor M

    2017-07-28

    Targeted drug delivery has become extremely important in enhancing efficacy and reducing the toxicity of therapeutics in the treatment of various disease conditions. Current approaches include passive targeting, which relies on naturally occurring differences between healthy and diseased tissues, and active targeting, which utilizes various ligands that can recognize targets expressed preferentially at the diseased site. Clinical translation of these mechanisms faces many challenges including the immunogenic and toxic effects of these non-natural systems. Thus, use of endogenous targeting systems is increasingly gaining momentum. This review is focused on strategies for employing endogenous moieties, which could serve as safe and efficient carriers for targeted drug delivery. The first part of the review involves cells and cellular components as endogenous carriers for therapeutics in multiple disease states, while the second part discusses the use of endogenous plasma components as endogenous carriers. Further understanding of the biological tropism with cells and proteins and the newer generation of delivery strategies that exploits these endogenous approaches promises to provide better solutions for site-specific delivery and could further facilitate clinical translations. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance.

    Science.gov (United States)

    Nuti, Ramya; Goud, Nerella S; Saraswati, A Prasanth; Alvala, Ravi; Alvala, Mallika

    2017-01-01

    Antimicrobial resistance (AMR) has posed a serious threat to global public health and it requires immediate action, preferably long term. Current drug therapies have failed to curb this menace due to the ability of microbes to circumvent the mechanisms through which the drugs act. From the drug discovery point of view, the majority of drugs currently employed for antimicrobial therapy are small molecules. Recent trends reveal a surge in the use of peptides as drug candidates as they offer remarkable advantages over small molecules. Newer synthetic strategies like organometalic complexes, Peptide-polymer conjugates, solid phase, liquid phase and recombinant DNA technology encouraging the use of peptides as therapeutic agents with a host of chemical functions, and tailored for specific applications. In the last decade, many peptide based drugs have been successfully approved by the Food and Drug Administration (FDA). This success can be attributed to their high specificity, selectivity and efficacy, high penetrability into the tissues, less immunogenicity and less tissue accumulation. Considering the enormity of AMR, the use of Antimicrobial Peptides (AMPs) can be a viable alternative to current therapeutics strategies. AMPs are naturally abundant allowing synthetic chemists to develop semi-synthetics peptide molecules. AMPs have a broad spectrum of activity towards microbes and they possess the ability to bypass the resistance induction mechanisms of microbes. The present review focuses on the potential applications of AMPs against various microbial disorders and their future prospects. Several resistance mechanisms and their strategies have also been discussed to highlight the importance in the current scenario. Breakthroughs in AMP designing, peptide synthesis and biotechnology have shown promise in tackling this challenge and has revived the interest of using AMPs as an important weapon in fighting AMR. Copyright© Bentham Science Publishers; For any queries

  1. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease.

    Science.gov (United States)

    Horowitz, Alana M; Villeda, Saul A

    2017-01-01

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

  2. Cell-based therapeutic strategies for multiple sclerosis

    DEFF Research Database (Denmark)

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C

    2017-01-01

    The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system......, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved...... questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials....

  3. STAT3 targeting by polyphenols: Novel therapeutic strategy for melanoma.

    Science.gov (United States)

    Momtaz, Saeideh; Niaz, Kamal; Maqbool, Faheem; Abdollahi, Mohammad; Rastrelli, Luca; Nabavi, Seyed Mohammad

    2017-05-06

    Melanoma or malignant melanocytes appear with the low incidence rate, but very high mortality rate worldwide. Epidemiological studies suggest that polyphenolic compounds contribute for prevention or treatment of several cancers particularly melanoma. Such findings motivate to dig out novel therapeutic strategies against melanoma, including research toward the development of new chemotherapeutic and biologic agents that can target the tumor cells by different mechanisms. Recently, it has been found that signal transducer and activator of transcription 3 (STAT3) is activated in many cancer cases surprisingly. Different evidences supply the aspect that STAT3 activation plays a vital role in the metastasis, including proliferation of cells, survival, invasion, migration, and angiogenesis. This significant feature plays a vital role in various cellular processes, such as cell proliferation and survival. Here, we reviewed the mechanisms of the STAT3 pathway regulation and their role in promoting melanoma. Also, we have evaluated the emerging data on polyphenols (PPs) specifically their contribution in melanoma therapies with an emphasis on their regulatory/inhibitory actions in relation to STAT3 pathway and current progress in the development of phytochemical therapeutic techniques. An understanding of targeting STAT3 by PPs brings an opportunity to melanoma therapy. © 2016 BioFactors, 43(3):347-370, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

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

    Directory of Open Access Journals (Sweden)

    Dereck Sena de Lima

    2017-02-01

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

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

    Science.gov (United States)

    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

  6. [Therapeutic strategies and systemic treatment of brain melanoma metastases].

    Science.gov (United States)

    Durando, Xavier; Mansard, Sandrine; Daste, Amaury; Gimbergues, Pierre; Brocard, Laura; Magné, Nicolas; Thivat, Emilie

    2013-01-01

    Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.

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

    Directory of Open Access Journals (Sweden)

    Melissa Bowerman

    2017-08-01

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

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

    Science.gov (United States)

    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

  9. Therapeutic strategies for secondary hyperparathyroidism in dialysis patients.

    Science.gov (United States)

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

    2006-08-01

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

  10. Cell-based therapeutic strategies for multiple sclerosis.

    Science.gov (United States)

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

    2017-11-01

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

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

    Science.gov (United States)

    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.

  12. Therapeutic strategies in an animal model of neurodegeneration

    NARCIS (Netherlands)

    Borre, Y.E.

    2013-01-01

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

  13. Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

    International Nuclear Information System (INIS)

    2003-01-01

    Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching

  14. Marketing skills as determinants that underpin the competitiveness of the rice industry in Yaguachi canton. Application of SVN numbers to the prioritization of strategies

    Directory of Open Access Journals (Sweden)

    Pablo José Menéndez Vera

    2016-12-01

    Full Text Available In Ecuador, specifically in the Yaguachi Canton, there is an enormous potential in the rice production, which unfortunately is not being well used and driven by marketing strategies. In this work, marketing strategies were developed that help to sustain the commercial activity of rice in Yaguachi Canton and its surroundings. The proposed strategies were analyzed and prioritized using SVN and Euclidean distance for the treatment of neutralities. The paper ends with conclusion and future work proposal for the application of neutrosophy to new areas of marketing.

  15. Extracellular vesicles: A new therapeutic strategy for joint conditions.

    Science.gov (United States)

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

    2018-02-07

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

  16. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

    Science.gov (United States)

    Barage, Sagar H; Sonawane, Kailas D

    2015-08-01

    Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Personalized therapeutic strategies for patients with retinitis pigmentosa.

    Science.gov (United States)

    Zheng, Andrew; Li, Yao; Tsang, Stephen H

    2015-03-01

    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. 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. 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.

  18. Transgenic plants for therapeutic proteins: linking upstream and downstream strategies.

    Science.gov (United States)

    Cramer, C L; Boothe, J G; Oishi, K K

    1999-01-01

    We have described two very different and innovative plant-based production systems--postharvest production and recovery of recombinant product from tobacco leaves using an inducible promoter and oleosin-mediated recovery of recombinant product from oilseeds using a seed-specific promoter. Both base technologies are broadly applicable to numerous classes of pharmaceutical and industrial proteins. As with any emerging technology, the key to success may lie in identifying those products and applications that would most benefit from the unique advantages offered by each system. The postharvest tobacco leaf system appears effective for proteins requiring complex posttranslational processing and endomembrane targeting. Because of the remarkable fecundity and biomass production capacity of tobacco, biomass scale-up is very rapid and production costs are low. Clearly the development of equally cost-effective extraction and purification technologies will be critical for full realization of the commercial opportunities afforded by transgenic plant-based bioproduction. The recovery of protein from tobacco leaves or oleosin-partitioned proteins by oil-body separations represent significant break-throughs for cost-effective commercialization strategies. Additional low-cost, high-affinity separation technologies need to be developed for effective scale-up purification of plant-synthesized recombinant proteins. Clearly successful commercialization of plant-synthesized biopharmaceuticals must effectively link upstream strategies involving gene and protein design with downstream strategies for reproducible GMP-level recovery of bioactive recombinant protein. Both the tobacco and oilseed systems are uniquely designed to address issues of biomass storage, product recovery, quality assurance, and regulatory scrutiny in addition to issues of transgene expression and protein processing.

  19. Management of constipation in the elderly: emerging therapeutic strategies.

    Science.gov (United States)

    Kapoor, Shailendra

    2008-09-07

    A number of new, novel strategies for managing constipation in the elderly have emerged over the past few years. Prucalopride is one such new agent that is highly efficacious in managing chronic constipation. In fact, Camilleri et al in a recent study reported that the average number of bowel movements increased by at least one in nearly 47% of the patients who were administered a dose of 4 mg. Lubiprostone is another new agent recently approved by the FDA that shows efficacy in managing the symptoms of constipation. Neostigmine has also been successfully used for the management of recalcitrant constipation. Most of these studies have used subcutaneous neostigmine. Symbiotic yogurt containing components, such as Bifidobacterium and fructoligosaccharide, have also been recently shown to be highly effective in improving symptoms of constipation. Elderly patients especially those in hospices and nursing homes are often on opioids for pain management. Constipation secondary to opioid use is extremely common in nursing homes. Subcutaneous methylnaltrexone has recently been shown to be highly effective in the management of opioid-related constipation, and was recently approved by the FDA. Sacral nerve stimulation is another emerging strategy. A recent analysis by Mowatt et al supports the efficacy of this technique. Botulinum toxin is another agent that has already been successfully used for the management of chronic, refractory constipation in children and may be very effective for elderly constipation. Further larger studies are needed to confirm the findings noted in these studies. Constipation is clearly a major issue in the elderly and these new, emerging strategies will hopefully improve the quality of life and relieve the symptoms of constipation in this population.

  20. Management of constipation in the elderly: Emerging therapeutic strategies

    OpenAIRE

    Kapoor, Shailendra

    2008-01-01

    A number of new, novel strategies for managing constipation in the elderly have emerged over the past few years. Prucalopride is one such new agent that is highly efficacious in managing chronic constipation. In fact, Camilleri et al in a recent study reported that the average number of bowel movements increased by at least one in nearly 47% of the patients who were administered a dose of 4 mg. Lubiprostone is another new agent recently approved by the FDA that shows efficacy in managing the ...

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  2. Therapeutic strategies utilizing SDF-1α in ischaemic cardiomyopathy.

    Science.gov (United States)

    Ziff, Oliver J; Bromage, Daniel I; Yellon, Derek M; Davidson, Sean M

    2018-03-01

    Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

  3. Advances in therapeutic strategies for the treatment of pruritus.

    Science.gov (United States)

    Stull, Carolyn; Lavery, Michael J; Yosipovitch, Gil

    2016-01-01

    Chronic pruritus is a common symptom that arises from both dermatologic and non-dermatologic conditions including chronic kidney disease, cholestasis, lymphoma and neuropathy. Over the past decade, research has elucidated many of the receptors, neuropeptides and cytokines involved in itch sensation and transmission. In addition, the first biomarker for cholestatic itch has been discovered. These findings have led to the development of a host of novel antipruritic medications, both on the market and in the pipeline. A summary of new and emerging treatments for pruritus, as well as possible targets for future therapeutic development is provided. At present, there is no universally effective treatment available for all types of chronic pruritus. A combination of topical and systemic therapies addressing peripheral mediators, and a top-down approach targeting the brain and spinal cord, seems preferable to a single agent approach. Neural hypersensitization plays a significant role in many forms of chronic pruritus and may be downregulated by new treatments. In addition, specific neuropeptides are now targeted by novel antipruritic therapies. Furthermore, targeted biologic agents are anticipated to play a significant role in treating pruritus of inflammatory origin.

  4. A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine

    Science.gov (United States)

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

    2013-01-01

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

  5. Plasma cells in immunopathology: concepts and therapeutic strategies.

    Science.gov (United States)

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

    2014-05-01

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

  6. Therapeutic strategies to prevent contrast-induced acute kidney injury.

    Science.gov (United States)

    Quintavalle, Cristina; Donnarumma, Elvira; Fiore, Danilo; Briguori, Carlo; Condorelli, Gerolama

    2013-11-01

    Contrast-induced acute kidney injury (CI-AKI) accounts for approximately 10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay, and represents a powerful predictor of poor early and late outcome. Here, we highlight endpoints used to assess major strategies to prevent CI-AKI. A general consensus exists on the beneficial prophylactic effect of hydration. This seems to act by increasing urine flow rate and, thereby, by limiting the time of contact between the contrast media and the epithelial tubular cells. On the contrary, both observational trials and randomized studies are often controversial in their conclusions on the efficacy of several drugs tested to prevent CI-AKI. Compounds evaluated include diuretics (furosemide), antioxidants (i.e., N-acetylcysteine and statins), and vasodilators (i.e., calcium antagonists, dopamine, and fenoldopam). Due to the negative and/or controversial clinical results, none of these drugs has been currently recommended to prevent CI-AKI. More reliable markers of acute kidney injury and new prophylactic strategies are warranted to prevent the incidence of CI-AKI.

  7. [Complications and postoperative therapeutic strategies in cross-linking].

    Science.gov (United States)

    Kohlhaas, M

    2017-08-01

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

  8. Role of inflammatory response in liver diseases: Therapeutic strategies.

    Science.gov (United States)

    Del Campo, José A; Gallego, Paloma; Grande, Lourdes

    2018-01-27

    Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus (HCV) infection, and sterile stressors (oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1β and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro- or anti-apoptotic. Acute and chronic liver diseases are cytokine-driven diseases as several proinflammatory cytokines (IL-1α, IL-1β, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1β production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases.

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

    Directory of Open Access Journals (Sweden)

    Jaume Folch

    2016-01-01

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

  10. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy.

    Science.gov (United States)

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

    2015-12-01

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

  11. Strategies to Target Matrix Metalloproteinases as Therapeutic Approach in Cancer.

    Science.gov (United States)

    Piperigkou, Zoi; Manou, Dimitra; Karamanou, Konstantina; Theocharis, Achilleas D

    2018-01-01

    Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are capable of degrading numerous extracellular matrix (ECM) components thus participating in physiological and pathological processes. Apart from the remodeling of ECM, they affect cell-cell and cell-matrix interactions and are implicated in the development and progression of various diseases such as cancer. Numerous studies have demonstrated that MMPs evoke epithelial to mesenchymal transition (EMT) of cancer cells and affect their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Various studies have suggested MMPs as suitable targets for treatment of malignancies, and several MMP inhibitors (MMPIs) have been developed. Although initial trials have failed to establish MMPIs as anticancer agents due to lack of specificity and side effects, new MMPIs have been developed with improved action that are currently being investigated. Furthermore, novel strategies that target MMPs for improving drug delivery and regulating their activity in tumors are presented. This review summarizes the implication of MMPs in cancer progression and discusses the advancements in their targeting.

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

    Directory of Open Access Journals (Sweden)

    Hiroshi Katoh

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Zhong SHI

    2015-02-01

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

  14. Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke.

    Science.gov (United States)

    Kanazawa, Masato; Takahashi, Tetsuya; Nishizawa, Masatoyo; Shimohata, Takayoshi

    2017-03-01

    This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still <5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.

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

    NARCIS (Netherlands)

    Bungener, Laura Barbara

    2004-01-01

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

  16. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury.

    Science.gov (United States)

    Chen, Xing-miao; Chen, Han-sen; Xu, Ming-jing; Shen, Jian-gang

    2013-01-01

    Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury.

  17. [Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus].

    Science.gov (United States)

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

    2011-06-01

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

  18. Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies.

    Science.gov (United States)

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

    2017-10-01

    Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm 3 absolute mean difference; p Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

  19. [Work-related musculoskeletal disorders in dentistry professionals. 2. Prevention, ergonomic strategies and therapeutic programs].

    Science.gov (United States)

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

    2005-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Hun Soon Jung

    2015-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Abdelouahid El-Khattouti

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Zhang J

    2016-10-01

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

  3. Novel therapeutic strategies for degenerative disc disease: Review of cell biology and intervertebral disc cell therapy.

    Science.gov (United States)

    Fernandez-Moure, Joseph; Moore, Caitlyn A; Kim, Keemberly; Karim, Azim; Smith, Kevin; Barbosa, Zonia; Van Eps, Jeffrey; Rameshwar, Pranela; Weiner, Bradley

    2018-01-01

    Intervertebral disc degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to loss of disc integrity. Degeneration of the disc can be a normal process of ageing, but can also be precipitated by other factors. Literature has made substantial progress in understanding the biological basis of intervertebral disc, which is reviewed here. Current medical and surgical management strategies have shortcomings that do not lend promise to be effective solutions in the coming years. With advances in understanding the cell biology and characteristics of the intervertebral disc at the molecular and cellular level that have been made, alternative strategies for addressing disc pathology can be discovered. A brief overview of the anatomic, cellular, and molecular structure of the intervertebral disc is provided as well as cellular and molecular pathophysiology surrounding intervertebral disc degeneration. Potential therapeutic strategies involving stem cell, protein, and genetic therapy for intervertebral disc degeneration are further discussed.

  4. Delivery of growth factor-based therapeutics in vascular diseases: Challenges and strategies.

    Science.gov (United States)

    Xu, He-Lin; Yu, Wen-Ze; Lu, Cui-Tao; Li, Xiao-Kun; Zhao, Ying-Zheng

    2017-05-01

    Either cardiovascular or peripheral vascular diseases have become the major cause of morbidity and mortality worldwide. Recently, growth factors therapeutics, whatever administrated in form of exogenous growth factors or their relevant genes have been discovered to be an effective strategy for the prevention and therapy of vascular diseases, because of their promoting angiogenesis. Besides, as an alternative, stem cell-based therapy has been also developed in view of their paracrine-mediated effect or ability of differentiation toward angiogenesis-related cells under assistance of growth factors. Despite of being specific and potent, no matter growth factors or stem cells-based therapy, their full clinical transformation is limited from bench to bedside. In this review, the potential choices of therapeutic modes based on types of different growth factors or stem cells were firstly summarized for vascular diseases. The confronted various challenges such as lack of non-invasive delivery method, the physiochemical challenge, the short half-life time, and poor cell survival, were carefully analyzed for these therapeutic modes. Various strategies to overcome these limitations are put forward from the perspective of drug delivery. The expertised design of a suitable delivery form will undoubtedly provide valuable insight into their clinical application in the regenerative medicine. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Coping with hallucinated voices in schizophrenia: a review of self-initiated strategies and therapeutic interventions.

    Science.gov (United States)

    Farhall, John; Greenwood, Kenneth Mark; Jackson, Henry J

    2007-05-01

    This article reviews the state of knowledge about strategies used by people with a diagnosis of schizophrenia to cope with hallucinated voices, and considers the role of coping in psychological treatments for persisting symptoms. The use of self-initiated ('natural') coping strategies appears almost universal amongst voice-hearers. These strategies are similar across cultures, and include diverse behaviours, only a minority of which is specific to hallucinations. Most strategies are reported by at least some users to be effective, but more sophisticated outcome studies are lacking. Some evidence for the efficacy of certain behavioural techniques of coping, for the manipulation of auditory input, and for strategies involving subvocalisation, is available from experimental studies. Therapeutic enhancement of natural coping strategies for persisting symptoms has demonstrated some efficacy, but its benefit for voices is unknown. Despite this, it has become an established part of some CBT interventions for psychosis. Further advances in knowledge and practice may come from utilisation of coping models in research, longitudinal and ideographic methods of study and a movement away from descriptive coping lists to investigations of coping styles, mechanisms of action, and the process of coping.

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

    Directory of Open Access Journals (Sweden)

    Seung Taek Ji

    2017-01-01

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

  7. Secular trends in mortality associated with new therapeutic strategies in surgical critical illness.

    Science.gov (United States)

    Hartl, Wolfgang H; Wolf, Hilde; Schneider, Christian P; Küchenhoff, Helmut; Jauch, Karl-Walter

    2007-10-01

    Since 1999 randomized controlled trials have shown that new therapeutic strategies, such as strict glycemic control, increased use of noninvasive ventilation and of lung-protective ventilation, and early goal-oriented shock therapy, may reduce mortality in selected groups of critically ill patients. Whether these benefits can be translated to a surgical clinical setting is unclear. We wanted to evaluate longitudinally the successive routine implementation of new therapeutic measures and its effect on postsurgical patients admitted to the intensive care unit. We performed a retrospective analysis on data collected prospectively from March 1, 1993 through February 28, 2005. A cohort of 1,802 consecutive cases requiring intensive care therapy for more than 4 days was analyzed. A significant decrease in mortality was observed in the last years of the study. With adjustment for relevant covariates, treatment after the implementation of new therapeutic strategies was identified as an independent factor linked with a reduced risk of death (odds ratio [OR] .518; 95% confidence interval [CI] .337-.796), whereas older age (OR 1.030; 95% CI 1.015-1.045), a high severity score on admission (OR 1.155; 95% CI 1.113-1.198) or during intensive care unit stay (OR 1.187; 95% CI 1.145-1.231), a high number of failing organs (OR 1.918; 95% CI 1.635-2.250), and peritonitis (OR 3.277; 95% CI 2.046-5.246) were independently associated with death. Implementing of a variety of new therapeutic measures into routine care of critically ill surgical patients was associated with improved survival after 2001.

  8. [Preliminary discussion of therapeutic strategies in persistent inflammation immunosuppression catabolism syndrome].

    Science.gov (United States)

    Su, Heyi; Guo, Zhenhui

    2017-12-25

    So far, there is still lack of effective treatment to control persistent inflammation immunosuppression catabolism syndrome (PICS) appeared generally in those chronic critical illnesses (CCI) patients, restricted by the development of medicine and scientific research nowadays. Because the uncontrolled PICS aggravates continuously, ICU stay of the CCI patients has been obviously prolonging and the late mortality elevates greatly. So exploring effective therapeutic strategies is obviously pressing. With the characteristics in PICS such as that elderly with sepsis or severe trauma tops the list of morbidity, progressing illness is difficult to intervent and various pathology changes occur simultaneously, the fundamental principle of treatment, "Focal screening, early control, joint intervention" must be followed. As for the specific intervention, lessoning from some diseases with immune and metabolic disorders to take "anabolic nutrition support", is a research focus presently as well as a considerably potential breakthrough at the treatment research in the future. This review retrospects a series of therapeutic strategies of PICS, such as immunity, metabolism regulation, nutrition support, glucose control and physiotherapy, in the purpose of laying the foundation of the development of joint intervention strategy for PICS.

  9. Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis

    Science.gov (United States)

    Di Rocco, Giuliana; Baldari, Silvia

    2016-01-01

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

  10. Understanding HIV infection for the design of a therapeutic vaccine. Part II: Vaccination strategies for HIV.

    Science.gov (United States)

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

    2015-05-01

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

  11. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... diseases. Contact Us NIAMS Archive Viewers and Players Social Media Moderation Policy FOIA Privacy Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data ...

  12. Central Pain Mechanisms and Novel Therapeutic Strategies in a Model of Closed Head Injury

    Science.gov (United States)

    2016-10-01

    de nt ifi ed a t le as t th re e un iq ue p ar am et er s th at i de nt ify r C H I an im al s, a nd th at w ill se rv e as e xc el le...system reverses amyloid‐induced memory deficiency. Neurobiol  Aging , 2013. 34(3): p. 791‐804. Central pain mechanisms and novel therapeutic strategies in

  13. Therapeutic strategies in Sickle Cell Anemia: The past present and future.

    Science.gov (United States)

    Fernandes, Queenie

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Xiaozheng KANG

    2012-04-01

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

  15. Cell death-based treatments of melanoma:conventional treatments and new therapeutic strategies.

    Science.gov (United States)

    Mattia, Gianfranco; Puglisi, Rossella; Ascione, Barbara; Malorni, Walter; Carè, Alessandra; Matarrese, Paola

    2018-01-25

    The incidence of malignant melanoma has continued to rise during the past decades. However, in the last few years, treatment protocols have significantly been improved thanks to a better understanding of the key oncogenes and signaling pathways involved in its pathogenesis and progression. Anticancer therapy would either kill tumor cells by triggering apoptosis or permanently arrest them in the G1 phase of the cell cycle. Unfortunately, melanoma is often refractory to commonly used anticancer drugs. More recently, however, some new anticancer strategies have been developed that are "external" to cancer cells, for example stimulating the immune system's response or inhibiting angiogenesis. In fact, the increasing knowledge of melanoma pathogenetic mechanisms, in particular the discovery of genetic mutations activating specific oncogenes, stimulated the development of molecularly targeted therapies, a form of treatment in which a drug (chemical or biological) is developed with the goal of exclusively destroying cancer cells by interfering with specific molecules that drive growth and spreading of the tumor. Again, after the initial exciting results associated with targeted therapy, tumor resistance and/or relapse of the melanoma lesion have been observed. Hence, very recently, new therapeutic strategies based on the modulation of the immune system function have been developed. Since cancer cells are known to be capable of evading immune-mediated surveillance, i.e., to block the immune system cell activity, a series of molecular strategies, including monoclonal antibodies, have been developed in order to "release the brakes" on the immune system igniting immune reactivation and hindering metastatic melanoma cell growth. In this review we analyze the various biological strategies underlying conventional chemotherapy as well as the most recently developed targeted therapies and immunotherapies, pointing at the molecular mechanisms of cell injury and death engaged by

  16. Therapeutic strategies in severe neuropsychiatric systemic lupus erythematosus: experience from a tertiary referral centre

    Directory of Open Access Journals (Sweden)

    F. De Leonardis

    2012-12-01

    Full Text Available The management of neuropsychiatric systemic lupus erythematosus (NPSLE still remains empirical and based on clinical experience due to the lack of randomized controlled trials. Objective: to report the experience accumulated in a single tertiary referral centre about treatment of severe cases of NPSLE patients and to discuss therapeutic strategies on the background of EULAR recommendations. Methods: retrospective analysis of all consecutive cases of severe NPSLE treated in our centre since 1990 to 2010, satisfying the 1999 ACR criteria. Results: among 633 SLE patients who consecutively attended our centre, 231 (36% displayed at least one neuropsychiatric (NP manifestation for a total of 408 events attributable to SLE. Thirty-one patients (4.8%, 27 females and 4 males, experienced 35 major NP events requiring immunosuppressive therapy (including 3 relapses and 1 new event. An aggressive immunosuppressive strategy was applied to those patients with an immune mediated inflammatory NP event and to those patients with an increased disease activity as judged by ECLAM and SLEDAI scores. Overall at the end of the therapy 74% of the patients reached clinical remission or significant improvement of their symptoms measured by mean SLEDAI (from 10.09±1.09 to 2.04±0.52, PConclusions: the prevalence of NP involvement, described in our case series, is similar to those reported in literature as well as the treatment strategies applied. Nowadays, it is not possible to establish a standardized approach for each single NPSLE manifestation, and different therapeutic strategies must be tailored taking into account the most probable pathogenic mechanism involved, the general disease activity background, the co-morbidities, the type and the stage of the systemic involvement.

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

    Science.gov (United States)

    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

  18. Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

    Science.gov (United States)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Brannon JR

    2016-05-01

    Full Text Available John R Brannon,1 Maria Hadjifrangiskou1,21Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, 2Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN, USAAbstract: 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.Keywords: virulence factors, antivirulence therapeutics, biofilms, regulation, Escherichia coli, quorum sensing, persister cells

  20. Therapeutic strategies for the treatment of accidental radiation-induced hematopoietic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Bertho, J.M.; Frick, J.; Demarquay, C.; Prat, M.; Dudoignon, N.; Thierry, D.; Gourmelon, P. [Institut de Radioprotection et de Surete Nucleaire (IRSN) DRPH/SRBE, LTCRA, 92 - Fontenay aux Roses (France)

    2006-07-01

    The hematopoietic syndrome induced by large field high dose accidental irradiation remains difficult to treat, mainly due to the heterogeneity of irradiation. As a result, there always remains an area of active hematopoiesis that was partly protected from irradiation. The choice of a therapeutic strategy thus must be based upon the estimate of radiation damage to the bone marrow. This can be achieved by the use of biological indicators of damage to specific organs. With this respect, we recently showed that the follow up of Flt3 ligand concentration in the blood allowed a direct evaluation of residual hematopoiesis soon after irradiation in animal models as well as in humans. Nevertheless, the possible therapeutic strategies available for the treatment of radiation-induced hematopoietic syndrome are limited to the choice between either stem cell transplantation or supportive care. Recently, the use of autologous cell therapy was proposed. The principle is to harvest the hematopoietic cells surviving to irradiation, to expand these cells in vitro and to re inject these cells to the patient. This is based upon the existence of a residual hematopoiesis and on the possibility to expand in vitro irradiated hematopoietic cells. Experimental work in a non human primate model of high-dose, heterogeneous irradiation showed that it was possible to harvest surviving hematopoietic cells after irradiation and to amplify these cells in vitro. However, the therapeutic efficiency of the reinjected cells was limited by the occurrence of a combined disease, implicating the lungs, the kidney and the liver, but also a severe vascular damage. Such a multiple organ disease syndrome induced by ionizing radiations was already observed in two radiation accidents, the Tokai MURA accident and the Neshvish accident. In an attempt to accelerate the hematopoietic recovery, we combined autologous cell therapy with G-CSF injections in the same model of heterogeneous irradiation with non human

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

    Science.gov (United States)

    Holm-Hadulla, Rainer M

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sumit Sarkar

    2016-06-01

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

  3. MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Marcelo E Ezquer

    2012-01-01

    Full Text Available Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN, a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular filtration rate and the loss of glomerular podocytes, tubulointerstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational effort to control the disease, a significant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs. The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.

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

    Science.gov (United States)

    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

  5. Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

    Science.gov (United States)

    Jones, Melissa K.; Lu, Bin; Girman, Sergey; Wang, Shaomei

    2017-01-01

    Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments. PMID:28111323

  6. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... diseases. Contact Us NIAMS Archive Viewers and Players Social Media Moderation Policy FOIA Privacy Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data Listing NIH...Turning ...

  7. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... NIAMS Archive Viewers and Players Social Media Moderation Policy FOIA Privacy Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data Listing NIH...Turning Discovery Into Health® National ...

  8. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... 29, 2018 NIAMS Update | March 29, 2018 Communicating Science to the Public: Context and Curiosity Letter from ... Privacy Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data Listing NIH...Turning Discovery Into Health® ...

  9. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data Listing NIH...Turning Discovery Into Health® National Institutes of Health, 9000 Rockville Pike, Bethesda, ...

  10. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... community. NIAMS Scientific Retreats Scientific and lay representatives discuss needs, gaps, and opportunities in the biomedical research ... Privacy Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data Listing NIH...Turning Discovery Into Health® ...

  11. Genetic Underpinnings of Alopecia Areata

    Medline Plus

    Full Text Available ... of Health Get Email Updates Contact Us Top Utility Nav Community Outreach Publications in Asian Languages Portal ... Statement Accessibility Disclaimer Digital Strategy Open Source Data Public Data Listing NIH...Turning Discovery Into Health® National ...

  12. Improving Cerebral Blood Flow after Arterial Recanalization: A Novel Therapeutic Strategy in Stroke.

    Science.gov (United States)

    El Amki, Mohamad; Wegener, Susanne

    2017-12-09

    Ischemic stroke is caused by a disruption in blood supply to a region of the brain. It induces dysfunction of brain cells and networks, resulting in sudden neurological deficits. The cause of stroke is vascular, but the consequences are neurological. Decades of research have focused on finding new strategies to reduce the neural damage after cerebral ischemia. However, despite the incredibly huge investment, all strategies targeting neuroprotection have failed to demonstrate clinical efficacy. Today, treatment for stroke consists of dealing with the cause, attempting to remove the occluding blood clot and recanalize the vessel. However, clinical evidence suggests that the beneficial effect of post-stroke recanalization may be hampered by the occurrence of microvascular reperfusion failure. In short: recanalization is not synonymous with reperfusion. Today, clinicians are confronted with several challenges in acute stroke therapy, even after successful recanalization: (1) induce reperfusion, (2) avoid hemorrhagic transformation (HT), and (3) avoid early or late vascular reocclusion. All these parameters impact the restoration of cerebral blood flow after stroke. Recent advances in understanding the molecular consequences of recanalization and reperfusion may lead to innovative therapeutic strategies for improving reperfusion after stroke. In this review, we will highlight the importance of restoring normal cerebral blood flow after stroke and outline molecular mechanisms involved in blood flow regulation.

  13. Improving Cerebral Blood Flow after Arterial Recanalization: A Novel Therapeutic Strategy in Stroke

    Directory of Open Access Journals (Sweden)

    Mohamad El Amki

    2017-12-01

    Full Text Available Ischemic stroke is caused by a disruption in blood supply to a region of the brain. It induces dysfunction of brain cells and networks, resulting in sudden neurological deficits. The cause of stroke is vascular, but the consequences are neurological. Decades of research have focused on finding new strategies to reduce the neural damage after cerebral ischemia. However, despite the incredibly huge investment, all strategies targeting neuroprotection have failed to demonstrate clinical efficacy. Today, treatment for stroke consists of dealing with the cause, attempting to remove the occluding blood clot and recanalize the vessel. However, clinical evidence suggests that the beneficial effect of post-stroke recanalization may be hampered by the occurrence of microvascular reperfusion failure. In short: recanalization is not synonymous with reperfusion. Today, clinicians are confronted with several challenges in acute stroke therapy, even after successful recanalization: (1 induce reperfusion, (2 avoid hemorrhagic transformation (HT, and (3 avoid early or late vascular reocclusion. All these parameters impact the restoration of cerebral blood flow after stroke. Recent advances in understanding the molecular consequences of recanalization and reperfusion may lead to innovative therapeutic strategies for improving reperfusion after stroke. In this review, we will highlight the importance of restoring normal cerebral blood flow after stroke and outline molecular mechanisms involved in blood flow regulation.

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

    Directory of Open Access Journals (Sweden)

    Alana M. Horowitz

    2017-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Claudia P. Miller

    2011-01-01

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

  16. Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment.

    Science.gov (United States)

    Kintzing, James R; Filsinger Interrante, Maria V; Cochran, Jennifer R

    2016-12-01

    Protein-based therapeutics have been revolutionizing the oncology space since they first appeared in the clinic two decades ago. Unlike traditional small-molecule chemotherapeutics, protein biologics promote active targeting of cancer cells by binding to cell-surface receptors and other markers specifically associated with or overexpressed on tumors versus healthy tissue. While the first approved cancer biologics were monoclonal antibodies, the burgeoning field of protein engineering is spawning research on an expanded range of protein formats and modifications that allow tuning of properties such as target-binding affinity, serum half-life, stability, and immunogenicity. In this review we highlight some of these strategies and provide examples of modified and engineered proteins under development as preclinical and clinical-stage drug candidates for the treatment of cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Belayev Ludmila

    2016-01-01

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

  18. Advanced Therapeutic Strategies for Chronic Lung Disease Using Nanoparticle-Based Drug Delivery

    Directory of Open Access Journals (Sweden)

    Ji Young Yhee

    2016-09-01

    Full Text Available Chronic lung diseases include a variety of obstinate and fatal diseases, including asthma, chronic obstructive pulmonary disease (COPD, cystic fibrosis (CF, idiopathic pulmonary fibrosis (IPF, and lung cancers. Pharmacotherapy is important for the treatment of chronic lung diseases, and current progress in nanoparticles offers great potential as an advanced strategy for drug delivery. Based on their biophysical properties, nanoparticles have shown improved pharmacokinetics of therapeutics and controlled drug delivery, gaining great attention. Herein, we will review the nanoparticle-based drug delivery system for the treatment of chronic lung diseases. Various types of nanoparticles will be introduced, and recent innovative efforts to utilize the nanoparticles as novel drug carriers for the effective treatment of chronic lung diseases will also be discussed.

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

    Directory of Open Access Journals (Sweden)

    Caroline Perronnet

    2010-01-01

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

  20. Potential Therapeutic Strategies to Overcome Acquired Resistance to BRAF or MEK Inhibitors in BRAF Mutant Cancers

    Science.gov (United States)

    Corcoran, Ryan B.; Settleman, Jeffrey; Engelman, Jeffrey A.

    2011-01-01

    Recent clinical trials with selective inhibitors of the BRAF and MEK kinases have shown promising results in patients with tumors harboring BRAF V600 mutations. However, as has been observed previously with similarly successful targeted therapies, acquired resistance to these agents is an emerging problem that limits their clinical benefit. Several recent studies from our laboratory and others have investigated the causes of acquired resistance to BRAF and MEK inhibitors, and multiple resistance mechanisms have been identified. Here, we review these mechanisms and suggest that they can be broadly grouped into two main classes: ERK-dependent and ERK-independent. We also propose distinct therapeutic strategies that might be employed to overcome each class of acquired resistance. PMID:21505228

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

    Directory of Open Access Journals (Sweden)

    Shyi-Jou Chen

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Fiszer Agnieszka

    2012-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2015-06-15

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

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

    International Nuclear Information System (INIS)

    2015-01-01

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

  5. [Medico-economic evaluation of therapeutic strategies at hospital: A systematic review of French studies].

    Science.gov (United States)

    Baudouin, A; Armoiry, X; Dussart, C

    2017-05-01

    Therapeutic innovation contributes to the increase of health care expenditures in France. Medico-economic evaluation has still a minor role in the decision-making for the registration of drugs and medical devices in hospitals. This study aimed to systematically review published works on medico-economic studies conducted within French hospitals. A literature review was carried out to search for medico-economic studies conducted by hospital teams on therapeutic or diagnostic strategies employed within French hospitals and published from 2010 to 2014. Quality assessment of selected studies was performed according to Drummond et al.'s checklist, which is also used within French guidelines. Of the 44 analyzed articles, methods for identification and measure of costs and results complied with guidelines in 95 % of cases. For results interpretation, compliance was 91 %. Costs discounting (29 %) and the use of sensitivity analysis to account for results uncertainty (70 %) were the parameters with the lowest compliance to guidelines. A good training of health professionals in using economic and statistic tools, and the transferability of results of medico-economic studies are essential and should be optimized to enable a broader use of medico-economic evaluation within the scope of decision-making in French hospitals. Copyright © 2016 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

  6. Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications.

    Science.gov (United States)

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

    2017-11-28

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

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

    Science.gov (United States)

    Zhen, Shuai; Li, Xu

    2017-01-01

    Oncogenic human papillomaviruses (HPVs) cause different types of cancer especially cervical cancer. HPV-associated carcinogenesis provides a classical model system for clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) based cancer therapies since the viral oncogenes E6 and E7 are exclusively expressed in cancerous cells. Sequence-specific gene knockdown/knockout using CRISPR/Cas9 shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, CRISPR/Cas9-based targeting therapy requires further validation of its efficacy in vitro and in vivo to eliminate the potential off-target effects, necessitates verification of the delivery vehicles and the combinatory use of conventional therapies with CRISPR/Cas9 to ensure the feasibility and safety. In this review we discuss the potential of combining CRISPR/Cas9 with other treatment options as therapies for oncogenic HPVs-associated carcinogenesis. and present our assessment of the promising path to the development of CRISPR/Cas9 therapeutic strategies for clinical settings. © 2017 The Author(s). Published by S. Karger AG, Basel.

  8. IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

    Science.gov (United States)

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

    2015-05-14

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

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

    Directory of Open Access Journals (Sweden)

    Shuai Zhen

    2017-12-01

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

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

    Science.gov (United States)

    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

  11. A therapeutic HIV vaccine using coxsackie-HIV recombinants: a possible new strategy.

    Science.gov (United States)

    Halim, S S; Collins, D N; Ramsingh, A I

    2000-10-10

    The ultimate goal in the treatment of HIV-infected persons is to prevent disease progression. A strategy to accomplish this goal is to use chemotherapy to reduce viral load followed by immunotherapy to stimulate HIV-specific immune responses that are observed in long-term asymptomatic individuals. An effective, live, recombinant virus, expressing HIV sequences, would be capable of inducing both CTL and CD4(+) helper T cell responses. To accomplish these goals, the viral vector must be immunogenic yet retain its avirulent phenotype in a T cell-deficient host. We have identified a coxsackievirus variant, CB4-P, that can induce protective immunity against a virulent variant. In addition, the CB4-P variant remains avirulent in mice lacking CD4(+) helper T cells, suggesting that CB4-P may be uniquely suited as a viral vector for a therapeutic HIV vaccine. Two strategies designed to elicit CTL and CD4(+) helper T cell responses were used to construct CB4-P/HIV recombinants. Recombinant viruses were viable, genetically stable, and retained the avirulent phenotype of the parental virus. In designing a viral vector for vaccine development, an issue that must be addressed is whether preexisting immunity to the vector would affect subsequent administration of the recombinant virus. Using a test recombinant, we showed that prior exposure to the parental CB4-P virus did not affect the ability of the recombinant to induce a CD4(+) T cell response against the foreign sequence. The results suggest that a "cocktail" of coxsackie/HIV recombinants may be useful as a therapeutic HIV vaccine.

  12. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

    Science.gov (United States)

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

    2014-05-01

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

  13. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

    Science.gov (United States)

    Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

    2017-12-27

    The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

    Science.gov (United States)

    Ma, Hongwei; Yang, Fan; Butler, Michael R; Belcher, Joshua; Redmond, T Michael; Placzek, Andrew T; Scanlan, Thomas S; Ding, Xi-Qin

    2017-08-01

    Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB , encode TRs; THRB 2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30-40% in the Rpe65 -/- mouse model of Leber congenital amaurosis and reduced the number of TUNEL + cells. Cone survival was significantly improved in Rpe65 -/- and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb2 -/- and Rpe65 -/- / Thrb2 -/- mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.-Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

  15. Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease.

    Science.gov (United States)

    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

    2015-02-01

    Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies

    International Nuclear Information System (INIS)

    Obermiller, Patrice S; Tait, David L; Holt, Jeffrey T

    2000-01-01

    Gene therapy is a therapeutic approach that is designed to correct specific molecular defects that contribute to the cause or progression of cancer. Genes that are mutated or deleted in cancers include the cancer susceptibility genes p53 and BRCA1. Because mutational inactivation of gene function is specific to tumor cells in these settings, cancer gene correction strategies may provide an opportunity for selective targeting without significant toxicity for normal nontumor cells. Both p53 and BRCA1 appear to inhibit cancer cells that lack mutations in these genes, suggesting that the so-called gene correction strategies may have broader potential than initially believed. Increasing knowledge of cancer genetics has identified these and other genes as potential targets for gene replacement therapy. Initial patient trials of p53 and BRCA1 gene therapy have provided some indications of potential efficacy, but have also identified areas of basic and clinical research that are needed before these approaches may be widely used in patient care

  17. Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Isaac G Onyango

    2018-01-01

    Full Text Available Alzheimer's disease (AD is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

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

    Directory of Open Access Journals (Sweden)

    Van Lint Carine

    2009-12-01

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

  19. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.

    Science.gov (United States)

    Hira, Vashendriya V V; Van Noorden, Cornelis J F; Carraway, Hetty E; Maciejewski, Jaroslaw P; Molenaar, Remco J

    2017-08-01

    Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Hyunyun Kim

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Laetitia Devy

    2011-01-01

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

  2. Photochemical internalization of therapeutic macromolecular agents: a novel strategy to kill multidrug-resistant cancer cells.

    Science.gov (United States)

    Selbo, Pål K; Weyergang, Anette; Bonsted, Anette; Bown, Stephen G; Berg, Kristian

    2006-11-01

    Drug resistance is a major problem for chemotherapy. Entrapment of anticancer drugs in endolysosomal compartments or active extrusions by plasma membrane proteins of the ATP-binding cassette (ABC) superfamily are important resistance mechanisms. This study evaluated photochemical internalization (PCI) of membrane-impermeable macromolecules that are not the target of ABC drug pumps for treating multidrug-resistant (MDR) cancer cells. We used the drug-sensitive uterine fibrosarcoma cell line MES-SA and its MDR, P-glycoprotein (P-gp)-overexpressing derivative MES-SA/Dx5 with the photosensitizer disulfonated meso-tetraphenylporphine (TPPS(2a)) and broad spectrum illumination. The PCI of doxorubicin, the ribosome-inactivating protein gelonin and adenoviral transduction were assessed in both cell lines, together with the uptake and excretion of TPPS(2a) and of two fluid phase markers easily detectable by fluorescence [lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran], as a model of gelonin uptake. Both cell lines were resistant to PCI of doxorubicin, but equally sensitive to PCI of gelonin, even though the endocytosis rates of LY and FITC-dextran were significantly lower in the MDR cells. In control studies, MES-SA/Dx5 cells were more resistant to photodynamic therapy (TPPS(2a) + light only). This was not mediated by P-gp, as there were no differences in the uptake and efflux of TPPS(2a) between the cell lines. After adenoviral infection, PCI enhanced gene delivery in both cell lines. In conclusion, PCI of macromolecular therapeutic agents that are not targets of P-gp is a novel therapeutic strategy to kill MDR cancer cells.

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

    Directory of Open Access Journals (Sweden)

    Zoey Harris

    2016-10-01

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

  4. Eosinophilic Esophagitis: Impact of Latest Insights Into Pathophysiology on Therapeutic Strategies.

    Science.gov (United States)

    Schoepfer, Alain; Safroneeva, Ekaterina; Straumann, Alex

    underlying inflammation. This review highlights the latest insights regarding pathophysiology and its impact regarding current and future therapeutic strategies. © 2016 S. Karger AG, Basel.

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

    Directory of Open Access Journals (Sweden)

    Dimitropoulos K

    2016-04-01

    Full Text Available Konstantinos Dimitropoulos, Stavros Gravas Department of Urology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece Abstract: 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

  6. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

    Science.gov (United States)

    Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

    2016-12-01

    Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

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

    Directory of Open Access Journals (Sweden)

    Ebbe Toftgaard Poulsen

    2015-12-01

    Full Text Available 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.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Angel L. Pey

    2013-01-01

    Full Text Available 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.

  10. Neurogenesis in Huntington's disease: can studying adult neurogenesis lead to the development of new therapeutic strategies?

    Science.gov (United States)

    Gil-Mohapel, Joana; Simpson, Jessica M; Ghilan, Mohamed; Christie, Brian R

    2011-08-11

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of CAG repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairments. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, although other regions including the hippocampus are also affected. In this review we discuss the different mouse models of HD, and how the process of neurogenesis in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) is affected in each. Deficits in adult hippocampal neurogenesis have been repeatedly shown in different genetic models of HD, raising the possibility that an impairment of the neurogenic process might underlie some of the cognitive deficits associated with this neurodegenerative disorder. On the other hand, an increase in SVZ neurogenesis has been observed in human HD brains while no differences in SVZ cell proliferation have been detected in the mouse models. In this review we will discuss the discrepancies between these findings as well as the several mechanisms that might contribute to a dysregulation of adult neurogenesis in HD. Finally, we will provide an overview of the various therapeutic strategies aimed at stimulating the endogenous neurogenic capacity that have been tested in HD genetic models. Ultimately, the insights obtained from these and future studies will greatly improve our understanding of the cognitive impairment characteristic of HD. Copyright © 2011 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  12. Proteasome inhibitors: possible novel therapeutic strategy for ischemia-reperfusion injury?

    Science.gov (United States)

    Kandilis, Apostolos N; Karidis, Nikolaos P; Kouraklis, Gregory; Patsouris, Efstratios; Vasileiou, Ioanna; Theocharis, Stamatios

    2014-01-01

    The ubiquitin-proteasome system (UPS) is responsible for the degradation of misfolded or damaged proteins, regulating inflammatory processes and cell cycle progression. The aim of this article is to summarize the currently available data regarding the possible utility of proteasome inhibitors (PIs) in the treatment of ischemia-reperfusion injury (IRI). Data were reviewed from the published literature using the Medline database. The effect of PIs on IRI is dependent on the dosage, time of administration (prior to or post IRI induction), the affected organ, and the experimental model used. Undoubtedly, in most cases PIs' application resulted in attenuated IRI, although it was uniformly shown that inhibition of the UPS prior to ischemic preconditioning (IPC) abolished the protective effect of IPC in IRI. Mechanism of action involves several pathways, including nuclear factor kappa-B (NF-κB) inactivation, antineutrophil action, decreased intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, and the cytoprotective proteins eNOS, heme oxigenase 1 and hsp70 up-regulation. Current data are limited, but appear promising with regard to PI consideration as an effective future therapeutic strategy for IRI. Nevertheless, further investigation is required in terms of safety and validation of the appropriate for each agent dosage, in order to establish their possible contribution in human IRI.

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

    Directory of Open Access Journals (Sweden)

    Michal Mielcarek

    2013-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Anna Rita Bilia

    2014-01-01

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

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

    Science.gov (United States)

    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

    2015-11-03

    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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Gregory A. Watson

    2006-11-01

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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Anja Geiselhart

    2012-01-01

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

  19. Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis

    DEFF Research Database (Denmark)

    Köhler, Ralf; Wulff, Heike; Eichler, Ines

    2003-01-01

    hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content. CONCLUSIONS: The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent...

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

    Directory of Open Access Journals (Sweden)

    Ito K

    2012-09-01

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

  1. Targeting HER2 signaling pathway for radiosensitization: alternative strategy for therapeutic resistance.

    Science.gov (United States)

    No, Mina; Choi, Eun Jung; Kim, In Ah

    2009-12-01

    Several studies have indicated the potential value of targeting HER-2 signaling to enhance the anti-tumor activity of ionizing radiation. However, therapeutic resistance resulting from several factors, including activation of the downstream pathway, represents a major obstacle to treatment. Here, we investigated whether inhibitors targeting downstream of HER-2 signaling would radiosensitize SKBR3 breast cancer cells that exhibit overamplification of HER2. Selective inhibition of MEK-ERK signaling using pharmacologic inhibitors (PD98059, UO126) did not increase the radiosensitivity of SKBR3 cells. Selective inhibition of the PI3K-AKT-mTOR pathway using pharmacologic inhibitors (LY294002, AKT inhibitor VIII, Rapamycin) significantly attenuated expression of p-AKT and p-70S6K, respectively and radiosensitized SKBR3 cells. MCF-7 cells those did not overexpress HER-2, showed less radiosensitization compared to SKBR3 cells by inhibition of this pathway. Pre-treatment with these inhibitors also caused significant abrogation of typical G(2) arrest following ionizing radiation and induced marked prolongation of gammaH2AX foci indicating impairment of DNA damage repair. A dual inhibitor of Class I PI3K and mTOR, PI103 effectively radiosensitized SKBR3 cells and showed significant prolongation of gammaH2AX foci. Inhibition of PI3K-AKT signaling was associated with downregulation of DNA-PKs, respectively. While apoptosis was the major mode of cell death when the cells were pretreated with LY294002 or AKT inhibitor VIII, the cells were pretreated by rapamycin or PI103 showed mixed mode of cell death including autophagy. Our results suggest possible mechanisms to counteract the HER-2 prosurvival signaling implicated in radioresistance, and offer an alternative strategy to overcome resistance to HER-2 inhibitors combined with radiation.

  2. N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution.

    Science.gov (United States)

    Skaper, Stephen D; Facci, Laura; Barbierato, Massimo; Zusso, Morena; Bruschetta, Giuseppe; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Giusti, Pietro

    2015-10-01

    Inflammation is fundamentally a protective cellular response aimed at removing injurious stimuli and initiating the healing process. However, when prolonged, it can override the bounds of physiological control and becomes destructive. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders. Glia, key players in such nervous system disorders, are not only capable of expressing a pro-inflammatory phenotype but respond also to inflammatory signals released from cells of immune origin such as mast cells. Chronic inflammatory processes may be counteracted by a program of resolution that includes the production of lipid mediators endowed with the capacity to switch off inflammation. These naturally occurring lipid signaling molecules include the N-acylethanolamines, N-arachidonoylethanolamine (an endocannabinoid), and its congener N-palmitoylethanolamine (palmitoylethanolamide or PEA). PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation. PEA is efficacious in mast cell-mediated models of neurogenic inflammation and neuropathic pain and is neuroprotective in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease. PEA in micronized/ultramicronized form shows superior oral efficacy in inflammatory pain models when compared to naïve PEA. Intriguingly, while PEA has no antioxidant effects per se, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treat neuroinflammation. This review is intended to discuss the role of mast cells and glia in neuroinflammation and strategies to modulate their activation based on leveraging natural mechanisms with the capacity for self-defense against inflammation.

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

    Directory of Open Access Journals (Sweden)

    Deyan Luan

    2007-07-01

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

  4. Pneumonia in nursing home patients: is it time for a specific therapeutic strategy?

    Directory of Open Access Journals (Sweden)

    Gualberto Gussoni

    2013-04-01

    Full Text Available Background: Nursing home-acquired pneumonia (NHAP was described in 1978, but only in 2005 it has been proposed as part of a new category (health care-associated pneumonia distinct from community- or hospital-acquired infections. However, limited clinical data exist to validate this proposal. Aim of the study: To compare characteristics and outcome of patients hospitalised for pneumonia and coming from private residence or nursing home. Methods: Post-hoc analysis of the prospective phase of the FASTCAP study, performed to evaluate the impact of the Recommendations issued by the Italian Federation of Internal Medicine (FADOI in 2002 on the management of hospitalised community-acquired pneumonia (CAP. Results: The study examined 1,219 patients coming from private residence, and 179 with NHAP. Failures of therapy were significantly more frequent in patients with NHAP (35.8% vs 24.9%; Odds Ratio 1.48; 95% confidence interval 1.05-2.09. Mortality was higher in patients coming from nursing home (24.0% vs 9.8%; OR 2.59; 95% CI 1.72-3.90. Antibiotic treatment was more frequently performed as monotherapy in case of NHAP. Conclusions: At the time of FASTCAP, NHAP was included in the category of CAP, and coherently, treatment of NHAP was not more aggressive if compared to community-acquired infections. However, our results confirm that NHAP is at increased risk for worst outcome, and probably worth considering for specific therapeutic strategies. Future studies are needed to better assess the microbiology of NHAP, and to evaluate if specific treatments, as those recommended by recent guidelines, may improve the outcome for these high-risk patients.

  5. Photochemical Internalization of Peptide Antigens Provides a Novel Strategy to Realize Therapeutic Cancer Vaccination

    Directory of Open Access Journals (Sweden)

    Markus Haug

    2018-04-01

    Full Text Available Effective priming and activation of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs is crucial for realizing the potential of therapeutic cancer vaccination. This requires cytosolic antigens that feed into the MHC class I presentation pathway, which is not efficiently achieved with most current vaccination technologies. Photochemical internalization (PCI provides an emerging technology to route endocytosed material to the cytosol of cells, based on light-induced disruption of endosomal membranes using a photosensitizing compound. Here, we investigated the potential of PCI as a novel, minimally invasive, and well-tolerated vaccination technology to induce priming of cancer-specific CTL responses to peptide antigens. We show that PCI effectively promotes delivery of peptide antigens to the cytosol of antigen-presenting cells (APCs in vitro. This resulted in a 30-fold increase in MHC class I/peptide complex formation and surface presentation, and a subsequent 30- to 100-fold more efficient activation of antigen-specific CTLs compared to using the peptide alone. The effect was found to be highly dependent on the dose of the PCI treatment, where optimal doses promoted maturation of immature dendritic cells, thus also providing an adjuvant effect. The effect of PCI was confirmed in vivo by the successful induction of antigen-specific CTL responses to cancer antigens in C57BL/6 mice following intradermal peptide vaccination using PCI technology. We thus show new and strong evidence that PCI technology holds great potential as a novel strategy for improving the outcome of peptide vaccines aimed at triggering cancer-specific CD8+ CTL responses.

  6. Limited-Sampling Strategies for Therapeutic Drug Monitoring of Moxifloxacin in Patients With Tuberculosis

    NARCIS (Netherlands)

    Pranger, Arianna D.; Kosterink, Jos G. W.; van Altena, Richard; Aarnoutse, Rob E.; van der Werf, Tjip S.; Uges, Donald R. A.; Alffenaar, Jan-Willem C.

    Background: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

  7. Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis

    NARCIS (Netherlands)

    Pranger, A.D.; Kosterink, J.G.W.; Altena, R. van; Aarnoutse, R.E.; Werf, T.S. van der; Uges, D.R.A.; Alffenaar, J.W.C.

    2011-01-01

    BACKGROUND: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

  8. The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein

    NARCIS (Netherlands)

    McLoughlin, N.M.; Mueller, C.; Grossmann, T.N.

    2018-01-01

    Two decades have passed since the discovery of the tumor suppressor, PTEN. A multitude of biological functions have since been revealed, suggesting potential therapeutic applications for both PTEN activation (e.g., cancer) and inhibition (e.g., neuroregeneration). Nevertheless, PTEN's therapeutic

  9. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin. Addendum

    Science.gov (United States)

    2014-07-01

    KS, Abrahamson DR, De Lisle RC, Wallace DP, Maser RL, Grantham JJ, and Calvet JP. Early embryonic renal tubules of wild-type and polycystic kidney ...embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance...AD_________________ Award Number: W81XWH-10-1-0504 TITLE: A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation

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

    Science.gov (United States)

    Valor, Lara; López-Longo, Francisco Javier

    2015-09-07

    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. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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. Neural and psychological underpinnings of gambling disorder

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian L; Chamberlain, Samuel R

    2016-01-01

    Gambling disorder affects 0.4 to 1.6% of adults worldwide, and is highly comorbid with other mental health disorders. This article provides a concise primer on the neural and psychological underpinnings of gambling disorder based on a selective review of the literature. Gambling disorder is assoc......Gambling disorder affects 0.4 to 1.6% of adults worldwide, and is highly comorbid with other mental health disorders. This article provides a concise primer on the neural and psychological underpinnings of gambling disorder based on a selective review of the literature. Gambling disorder...... is required to evaluate whether cognitive dysfunction and personality aspects influence the longitudinal course and treatment outcome for gambling disorder. It is hoped that improved understanding of the biological and psychological components of gambling disorder, and their interactions, may lead to improved...

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-05-15

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

  16. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

    OpenAIRE

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

    2014-01-01

    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sc...

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

    DEFF Research Database (Denmark)

    Roizman, Dan; Vidaillac, Celine; Givskov, Michael

    2017-01-01

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

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

    NARCIS (Netherlands)

    Temming, K; Molema, G; Kok, RJ

    2005-01-01

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

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

    Science.gov (United States)

    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. © 2016 John Wiley & Sons A/S.

  20. Myocardial Bridging: Contemporary Understanding of Pathophysiology with Implications for Diagnostic and Therapeutic Strategies

    Science.gov (United States)

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

    2014-01-01

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

  1. Emerging nanotechnology based strategies for diagnosis and therapeutics of urinary tract infections: A review.

    Science.gov (United States)

    Kumar, M S; Das, A P

    2017-11-01

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

  2. Effectiveness of multiple therapeutic strategies in neovascular glaucoma patients: A PRISMA-compliant network meta-analysis.

    Science.gov (United States)

    Dong, Zixian; Gong, Jianyang; Liao, Rongfeng; Xu, Shaojun

    2018-04-01

    Neovascular glaucoma (NVG) is a severe secondary glaucoma with uncontrolled intraocular pressure that leads to serious eye pain and vision loss. Presently, the therapeutic strategies for NVG are diverse, but the therapeutic effects are still not ideal. We performed a network analysis to assess the effect of multiple therapeutic strategies on the treatment of NVG patients. We searched public electronic databases through April 2017 using the following keywords "neovascular glaucoma," "iris neovascularization," "hemorrhagic glaucoma," and "random" without language restrictions. The outcome considered in the present analysis was treatment success rate. A network meta-analysis and multilevel mixed-effects logistic regression were used to compare regimens. We included 27 articles assessing a total of 1884 NVG patients in our analysis. According to the network analysis, interferon and mitomycin plus trabeculectomy (94.9%), glaucoma valve implantation (86.9%), and iris photocoagulation plus trabeculectomy (81.9%) were the most likely to improve treatment success rate in NVG patients. The multilevel logistic regression analysis showed that glaucoma valve, bevacizumab, interferon, cyclophotocoagulation, trabeculectomy, iris photocoagulation, ranibizumab, and mitomycin had advantages in terms of improving treatment success rate in NVG patients. However, the application of retinal photocoagulation and vitrectomy reduced patient treatment success rate. The regimen including mitomycin, interferon, and trabeculectomy was the most likely to improve the treatment success rate in NVG patients. The application of glaucoma valve and bevacizumab were more beneficial for improving patient treatment success rate as a surgery and as an agent, respectively.

  3. Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives.

    Science.gov (United States)

    Bose, Bipasha; Sen, Utsav; Shenoy P, Sudheer

    2018-01-01

    Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Impact of the scintigraphy of somatostatin receptors upon the therapeutic strategy in patients bearing digestive endocrine tumors

    International Nuclear Information System (INIS)

    Lebtahi, R.; Cadiot, G.; Genin, R.; Delahaye, N.; Faraggi, M.; Daou, D.; Peker, C.; Migon, M.; Le Guludec, D.

    1997-01-01

    The scintigraphy of somatostatin receptors (SSR) is a sensible method for detecting the gastroenteric-pancreatic endocrine tumors and their metastases. The aim of this study is to evaluate the clinical impact of the results of SSR in taking patients in therapeutic charge. A hundred and sixty patients bearing biologically and/or histologically proved digestive endocrine tumors were prospectively studied. The patients were classified in 3 groups: group I - 90 patients with no known metastases; group II - 59 patients with liver metastases and group III - 11 patients with known extra-hepatic metastases. The results of the scintigraphy were compared with those of conventional imaging. The following results were obtained: in group 1 (90 patients) the conventional imaging has allowed detecting 53 primitive tumors in 44 patients. The SSR visualized 68% of these sites and has detected 26 supplementary primitive sites in 20 patients and 29 metastatic sites in 25 patients. In group II the scintigraphy has detected 95% of hepatic metastases and revealed 23 new metastasis sites and 18/59 patients. In group III the scintigraphy has detected 11 new sites in 7 patients. The results of scintigraphy modified the patient's classification in 38 cases (24%). The therapeutic strategy was modified for 40 patients (25%). In conclusion, the scintigraphy of somatostatin receptors is able to detect a significant number of digestive endocrine tumors what has important implications for therapeutical planning of the treatment of patients. It must be carried out during pre-therapeutic extension examination of these tumors

  5. Recent advances in therapeutic recruitment of mammalian RNAi and bacterial CRISPR-Cas DNA interference pathways as emerging antiviral strategies.

    Science.gov (United States)

    Chin, Wei-Xin; Ang, Swee Kim; Chu, Justin Jang Hann

    2017-01-01

    In invertebrate eukaryotes and prokaryotes, respectively, the RNAi and clustered regularly interspaced short palindromic repeats-CRISPR-associated (CRISPR-Cas) pathways are highly specific and efficient RNA and DNA interference systems, and are well characterised as potent antiviral systems. It has become possible to recruit or reconstitute these pathways in mammalian cells, where they can be directed against desired host or viral targets. The RNAi and CRISPR-Cas systems can therefore yield ideal antiviral therapeutics, capable of specific and efficient viral inhibition with minimal off-target effects, but development of such therapeutics can be slow. This review covers recent advances made towards developing RNAi or CRISPR-Cas strategies for clinical use. These studies address the delivery, toxicity or target design issues that typically plague the in vivo or clinical use of these technologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy

    OpenAIRE

    Park, Geon-Tae; Choi, Kyung-Chul

    2016-01-01

    The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migra...

  7. Developing a Novel Therapeutic Strategy Targeting Kallikrein-4 to Inhibit Prostate Cancer Growth and Metastasis

    Science.gov (United States)

    2015-08-01

    Kallikrein-related peptidase 4 (KLK4) is a rational therapeutic target for prostate cancer (PCa) as it is up-regulated in both localised and bone...both localised and bone metastatic cancerous tissue, and is an independent biomarker discriminating between benign and malignant prostate tissue [1,2...cellular function . siKLK4(A), siKLK4(B) and siControl are currently being conjugated onto HBP-peptide by collaborators from AIBN. siRNA sequences are

  8. Vatuximab(Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

    Science.gov (United States)

    2010-01-01

    therapeutic efficacy in experimental diabetic retinopathy . Invest Ophthalmol Vis Sci, 42, 2964-9 (2001) 141. Berkowitz, B. A., C. McDonald, Y. Ito, P...tumors measured over a period of 11 weeks of thrice weekly treatment with bavituximab (2.5 mg/kg IP). A predicted mean growth rate for untreated... predicted control tumor in Figure 18. However, R1L1 and R0L0 both show growth rates considerably slower than control and greatly increased DCE

  9. Therapeutic step-up strategy for management of hereditary pancreatitis in children.

    Science.gov (United States)

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

    2015-04-01

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

  10. GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators.

    Science.gov (United States)

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

    2015-01-01

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

  11. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study.

    Science.gov (United States)

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

    2009-09-01

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

  12. New drugs, therapeutic strategies, and future direction for the treatment of Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Mercurio, Valentina; Bianco, Anna; Campi, Giacomo; Cuomo, Alessandra; Diab, Nermin; Mancini, Angela; Parrella, Paolo; Petretta, Mario; Hassoun, Paul; Bonaduce, Domenico

    2018-01-31

    Despite recent advances in pulmonary arterial hypertension (PAH) treatment, this condition is still characterized by an extremely poor prognosis. In this review, we discuss the use of newly-approved drugs for PAH treatment with already known mechanisms of action (macitentan), innovative targets (riociguat and selexipag), and novel therapeutic approaches with initial up-front combination therapy. Secondly, we describe new potential signalling pathways and investigational drugs with promising role in the treatment of PAH. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics.

    Science.gov (United States)

    Selbo, Pål Kristian; Bostad, Monica; Olsen, Cathrine Elisabeth; Edwards, Victoria Tudor; Høgset, Anders; Weyergang, Anette; Berg, Kristian

    2015-08-01

    Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex® as a rational, non-invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS-generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of-concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT-resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells.

  14. Cell- and gene-based therapeutic strategies for periodontal regenerative medicine.

    Science.gov (United States)

    Rios, Hector F; Lin, Zhao; Oh, Bina; Park, Chan Ho; Giannobile, William V

    2011-09-01

    Inflammatory periodontal diseases are a leading cause of tooth loss and are linked to multiple systemic conditions, such as cardiovascular disease and stroke. Reconstruction of the support and function of affected tooth-supporting tissues represents an important therapeutic endpoint for periodontal regenerative medicine. An improved understanding of periodontal biology coupled with current advances in scaffolding matrices has introduced novel treatments that use cell and gene therapy to enhance periodontal tissue reconstruction and its biomechanical integration. Cell and gene delivery technologies have the potential to overcome limitations associated with existing periodontal therapies, and may provide a new direction in sustainable inflammation control and more predictable tissue regeneration of supporting alveolar bone, periodontal ligament, and cementum. This review provides clinicians with the current status of these early-stage and emerging cell- and gene-based therapeutics in periodontal regenerative medicine, and introduces their future application in clinical periodontal treatment. The paper concludes with prospects on the application of cell and gene tissue engineering technologies for reconstructive periodontology.

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

    Science.gov (United States)

    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. © 2016 John Wiley & Sons Ltd.

  16. Mesenchymal Stem Cells-Derived Exosomes: A Possible Therapeutic Strategy for Osteoporosis.

    Science.gov (United States)

    Li, Yue; Jin, Daxiang; Xie, Weixing; Wen, Longfei; Chen, Weijian; Xu, Jixi; Ding, Jinyong; Ren, Dongcheng; Xiao, Zenglin

    2018-04-03

    Osteoporosis is a common age-related disorder characterized by low bone mass and deterioration in bone microarchitecture, leading to increased skeletal fragility and fracture risk. The pathophysiology of osteoporosis is multifactorial. It is related to the imbalance between osteoblasts and osteoclasts; reduced bone mass and increased adipogenesis in the bone marrow. Moreover, angiogenesis, inflammatory process and miRNAs have shown effects in the formation of osteoporosis. In the recent years, mesenchymal stem cells (MSCs) have been regarded as an excellent choice for cell-based tissue engineering therapy of osteoporosis. Growing evidence showed that, paracrine effect have been considered as the predominant mechanism for the role of MSCs in tissue repair. Recently, many studies have proposed that MSCs-derived exosomes are effective for a variety of diseases like cancer, cardiovascular diseases, etc. However, whether the MSCs-derived exosomes could serve as a novel therapeutic tool for osteoporosis has not clearly described. In this review, we summarize the MSCs-derived exosomes and the relationship with osteogenesis, osteoclast differentiation, angiogenesis, immune processes and miRNAs. Finally, we suggest that MSCs-derived exosomes might be a promising therapeutic method for osteoporosis in the future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress

    Science.gov (United States)

    Booz, George W.

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Matthew J Haney

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

  19. Insights into the molecular pathogenesis of atherosclerosis and therapeutic strategies using gene transfer.

    Science.gov (United States)

    Hiltunen, M O; Turunen, M P; Laitinen, M; Ylä-Herttuala, S

    2000-01-01

    Gene therapy for the treatment of atherosclerosis and related diseases has shown its potential in animal models and in the first human trials. Gene transfer to the vascular system can be performed both via intravascular and extravascular periadventitial routes. Intravascular gene transfer can be done with several types of catheters under fluoroscopic control. Extravascular gene transfer, on the other hand, provides a well-targeted gene delivery route available during vascular surgery. It can be done with direct injection or by using perivascular cuffs or surgical collagen sheets. Ex vivo gene delivery via transfected smooth muscle cells or endothelial cells might be useful for the production of secreted therapeutic compounds. Gene transfer to the liver has been used for the treatment of hyperlipidemia. The first clinical trials for the induction of therapeutic angiogenesis in ischemic myocardium or peripheral muscles with VEGF or FGF gene transfer are under way and preliminary results are promising. VEGF has also been used for the prevention of postangioplasty restenosis because of its capability to induce endothelial repair and production of NO and prostacyclin. However, further basic research is needed to fully understand the pathophysiological mechanisms involved in conditions related to atherosclerosis. Also, further development of gene transfer vectors and gene delivery techniques will improve the efficacy and safety of human gene therapy.

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

    Directory of Open Access Journals (Sweden)

    Sampath P

    2015-06-01

    Full Text Available Padma Sampath, Steve H Thorne Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA Abstract: 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. Keywords: oncolytic virus, CAR T-cell, adoptive cell therapy, immune checkpoint inhibitor 

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

    Directory of Open Access Journals (Sweden)

    Jing Lin

    2017-12-01

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

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

    Science.gov (United States)

    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

  3. Utilizing TH9 cells as a novel therapeutic strategy for malignancies

    OpenAIRE

    Lu, Yong; Yi, Qing

    2013-01-01

    TH9 cells join the ever-growing list of CD4+ T helper subsets and primarily mediate anti-parasite immune responses. We have recently demonstrated that tumor-specific TH9 cells induce a CCL20-CCR6-dependent regulation of DCs while stimulating CD8+ T cell-mediated antitumor immunity. These findings offer a novel immunotherapeutic strategy against cancer.

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

    Directory of Open Access Journals (Sweden)

    Jeehoon Kang

    2016-11-01

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

  5. MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations.

    Science.gov (United States)

    Kerstjens, Mark; Driessen, Emma M C; Willekes, Merel; Pinhanços, Sandra S; Schneider, Pauline; Pieters, Rob; Stam, Ronald W

    2017-02-28

    Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RAS-mutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity, both in RAS-mutant and RAS-wildtype cells. In conclusion, MEK inhibition represents a promising therapeutic strategy for MLL-rearranged ALL patients harboring RAS mutations, while patients without RAS mutations may benefit through prednisolone sensitization.

  6. Codon optimization underpins generalist parasitism in fungi.

    Science.gov (United States)

    Badet, Thomas; Peyraud, Remi; Mbengue, Malick; Navaud, Olivier; Derbyshire, Mark; Oliver, Richard P; Barbacci, Adelin; Raffaele, Sylvain

    2017-02-03

    The range of hosts that parasites can infect is a key determinant of the emergence and spread of disease. Yet, the impact of host range variation on the evolution of parasite genomes remains unknown. Here, we show that codon optimization underlies genome adaptation in broad host range parasites. We found that the longer proteins encoded by broad host range fungi likely increase natural selection on codon optimization in these species. Accordingly, codon optimization correlates with host range across the fungal kingdom. At the species level, biased patterns of synonymous substitutions underpin increased codon optimization in a generalist but not a specialist fungal pathogen. Virulence genes were consistently enriched in highly codon-optimized genes of generalist but not specialist species. We conclude that codon optimization is related to the capacity of parasites to colonize multiple hosts. Our results link genome evolution and translational regulation to the long-term persistence of generalist parasitism.

  7. Gut Microbiota Dysbiosis Drives and Implies Novel Therapeutic Strategies for Diabetes Mellitus and Related Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Xuan Li

    2017-12-01

    Full Text Available Accumulating evidence over the past decade has linked the development of metabolic syndrome related to diabetes to variations in gut microbiota, an emerging, critical homeostatic regulator of host energy metabolism and immune responses. Mechanistic studies in rodent models have revealed an ever-increasing multitude of molecular mechanisms whereby the gut microbiota interacts with various host sensing and signaling pathways, leading to modulation of endocrine system, immune responses, nervous system activity, and hence, the predisposition to metabolic diseases. Remarkably, the microbiota-driven immune responses in metabolic tissues and the host nutrient-sensing mechanisms of gut microbial metabolites, in particular short-chain fatty acids, have been significantly associated with the proneness to diabetes and related disorders. This review will synthesize the recent efforts on unraveling the mediating role of gut microbiota in the pathogenesis of metabolic diseases, aiming to reveal new therapeutic opportunities.

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

    LENUS (Irish Health Repository)

    Wander, Seth A

    2011-04-01

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

  9. Novel strategies and therapeutic options for the management of primary biliary cholangitis.

    Science.gov (United States)

    Khanna, Amardeep; Jones, David E

    2017-10-01

    Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. It has a varied course of progression ranging from being completely asymptomatic to aggressive disease leading to cirrhosis and resulting in liver transplantation. In addition, symptoms can be debilitating and can have a major impact on quality of life. For decades, there was only one anti-cholestatic agent available to target this disease and that was only effective in around half of patients, with little or no effect on symptoms. With increasing understanding of the pathogenic mechanisms of PBC and potential targets for drug treatment, pharmaceutical companies have shown a greater interest in this rare disease. A large number of novel therapeutic molecules have been developed and are currently being evaluated. In this review article all the novel molecules in use and in trials targeting cholestasis and symptoms in PBC are discussed.

  10. The Capsular Polysaccharide of Acinetobacter baumannii Is an Obstacle for Therapeutic Passive Immunization Strategies.

    Science.gov (United States)

    Wang-Lin, Shun Xin; Olson, Ruth; Beanan, Janet M; MacDonald, Ulrike; Balthasar, Joseph P; Russo, Thomas A

    2017-12-01

    Acinetobacter baumannii has become an important concern for human health due to rapid development and wide spread of antimicrobial-resistant strains and high mortality associated with the infection. Passive immunizations with antisera targeting outer membrane proteins (OMPs) have shown encouraging results in protecting mice from A. baumannii infection, but monoclonal anti-OMP antibodies have not been developed, and their potential therapeutic properties have not been explored. The goal of this report is to evaluate the antibacterial activity of monoclonal antibodies (MAbs) targeting outer membrane protein A (OmpA) of A. baumannii Five anti-OmpA MAbs were developed using hybridoma technology and showed strong binding to strain ATCC 19606. However, low antibody binding was observed when they were tested against six clinical isolates, which included extensively drug-resistant strains. In contrast, high binding to an isogenic K1 capsule-negative mutant (AB307.30) was shown, suggesting that capsular polysaccharide mediated the inhibition of MAb binding to OmpA. Anti-OmpA MAbs increased the macrophage-mediated bactericidal activity of AB307.30 but failed to increase phagocytic killing of capsule-positive strains. Capsular polysaccharide was also protective against complement-mediated bactericidal activity in human ascites in the presence and absence of opsonization. Lastly, passive immunization with anti-OmpA MAbs did not confer protection against challenge with AB307-0294, the encapsulated parent strain of AB307.30, in a mouse sepsis infection model. These results reveal the important role of capsule polysaccharide in shielding OmpA and thereby inhibiting anti-OmpA MAb binding to clinical isolates. This property of capsule hindered the therapeutic utility of anti-OmpA MAbs, and it may apply to other conserved epitopes in A. baumannii . Copyright © 2017 American Society for Microbiology.

  11. Utilizing TH9 cells as a novel therapeutic strategy for malignancies.

    Science.gov (United States)

    Lu, Yong; Yi, Qing

    2013-03-01

    T H 9 cells join the ever-growing list of CD4 + T helper subsets and primarily mediate anti-parasite immune responses. We have recently demonstrated that tumor-specific T H 9 cells induce a CCL20-CCR6-dependent regulation of DCs while stimulating CD8 + T cell-mediated antitumor immunity. These findings offer a novel immunotherapeutic strategy against cancer.

  12. Recent advancement to prevent the development of allergy and allergic diseases and therapeutic strategy in the perspective of barrier dysfunction.

    Science.gov (United States)

    Natsume, Osamu; Ohya, Yukihiro

    2018-01-01

    Therapeutic strategy in late 20th century to prevent allergic diseases was derived from a conceptual framework of allergens elimination which was as same as that of coping with them after their onset. Manifold trials were implemented; however, most of them failed to verify the effectiveness of their preventive measures. Recent advancement of epidemiological studies and cutaneous biology revealed epidermal barrier dysfunction plays a major role of allergen sensitization and development of atopic dermatitis which ignites the inception of allergy march. For this decade, therapeutic strategy to prevent the development of food allergy has been confronted with a paradigm shift from avoidance and delayed introduction of allergenic foods based on the theoretical concept to early introduction of them based on the clinical and epidemiological evidences. Especially, prevention of peanut allergy and egg allergy has been established with the highest evidence verified by randomized controlled trials, although application in clinical practice should be done with attention. This paradigm shift concerning food allergy was also due to the discovery of cutaneous sensitization risk of food allergens for an infant with eczema revealed by prospective studies. Here we have recognized the increased importance of prevention of eczema/atopic dermatitis in infancy. Two randomized controlled trials using emollients showed successful results in prevention of atopic dermatitis in infancy; however, longer term safety and prognosis including allergy march should be pursued. To establish more fundamental strategy for prevention of the development of allergy, further studies clarifying the mechanisms of interaction between barrier dysfunction and microbial milieu are needed with macroscope to understand the relationship between allergic diseases and a diversity of environmental influences. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    LU Yun-tao

    2012-12-01

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

  14. New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature

    Directory of Open Access Journals (Sweden)

    Gisele Zandman-Goddard

    2005-01-01

    Full Text Available 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.

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

    OpenAIRE

    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

    2015-01-01

    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 crystallograp...

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

    Science.gov (United States)

    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. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Miłkowska-Dymanowska J

    2017-10-01

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

  18. [Therapeutics strategies for the management of urinary tract infection in children].

    Science.gov (United States)

    Launay, E; Bingen, E; Cohen, R

    2012-11-01

    Urinary tract infections is one of the most common bacterial infections in pediatrics The increasing involvement of multiresistant bacteria including E. coli producing extended spectrum ß-lactamase (ESBL) makes its management difficult. The purpose of this article is to evaluate the state of the art and to propose ways of thinking about the management of E. coli urinary tract infection in children. The current percentage (less than 10%) of E. coli strains resistant to third generation cephalosporins and the relative efficiency of the latter, should not led to an immediate change of our protocols. Nevertheless, we should verify as soon as possible susceptibility of E. coli responsible for urinary tract infections and consider other therapeutic options for initial therapy and adaptation after obtaining antibiogram. The use of an aminoglycosid as initial treatment seems very interesting. Aminoglycosides have a very good distribution in the renal parenchyma and are still working on the majority of ESBL-producing bacteria. A rapid oral relay after 48 to 72 hours may be proposed according to the results of the susceptibility with either cotrimoxazole, cefixime, ciprofloxacin or an association cefixime-amoxicilline/clavulanate. The treatment of cystitis due to ESBL E. coli is much less problematic given the good urinary beta-lactam antibiotics diffusion. If clinical improvement occurs, even if antibiogram shows that the strain is resistant to the antibiotic prescribed, it is usually unnecessary to change treatment. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  19. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research.

    Science.gov (United States)

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

    2014-09-01

    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood-and adolescent-onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Gene Editing and CRISPR Therapeutics: Strategies Taught by Cell and Gene Therapy.

    Science.gov (United States)

    Ramirez, Juan C

    2017-01-01

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

  1. The third therapeutic system: faith healing strategies in the context of a generalized AIDS epidemic.

    Science.gov (United States)

    Manglos, Nicolette D; Trinitapoli, Jenny

    2011-03-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Nancy Y. Villa

    2016-03-01

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

  3. Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

    Directory of Open Access Journals (Sweden)

    Martin Leustik

    2013-07-01

    Full Text Available Severe pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of pneumonia is the G+ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can still die days after commencing antibiotic treatment due to the development of permeability edema, although the pathogen was successfully cleared from their lungs. This condition is characterized by a dramatically impaired alveolar epithelial-capillary barrier function and a dysfunction of the sodium transporters required for edema reabsorption, including the apically expressed epithelial sodium channel (ENaC and the basolaterally expressed sodium potassium pump (Na+-K+-ATPase. The main agent inducing this edema formation is the virulence factor pneumolysin, a cholesterol-binding pore-forming toxin, released in the alveolar compartment of the lungs when pneumococci are being lysed by antibiotic treatment or upon autolysis. Sub-lytic concentrations of pneumolysin can cause endothelial barrier dysfunction and can impair ENaC-mediated sodium uptake in type II alveolar epithelial cells. These events significantly contribute to the formation of permeability edema, for which currently no standard therapy is available. This review focuses on discussing some recent developments in the search for the novel therapeutic agents able to improve lung function despite the presence of pore-forming toxins. Such treatments could reduce the potentially lethal complications occurring after antibiotic treatment of patients with severe pneumonia.

  4. Bariatric Surgery for Adolescents with Type 2 Diabetes: an Emerging Therapeutic Strategy.

    Science.gov (United States)

    Stefater, M A; Inge, T H

    2017-08-01

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

  5. Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer.

    Science.gov (United States)

    Wang, Meng; Medeiros, Bruno C; Erba, Harry P; DeAngelo, Daniel J; Giles, Francis J; Swords, Ronan T

    2011-03-01

    The NEDD8 (neural precursor cell-expressed developmentally downregulated 8) conjugation pathway regulates the post-translational modification of oncogenic proteins. This pathway has important potential for cancer therapeutics. Several proteins vital in cancer biology are regulated by protein neddylation. These observations led to the development of a small molecule inhibitor that disrupts protein neddylation and leads to cancer cell death and important activity in early phase clinical trials. This review provides an extensive coverage of cellular protein homeostasis with particular emphasis on the NEDD8 conjugation pathway. Insights into a new investigational drug that specifically disrupts the NEDD8 pathway are discussed. The clinical data for this agent are also updated. Neddylation controls key cellular pathways found to be dysregulated in many cancers. Protein neddylation is a relatively under-explored pathway for pharmacologic inhibition in cancer. Selective disruption of this pathway has demonstrated clinical activity in patients with myeloid neoplasms and is worth exploring further in combination with other anti-leukemia agents.

  6. Exploring RNAi as a therapeutic strategy for controlling disease in aquaculture.

    Science.gov (United States)

    Lima, Paula C; Harris, James O; Cook, Mathew

    2013-03-01

    Aquatic animal diseases are one of the most significant constraints to the development and management of aquaculture worldwide. As a result, measures to combat diseases of fish and shellfish have assumed a high priority in many aquaculture-producing countries. RNA interference (RNAi), a natural mechanism for post-transcriptional silencing of homologous genes by double-stranded RNA (dsRNA), has emerged as a powerful tool not only to investigate the function of specific genes, but also to suppress infection or replication of many pathogens that cause severe economic losses in aquaculture. However, despite the enormous potential as a novel therapeutical approach, many obstacles must still be overcome before RNAi therapy finds practical application in aquaculture, largely due to the potential for off-target effects and the difficulties in providing safe and effective delivery of RNAi molecules in vivo. In the present review, we discuss the current knowledge of RNAi as an experimental tool, as well as the concerns and challenges ahead for the application of such technology to combat infectious disease of farmed aquatic animals. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  7. Rendering factor Xa zymogen-like as a therapeutic strategy to treat bleeding.

    Science.gov (United States)

    Thalji, Nabil K; Camire, Rodney M

    2017-09-01

    New therapies are needed to control bleeding in a range of clinical conditions. This review will discuss the biochemical properties of zymogen-like factor Xa, its preclinical assessment in different model systems, and future development prospects. Underlying many procoagulant therapeutic approaches is the rapid generation of thrombin to promote robust clot formation. Clinically tested prohemostatic agents (e.g., factor VIIa) can provide effective hemostasis to mitigate bleeding in hemophilia and other clinical situations. Over the past decade, we explored the possibility of using zymogen-like factor Xa variants to rapidly improve clot formation for the treatment of bleeding conditions. Compared to the wild-type enzyme, these variants adopt an altered, low activity, conformation which enables them to resist plasma protease inhibitors. However, zymogen-like factor Xa variants are conformationally dynamic and ligands such as its cofactor, factor Va, stabilize the molecule rescuing procoagulant activity. At the site of vascular injury, the variants in the presence of factor Va serve as effective prohemostatic agents. Preclinical data support their use to stop bleeding in a variety of clinical settings. Phase 1 studies suggest that zymogen-like factor Xa is safe and well tolerated, and a phase 1b is ongoing to assess safety in patients with intracerebral hemorrhage. Zymogen-like factor Xa is a unique prohemostatic agent for the treatment of a range of bleeding conditions.

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

    Science.gov (United States)

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

    2017-10-15

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

  9. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Seunghoon Lee

    2015-08-01

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

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

    Science.gov (United States)

    Lee, Seunghoon; Park, Sookyoung; Won, Jinyoung; Lee, Sang-Rae; Chang, Kyu-Tae; Hong, Yonggeun

    2015-08-19

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

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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. © 2015 UICC.

  14. Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases

    Directory of Open Access Journals (Sweden)

    Singh R

    2018-03-01

    Full Text Available Rajan Singh,1,2 Shehla Pervin,1,2 Se-Jin Lee,3,4 Alan Kuo,5 Victor Grijalva,6 John David,7 Laurent Vergnes,8 Srinivasa T Reddy1,6 1Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, CA, USA; 2Division of Endocrinology and Metabolism, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; 3The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; 4Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, CT, USA; 5Department of Biology, California State University Dominguez Hills, CA, USA; 6Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA; 7Department of Comparative Medicine, Pfizer Inc, San Diego, CA, USA; 8Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA, USA Background: Follistatin (Fst promotes brown adipocyte characteristics in adipose tissues.Methods: Abdominal fat volume (CT scan, glucose clearance (GTT test, and metabolomics analysis (mass spectrometry of adipose tissues from Fst transgenic (Fst-Tg and wild type (WT control mice were analyzed. Oxygen consumption (Seahorse Analyzer and lipidomics (gas chromatography was analyzed in 3T3-L1 cells.Results: Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion: Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention. Keywords: follistatin, transgenic, adipocyte, fibroblast growth factor 21, AdipoQ

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

    Directory of Open Access Journals (Sweden)

    Clara eDe Palma

    2014-07-01

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

  16. Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation.

    Science.gov (United States)

    Rahimifard, Mahban; Maqbool, Faheem; Moeini-Nodeh, Shermineh; Niaz, Kamal; Abdollahi, Mohammad; Braidy, Nady; Nabavi, Seyed Mohammad; Nabavi, Seyed Fazel

    2017-07-01

    A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to normal cellular survival. Moreover, the important role of NF-κB factors in the central nervous system (CNS) through toll-like receptor (TLR) activation has been well established. This review demonstrates recent findings regarding therapeutic aspects of polyphenolic compounds for the treatment of neuroinflammation, with the aim of regulating TLR4. Polyphenols including flavonoids, phenolic acids, phenolic alcohols, stilbenes and lignans, can target TLR4 signaling pathways in multiple ways. Toll interacting protein expression could be modulated by epigallocatechin-3-gallate. Resveratrol may also exert neuroprotective effects via the TLR4/NF-κB/STAT signaling cascade. Its role in activation of cascade via interfering with TLR4 oligomerization upon receptor stimulation has also been reported. Curcumin, another polyphenol, can suppress overexpression of inflammatory mediators via inhibiting the TLR4-MAPK/NF-κB pathway. It can also reduce neuronal apoptosis via a mechanism concerning the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages. Despite a symphony of in vivo and in vitro studies, many molecular and pharmacological aspects of neuroinflammation remain unclear. It is proposed that natural compounds targeting TLR4 may serve as important pharmacophores for the development of potent drugs for the treatment of neurological disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Physical Characteristics Underpinning Repetitive Lunging in Fencing.

    Science.gov (United States)

    Turner, Anthony N; Marshall, Geoff; Phillips, James; Noto, Angelo; Buttigieg, Conor; Chavda, Shyam; Downing, William; Atlay, Nathan; Dimitriou, Lygeri; Kilduff, Laim

    2016-11-01

    Turner, AN, Marshall, G, Phillips, J, Noto, A, Buttigieg, C, Chavda, S, Downing, W, Atlay, N, Dimitriou, L, and Kilduff, L. Physical characteristics underpinning repetitive lunging in fencing. J Strength Cond Res 30(11): 3134-3139, 2016-Given the repetitive demand to execute lunging and changes in direction within fencing, the ability to sustain these at maximal capacity is fundamental to performance. The aim of this study was threefold. First, to provide normative values for this variable referred to as repeat lunge ability (RLA) and second to identify the physical characteristics that underpin it. Third, was to establish if a cause and effect relationship existed by training the associated characteristics. Assessment of lower-body power, reactive strength, speed, change of direction speed (CODS), and a sport-specific RLA were conducted on senior and junior elite male fencers (n = 36). Fencers were on average (±SD) 18.9 ± 3.2 years of age, 174.35 ± 10.42 cm tall, 70.67 ± 7.35 kg in mass, and 8.5 ± 4.2 years fencing experience. The RLA test had average work times of 16.03 ± 1.40 seconds and demonstrated "large" to "very large" associations with all tested variables, but in particular CODS (r = 0.70) and standing broad jump (SBJ; r = -0.68). Through linear regression analysis, these also provided a 2-predictor model accounting for 61% of the common variance associated with RLA. A cause and effect relationship with SBJ and CODS was confirmed by the training group, where RLA performance in these fencers improved from 15.80 ± 1.07 to 14.90 ± 0.86 seconds, with the magnitude of change reported as "moderate" (effect size (ES) = 0.93). Concurrent improvements were also noted in both SBJ (216.86 ± 17.15 vs. 221.71 ± 17.59 cm) and CODS (4.44 ± 0.29 vs. 4.31 ± 0.09 seconds) and while differences were only significant in SBJ, magnitudes of change were classed as "small" (ES = 0.28) and "moderate" (ES = 0.61), respectively. In conclusion, to improve RLA strength

  18. Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes.

    Science.gov (United States)

    Lai, Mei-Yin; Hsu, Jen-Fu; Chu, Shih-Ming; Wu, I-Hsyuan; Huang, Hsuan-Rong; Lin, Chun-Chih; Lee, I-Ta; Chiang, Ming-Chou; Fu, Ren-Huei; Tsai, Ming-Horng

    2017-06-01

    To assess the characteristics, treatments, risk factors and outcomes of breakthrough candidemia in children. Episodes of breakthrough candidemia in children were compared with the remaining episodes in a 13-year cohort study. Out of 319 episodes, 45 (14.1%) were breakthrough candidemia. Breakthrough candidemia occurred in patients with more acutely ill conditions, and the majority was caused by non-albicans Candida species (73.3%; 33 episodes). A total of 79.1% of breakthrough candidemia were caused by antifungal-susceptible Candida isolates and emergence of resistance was the mechanism in five cases of patients receiving fluconazole. Episodes of breakthrough candidemia had significantly higher illness severity and higher rates of fungemia-attributable mortality. Breakthrough candidemia independently contributed to unfavorable outcomes, and more aggressive treatment strategies are warranted when breakthrough candidemia is encountered.

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

    Science.gov (United States)

    Hui, Kwai Fung; Tam, Kam Pui; Chiang, Alan Kwok Shing

    2017-11-21

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

  20. [Resistances to targeted therapies and strategy for following therapeutic lines in metastatic NSCLC].

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

    Manna, Prasenjit

    2015-01-01

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

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Siddhartha Mondragón-Rodríguez

    2012-01-01

    Full Text Available 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.

  4. Strategy for selecting nanotechnology carriers to overcome immunological and hematological toxicities challenging clinical translation of nucleic acid-based therapeutics.

    Science.gov (United States)

    Dobrovolskaia, Marina A; McNeil, Scott E

    2015-07-01

    Clinical translation of nucleic acid-based therapeutics (NATs) is hampered by assorted challenges in immunotoxicity, hematotoxicity, pharmacokinetics, toxicology and formulation. Nanotechnology-based platforms are being considered to help address some of these challenges due to the nanoparticles' ability to change drug biodistribution, stability, circulation half-life, route of administration and dosage. Addressing toxicology and pharmacology concerns by various means including NATs reformulation using nanotechnology-based carriers has been reviewed before. However, little attention was given to the immunological and hematological issues associated with nanotechnology reformulation. This review focuses on application of nanotechnology carriers for delivery of various types of NATs, and how reformulation using nanoparticles affects immunological and hematological toxicities of this promising class of therapeutic agents. NATs share several immunological and hematological toxicities with common nanotechnology carriers. In order to avoid synergy or exaggeration of undesirable immunological and hematological effects of NATs by a nanocarrier, it is critical to consider the immunological compatibility of the nanotechnology platform and its components. Since receptors sensing nucleic acids are located essentially in all cellular compartments, a strategy for developing a nanoformulation with reduced immunotoxicity should first focus on precise delivery to the target site/cells and then on optimizing intracellular distribution.

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

    Directory of Open Access Journals (Sweden)

    Ion Cristóbal

    2015-05-01

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

  6. Postpartum depression: psychoneuroimmunological underpinnings and treatment

    Directory of Open Access Journals (Sweden)

    Anderson G

    2013-02-01

    Full Text Available George Anderson,1 Michael Maes21CRC Clincial Research Centre/Communications, Glasgow, Scotland; 2Department of Psychiatry, Chulalongkorn University, Bangkok, ThailandAbstract: Postpartum depression (PPD is common, occurring in 10%–15% of women. Due to concerns about teratogenicity of medications in the suckling infant, the treatment of PPD has often been restricted to psychotherapy. We review here the biological underpinnings to PPD, suggesting a powerful role for the tryptophan catabolites, indoleamine 2,3-dixoygenase, serotonin, and autoimmunity in mediating the consequences of immuno-inflammation and oxidative and nitrosative stress. It is suggested that the increased inflammatory potential, the decreases in endogenous anti-inflammatory compounds together with decreased omega-3 poly-unsaturated fatty acids, in the postnatal period cause an inflammatory environment. The latter may result in the utilization of peripheral inflammatory products, especially kynurenine, in driving the central processes producing postnatal depression. The pharmacological treatment of PPD is placed in this context, and recommendations for more refined and safer treatments are made, including the better utilization of the antidepressant, and the anti-inflammatory and antioxidant effects of melatonin.Keywords: SSRI, kynurenine, IDO, TDO, melatonin

  7. Scientific underpinnings of biotechnology regulatory frameworks.

    Science.gov (United States)

    Gleim, Savannah; Smyth, Stuart J

    2018-05-25

    Part of what is presently missing at domestic regulatory levels (and that is important at the international level as well) is a detailed understanding of what the rules of, and for, regulation should be, who the actors, stakeholders and major decision makers are and finally, how to get agreement about the rules. Greater insights into the system of rules that underpin regulatory frameworks for agri-food and biotechnology products in genetically modified (GM) crop- adopting nations will provide value by clarifying the evidence used to commercialize these technologies. This article examines the public documents available from Canada, the United States, the European Union and the Organisation for Economic Cooperation and Development regarding the development of regulatory risk assessment frameworks for products of biotechnology to determine what science grounds these frameworks. The documentation used to provide the initial structure to the existing regulatory frameworks identifies the linkages, connections and relationships that exist between science, risk assessment and regulatory policy. The relationship between risk and regulation has never been more critical to the commercialization of innovative agricultural products. Documenting the role of science-based risk assessment in regulations and how this has changed over the 20 years of experience in regulating GM crops will identify changes in the risk/regulation relationship. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Heechul Jun

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

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

  10. The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies

    Science.gov (United States)

    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. Transcutaneous spinal stimulation as a therapeutic strategy for spinal cord injury: state of the art

    Directory of Open Access Journals (Sweden)

    Grecco LH

    2015-03-01

    Full Text Available Leandro H Grecco,1,3,4,* Shasha Li,1,5,* Sarah Michel,1,6,* Laura Castillo-Saavedra,1 Andoni Mourdoukoutas,7 Marom Bikson,7 Felipe Fregni1,21Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, 2Spaulding-Harvard Spinal Cord Injury Model System, Spaulding Rehabilitation Hospital, Harvard Medical School, Charlestown, MA, USA; 3Special Laboratory of Pain and Signaling, Butantan Institute, 4Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil; 5Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China; 6Department of Pharmacy and Biomedical Sciences, University of Namur, Belgium; 7Department of Biomedical Engineering, The City College of New York, New York, NY, USA*These authors contributed equally to this workAbstract: Treatments for spinal cord injury (SCI still have limited effects. Electrical stimulation might facilitate plastic changes in affected spinal circuitries that may be beneficial in improving motor function and spasticity or SCI-related neuropathic pain. Based on available animal and clinical evidence, we critically reviewed the physiological basis and therapeutic action of transcutaneous spinal cord stimulation in SCI. We analyzed the literature published on PubMed to date, looking for the role of three main noninvasive stimulation techniques in the recovery process of SCI and focusing mainly on transcutaneous spinal stimulation. This review discusses the main clinical applications, latest advances, and limitations of noninvasive electrical stimulation of the spinal cord. Although most recent research in this topic has focused on transcutaneous spinal direct current stimulation (tsDCS, we also reviewed the technique of transcutaneous electric nerve stimulation (TENS and neuromuscular electrical stimulation (NMES as potential methods to modulate spinal cord

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

    Directory of Open Access Journals (Sweden)

    Kenneth Maiese

    2016-01-01

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

  13. Deciphering the therapeutic stem cell strategies of large and midsize pharmaceutical firms.

    Science.gov (United States)

    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.

  14. Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections.

    Science.gov (United States)

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

    2015-12-01

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

  15. Modulation of valosin-containing protein by Kyoto University Substances (KUS as a novel therapeutic strategy for ischemic neuronal diseases

    Directory of Open Access Journals (Sweden)

    Masayuki Hata

    2017-01-01

    Full Text Available Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate (ATP depletion and subsequent induced endoplasmic reticulum (ER stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances (KUSs, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.

  16. Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.

    Science.gov (United States)

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

    2017-04-01

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

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

    International Nuclear Information System (INIS)

    Mehta, Adi; Shervington, Leroy; Munje, Chinmay; Shervington, Amal

    2011-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-01-24

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

  19. The educational theory underpinning a clinical workbook for VERT

    International Nuclear Information System (INIS)

    Nisbet, Heather; Matthews, Sara

    2011-01-01

    The introduction of VERT (Virtual Environment for Radiotherapy Training) into radiotherapy departments across England was in response to the National Radiotherapy Advisory Group's (NRAG) recommendation to the Department of Health that it may assist in enhancing the clinical learning experience of student radiotherapy radiographers. It was suggested that this may help to reduce the high attrition rate of students currently experienced, particularly in the first year of training. This paper investigates how VERT may be used in the clinical setting to develop the skills of students, in order to meet this vision. We argue that using an epistemological approach, i.e. using the theory of knowledge, to support the design of the learning resource, is key to enabling the educator to fulfil these expectations. We describe the design of a generic VERT workbook for use in the clinical departments that train students for the University of Hertfordshire. The use of educational theory to underpin the aims and inform the development of the workbook is examined. We then discuss the alignment of the workbook with the curriculum in order to enhance the students' learning experience and nurture their clinical competence. Finally, we will consider the teaching strategies used during the delivered sessions and discuss how we believe they will allow us to achieve these aims.

  20. The Traceable Radiometry Underpinning Terrestrial and Helio Studies (TRUTHS) mission

    Science.gov (United States)

    Green, Paul D.; Fox, Nigel P.; Lobb, Daniel; Friend, Jonathan

    2015-10-01

    TRUTHS (Traceable Radiometry Underpinning Terrestrial- and Helio-Studies) is a proposed small satellite mission to enable a space-based climate observing system capable of delivering data of the quality needed to provide the information needed by policy makers to make robust mitigation and adaptation decisions. This is achieved by embedding trust and confidence in the data and derived information (tied to international standards) from both its own measurements and by upgrading the performance and interoperability of other EO platforms, such as the Sentinels by in-flight reference calibration. TRUTHS would provide measurements of incoming (total and spectrally resolved) and global reflected spectrally and spatially (50 m) solar radiation at the 0.3% uncertainty level. These fundamental climate data products can be convolved into the building blocks for many ECVs and EO applications as envisaged by the 2015 ESA science strategy; in a cost effective manner. We describe the scientific drivers for the TRUTHS mission and how the requirements for the climate benchmarking and cross-calibration reference sensor are both complementary and simply implemented, with a small additional complexity on top of heritage calibration schemes. The calibration scheme components and the route to SI-traceable Earth-reflected solar spectral radiance and solar spectral irradiance are described.

  1. Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy--an Aide et Recherche en Cancerologie Digestive Group Study.

    Science.gov (United States)

    Chibaudel, Benoist; Bonnetain, Franck; Shi, Qian; Buyse, Marc; Tournigand, Christophe; Sargent, Daniel J; Allegra, Carmen J; Goldberg, Richard M; de Gramont, Aimery

    2011-11-01

    Progression-free survival (PFS) is not an optimal end point to evaluate therapeutic strategies in advanced colorectal cancer (ACRC). Therefore, composite end points have been proposed to evaluate a chemotherapy strategy when sequential treatments are available: duration of disease control (DDC) and time to failure of strategy (TFS). The goal of this study was to evaluate these alternative end points and their potential surrogacy for overall survival (OS). We pooled individual patient data from three randomized trials evaluating chemotherapy strategy, which accrued 1,042 patients with previously untreated ACRC. In these trials, first-line treatment was either oxaliplatin- or irinotecan-based chemotherapy. Compared with TFS, DDC included neither time interval between progression and next sequence of treatment nor time to progression if the best result of the next sequence of treatment was progression. There was good correlation between DDC and OS (correlation of median: r, 0.62; correlation of hazard ratio [HR]: adjusted copula R(2), 0.72) and between TFS and OS (correlation of median: r, 0.59; correlation of HR: adjusted copula R(2), 0.67). There was no correlation between PFS and OS (correlation of median: r, 0.45; correlation of HR: adjusted copula R(2), 0.47). DDC and TFS roughly achieved the same results. Both are acceptable new end points to evaluate a therapeutic strategy in ACRC. Although TFS achieved a pragmatic evaluation of a multiline strategy, DDC captured the effect of a specific sequence in a therapeutic strategy.

  2. An Optimized Voriconazole Dosing Strategy to Achieve Therapeutic Serum Concentrations in Children Younger than 2 Years Old.

    Science.gov (United States)

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

    2016-10-01

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

  3. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

    Science.gov (United States)

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

    2018-04-07

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

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

    Directory of Open Access Journals (Sweden)

    Hanumantha Rao Madala

    2018-02-01

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

  5. Eyes to See: The Foothold of Jihadi Underpinnings

    National Research Council Canada - National Science Library

    Klein, Jr, John M

    2007-01-01

    .... These underpinnings are well-established and rigorously authenticated precepts that serve as a foothold for Jihadi conduct, making Islam a ready-made ideology that suits the Jihadis' insatiable goals...

  6. Therapeutic substitution and therapeutic conservatism as cost-containment strategies in primary care: a study of fundholders and non-fundholders.

    OpenAIRE

    Wilson, R P; Hatcher, J; Barton, S; Walley, T

    1999-01-01

    BACKGROUND: General practice (GP) fundholders contained prescribing costs by restricting the rise in volume of prescribing and by increasing generic prescribing. It is uncertain whether they used more sophisticated approaches to medicine choice in attempts to contain costs. AIM: To examine whether fundholding practices have adopted medicine-specific strategies to contain prescribing costs--i.e. switching to less expensive but equally effective medicines or resisting the uptake of newer more e...

  7. Investigating Philosophies Underpinning Dietetic Private Practice

    Directory of Open Access Journals (Sweden)

    Claudia Harper

    2017-03-01

    Full Text Available There is limited theory or knowledge regarding dietitians’ practice philosophies and how these philosophies are generated and incorporated into their professional practices. For the purposes of this study, a conceptual framework will explain and define the ‘philosophies’ as three different types of knowledge; episteme, techne, and phronesis. This study aimed to develop an explanatory theory of how dietitians in private practice source, utilise, and integrate practice philosophies. A grounded theory qualitative methodology was used to inform the sampling strategy, data collection, and analytical processes. Semi-structured interviews with dietitians in private practice were undertaken and data were collected and analysed concurrently. The results show that dietitians form collaborative relationships with their clients, in order to nurture change over time. They use intrinsic and intertwined forms of episteme, techne, and phronesis, which allow them to respond both practically and sensitively to their clients’ needs. The learning and integration of these forms of knowledge are situated in their own practice experience. Dietitians adapt through experience, feedback, and reflection. This study highlights that private practice offers a unique context in which dietitians deal with complex issues, by utilising and adapting their philosophies.

  8. [The role of selective monoamine oxidase B inhibitors in the therapeutic strategy of Parkinson's disease in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital].

    Science.gov (United States)

    Szász, József Attila; Constantin, Viorelia; Fazakas, Péter Alpár; Blényesi, Eszter; Grieb, Levente Gábor; Balla, Antal; Sárig, Mónika; Szegedi, Kinga; Bartha, Eszter Noémi; Szatmári, Szabolcs

    2017-12-01

    Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons's disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors. This retrospective study includes all records of patients with Parkinson's disease hospitalized between 1 January 2003 and 31 December 2016. From the 2194 reports we used data focusing on the therapeutic recommendations. Regarding disease duration, we divided the patients in two groups: less than or equal to 5 years and more than 5 years. From the 1183 patients in first group, 243 received monoamine oxidase inhibitors: 12 as monotherapy, 52 together with dopamine agonists, in 61 cases combined with levodopa. In 118 cases monoamine oxidase inhibitors were combined with levodopa and dopamine agonists. From 582 cases whith Parkinson's disease for more than 5 years, 195 received monoamine oxidase B inhibitors (selegiline: 10 cases, rasagiline: 185 cases). In 429 cases we did not find accurate data regarding disease duration (selegiline: 5 cases, rasagiline: 93 cases). The use of monoamine oxidase B inhibitors was similar to those found in literature. The treating physicians should utilise more confidently the available therapeutical combinations. Orv Hetil. 2017; 158(51): 2023-2028.

  9. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies.

    Science.gov (United States)

    Vogel, Kara R; Ainslie, Garrett R; Walters, Dana C; McConnell, Alice; Dhamne, Sameer C; Rotenberg, Alexander; Roullet, Jean-Baptiste; Gibson, K Michael

    2018-02-19

    We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived from aldehyde dehydrogenase 5a1 -/- (aldh5a1 -/- ) mice, the murine model of SSADHD, has highlighted NSC utility as an in vitro system in which to study therapeutics and associated toxicological properties. Gene expression analyses have revealed that transcripts encoding GABA A receptors are down-regulated and may remain largely immature in aldh5a1 -/- brain, characterized by excitatory as opposed to inhibitory outputs, the latter being the expected action in the mature central nervous system. This indicates that agents altering chloride channel activity may be therapeutically relevant in SSADHD. The most recent therapeutic prospects include mTOR (mechanistic target of rapamycin) inhibitors, drugs that have received attention with the elucidation of the effects of elevated GABA on autophagy. The outlook for novel therapeutic trials in SSADHD continues to improve.

  10. Marxism and the Theoretical Underpinnings of the Bolshevic ...

    African Journals Online (AJOL)

    Research has identified in Marxism, a useful political strength in an aggrieved masses, the unforgivable hatred of victims of capitalism for the system and an unwavering passion in an oppressed class for change, as some of the theoretical underpinnings behind all communist revolutions. This essay discusses Marxism while ...

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

    Directory of Open Access Journals (Sweden)

    Andrew S Holpuch

    2011-01-01

    Full Text Available 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.

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

    Directory of Open Access Journals (Sweden)

    Apoorva Shankar

    2017-09-01

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

  13. 3p22.1p21.31 microdeletion identifies CCK as Asperger syndrome candidate gene and shows the way for therapeutic strategies in chromosome imbalances.

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Munteanu Constantin

    2012-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Kevin eD'Ostilio

    2016-04-01

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

  16. The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson’s Disease

    Science.gov (United States)

    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

  17. Assessment of refractive astigmatism and simulated therapeutic refractive surgery strategies in coma-like-aberrations-dominant corneal optics.

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2018-02-05

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

  19. The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Crouch, Peter J; White, Anthony R; Bush, Ashley I

    2007-08-01

    The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.

  20. Neural and psychological underpinnings of gambling disorder: A review

    OpenAIRE

    Grant, Jon E; Odlaug, Brian L; Chamberlain, Sam

    2015-01-01

    Gambling disorder affects 0.4 to 1.6% of adults worldwide, and is highly comorbid with other mental health disorders. This article provides a concise primer on the neural and psychological underpinnings of gambling disorder based on a selective review of the literature. Gambling disorder is associated with dysfunction across multiple cognitive domains which can be considered in terms of impulsivity and compulsivity. Neuroimaging data suggest structural and functional abnormalities of networks...

  1. Conclusion: imaging in strategy of endocrine diagnosis and therapeutics; Place de l`imagerie dans la strategie d`exploration et de suivi therapeutique des pathologies endocriniennes

    Energy Technology Data Exchange (ETDEWEB)

    Mornex, R. [Hopital Edouard-Herriot, 69 - Lyon (France)

    1995-12-31

    Images in medicine have to help the doctor in a diagnostic or therapeutic aim. The choice must be made in function of pathology or organ as known (it is not necessary to ask for a computed tomography where we know that only an echography can give the answer to the question we ask ), the criteria must stay the best performance for the cheapest price, but the quality of interpretation is a more important thing. It is important to avoid a lot of examinations which do not give better informations but are heavy to endure for the patients. In conclusion, the aim of this kind of proceedings is to assure to the patients who come confidently to us, the best service at the less constraints price without forgetting that a conclusion depends on a given methodological situation and reminding of beside machines we have not to forget the men.

  2. EBNA1: Oncogenic Activity, Immune Evasion and Biochemical Functions Provide Targets for Novel Therapeutic Strategies against Epstein-Barr Virus- Associated Cancers.

    Science.gov (United States)

    Wilson, Joanna B; Manet, Evelyne; Gruffat, Henri; Busson, Pierre; Blondel, Marc; Fahraeus, Robin

    2018-04-06

    The presence of the Epstein-Barr virus (EBV)-encoded nuclear antigen-1 (EBNA1) protein in all EBV-carrying tumours constitutes a marker that distinguishes the virus-associated cancer cells from normal cells and thereby offers opportunities for targeted therapeutic intervention. EBNA1 is essential for viral genome maintenance and also for controlling viral gene expression and without EBNA1, the virus cannot persist. EBNA1 itself has been linked to cell transformation but the underlying mechanism of its oncogenic activity has been unclear. However, recent data are starting to shed light on its growth-promoting pathways, suggesting that targeting EBNA1 can have a direct growth suppressing effect. In order to carry out its tasks, EBNA1 interacts with cellular factors and these interactions are potential therapeutic targets, where the aim would be to cripple the virus and thereby rid the tumour cells of any oncogenic activity related to the virus. Another strategy to target EBNA1 is to interfere with its expression. Controlling the rate of EBNA1 synthesis is critical for the virus to maintain a sufficient level to support viral functions, while at the same time, restricting expression is equally important to prevent the immune system from detecting and destroying EBNA1-positive cells. To achieve this balance EBNA1 has evolved a unique repeat sequence of glycines and alanines that controls its own rate of mRNA translation. As the underlying molecular mechanisms for how this repeat suppresses its own rate of synthesis in cis are starting to be better understood, new therapeutic strategies are emerging that aim to modulate the translation of the EBNA1 mRNA. If translation is induced, it could increase the amount of EBNA1-derived antigenic peptides that are presented to the major histocompatibility (MHC) class I pathway and thus, make EBV-carrying cancers better targets for the immune system. If translation is further suppressed, this would provide another means to cripple

  3. Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy.

    Science.gov (United States)

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

    2017-05-25

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

  4. Color-flow duplex screening for upper extremity proximity injuries: a low-yield strategy for therapeutic intervention.

    Science.gov (United States)

    Mollberg, Nathan M; Wise, Stephen R; Banipal, Simpledeep; Sullivan, Ryan; Holevar, Michelle; Vafa, Amir; Clark, Elizabeth; Merlotti, Gary J

    2013-07-01

    Although the incidence of injury to the upper extremity screened with angiography as a result of proximity penetrating trauma is similar to that of the lower extremity, intervention rates seem to be higher. However, studies evaluating the incidence of injury as a result of proximity penetrating trauma have primarily focused on the lower extremity. This study shows the incidence and clinical significance of vascular injury as a result of proximity trauma to the upper extremity in a large cohort of patients screened with color-flow duplex. A retrospective study was conducted from January 1, 2005 to January 1, 2012 on all patients undergoing color-flow duplex as a result of proximity penetrating trauma to the upper extremity. Data on injury location, mechanism, associated extremity and nonextremity injuries, and use and results of color-flow duplex were recorded and analyzed. A total of 341 patients were identified who underwent color-flow duplex because of proximity penetrating trauma to the upper extremity. Injuries occurred in 370 extremities, with 253 located in the upper arm and 117 in the forearm. Overall, 18 (4.9%) injuries were identified on screening duplex ultrasound, of which 12 (3.2%) were arterial and 5 (1.4%) were venous. The therapeutic intervention rate for detected injuries to the upper arm was 1.6% (4/253), whereas no injuries of the forearm were identified that necessitated intervention. Although color-flow duplex is an inexpensive and noninvasive means of detecting injuries as a result of proximity penetrating trauma, screening upper extremity wounds is unlikely to detect clinically significant arterial injuries in need of therapeutic intervention. Venous injuries in the form of deep venous thromboses were detected in only 1.4% of patients. These findings suggest that screening for proximity penetrating trauma of the upper extremity is unlikely to detect injuries at a rate that would prove cost-effective on formal decision analysis. Copyright

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

    Science.gov (United States)

    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

  6. Haemophilia at various stages of life: design of new therapeutic strategies through an interactive course--the Kogeniale project.

    Science.gov (United States)

    Santagostino, Elena; Messina, Maria; Tagliaferri, Annarita; Iorio, Alfonso; Morfini, Massimo

    2013-04-01

    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. 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. 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. This project helped to outline useful decision-making tools for handling diagnostic and treatment issues in the field of haemophilia.

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

    Directory of Open Access Journals (Sweden)

    Bernard Waeber

    2008-02-01

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

  8. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

    Science.gov (United States)

    Hendry, Shona A; Farnsworth, Rae H; Solomon, Benjamin; Achen, Marc G; Stacker, Steven A; Fox, Stephen B

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

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

    Science.gov (United States)

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

    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

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

    Science.gov (United States)

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

    2015-01-01

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

  11. Regulation of sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease

    Science.gov (United States)

    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.

    2016-01-01

    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 to 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 BM 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 confirms the role of sclerostin as a potential therapeutic target in MM bone disease, and

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

    Directory of Open Access Journals (Sweden)

    Protim Sarker

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

  13. The Use of Comprehensive Molecular Profiling with Network and Control Theory to Better Understand GWI and Model Therapeutic Strategies

    Science.gov (United States)

    2012-07-01

    Fosså o Levels of circulating interleukin-1 receptor antagonist and C-reactive protein in long-term survivors of testicular cancer with chronic...Importantly, these models serve to simulate strategies for re‐directing immune and  endocrine processes using well‐chosen sequence of  interventions .   15...computational model of illness and relapse, with the hopes to use this modeling method to propose  virtual clinical trials and  intervention  modeling that could

  14. Combined effect of therapeutic strategies for bleeding injury on early survival, transfusion needs and correction of coagulopathy

    DEFF Research Database (Denmark)

    Balvers, K.; van Dieren, S.; Baksaas-Aasen, K.

    2017-01-01

    fibrinogen on the outcome of injured patients with bleeding. Methods: A prospective multicentre observational study was performed in six level 1 trauma centres. Injured patients who received at least 4 units of red blood cells (RBCs) were analysed and divided into groups receiving a low (less than 1 : 1......Background: The combined effects of balanced transfusion ratios and use of procoagulant and antifibrinolytic therapies on trauma-induced exsanguination are not known. The aim of this study was to investigate the combined effect of transfusion ratios, tranexamic acid and products containing......) or high (1 or more : 1) ratio of plasma or platelets to RBCs, and in receipt or not of tranexamic acid or fibrinogen products (fibrinogen concentrates or cryoprecipitate). Logistic regression models were used to assess the effect of transfusion strategies on the outcomes ‘alive and free from massive...

  15. Therapeutic strategy for hepatocellular carcinoma with tumor thrombi in the major portal branches by using 3 dimensional-conformal radiation therapies

    International Nuclear Information System (INIS)

    Yamada, Terumasa; Sasaki, Yo; Nishiyama, Kinji; Eguchi, Hidetoshi; Ohigashi, Hiroaki; Ishikawa, Osamu; Kasugai, Hiroshi; Inoue, Atsuo; Imaoka, Shingi

    2004-01-01

    The prognosis of hepatocellular carcinoma with tumor thrombus in the major portal branches (Vp-HCC) is extremely poor. Twenty-six inoperable patients and 5 operable patients with Vp-HCC were treated with 3-dimensional conformal radiation therapy (3D-CRT). All patients except for one could receive full-dose 3D-CRT without severe side effects. Six of 21 inoperable patients could receive additional treatments and showed better prognosis than the other patients. Five patients who had received curative hepatectomy after 3D-CRT, showed better prognosis than the patients with Vp-HCC who received hepatectomies without 3D-CRT. These results indicated the usefulness of 3D-CRT as a new therapeutic strategy for Vp-HCCs. (author)

  16. Identification of new tumor associated antigens and their usage for new therapeutic strategies based on the combination of chemotherapy and immunotherapy for colorectal cancer patients

    International Nuclear Information System (INIS)

    Proietti, E.; Maccalli, C.; Rosenberg, S.A.; Robbins, P.F.

    2009-01-01

    The main general objective of this project was to characterize a new colorectal carcinoma (CRC) tumor-associated antigen (TAA) and validate a new therapeutic strategy combining chemotherapy and tumor vaccination for the treatment of cancer patients. To this purpose a strategic interaction between Drs. Proietti/Maccali at the ISS and the group of Drs. Rosenberg/Robbins at the NIH was established. A stage of Dr. Maccalli at the NIH allowed to carry out the first steps for the identification and the initial characterization of the CRC TAA named COA-1. A laboratory meeting with Dr. Robbins has been planned on May 24-25 2006 at the ISS, during the International Meeting on Immunotherapy of Cancer: Challenges and Needs, for discussing results and perspectives of this research project

  17. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    Science.gov (United States)

    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

  18. Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: a Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?

    Science.gov (United States)

    Herrera-Marschitz, Mario; Perez-Lobos, Ronald; Lespay-Rebolledo, Carolyne; Tapia-Bustos, Andrea; Casanova-Ortiz, Emmanuel; Morales, Paola; Valdes, Jose-Luis; Bustamante, Diego; Cassels, Bruce K

    2018-02-01

    Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult.PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1α (HIF-1α) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD + exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-κB subunit p65, overexpression of the pro-inflammatory cytokines IL-1β and TNF-α, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss

  19. Therapeutic strategies for adenoid cystic carcinoma of the nasal and paranasal sinus from the long-term treatment results

    International Nuclear Information System (INIS)

    Terada, Nobuhisa; Numata, Tsutomu; Mutoh, Hiroyuki; Ueki, Yuji; Gorai, Shigeki; Konno, Akiyoshi

    2001-01-01

    This article presents long-term treatment results by analyzing 24 cases with adenoid cystic carcinoma (ACC) of the nasal and paranasal sinus treated from 1975 to 1995 at Akita University Hospital and Chiba University Hospital. The basic strategies for treatment for ACC of the nasal and paranasal sinuses are en bloc tumor resection, followed by primary reconstruction of the maxilla. Preoperative and postoperative radiation were combined. Cumulative 5-year and 10-year survival rates were 70.6% and 47.1% for maxillary sinus tumors, respectively. Cumulative 5-year and 10-year survival rates for nasal tumors were 100% and 75.0%, and those for sphenoid sinus tumors were 50.0% and 0%, respectively. The patient with ethomoid sinus who needed skull base surgery is alive at 8.1 years after therapy. Treatment results closely correlated with tumor extension. Cumulative 5-year survival rates for T2, T3 and, T4 patients with maxillary sinus tumors were 85.7%, 71.4%, and 33.3%, respectively. And cumulative 10-year survival rates for T2, T3, and T4 were 71.4%, 42.9%, and 0%, respectively. The histopathological effects of preoperative radiation were Shimosato II a in 6 out of 10 patients, II b in 2, and III in 2, respectively. Only fast neutron therapy reached Shimosato III. Two of the patients with Shimosato II a died of distant metastasis. The above data suggests that, although radiation therapy alone cannot cure tumors, preoperative full-dose radiation may prevent the development of distant metastasis if it can achieve histopathological effects of a higher classification than Shimosato II b. Because chemotherapy and radiation is not very effective on ACC, the role of skull base surgeries for nasal-paranasal sinus malignancies that invade the skull base is valuable, particularly in cases having a relatively small mass in the ethmoid sinus. (author)

  20. Blocking Aβ seeding-mediated aggregation and toxicity in an animal model of Alzheimer's Disease: A novel therapeutic strategy for neurodegeneration

    Science.gov (United States)

    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

  1. Oxidative Stress: A Unifying Mechanism for Cell Damage Induced by Noise, (Water-Pipe) Smoking, and Emotional Stress-Therapeutic Strategies Targeting Redox Imbalance.

    Science.gov (United States)

    Golbidi, Saeid; Li, Huige; Laher, Ismail

    2018-03-20

    Modern technologies have eased our lives but these conveniences can impact our lifestyles in destructive ways. Noise pollution, mental stresses, and smoking (as a stress-relieving solution) are some environmental hazards that affect our well-being and healthcare budgets. Scrutinizing their pathophysiology could lead to solutions to reduce their harmful effects. Recent Advances: Oxidative stress plays an important role in initiating local and systemic inflammation after noise pollution, mental stress, and smoking. Lipid peroxidation and release of lysolipid by-products, disturbance in activation and function of nuclear factor erythroid 2-related factor 2 (Nrf2), induction of stress hormones and their secondary effects on intracellular kinases, and dysregulation of intracellular Ca 2+ can all potentially trigger other vicious cycles. Recent clinical data suggest that boosting the antioxidant system through nonpharmacological measures, for example, lifestyle changes that include exercise have benefits that cannot easily be achieved with pharmacological interventions alone. Indiscriminate manipulation of the cellular redox network could lead to a new series of ailments. An ideal approach requires meticulous scrutiny of redox balance mechanisms for individual pathologies so as to create new treatment strategies that target key pathways while minimizing side effects. Extrapolating our understanding of redox balance to other debilitating conditions such as diabetes and the metabolic syndrome could potentially lead to devising a unifying therapeutic strategy. Antioxid. Redox Signal. 28, 741-759.

  2. Symptom Science: Omics Supports Common Biological Underpinnings Across Symptoms.

    Science.gov (United States)

    McCall, Maura K; Stanfill, Ansley Grimes; Skrovanek, Elizabeth; Pforr, Jessica Renee; Wesmiller, Susan W; Conley, Yvette P

    2018-03-01

    For precision health care to be successful, an in-depth understanding of the biological mechanisms for symptom development and severity is essential. Omics-based research approaches facilitate identification of the biological underpinnings of symptoms. We reviewed literature for omics-based approaches and exemplar symptoms (sleep disruption, cognitive impairment, fatigue, gastrointestinal [GI] distress, and pain) to identify genes associated with the symptom or symptoms across disease processes. The review yielded 27 genes associated with more than one symptom. ABCB1 (MDR1), APOE, BDNF, CNR1, COMT, DAT1 (SLC6A3), DRD4, ESR1, HLA-DRB1, IL10, IL1B, IL6, LTA, PTGS2 (COX-2), SLC6A4, and TNF were associated with cognitive impairment and pain, which had the most genes in common. COMT and TNF were related to all symptoms except sleep disruption. IL1B was associated with all symptoms except cognitive impairment. IL10, IL1A, IL1B, IL1RN, IL6, and IL8 (CXCL8) were linked with all the exemplar symptoms in various combinations. ABCB1 (MDR1) and SLC6A4 were associated with cognitive impairment, GI distress, and pain. IL10 and IL6 were linked to cognitive impairment, fatigue, and pain. APOE and BDNF were associated with sleep disruption, cognitive impairment, and pain. The 27 genes were associated with canonical pathways including immune, inflammatory, and cell signaling. The pathway analysis generated a 15-gene model from the 27 as well as 3 networks, which incorporated new candidate genes. The findings support the hypothesis of overlapping biological underpinnings across the exemplar symptoms. Candidate genes may be targeted in future omics research to identify mechanisms of co-occurring symptoms for potential precision treatments.

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

    Directory of Open Access Journals (Sweden)

    Tao Y

    2017-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Teik Hin Tan

    2016-07-01

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

  5. [Alzheimer's disease: New therapeutic strategies].

    Science.gov (United States)

    Villegas, Sandra

    2015-07-20

    The rapid increase in prevalence rates of Alzheimer's disease means that treatments to prevent, stop or reverse this devastating disease are urgently needed. Despite advances in understanding its molecular pathology, there are no drugs that can halt its progression. This review takes a tour through phase 2, or higher studies, probing receptor agonist agents interfering with aggregation, inhibitors/modulators of secretases, lipid-lowering agents, and, finally and most extensively, immunotherapy. The fact that phase 3 studies with bapineuzumab and solaneuzumab have recently failed does not invalidate the potential of immunotherapy, as more information is available and new clinical trials are being initiated. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  6. The digital national framework - underpinning the knowledge economy

    Directory of Open Access Journals (Sweden)

    K J Murray

    2003-10-01

    Full Text Available Providing a sustainable spatial data infrastructure creates responsibility and high demand by continually meeting and satisfying the needs of all kinds of users. It is essential to provide the right information at the right level of quality and reliability and at the right time. Geographic information (GI is today being universally recognised as a key part of the national information infrastructure, especially by government. GI is an enabler in the knowledge economy since the power of geography can be used to underpin the sharing (and trading of vital georeferenced information collected by all kinds of organisations. From this information reliable conclusions can and will be drawn and decisions made. However, achieving such an environment does not just happen. It has to be led, nurtured and developed in line with user needs. Funding requires sustained investment, and it all has to be implemented and maintained whether the economy enjoys good times or bad, and through periods of political change. These are all big challenges encountered by just about every national economy. The aim of many national governments around the world is to establish a reliable and integrated reference base for GI that can underpin the e-economy. This base needs to support government and the commercial sector who need to reference information, and potentially share it with others (eg land ownership or link it up to form an application.(eg location based services. To achieve this a consistent method of georefererencing is required and the Digital National Framework is intended to fulfil that need in Great Britain. This paper will describe what has been happening in Great Britain to build on the firm foundations of the past, and develop a modern and sustainable framework for geographic information for the future. In particular it will be shown that the business model adopted by Ordnance Survey in recent years (ie the users pay for the data has played a key role in securing

  7. The neural underpinnings of music listening under different attention conditions.

    Science.gov (United States)

    Jäncke, Lutz; Leipold, Simon; Burkhard, Anja

    2018-05-02

    Most studies examining the neural underpinnings of music listening have no specific instruction on how to process the presented musical pieces. In this study, we explicitly manipulated the participants' focus of attention while they listened to the musical pieces. We used an ecologically valid experimental setting by presenting the musical stimuli simultaneously with naturalistic film sequences. In one condition, the participants were instructed to focus their attention on the musical piece (attentive listening), whereas in the second condition, the participants directed their attention to the film sequence (passive listening). We used two instrumental musical pieces: an electronic pop song, which was a major hit at the time of testing, and a classical musical piece. During music presentation, we measured electroencephalographic oscillations and responses from the autonomic nervous system (heart rate and high-frequency heart rate variability). During passive listening to the pop song, we found strong event-related synchronizations in all analyzed frequency bands (theta, lower alpha, upper alpha, lower beta, and upper beta). The neurophysiological responses during attentive listening to the pop song were similar to those of the classical musical piece during both listening conditions. Thus, the focus of attention had a strong influence on the neurophysiological responses to the pop song, but not on the responses to the classical musical piece. The electroencephalographic responses during passive listening to the pop song are interpreted as a neurophysiological and psychological state typically observed when the participants are 'drawn into the music'.

  8. Maximum entropy principle for stationary states underpinned by stochastic thermodynamics.

    Science.gov (United States)

    Ford, Ian J

    2015-11-01

    The selection of an equilibrium state by maximizing the entropy of a system, subject to certain constraints, is often powerfully motivated as an exercise in logical inference, a procedure where conclusions are reached on the basis of incomplete information. But such a framework can be more compelling if it is underpinned by dynamical arguments, and we show how this can be provided by stochastic thermodynamics, where an explicit link is made between the production of entropy and the stochastic dynamics of a system coupled to an environment. The separation of entropy production into three components allows us to select a stationary state by maximizing the change, averaged over all realizations of the motion, in the principal relaxational or nonadiabatic component, equivalent to requiring that this contribution to the entropy production should become time independent for all realizations. We show that this recovers the usual equilibrium probability density function (pdf) for a conservative system in an isothermal environment, as well as the stationary nonequilibrium pdf for a particle confined to a potential under nonisothermal conditions, and a particle subject to a constant nonconservative force under isothermal conditions. The two remaining components of entropy production account for a recently discussed thermodynamic anomaly between over- and underdamped treatments of the dynamics in the nonisothermal stationary state.

  9. False memories with age: Neural and cognitive underpinnings.

    Science.gov (United States)

    Devitt, Aleea L; Schacter, Daniel L

    2016-10-01

    As we age we become increasingly susceptible to memory distortions and inaccuracies. Over the past decade numerous neuroimaging studies have attempted to illuminate the neural underpinnings of aging and false memory. Here we review these studies, and link their findings with those concerning the cognitive properties of age-related changes in memory accuracy. Collectively this evidence points towards a prominent role for age-related declines in medial temporal and prefrontal brain areas, and corresponding impairments in associative binding and strategic monitoring. A resulting cascade of cognitive changes contributes to the heightened vulnerability to false memories with age, including reduced recollective ability, a reliance on gist information and familiarity-based monitoring mechanisms, as well as a reduced ability to inhibit irrelevant information and erroneous binding of features between memory traces. We consider both theoretical and applied implications of research on aging and false memories, as well as questions remaining to be addressed in future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Pan Genome of the Phytoplankton Emiliania Underpins its Global Distribution

    Energy Technology Data Exchange (ETDEWEB)

    Read, Betsy A. [California State Univ. (CalState), San Marcos, CA (United States); Kegel, Jessica [Alfred Wegener Inst. for Polar and Marine Research, Bremerhaven (Germany); Klute, Mary J. [Univ. of Alberta, Edmonton, AB (Canada); Kuo, Alan [USDOE Joint Genome Inst., Walnut Creek, CA (United States); Lefebvre, Stephane C. [J. Craig Venter Inst., San Diego, CA (United States); Maumus, Florian [National Institute of Agricultural Research, Versailles (France); Mayer, Christoph [Alexander Koenig Research Museum, Bonn (Germany); Ruhr Univ., Bochum (Germany); Miller, John [Univ. of Maryland, College Park, MD (United States); Monier, Adam [Monterey Bay Aquarium Research Inst., Moss Landing, CA (United States); Salamov, Asaf [USDOE Joint Genome Inst., Walnut Creek, CA (United States); Young, Jeremy [Univ. College London (United Kingdom); Aguilar, Maria [Univ. of Alberta, Edmonton, AB (Canada); Claverie, Jean-Michel [Aix-Marseille Univ. (France); Frickenhaus, Stephan [Alfred Wegener Inst. for Polar and Marine Research, Bremerhaven (Germany); Univ. of Bremerhaven (Germany); Gonzalez, Karina [Harvard Medical School, Boston, MA (United States); Herman, Emily K. [Univ. of Alberta, Edmonton, AB (Canada); Lin, Yao-Cheng [Ghent Univ. (Belgium); Napier, Johnathan [Rothamstead Research, Harpenden (United Kingdom); Ogata, Hiroyuki [Aix-Marseille Univ. (France); Sarno, Analissa F. [California State Univ. (CalState), San Marcos, CA (United States); Schmutz, Jeremy [USDOE Joint Genome Inst., Walnut Creek, CA (United States); HudsonAlpha Genome Sequencing Center, Huntsville, AL (United States); Schroeder, Declan [Marine Biological Association of the UK, Plymouth (United Kingdom); de Vargas, Columban [CNRS. Univ. Pierre and Marie Curie (France).; Verret, Frederic [Univ. of Essex, Colchester (United Kingdom); von Dassow, Peter [Pontifical Catholic University of Chile, Santiago (Chile); Valentin, Klaus [Alfred Wegener Inst. for Polar and Marine Research, Bremerhaven (Germany); Van de Peer, Yves [Ghent Univ. (Belgium); Wheeler, Glen [Marine Biological Association of the UK, Plymouth (United Kingdom); Plymouth Marine Lab. (United Kingdom); Annotation Consortium, Emiliania huxleyi; Dacks, Joel B. [Univ. of Alberta, Edmonton, AB (Canada); Delwiche, Charles F. [Univ. of Maryland, College Park, MD (United States); Dyhrman, Sonya T. [Woods Hole Oceanographic Inst., MA (United States); Columbia Univ., Palisades, NY (United States); Glockner, Gernot [Univ. of Cologne (Germany); John, Uwe [Alfred Wegener Inst. for Polar and Marine Research, Bremerhaven (Germany); Richards, Thomas [National History Museum, London (United Kingdom); Worden, Alexandra Z. [Monterey Bay Aquarium Research Inst., Moss Landing, CA (United States); Zhang, Xiaoyu [California State Univ. (CalState), San Marcos, CA (United States); Grigoriev, Igor V. [USDOE Joint Genome Inst., Walnut Creek, CA (United States)

    2012-06-18

    Coccolithophores have influenced the global climate for over 200 million years1. These marine phytoplankton can account for 20 per cent of total carbon fixation in some systems2. They form blooms that can occupy hundreds of thousands of square kilometres and are distinguished by their elegantly sculpted calcium carbonate exoskeletons (coccoliths), rendering themvisible fromspace3.Although coccolithophores export carbon in the form of organic matter and calcite to the sea floor, they also release CO2 in the calcification process. Hence, they have a complex influence on the carbon cycle, driving either CO2 production or uptake, sequestration and export to the deep ocean4. Here we report the first haptophyte reference genome, from the coccolithophore Emiliania huxleyi strain CCMP1516, and sequences from 13 additional isolates. Our analyses reveal a pan genome (core genes plus genes distributed variably between strains) probably supported by an atypical complement of repetitive sequence in the genome. Comparisons across strains demonstrate thatE. huxleyi, which has long been considered a single species, harbours extensive genome variability reflected in different metabolic repertoires. Genome variability within this species complex seems to underpin its capacity both to thrive in habitats ranging from the equator to the subarctic and to form large-scale episodic blooms under a wide variety of environmental conditions.

  11. Renewable energy technology from underpinning physics to engineering application

    International Nuclear Information System (INIS)

    Infield, D G

    2008-01-01

    The UK Energy Research Centre (UKERC) in it's submission to the DTI's 2006 Energy Review reminded us that the 'UK has abundant wind, wave and tidal resources available; its mild climate lends itself to bio-energy production, and solar radiation levels are sufficient to sustain a viable solar industry'. These technologies are at different stages of development but they all draw on basic and applied Science and Engineering. The paper will briefly review the renewable energy technologies and their potential for contributing to a sustainable energy supply. Three research topics will be highlighted that bridge the gap between the physics underpinning the energy conversion, and the engineering aspects of development and deployment; all three are highly relevant to the Government's programme on micro-generation. Two are these are taken from field of thin film photovoltaics (PV), one related to novel device development and the other to a measurement technique for assessing the manufacturing quality of PV modules and their performance. The third topic concerns the development of small building integrated wind turbines and examines the complex flow associated with such applications. The paper will conclude by listing key research challenges that are central to the search for efficient and cost-effective renewable energy generation

  12. Triangulation of the neurocomputational architecture underpinning reading aloud

    Science.gov (United States)

    Hoffman, Paul; Lambon Ralph, Matthew A.; Woollams, Anna M.

    2015-01-01

    The goal of cognitive neuroscience is to integrate cognitive models with knowledge about underlying neural machinery. This significant challenge was explored in relation to word reading, where sophisticated computational-cognitive models exist but have made limited contact with neural data. Using distortion-corrected functional MRI and dynamic causal modeling, we investigated the interactions between brain regions dedicated to orthographic, semantic, and phonological processing while participants read words aloud. We found that the lateral anterior temporal lobe exhibited increased activation when participants read words with irregular spellings. This area is implicated in semantic processing but has not previously been considered part of the reading network. We also found meaningful individual differences in the activation of this region: Activity was predicted by an independent measure of the degree to which participants use semantic knowledge to read. These characteristics are predicted by the connectionist Triangle Model of reading and indicate a key role for semantic knowledge in reading aloud. Premotor regions associated with phonological processing displayed the reverse characteristics. Changes in the functional connectivity of the reading network during irregular word reading also were consistent with semantic recruitment. These data support the view that reading aloud is underpinned by the joint operation of two neural pathways. They reveal that (i) the ATL is an important element of the ventral semantic pathway and (ii) the division of labor between the two routes varies according to both the properties of the words being read and individual differences in the degree to which participants rely on each route. PMID:26124121

  13. Emerging Technological Risk Underpinning the Risk of Technology Innovation

    CERN Document Server

    Anderson, Stuart

    2012-01-01

    Classes of socio-technical hazards allow a characterization of the risk in technology innovation and clarify the mechanisms underpinning emergent technological risk. Emerging Technological Risk provides an interdisciplinary account of risk in socio-technical systems including hazards which highlight: ·         How technological risk crosses organizational boundaries, ·         How technological trajectories and evolution develop from resolving tensions emerging between social aspects of organisations and technologies and ·         How social behaviour shapes, and is shaped by, technology. Addressing an audience from a range of academic and professional backgrounds, Emerging Technological Risk is a key source for those who wish to benefit from a detail and methodical exposure to multiple perspectives on technological risk. By providing a synthesis of recent work on risk that captures the complex mechanisms that characterize the emergence of risk in technology innovation, Emerging Tec...

  14. Neuroendocrine underpinnings of sex differences in circadian timing systems.

    Science.gov (United States)

    Yan, Lily; Silver, Rae

    2016-06-01

    There are compelling reasons to study the role of steroids and sex differences in the circadian timing system. A solid history of research demonstrates the ubiquity of circadian changes that impact virtually all behavioral and biological responses. Furthermore, steroid hormones can modulate every attribute of circadian responses including the period, amplitude and phase. Finally, desynchronization of circadian rhythmicity, and either enhancing or damping amplitude of various circadian responses can produce different effects in the sexes. Studies of the neuroendocrine underpinnings of circadian timing systems and underlying sex differences have paralleled the overall development of the field as a whole. Early experimental studies established the ubiquity of circadian rhythms by cataloging daily and seasonal changes in whole organism responses. The next generation of experiments demonstrated that daily changes are not a result of environmental synchronizing cues, and are internally orchestrated, and that these differ in the sexes. This work was followed by the revelation of molecular circadian rhythms within individual cells. At present, there is a proliferation of work on the consequences of these daily oscillations in health and in disease, and awareness that these may differ in the sexes. In the present discourse we describe the paradigms used to examine circadian oscillation, to characterize how these internal timing signals are synchronized to local environmental conditions, and how hormones of gonadal and/or adrenal origin modulate circadian responses. Evidence pointing to endocrinologically and genetically mediated sex differences in circadian timing systems can be seen at many levels of the neuroendocrine and endocrine systems, from the cell, the gland and organ, and to whole animal behavior, including sleep/wake or rest/activity cycles, responses to external stimuli, and responses to drugs. We review evidence indicating that the analysis of the circadian

  15. Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

    Science.gov (United States)

    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). © 2015 Authors; published by Portland Press Limited.

  16. Wharton’s Jelly-Derived Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for the Management of Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Joseph P. McGuirk

    2015-04-01

    Full Text Available Allogeneic hematopoietic cell transplantation (allo-HCT, a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD. The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ-derived mesenchymal stromal cells (MSCs as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

  17. Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells

    Science.gov (United States)

    Cengiz, Bagdat Burcu; Asik, Mehmet Dogan; Kara, Goknur; Turk, Mustafa; Denkbas, Emir Baki

    2015-04-01

    In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

  18. Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cengiz, Bagdat Burcu; Asik, Mehmet Dogan [Hacettepe University, Nanotechnology and Nanomedicine Division (Turkey); Kara, Goknur [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey); Turk, Mustafa [Kirikkale University, Bioengineering Department (Turkey); Denkbas, Emir Baki, E-mail: denkbas@hacettepe.edu.tr [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey)

    2015-04-15

    In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

  19. Theoretical underpinnings of transformation: a case study | Blunt ...

    African Journals Online (AJOL)

    Encouraged by this information, the Faculty moved quickly towards creating viable new Programmes presented by multi disciplinary teams using innovative modes of delivery. The new strategy met with immediate success in some respects, less so in others. The article traces the ways in which the Faculty has continued to ...

  20. Treatment with Rutin - A Therapeutic Strategy for Neutrophil-Mediated Inflammatory and Autoimmune Diseases - Anti-inflammatory Effects of Rutin on Neutrophils -

    Directory of Open Access Journals (Sweden)

    Bahareh Abd Nikfarjam

    2017-03-01

    due to its inhibiting NO and TNF-α productions, as well as MPO activity, in activated human neutrophils. Treatment with rutin may be considered as a therapeutic strategy for neutrophil-mediated inflammatory/ autoimmune diseases.

  1. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Su [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jeon, Seong-Uk; Lee, Chan-Ju; Kim, Young-Eun; Bok, Seoyeon; Hong, Beom-Ju; Park, Dong-Young [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Ahn, G-One, E-mail: goneahn@postech.ac.kr [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Kim, Hak Jae, E-mail: khjae@snu.ac.kr [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-07-01

    in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.

  2. Targeting immune co-stimulatory effects of PD-L1 and PD-L2 might represent an effective therapeutic strategy in stroke.

    Science.gov (United States)

    Bodhankar, Sheetal; Chen, Yingxin; Lapato, Andrew; Vandenbark, Arthur A; Murphy, Stephanie J; Offner, Halina

    2014-01-01

    -L1 and PD-L2 might represent a valuable therapeutic strategy in stroke.

  3. A new era of therapeutic strategies for chronic thromboembolic pulmonary hypertension by two different interventional therapies; pulmonary endarterectomy and percutaneous transluminal pulmonary angioplasty.

    Directory of Open Access Journals (Sweden)

    Takumi Inami

    and catheter-based interventional therapies leads us to expect the dawn of a new era of therapeutic strategies for CTEPH.

  4. Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines.

    Science.gov (United States)

    Criscione, S M

    2011-11-01

    There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity

  5. Visual strategies underpinning the development of visual-motor expertise when hitting a ball

    NARCIS (Netherlands)

    Sarpeshkar, Vishnu; Abernethy, B.; Mann, D.L.

    2017-01-01

    It is well known that skilled batters in fast-ball sports do not align their gaze with the ball throughout ball-flight, but instead adopt a unique sequence of eye and head movements that contribute toward their skill. However, much of what we know about visual-motor behavior in hitting is based on

  6. Neural computations underpinning the strategic management of influence in advice giving.

    Science.gov (United States)

    Hertz, Uri; Palminteri, Stefano; Brunetti, Silvia; Olesen, Cecilie; Frith, Chris D; Bahrami, Bahador

    2017-12-19

    Research on social influence has focused mainly on the target of influence (e.g., consumer and voter); thus, the cognitive and neurobiological underpinnings of the source of the influence (e.g., politicians and salesmen) remain unknown. Here, in a three-sided advice-giving game, two advisers competed to influence a client by modulating their own confidence in their advice about which lottery the client should choose. We report that advisers' strategy depends on their level of influence on the client and their merit relative to one another. Moreover, blood-oxygenation-level-dependent (BOLD) signal in the temporo-parietal junction is modulated by adviser's current level of influence on the client, and relative merit prediction error affects activity in medial-prefrontal cortex. Both types of social information modulate ventral striatum response. By demonstrating what happens in our mind and brain when we try to influence others, these results begin to explain the biological mechanisms that shape inter-individual differences in social conduct.

  7. Theoretical underpinnings of state institutionalisation of inclusion and struggles in collective health in Latin America.

    Science.gov (United States)

    Mahmood, Qamar; Muntaner, Carles

    2018-03-28

    Community participation as a strategy in health aims to increase the role of citizens in health decision-making which are contextualised within the institutions of democracy. Electoral representation as the dominant model of democracy globally is based on the elite theory of democracy that sees political decision-making a prerogative of political elites. Such political elitism is counter to the idea of democratic participation. Neoliberalism together with elitism in political sphere have worsened social inequities by undermining working class interests. Latin America has seen adverse consequences of these social inequities. In response, social movements representing collective struggles of organised citizens arose in the region. This paper explores the theoretical underpinnings of democratic participation in contemporary Latin American context at the nexus of emerging social movement activism and policy responses. The paper will use empirical examples to highlight how such democratic practices at the societal level evolved while demanding political inclusion. These societal democratic practices in Latin America are redefining democracy, which continues to be seen in the political sphere only. Health reforms promoting participatory democracy in several Latin American countries have demonstrated that establishing institutions and mechanisms of democratic participation facilitate collective participation by the organised citizenry in state affairs.

  8. On the conceptual underpinnings of fair value accounting

    Directory of Open Access Journals (Sweden)

    Jatinder P. Singh

    2017-05-01

    Full Text Available The metamorphosis of business processes and corporate strategies is rapidly progressing across the globe. The critical role of intangibles in corporate performance is receiving its due recognition. Complex tradeable financial products are flooding financial markets. In attempts to gear up for the challenge of financial reporting in this upstaged environment, standard setters have substantively restructured reporting systems, with ‘fair value’ being the bedrock thereof. Moving away from the traditional ‘revenue/expense’ matching measure of income towards the ‘asset/liability’ measure together with the adoption of the Hicksian concept of income is clearly discernible in the pronouncements and ongoing projects of the US Financial Accounting Standards Board (hereinafter referred to as FASB and the International Accounting Standards Board (hereinafter referred to as IASB . In this article, an attempt is made to analyze the issues that are controversial and equivocal, or those that need further refinement insofar as fair value accounting is concerned.

  9. Underpinning the repurposing of anthracyclines towards colorectal cancer

    DEFF Research Database (Denmark)

    Nygård, Sune Boris; Christensen, Ib Jarle; Smith, David Hersi

    2013-01-01

    -fixed, paraffin-embedded material from 154 stage III colorectal cancer patients included in the RANX05 clinical trial was retrospectively assessed for TOP2A gene alterations using FISH. The TOP2A/CEN-17 ratio as well as the TOP2A gene copy number alone was used to define gene alterations and associations between...... in breast cancer. No prognostic characteristic of TOP2A was identified. Conclusion. TOP2A gene gain is present in numbers relevant to identify a subgroup of patients who may benefit from anthracycline therapy. Based on the present findings, we will initiate a prospective clinical trial designed to evaluate......Abstract Objective. We propose a repurposing strategy where anthracyclines are reintroduced to a subgroup of patients with metastatic colorectal cancer with the highest likelihood of response. In breast cancer, DNA topoisomerase II alpha gene (TOP2A) alterations predict incremental benefit...

  10. Too Much Fun for Therapy: Therapeutic Recreation as an Intervention Tool with At-Risk Youth. A Series of Solutions and Strategies.

    Science.gov (United States)

    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…

  11. Therapeutic radionuclides

    International Nuclear Information System (INIS)

    Choi, Sun Ju; Hong, Young Don; Lee, So Young

    2006-01-01

    Since the development of sophisticated molecular carriers such as octereotides for peptide receptor targeting and monoclonal antibodies against various associated with specific tumor types, radionuclide therapy (RNT) employing open sources of therapeutic agents is promising modality for treatment of tumors. Furthermore, the emerging of new therapeutic regimes and new approaches for tumor treatment using radionuclide are anticipated in near future. In targeted radiotherapy using peptides and other receptor based carrier molecules, the use of radionuclide with high specific activity in formulating the radiopharmaceutical is essential in order to deliver sufficient number of radionuclides to the target site without saturating the target. In order to develop effective radiopharmaceuticals for therapeutic applications, it is crucial to carefully consider the choice of appropriate radionuclides as well as the carrier moiety with suitable pharmacokinetic properties that could result in good in vivo localization and desired excretion. Up to date, only a limited number of radionuclides have been applied in radiopharmaceutical development due to the constraints in compliance with their physical half-life, decay characteristics, cost and availability in therapeutic applications. In this review article, we intend to provide with the improved understanding of the factors of importance of appropriate radionuclide for therapy with respect to their physical properties and therapeutic applications

  12. The immunological underpinnings of vaccinations to prevent cytomegalovirus disease.

    Science.gov (United States)

    McCormick, A Louise; Mocarski, Edward S

    2015-03-01

    A universal cytomegalovirus (CMV) vaccination promises to reduce the burden of the developmental damage that afflicts up to 0.5% of live births worldwide. An effective vaccination that prevents transplacental transmission would reduce CMV congenital disease and CMV-associated still births and leave populations less susceptible to opportunistic CMV disease. Thus, a vaccination against this virus has long been recognized for the potential of enormous health-care savings because congenital damage is life-long and existing anti-viral options are limited. Vaccine researchers, industry leaders, and regulatory representatives have discussed the challenges posed by clinical efficacy trials that would lead to a universal CMV vaccine, reviewing the links between infection and disease, and identifying settings where disrupting viral transmission might provide a surrogate endpoint for disease prevention. Reducing the complexity of such trials would facilitate vaccine development. Children and adolescents are the targets for universal vaccination, with the expectation of protecting the offspring of immunized women. Given that a majority of females worldwide experience CMV infection during childhood, a universal vaccine must boost natural immunity and reduce transmission due to reactivation and re-infection as well as primary infection during pregnancy. Although current vaccine strategies recognize the value of humoral and cellular immunity, the precise mechanisms that act at the placental interface remain elusive. Immunity resulting from natural infection appears to limit rather than prevent reactivation of latent viruses and susceptibility to re-infection, leaving a challenge for universal vaccination to improve upon natural immunity levels. Despite these hurdles, early phase clinical trials have achieved primary end points in CMV seronegative subjects. Efficacy studies must be expanded to mixed populations of CMV-naive and naturally infected subjects to understand the overall

  13. Transformational Teaching: Theoretical Underpinnings, Basic Principles, and Core Methods

    Science.gov (United States)

    Slavich, George M.; Zimbardo, Philip G.

    2012-01-01

    Approaches to classroom instruction have evolved considerably over the past 50 years. This progress has been spurred by the development of several learning principles and methods of instruction, including active learning, student-centered learning, collaborative learning, experiential learning, and problem-based learning. In the present paper, we suggest that these seemingly different strategies share important underlying characteristics and can be viewed as complimentary components of a broader approach to classroom instruction called transformational teaching. Transformational teaching involves creating dynamic relationships between teachers, students, and a shared body of knowledge to promote student learning and personal growth. From this perspective, instructors are intellectual coaches who create teams of students who collaborate with each other and with their teacher to master bodies of information. Teachers assume the traditional role of facilitating students’ acquisition of key course concepts, but do so while enhancing students’ personal development and attitudes toward learning. They accomplish these goals by establishing a shared vision for a course, providing modeling and mastery experiences, challenging and encouraging students, personalizing attention and feedback, creating experiential lessons that transcend the boundaries of the classroom, and promoting ample opportunities for preflection and reflection. We propose that these methods are synergistically related and, when used together, maximize students’ potential for intellectual and personal growth. PMID:23162369

  14. Coral identity underpins architectural complexity on Caribbean reefs.

    Science.gov (United States)

    Alvarez-Filip, Lorenzo; Dulvy, Nicholas K; Côte, Isabelle M; Watkinson, Andrew R; Gill, Jennifer A

    2011-09-01

    The architectural complexity of ecosystems can greatly influence their capacity to support biodiversity and deliver ecosystem services. Understanding the components underlying this complexity can aid the development of effective strategies for ecosystem conservation. Caribbean coral reefs support and protect millions of livelihoods, but recent anthropogenic change is shifting communities toward reefs dominated by stress-resistant coral species, which are often less architecturally complex. With the regionwide decline in reef fish abundance, it is becoming increasingly important to understand changes in coral reef community structure and function. We quantify the influence of coral composition, diversity, and morpho-functional traits on the architectural complexity of reefs across 91 sites at Cozumel, Mexico. Although reef architectural complexity increases with coral cover and species richness, it is highest on sites that are low in taxonomic evenness and dominated by morpho-functionally important, reef-building coral genera, particularly Montastraea. Sites with similar coral community composition also tend to occur on reefs with very similar architectural complexity, suggesting that reef structure tends to be determined by the same key species across sites. Our findings provide support for prioritizing and protecting particular reef types, especially those dominated by key reef-building corals, in order to enhance reef complexity.

  15. Conditions underpinning success in joint service-education workforce planning

    Directory of Open Access Journals (Sweden)

    Styles Laureen

    2009-02-01

    Full Text Available Abstract Vancouver Island lies just off the southwest coast of Canada. Separated from the large urban area of Greater Vancouver (estimated population 2.17 million by the Georgia Strait, this geographical location poses unique challenges in delivering health care to a mixed urban, rural and remote population of approximately 730 000 people living on the main island and the surrounding Gulf Islands. These challenges are offset by opportunities for the Vancouver Island Health Authority (VIHA to collaborate with four publicly funded post-secondary institutions in planning and implementing responses to existing and emerging health care workforce needs. In this commentary, we outline strategies we have found successful in aligning health education and training with local health needs in ways that demonstrate socially accountable outcomes. Challenges encountered through this process (i.e. regulatory reform, post-secondary policy reform, impacts of an ageing population, impact of private, for-profit educational institutions have placed demands on us to establish and build on open and collaborative working relationships. Some of our successes can be attributed to evidence-informed decision-making. Other successes result from less tangible but no less important factors. We argue that both rational and "accidental" factors are significant – and that strategic use of "accidental" features may prove most significant in our efforts to ensure the delivery of high-quality health care to our communities.

  16. Conditions underpinning success in joint service-education workforce planning.

    Science.gov (United States)

    Purkis, Mary Ellen; Herringer, Barbara; Stevenson, Lynn; Styles, Laureen; Van Neste-Kenny, Jocelyne

    2009-02-25

    Vancouver Island lies just off the southwest coast of Canada. Separated from the large urban area of Greater Vancouver (estimated population 2.17 million) by the Georgia Strait, this geographical location poses unique challenges in delivering health care to a mixed urban, rural and remote population of approximately 730,000 people living on the main island and the surrounding Gulf Islands. These challenges are offset by opportunities for the Vancouver Island Health Authority (VIHA) to collaborate with four publicly funded post-secondary institutions in planning and implementing responses to existing and emerging health care workforce needs. In this commentary, we outline strategies we have found successful in aligning health education and training with local health needs in ways that demonstrate socially accountable outcomes. Challenges encountered through this process (i.e. regulatory reform, post-secondary policy reform, impacts of an ageing population, impact of private, for-profit educational institutions) have placed demands on us to establish and build on open and collaborative working relationships. Some of our successes can be attributed to evidence-informed decision-making. Other successes result from less tangible but no less important factors. We argue that both rational and "accidental" factors are significant--and that strategic use of "accidental" features may prove most significant in our efforts to ensure the delivery of high-quality health care to our communities.

  17. Cognitive components underpinning the development of model-based learning.

    Science.gov (United States)

    Potter, Tracey C S; Bryce, Nessa V; Hartley, Catherine A

    2017-06-01

    Reinforcement learning theory distinguishes "model-free" learning, which fosters reflexive repetition of previously rewarded actions, from "model-based" learning, which recruits a mental model of the environment to flexibly select goal-directed actions. Whereas model-free learning is evident across development, recruitment of model-based learning appears to increase with age. However, the cognitive processes underlying the development of model-based learning remain poorly characterized. Here, we examined whether age-related differences in cognitive processes underlying the construction and flexible recruitment of mental models predict developmental increases in model-based choice. In a cohort of participants aged 9-25, we examined whether the abilities to infer sequential regularities in the environment ("statistical learning"), maintain information in an active state ("working memory") and integrate distant concepts to solve problems ("fluid reasoning") predicted age-related improvements in model-based choice. We found that age-related improvements in statistical learning performance did not mediate the relationship between age and model-based choice. Ceiling performance on our working memory assay prevented examination of its contribution to model-based learning. However, age-related improvements in fluid reasoning statistically mediated the developmental increase in the recruitment of a model-based strategy. These findings suggest that gradual development of fluid reasoning may be a critical component process underlying the emergence of model-based learning. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Novel epigallocatechin-3-gallate (EGCG) derivative as a new therapeutic strategy for reducing neuropathic pain after chronic constriction nerve injury in mice.

    Science.gov (United States)

    Xifró, Xavier; Vidal-Sancho, Laura; Boadas-Vaello, Pere; Turrado, Carlos; Alberch, Jordi; Puig, Teresa; Verdú, Enrique

    2015-01-01

    Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG) polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI). First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi). We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p.) during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN), a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain.

  19. Novel epigallocatechin-3-gallate (EGCG derivative as a new therapeutic strategy for reducing neuropathic pain after chronic constriction nerve injury in mice.

    Directory of Open Access Journals (Sweden)

    Xavier Xifró

    Full Text Available Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI. First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi. We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p. during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN, a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain.

  20. Avidin-conjugated polymers with monobiotinylated antibody fragments: a new strategy for the noncovalent attachment of recombinant proteins for polymer therapeutics

    Czech Academy of Sciences Publication Activity Database

    Laga, Richard; Pola, Robert; Ulbrich, Karel; Hořejší, Magdalena; Sieglová, Irena; Král, Vlastimil; Fábry, Milan; Pechar, Michal

    2013-01-01

    Roč. 28, č. 3 (2013), s. 289-299 ISSN 0883-9115 R&D Projects: GA ČR GCP207/12/J030; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:61389013 ; RVO:68378050 Keywords : avidin- biotin complex * polymer therapeutics * drug targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.500, year: 2013

  1. Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

    Directory of Open Access Journals (Sweden)

    Rainer Poltz

    2009-12-01

    Full Text Available Rainer Poltz1, Raimo Franke1,#, Katrin Schweitzer1, Steffen Klamt2, Ernst-Dieter Gilles2, Michael Naumann11Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany; 2Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; #Present address: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyAbstract: Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB. Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD, receptor-interacting protein 1 (RIP1, and protein inhibitor of activated STAT y (PIASy as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio- and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.Keywords: apoptosis, Boolean network, cancer therapy, DNA-damage response, NF-κB

  2. Therapeutic Nanodevices

    Science.gov (United States)

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

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

  3. Therapeutic Gardening

    OpenAIRE

    Turner, Phyllis; Fox, Laurie; Parkhurst, James A. (James Albert)

    2013-01-01

    Gardening can be therapeutic for anyone and has been used as therapy for those with physical, emotional and social disabilities, for children, and for those who are elderly. Through careful adaptations to the garden, the gardener and the plants, almost anyone can benefit from the activity of gardening

  4. Therapeutic cloning: The ethical limits

    International Nuclear Information System (INIS)

    Whittaker, Peter A.

    2005-01-01

    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

  5. Parrotfish erosion underpins reef growth, sand talus development and island building in the Maldives

    Science.gov (United States)

    Morgan, Kyle M.; Kench, Paul S.

    2016-07-01

    Parrotfish play a key functional role on coral reefs as external bioerosion agents and produce large quantities of carbonate sediment as a by-product of grazing on reef surfaces. Parrotfish are therefore an important potential source of sediment for island construction and maintenance within atoll reef environments, particularly under future scenarios of sea level rise and island morphological change. Here, we present the first field-based estimates of excavating parrotfish erosion (Chlorurus sordidus and Chlorurus strongylocephalus) within the Indian Ocean and quantify the contribution of parrotfish to the carbonate and sediment budgets of an atoll interior reef platform in the Maldives. We note that parrotfish erosion rates are high (6.3 kg m- 2 y- 1), generating large amounts of new coral-based sediment (2.6 kg m- 2 y- 1) that has a comparable grain size distribution to island deposits. Mean erosion rates by individual C. strongylocephalus (405 kg individual y- 1) were higher than C. sordidus (55 kg individual y- 1), but their contribution to erosion per unit area of reef was less due to a lower relative biomass (C. strongylocephalus: 1.3 kg m- 2 y- 1; C. sordidus: 5.0 kg m- 2 y- 1). Parrotfish also facilitate sediment export from reefs (0.7 kg m- 2 y- 1), which contributes extensively to the development of the sand talus on the fore-reef slope and to the evolution of the wider atoll basin. Our results provide strong evidence that parrotfish erosion (and sediment generation) underpins island morphology on Maldivian reefs and highlight the importance of larger parrotfish as producers of island-grade sediment. Ecological processes must therefore be considered within future coastal management strategies for enhancing island stability.

  6. Does Gadoxetic acid-enhanced 3.0T MRI in addition to 64-detector-row contrast-enhanced CT provide better diagnostic performance and change the therapeutic strategy for the preoperative evaluation of colorectal liver metastases?

    Science.gov (United States)

    Sofue, Keitaro; Tsurusaki, Masakatsu; Murakami, Takamichi; Onoe, Shunsuke; Tokue, Hiroyuki; Shibamoto, Kentaro; Arai, Yasuaki; Sugimura, Kazuro

    2014-10-01

    To compare diagnostic performance in the detection of colorectal liver metastases between 64-detector-row contrast-enhanced CT (CE-CT) alone and the combination of CE-CT and gadoxetic acid-enhanced MRI (EOB-MRI) at 3.0T, and to assess whether EOB-MRI in addition to CE-CT results in a change to initially planned operative strategy. A total of 39 patients (27 men, mean age 65 years) with 85 histopathologically confirmed liver metastases were included. At EOB-MRI, unenhanced (T1- and T2-weighted), dynamic, and hepatocyte-phase images were obtained. At CE-CT, four-phase dynamic contrast-enhanced images were obtained. One on-site reader and three off-site readers independently reviewed both CE-CT alone and the combination of CE-CT and EOB-MRI. Sensitivity, positive predictive value, and alternative free-response receiver operating characteristic (AFROC) method were calculated. Differences in therapeutic strategy before and after the EOB-MRI examination were also evaluated. Sensitivity and area under the AFROC curve with the combination of CE-CT and EOB-MRI were significantly superior to those with CE-CT alone. Changes in surgical therapy were documented in 13 of 39 patients. The combination of CE-CT and EOB-MRI may provide better diagnostic performance than CE-CT alone for the detection of colorectal liver metastases, and EOB-MRI in addition to CE-CT resulted in changes to the planned operative strategy in one-third of the patients. • Accurate preoperative imaging is essential for surgical planning and successful hepatic resection. • Combination of CE-CT and EOB-MRI is useful to detect colorectal liver metastases. • EOB-MRI combined with CE-CT contributes to determine the correct therapeutic strategy.

  7. microRNAs as a New Mechanism Regulating Adipose Tissue Inflammation in Obesity and as a Novel Therapeutic Strategy in the Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Qian Ge

    2014-01-01

    Full Text Available Obesity is associated closely with the metabolic syndrome (MS. It is well known that obesity-induced chronic inflammation plays a fundamental role in the pathogenesis of MS. White adipose tissue (AT is the primary site for the initiation and exacerbation of obesity-associated inflammation. Exploring the mechanisms of white AT inflammation and resetting the immunological balance in white AT could be crucial for the management of MS. Several prominent molecular mechanisms have been proposed to mediate inflammation in white AT, including hypoxia, endoplasmic reticulum stress, lipotoxicity, and metabolic endotoxemia. Recently, a growing body of evidence supports the role of miRNAs as a new important inflammatory mediator by regulating both the adaptive and innate immunity. This review will focus on the implication of miRNAs in white AT inflammation in obesity, and will also highlight the potential of miRNAs as targets for therapeutic intervention in MS as well as the challenges lying in miRNA-targeting therapeutics.

  8. microRNAs as a new mechanism regulating adipose tissue inflammation in obesity and as a novel therapeutic strategy in the metabolic syndrome.

    Science.gov (United States)

    Ge, Qian; Brichard, Sonia; Yi, Xu; Li, QiFu

    2014-01-01

    Obesity is associated closely with the metabolic syndrome (MS). It is well known that obesity-induced chronic inflammation plays a fundamental role in the pathogenesis of MS. White adipose tissue (AT) is the primary site for the initiation and exacerbation of obesity-associated inflammation. Exploring the mechanisms of white AT inflammation and resetting the immunological balance in white AT could be crucial for the management of MS. Several prominent molecular mechanisms have been proposed to mediate inflammation in white AT, including hypoxia, endoplasmic reticulum stress, lipotoxicity, and metabolic endotoxemia. Recently, a growing body of evidence supports the role of miRNAs as a new important inflammatory mediator by regulating both the adaptive and innate immunity. This review will focus on the implication of miRNAs in white AT inflammation in obesity, and will also highlight the potential of miRNAs as targets for therapeutic intervention in MS as well as the challenges lying in miRNA-targeting therapeutics.

  9. Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Gergely Tóth

    Full Text Available The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228, that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.

  10. Examination of nanoformulated crosslinked polymers complexed with copper/zinc superoxide dismutase as a therapeutic strategy for angiotensin II-mediated hypertension

    Science.gov (United States)

    Savalia, Krupa

    Excessive generation of superoxide (O2·-) has been extensively implicated as a signaling molecule in cardiovascular pathologies, including hypertension. As a major risk factor for myocardial infarction, stroke, and heart failure, the morbidity and mortality associated with hypertension is a worldwide epidemic. Although there are several standard therapies that effectively lower blood pressure, many hypertensive patients have uncontrolled blood pressure despite taking available medications. Thus, there is a necessity to develop new pharmacotherapies that target novel molecular effectors (e.g. O2·-) that have been implicated to be integral in the pathogenesis of hypertension. To overcome the failed therapeutic impact of currently available antioxidants in cardiovascular disease, we developed a nanomedicine-based delivery system for the O2 ·- scavenging enzyme, copper/zinc superoxide dismutase (CuZnSOD), in which CuZnSOD protein is electrostatically bound to poly-L-lysine (PLL 50)-polyethylene glycol (PEG) block co-polymer to form CuZnSOD nanozyme. Different formulations of CuZnSOD nanozyme are covalently stabilized by either reducible or non-reducible crosslinked bonds between the PLL50-PEG polymers. Herein, we tested the overall hypothesis that PLL50-PEG CuZnSOD nanozyme delivers active CuZnSOD protein to neurons and decreases blood pressure in a model of Angll-dependent hypertension. As determined by electron paramagnetic resonance (EPR) spectroscopy, nanozymes retain full SOD enzymatic activity. Furthermore, non-reducible crosslinked nanozyme delivers active CuZnSOD protein to central neurons in culture (CATH.a neurons) without inducing significant neuronal toxicity. In vivo studies conducted in Angll-mediated hypertensive adult male C57BL/6 mice demonstrate that the non-reducible crosslinked nanozyme significantly attenuates blood pressure when given directly into the brain and prevents the further increase in hypertension when intravenously (IV) administered

  11. Antiviral cationic peptides as a strategy for innovation in global health therapeutics for dengue virus: high yield production of the biologically active recombinant plectasin peptide.

    Science.gov (United States)

    Rothan, Hussin A; Mohamed, Zulqarnain; Suhaeb, Abdulrazzaq M; Rahman, Noorsaadah Abd; Yusof, Rohana

    2013-11-01

    Dengue virus infects millions of people worldwide, and there is no vaccine or anti-dengue therapeutic available. Antimicrobial peptides have been shown to possess effective antiviral activity against various viruses. One of the main limitations of developing these peptides as potent antiviral drugs is the high cost of production. In this study, high yield production of biologically active plectasin peptide was inexpensively achieved by producing tandem plectasin peptides as inclusion bodies in E. coli. Antiviral activity of the recombinant peptide towards dengue serotype-2 NS2B-NS3 protease (DENV2 NS2B-NS3pro) was assessed as a target to inhibit dengue virus replication in Vero cells. Single units of recombinant plectasin were collected after applying consecutive steps of refolding, cleaving by Factor Xa, and nickel column purification to obtain recombinant proteins of high purity. The maximal nontoxic dose (MNTD) of the recombinant peptide against Vero cells was 20 μM (100 μg/mL). The reaction velocity of DENV2 NS2B-NS3pro decreased significantly after increasing concentrations of recombinant plectasin were applied to the reaction mixture. Plectasin peptide noncompetitively inhibited DENV2 NS2B-NS3pro at Ki value of 5.03 ± 0.98 μM. The percentage of viral inhibition was more than 80% at the MNTD value of plectasin. In this study, biologically active recombinant plectasin which was able to inhibit dengue protease and viral replication in Vero cells was successfully produced in E. coli in a time- and cost- effective method. These findings are potentially important in the development of potent therapeutics against dengue infection.

  12. Therapeutic ultrasound

    International Nuclear Information System (INIS)

    Crum, Lawrence A

    2004-01-01

    The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. These applications broadly include: tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally non-invasive, imageguided therapy. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the introduction of acoustic hemostasis, especially in organs which are difficult to treat using conventional medical and surgical techniques. (amum lecture)

  13. A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics.

    Science.gov (United States)

    Ruiz-Esparza, Guillermo U; Segura-Ibarra, Victor; Cordero-Reyes, Andrea M; Youker, Keith A; Serda, Rita E; Cruz-Solbes, Ana S; Amione-Guerra, Javier; Yokoi, Kenji; Kirui, Dickson K; Cara, Francisca E; Paez-Mayorga, Jesus; Flores-Arredondo, Jose H; Guerrero-Beltrán, Carlos E; Garcia-Rivas, Gerardo; Ferrari, Mauro; Blanco, Elvin; Torre-Amione, Guillermo

    2016-02-01

    Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure. © 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.

  14. Place of the brachytherapy in the therapeutic strategy of rhabdomyosarcomas of the nasogenian groove of children; Place de la curietherapie dans la strategie therapeutique des rhabdomyosarcomes du sillon nasogenien de l'enfant

    Energy Technology Data Exchange (ETDEWEB)

    Breton-Callu, C.; Haie-Meder, C.; Oberlin, O.; Delapierre, M.; Gerbaulet, A. [Institut Gustave Roussy, 94 - Villejuif (France)

    2000-12-01

    The brachytherapy in the treatment of rhabdomyosarcomas of the nasogenian groove has to be discussed when it exists a residual tumor after an initial chemotherapy and leads to good results, in term of local control. An advantage of the brachytherapy in comparison with external irradiation, in the treatment of children tumors, is the small size of the treated volume, that allows to decrease the aftereffects incidence. The brachytherapy comes in the frame of a therapeutic needing a multidisciplinary approach and a cooperation between surgeons, brachy-therapists and onco-pediatricians. (N.C.)

  15. Wearing the T-shirt: an exploration of the ideological underpinnings ...

    African Journals Online (AJOL)

    Wearing the T-shirt: an exploration of the ideological underpinnings of visual representations of the African body with HIV or AIDS. ... currency in relation to colonialism; 2) A matter of mor(t)ality examines the relationship between morality and the mortality of the African body; 3) The legacies endure analyses selected images ...

  16. Implementing AAC with Children with Profound and Multiple Learning Disabilities: A Study in Rationale Underpinning Intervention

    Science.gov (United States)

    Harding, Celia; Lindsay, Gemma; O'Brien, Aoife; Dipper, Lucy; Wright, Julie

    2011-01-01

    There is a developing research base to support the rationale underpinning augmentative and alternative communication (AAC) for people with learning disabilities. However, there is a paucity of research examining the process involved in implementing AAC support for people who have profound disabilities. This paper seeks to explore the processes…

  17. Perceived Sacrifice and Few Alternatives Commitments: The Motivational Underpinnings of Continuance Commitment's Subdimensions

    Science.gov (United States)

    Vandenberghe, Christian; Panaccio, Alexandra

    2012-01-01

    Using work on self-concepts and Conservation of Resources theory, the present research examined the motivational underpinnings of continuance commitment's subcomponents of perceived sacrifice and few alternatives. Study 1 (N=208) found job scope to be positively related to perceived sacrifice commitment, and negatively related to few alternatives…

  18. Cognitive Underpinnings of Moral Reasoning in Adolescence: The Contribution of Executive Functions

    Science.gov (United States)

    Vera-Estay, E.; Dooley, J. J.; Beauchamp, M. H.

    2015-01-01

    Adolescence is a developmental period characterized by intense changes, which impact the interaction between individuals and their environments. Moral reasoning (MR) is an important skill during adolescence because it guides social decisions between right and wrong. Identifying the cognitive underpinnings of MR is essential to understanding the…

  19. Therapeutic Vaccines for Chronic Infections

    Science.gov (United States)

    Autran, Brigitte; Carcelain, Guislaine; Combadiere, Béhazine; Debre, Patrice

    2004-07-01

    Therapeutic vaccines aim to prevent severe complications of a chronic infection by reinforcing host defenses when some immune control, albeit insufficient, can already be demonstrated and when a conventional antimicrobial therapy either is not available or has limited efficacy. We focus on the rationale and challenges behind this still controversial strategy and provide examples from three major chronic infectious diseases-human immunodeficiency virus, hepatitis B virus, and human papillomavirus-for which the efficacy of therapeutic vaccines is currently being evaluated.

  20. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions

    International Nuclear Information System (INIS)

    Hammerstingl, Renate; Vogl, Thomas J.; Huppertz, Alexander; Breuer, Josy; Balzer, Thomas; Blakeborough, Anthony; Carter, Rick; Castells Fuste, Lluis; Heinz-Peer, Gertraud; Judmaier, Werner; Laniado, Michael; Manfredi, Riccardo M.; Mathieu, Didier G.; Mueller, Dieter; Mortele, Koenraad; Reimer, Peter; Reiser, Maximilian F.; Robinson, Philip J.; Shamsi, Kohkan; Strotzer, Michael; Taupitz, Matthias; Tombach, Bernd; Valeri, Gianluca; Beers, Bernhard E. van

    2008-01-01

    A multicenter study has been employed to evaluate the diagnostic efficacy of magnetic resonance imaging (MRI) using the new liver-specific contrast agent gadoxetic acid (Gd-EOB-DTPA, Primovist), as opposed to contrast-enhanced biphasic spiral computed tomography (CT), in the diagnosis of focal liver lesions, compared with a standard of reference (SOR). One hundred and sixty-nine patients with hepatic lesions eligible for surgery underwent Gd-EOB-DTPA-enhanced MRI as well as CT within 6 weeks. Pathologic evaluation of the liver specimen combined with intraoperative ultrasound established the SOR. Data sets were evaluated on-site (14 investigators) and off-site (three independent blinded readers). Gd-EOB-DTPA was well tolerated. Three hundred and two lesions were detected in 131 patients valid for analysis by SOR. The frequency of correctly detected lesions was significantly higher on Gd-EOB-DTPA-enhanced MRI compared with CT in the clinical evaluation [10.44%; 95% confidence interval (CI): 4.88, 16.0]. In the blinded reading there was a trend towards Gd-EOB-DTPA-enhanced MRI, not reaching statistical significance (2.14%; 95% CI: -4.32, 8.6). However, the highest rate of correctly detected lesions with a diameter below 1 cm was achieved by Gd-EOB-DTPA-enhanced MRI. Differential diagnosis was superior for Gd-EOB-DTPA-enhanced MRI (82.1%) versus CT (71.0%). A change in surgical therapy was documented in 19 of 131 patients (14.5%) post Gd-EOB-DTPA-enhanced MRI. Gd-EOB-DTPA-enhanced MRI was superior in the diagnosis and therapeutic management of focal liver lesions compared with CT. (orig.)

  1. Co-delivery of HIV-1 entry inhibitor and nonnucleoside reverse transcriptase inhibitor shuttled by nanoparticles: cocktail therapeutic strategy for antiviral therapy.

    Science.gov (United States)

    Li, Wen; Yu, Fei; Wang, Qian; Qi, Qianqian; Su, Shan; Xie, Lan; Lu, Lu; Jiang, Shibo

    2016-03-27

    Traditionally, the antiviral efficacy of classic cocktail therapy is significantly limited by the distinct pharmacokinetic profiles of partner therapeutics that lead to inconsistent in-vivo biodistribution. Here we developed a new cocktail-like drug delivery vehicle using biodegradable polymeric nanoparticles (NP) encapsulating nonnucleoside reverse transcriptase inhibitor (NNRTI) DAAN-14f (14f), surface-conjugated with HIV-1 fusion inhibitor T1144, designated T1144-NP-DAAN-14f (T1144-NP-14f), and aiming to achieve enhanced cellular uptake, improved antiviral activity and prolonged blood circulation time. T1144-NP-14f was prepared through the emulsion/solvent evaporation technique and a maleimide-thiol coupling reaction. Particle size and morphology were determined by dynamic light scattering detection and transmission electron microscopy. Anti-HIV-1 activity was assessed by HIV-1 Env-mediated cell-cell fusion and infection by laboratory-adapted, primary, and resistant HIV-1 isolates, respectively. The in-vitro release of 14f was investigated using the equilibrium dialysis method, and the pharmacokinetic study of T1144-NP-14f was performed on Sprague-Dawley rats. T1144-NP-14f displayed a spherical shape under transmission electron microscopy observation and had a size of 117 ± 19 nm. T1144-NP-14f exhibited the strongest antiviral activity against a broad spectrum of HIV-1 strains, including NNRTI-, T1144-, or T20-resistant isolates, respectively. Both in-vitro release and in-vivo pharmacokinetic profile showed that T1144-NP-14f exhibited a sustained controlled release behavior. Our results demonstrated that the combination of entry inhibitor with NNRTI encapsulated in nanoparticles (T1144-NP-14f) was highly effective in inhibiting HIV-1 infection. This new cocktail-like drug delivery platform could serve as an effective anti-HIV-1 regimen by taking advantage of the extrinsic and intrinsic antiviral activity of individual drugs.

  2. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions

    Energy Technology Data Exchange (ETDEWEB)

    Hammerstingl, Renate; Vogl, Thomas J. [Johann Wolfgang Goethe-Univ., Inst. of Diagnostic and Interventional Radiology, Frankfurt am Main (Germany); Huppertz, Alexander [Imaging Science Inst., Charite - Siemens, Berlin (Germany); Breuer, Josy; Balzer, Thomas [Gobal Clinical Development Diagnostics, Bayer Schering Pharma AG, Berlin (Germany); Blakeborough, Anthony [Royal Hallamshire Hospital, Dept. of Radiology, Sheffield (United Kingdom); Carter, Rick [Bayer Health Care Ltd., Burgess Hill, West Sussex (United Kingdom); Castells Fuste, Lluis [Hospital Vall d' Hebron, Liver Unit, Dept. of Internal Medicine, Barcelona (Spain); Heinz-Peer, Gertraud [Universitaetsklinik fuer Radiodiagnostik, Allg. Krankenhaus der Stadt Wien, Wien (Germany); Judmaier, Werner [Univ. Hospital Innsbruck, Dept. of Magnetic Resonance Imaging and Spectroscopy, Innsbruck (Austria); Laniado, Michael [Universitaetsklinikum Carl Gustav Carus, Technische Univ. Dresden, Inst. for Diagnostic Radiology, Dresden (Germany); Manfredi, Riccardo M. [Univ. of Verona, Dept. of Radiology, Verona (Italy); Mathieu, Didier G. [Centre d' Imagerie, Aix en Provence (France); Mueller, Dieter [Georg-August Univ., Dept. of Radiology, Goettingen (Germany); Mortele, Koenraad [Brigham and Women' s Hospital, Dept. of Radiology (L1), Boston, MA (United States); Reimer, Peter [Klinikum Karlsruhe, Dept. of Radiology, Karlsruhe (Germany); Reiser, Maximilian F. [Ludwig-Maximilians-Univ. Munich - Klinikum Grosshadern, Inst. of Clinical Radiology, Munich (Germany); Robinson, Philip J. [St James' s Univ. Hospital, Dept. of Clinical Radiology, Leeds (United Kingdom); Shamsi, Kohkan [Berlex Labs. Inc., Montville, NJ (United States); Strotzer, Michael [Univ. Hospital, Dept. of Diagnostic Radiology, Regensburg (Germany); Taupitz, Matthias [Universitaetsklinikum Charite, Med. Fakultaet der Humboldt-Univ., Dept. of Radiology, Berlin (Germany); Tombach, Bernd; Valeri, Gianluca; Beers, Bernhard E. van [and others

    2008-03-15

    A multicenter study has been employed to evaluate the diagnostic efficacy of magnetic resonance imaging (MRI) using the new liver-specific contrast agent gadoxetic acid (Gd-EOB-DTPA, Primovist), as opposed to contrast-enhanced biphasic spiral computed tomography (CT), in the diagnosis of focal liver lesions, compared with a standard of reference (SOR). One hundred and sixty-nine patients with hepatic lesions eligible for surgery underwent Gd-EOB-DTPA-enhanced MRI as well as CT within 6 weeks. Pathologic evaluation of the liver specimen combined with intraoperative ultrasound established the SOR. Data sets were evaluated on-site (14 investigators) and off-site (three independent blinded readers). Gd-EOB-DTPA was well tolerated. Three hundred and two lesions were detected in 131 patients valid for analysis by SOR. The frequency of correctly detected lesions was significantly higher on Gd-EOB-DTPA-enhanced MRI compared with CT in the clinical evaluation [10.44%; 95% confidence interval (CI): 4.88, 16.0]. In the blinded reading there was a trend towards Gd-EOB-DTPA-enhanced MRI, not reaching statistical significance (2.14%; 95% CI: -4.32, 8.6). However, the highest rate of correctly detected lesions with a diameter below 1 cm was achieved by Gd-EOB-DTPA-enhanced MRI. Differential diagnosis was superior for Gd-EOB-DTPA-enhanced MRI (82.1%) versus CT (71.0%). A change in surgical therapy was documented in 19 of 131 patients (14.5%) post Gd-EOB-DTPA-enhanced MRI. Gd-EOB-DTPA-enhanced MRI was superior in the diagnosis and therapeutic management of focal liver lesions compared with CT. (orig.)

  3. Clinical Strategy for Optimal Traditional Chinese Medicine (TCM) Herbal Dose Selection in Disease Therapeutics: Expert Consensus on Classic TCM Herbal Formula Dose Conversion.

    Science.gov (United States)

    Zha, Lin-Hua; He, Li-Sha; Lian, Feng-Mei; Zhen, Zhong; Ji, Hang-Yu; Xu, Li-Peng; Tong, Xiao-Lin

    2015-01-01

    The clinical therapeutics of traditional Chinese medicine (TCM) constitutes a complicated process which involves theory, diagnosis, and formula prescription with specific herbal dosage. Zhang Zhong-Jing's classic work, Treatise on Febrile and Miscellaneous Diseases, has been influencing TCM practice for almost 2000 years. However, during this extended period of time in Chinese history, the Chinese weight measurement system experienced noticeable changes. This change in the weight measurement system inevitably, and perhaps even negatively, affected TCM herbal dosage determination and treatment outcome. Thus, in modern society, a full understanding of the accuracy of herbal dose selection has a critical importance in the TCM daily practice of delivering the best treatment to the patients suffering from different illnesses. In the 973 Project of the Chinese National Basic Research Program, expert consensus on classic TCM formula dose conversion has been reached based on extensive literature review and discussion on the dose-effect relationship of classic TCM formulas. One "liang" in classic TCM formulas is equivalent to 13.8 g. However, based on many TCM basic and clinical studies of variable herbal formula prescriptions and herbal drug preparations, the rule of one liang equals 13.8 g should be adjusted according to different disease conditions. Recommended by the committee on TCM formula dose-effect relationship of the China Association of Chinese Medicine and the World Federation of Chinese Medicine Societies, the following expert consensus has been reached: (i) One liang converts to 6-9 g for the severely and critically ill patients. (ii) One liang converts to 3-6 g for the patients suffering from chronic diseases. (iii) One liang converts to 1-3 g in preventive medicine. The above conversions should be used as a future TCM practice guideline. Using this recommended guideline should enhance the effectiveness of daily TCM practice.

  4. TRPC3-mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells.

    Science.gov (United States)

    Moccia, Francesco; Lucariello, Angela; Guerra, Germano

    2018-05-01

    Endothelial progenitor cells (EPCs) are a sub-population of bone marrow-derived mononuclear cells that are released in circulation to restore damaged endothelium during its physiological turnover or rescue blood perfusion after an ischemic insult. Additionally, they may be mobilized from perivascular niches located within larger arteries' wall in response to hypoxic conditions. For this reason, EPCs have been regarded as an effective tool to promote revascularization and functional recovery of ischemic hearts, but clinical application failed to exploit the full potential of patients-derived cells. Indeed, the frequency and biological activity of EPCs are compromised in aging individuals or in subjects suffering from severe cardiovascular risk factors. Rejuvenating the reparative phenotype of autologous EPCs through a gene transfer approach has, therefore, been put forward as an alternative approach to enhance their therapeutic potential in cardiovascular patients. An increase in intracellular Ca 2+ concentration constitutes a pivotal signal for the activation of the so-called endothelial colony forming cells (ECFCs), the only known truly endothelial EPC subset. Studies from our group showed that the Ca 2+ toolkit differs between peripheral blood- and umbilical cord blood (UCB)-derived ECFCs. In the present article, we first discuss how VEGF uses repetitive Ca 2+ spikes to regulate angiogenesis in ECFCs and outline how VEGF-induced intracellular Ca 2+ oscillations differ between the two ECFC subtypes. We then hypothesize about the possibility to rejuvenate the biological activity of autologous ECFCs by transfecting the cell with the Ca 2+ -permeable channel Transient Receptor Potential Canonical 3, which selectively drives the Ca 2+ response to VEGF in UCB-derived ECFCs. © 2017 Wiley Periodicals, Inc.

  5. The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis: perspectives for remyelination therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Adriana Octaviana Dulamea

    2017-01-01

    Full Text Available Oligodencrocytes (OLs are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis (MS, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells (OPCs and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.

  6. Novel on-line column extraction apparatus coupled with binary peak focusing for high-performance liquid chromatography determination of rifampicin in human plasma: a strategy for therapeutic drug monitoring.

    Science.gov (United States)

    Li, Wei; Peng, Min; Long, Minghui; Qiu, Ximin; Yang, Liping

    2014-12-01

    In order to develop a method that is completely suitable for the routine therapeutic drug monitoring, a sensitive and fully automated on-line column extraction apparatus in combination with high-performance liquid chromatography allowing binary peak focusing was developed and validated for the determination of rifampicin in human plasma. Rifapentine was used as an internal standard. The analytical cycle started with the injection of 100 μL of the sample pretreated by protein precipitation in a Venusil SCX extraction column. After the elution, the analytes were transferred and concentrated in an Xtimate C18 trap column. Finally, the trapped analytes were separated by an Xtimate C18 analytical column and were analyzed by an ultraviolet detector at 336 nm. With this new strategy, continuous on-line analysis of the compounds was successfully performed. The method showed excellent performance for the analysis of rifampicin in plasma samples, including calibration curve linearity (All r were larger than 0.9996), sensitivity (lowest limit of quantification was 0.12 μg/mL), method accuracy (within 6.6% in terms of relative error), and precision (relative standard deviations of intra- and interday precision were less than 7.8%). These results demonstrated that the simple, reliable, and automatic method based on on-line column extraction and binary peak focusing is a promising approach for therapeutic drug monitoring in complex biomatrix samples. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Alberto Malerba

    2012-01-01

    Full Text Available The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD. In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO. Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.

  8. Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer

    Directory of Open Access Journals (Sweden)

    Fávaro Wagner J

    2012-06-01

    . The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases.

  9. Cleanup strategies and advantages in the determination of several therapeutic classes of pharmaceuticals in wastewater samples by SPE-LC-MS/MS.

    Science.gov (United States)

    Sousa, M A; Gonçalves, C; Cunha, E; Hajšlová, J; Alpendurada, M F

    2011-01-01

    This work describes the development and validation of an offline solid-phase extraction with simultaneous cleanup capability, followed by liquid chromatography-(electrospray ionisation)-ion trap mass spectrometry, enabling the concurrent determination of 23 pharmaceuticals of diverse chemical nature, among the most consumed in Portugal, in wastewater samples. Several cleanup strategies, exploiting the physical and chemical properties of the analytes vs. interferences, alongside with the use of internal standards, were assayed in order to minimise the influence of matrix components in the ionisation efficiency of target analytes. After testing all combinations of adsorbents (normal-phase, ion exchange and mixed composition) and elution solvents, the best results were achieved with the mixed-anion exchange Oasis MAX cartridges. They provided recovery rates generally higher than 60%. The precision of the method ranged from 2% to 18% and 4% to 19% (except for diclofenac (22%) and simvastatin (26%)) for intra- and inter-day analysis, respectively. Method detection limits varied between 1 and 20 ng L(-1), while method quantification limits were diclofenac and bezafibrate were detected in concentrations ranging from 1 to 20 μg L(-1), while gemfibrozil, simvastatin, ketoprofen, azithromycin, bisoprolol, lorazepam and paroxetine were quantified in levels below 1 μg L(-1). These WWTPs were given particular attention since they discharge their effluents into the Douro river, where water is extracted for the production of drinking water. Some sampling spots in this river were also analysed.

  10. Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital.

    Science.gov (United States)

    Hotham, James E; Simpson, Patrick J D; Brooman-White, Rosalie S; Basu, Amlan; Ross, Callum C; Humphreys, Sharon A; Larkin, Fintan; Gupta, Nitin; Das, Mrigendra

    2014-10-01

    Clozapine is used in the management of treatment-resistant schizophrenia and is effective in reducing aggression; however a subgroup of patients is poorly responsive. For violent patients in this group, there is limited literature on the use of strategies to augment clozapine with other agents. Here we present a case series of 6 schizophrenia patients, within a high-security hospital, who have a history of serious violence and who were treated with clozapine augmented with amisulpride. We reviewed case notes and health records for evidence of violence/aggression and positive factors such as engagement in activities, and Clinical Global Impression (CGI) scores were formulated. We also examined metabolic parameters before and after augmentation. All 6 of the patients showed clinical improvement in symptoms and a reduction in their risk of violence to others. Five patients had a reduction in number of violent/aggressive incidents, and all patients showed improvement in engagement in occupational, vocational, and/or psychological work. Metabolic parameters were largely unchanged except for 1 patient whose Body Mass Index (BMI) increased. Five patients reported side effects as unchanged or improved. These schizophrenia patients with a history of violence showed clinical improvement and reduced aggression and violence with amisulpride augmentation of clozapine. To our knowledge, this is the first report of an antiaggressive benefit of this combination in forensic psychiatric patients. Further studies are warranted to establish the efficacy and anti-aggressive effects of amisulpride augmentation of clozapine.

  11. A Proposed Classification System and Therapeutic Strategy for Chyle Leak After Laparoscopic Living-Donor Nephrectomy: A Single-Center Experience and Review of the Literature.

    Science.gov (United States)

    Ng, Zi Qin; He, Bulang

    2018-04-01

    Chyle leak or chylous ascites remains a rare complication after laparoscopic living-donor nephrectomy. Its cause and management have not been well elucidated in the literature. Thus, the aim of this study was to review the incidence of chyle leak/chylous ascites after laparoscopic living-donor nephrectomy in our institute and in the literature to propose a classification system with its associated treatment strategy. In this retrospective review of laparoscopic living-donor nephrectomy patients from January 2005 to April 2016, we identified patients with chyle leak/chylous ascites along with the care performed. A proposed classification system based on our experience and literature is described. Chylous leak developed in 4 donors (2.25%). Of the 4 donors, 3 were treated nonoperatively with diet modification and subcutaneous octreotide injection. One patient required surgical intervention after not responding to second-line therapy with total parenteral nutrition. Chyle leak/chylous ascites after laparoscopic living-donor nephrectomy is rare, but a delayed diagnosis may lead to morbidity secondary to malnutrition and immunosuppression. Meticulous surgical dissection is essential to seal the lymphatic tubes during laparoscopic living-donor nephrectomy. The proposed classification system provides a practical and tailored guide to management based on the drainage volume of chyle leak and a guide to the earlier identification of refractory cases.

  12. Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy.

    Science.gov (United States)

    Ge, Lan; Zhou, Xin; Ji, Wen-Jie; Lu, Rui-Yi; Zhang, Yan; Zhang, Yi-Dan; Ma, Yong-Qiang; Zhao, Ji-Hong; Li, Yu-Ming

    2015-03-01

    Emerging evidence suggests a potential role of neutrophil extracellular traps (NETs) in linking sterile inflammation and thrombosis. We hypothesized that NETs would be induced during myocardial ischemia-reperfusion (I/R), and NET-mediated microthrombosis may contribute to myocardial "no-reflow". Male Wistar rats were randomly divided into I/R control, DNase (DNase I, 20 μg/rat), recombinant tissue-type plasminogen activator (rt-PA, 420 μg/rat), DNase + rt-PA, and sham control groups after 45-min myocardial ischemia. In situ NET formation, the anatomic "no re-flow" area, and infarct size were evaluated immediately after 3 h of reperfusion. Long-term left ventricular (LV) functional and histological analyses were performed 45 days after operation. Compared with the I/R controls, the DNase + rt-PA group exhibited reduced NET density [8.38 ± 1.98 vs. 26.86 ± 3.07 (per 200 × field), P injury-induced LV remodeling (LV ejection fraction: 64.22 ± 3.37 vs. 33.81 ± 2.98%, P reperfusion strategy (DNase I + rt-PA), which might be a promising option for the treatment of myocardial I/R injury and coronary no-reflow. Copyright © 2015 the American Physiological Society.

  13. Strategy; Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    2005-07-15

    Francois Loos, Minister of Industry, explains the French energy policy in the frame of Europe. ONERC is a French public body in charge of defining a national strategy against climate changes. It submits its first strategic elements to the Government. (authors)

  14. Single-stranded DNA aptamer targeting and neutralization of anti-D alloantibody: a potential therapeutic strategy for haemolytic diseases caused by Rhesus alloantibody.

    Science.gov (United States)

    Zhang, Yinze; Wu, Fan; Wang, Manni; Zhuang, Naibao; Zhou, Huayou; Xu, Hua

    2018-02-01

    Rhesus (Rh) D antigen is the most important antigen in the Rh blood group system because of its strong immunogenicity. When RhD-negative individuals are exposed to RhD-positive blood, they may produce anti-D alloantibody, potentially resulting in delayed haemolytic transfusion reactions and Rh haemolytic disease of the foetus and newborn, which are difficult to treat. Inhibition of the binding of anti-D antibody with RhD antigens on the surface of red blood cells may effectively prevent immune haemolytic diseases. In this study, single-stranded (ss) DNA aptamers, specifically binding to anti-D antibodies, were selected via systematic evolution of ligands by exponential enrichment (SELEX) technology. After 14 rounds of selection, the purified ssDNA was sequenced using a Personal Genome Machine system. Haemagglutination inhibition assays were performed to screen aptamers for biological activity in terms of blocking antigen-antibody reactions: the affinity and specificity of the aptamers were also determined. In addition to high specificity, the aptamers which were selected showed high affinity for anti-D antibodies with dissociation constant (K d ) values ranging from 51.46±14.90 to 543.30±92.59 nM. By the combined use of specific ssDNA aptamer 7 and auxiliary ssDNA aptamer 2, anti-D could be effectively neutralised at low concentrations of the aptamers. Our results demonstrate that ssDNA aptamers may be a novel, promising strategy for the treatment of delayed haemolytic transfusion reactions and Rh haemolytic disease of the foetus and newborn.

  15. Trapping the monomer of a non-amyloidogenic variant of transthyretin: exploring its possible use as a therapeutic strategy against transthyretin amyloidogenic diseases.

    Science.gov (United States)

    Palhano, Fernando L; Leme, Larissa P; Busnardo, Roberta G; Foguel, Debora

    2009-01-16

    Transthyretin (TTR) is a 127-residue homotetrameric beta-sheet-rich protein that transports thyroxine in the blood and cerebrospinal fluid. The deposition of fibrils and amorphous aggregates of TTR in patients' tissues is a hallmark of TTR amyloid disease. Familial amyloidotic polyneuropathy is a hereditary form of TTR amyloidosis that is associated with one among 80 different variants of TTR. The most aggressive variants of TTR are V30M, L55P, and A25T, and the propensity to undergo aggregation seems to be linked to tetramer stability. T119M is a very stable, non-amyloidogenic variant of TTR. Here we show that the combination of high hydrostatic pressure with subdenaturing concentrations of urea (4 m) at 1 degrees C irreversibly dissociates T119M into monomers in less than 30 min in a concentration-dependent fashion. After pressure and urea removal, long lived monomers are the only species present in solution. We took advantage of the slow reassociation kinetics of these monomers into tetramers to produce heterotetramers by mixing the T119M monomers with the tetramers of the aggressive mutants of TTR. Our data show that T119M monomers can be successfully incorporated into all of these tetramers even when the exchange is performed in a more physiological environment such as human plasma; these monomers render the resultant heterotetramers less amyloidogenic. The data presented here are relevant for the understanding of T119M folding and association reactions and provide a protocol for producing T119M monomers that function as inhibitors of TTR aggregation when incorporated in to tetramers. This protocol may provide a new strategy for treating TTR diseases for which there is no therapy available other than liver transplantation.

  16. Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies

    Science.gov (United States)

    Salizzato, Valentina; Borgo, Christian; Cesaro, Luca; Pinna, Lorenzo A.; Donella-Deana, Arianna

    2016-01-01

    Chronic myeloid leukaemia (CML) is a myeloproliferative disorder promoted by the constitutive tyrosine kinase activity of Bcr-Abl oncoprotein. Although treatment with the Bcr-Abl-inhibitor imatinib represents the first-line therapy against CML, almost 20-30% of patients develop chemotherapeutic resistance and require alternative therapy. Here we show that a strong hyper-phosphorylation/activation of ERK1/2, Akt Ser473, and 40S ribosomal protein S6 (rpS6) is detectable in imatinib-resistant KCL22 and K562 CML cells as compared to the -sensitive cell variants. In imatinib-resistant CML cells, high concentration of imatinib is required to strongly inhibit Bcr-Abl, ERK1/2 and Akt Ser473 phosphorylation, but under these conditions the phosphorylation of rpS6, a common downstream effector of MEK/ERK1/2 and PI3K/Akt/mTOR pathways is only slightly reduced. By contrast, down-regulation of the protein kinase CK2 by the inhibitor CX-5011 or by silencing the CK2 subunits does not affect the activation state of MEK/ERK1/2 or PI3K/Akt/mTOR signalling, but causes a drop in rpS6 phosphorylation in parallel with reduced protein synthesis. CK2-inhibition by CX-5011 induces cell death by apoptosis and acts synergistically with imatinib or the MEK-inhibitor U0126 in reducing the viability of imatinib-resistant CML cells. The ternary mixture containing CX-5011, imatinib and U0126 represents the most effective synergistic combination to counteract CML cell viability. These results disclose a novel CK2-mediated mechanism of acquired imatinib-resistance resulting in hyper-phosphorylation of rpS6. We suggest that co-targeting CK2 and MEK protein kinases is a promising strategy to restore responsiveness of resistant CML cells to imatinib. PMID:26919095

  17. SoTL Inquiry in Broader Curricular and Institutional Contexts: Theoretical Underpinnings and Emerging Trends

    Directory of Open Access Journals (Sweden)

    Harry Hubball

    2013-03-01

    reforms. This paper calls for a more expansive view and strategic use of SoTL inquiry in order to make substantive contributions to curriculum renewal, educational leadership practices, and, most importantly, the quality of undergraduate and graduate degree programs. Theoretical underpinnings, emerging trends, challenges, and strategic supports to enhance the effectiveness and efficiency of curricula within and across diverse disciplinary contexts are discussed.

  18. Therapeutic misadventure.

    Science.gov (United States)

    Langford, N J

    2010-10-01

    Therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Within the National Health Service there were over 86,000 reported adverse incidents in 2007. In the USA medication errors have been rated as the fourth highest cause of death. Unfortunately one of the greatest contributors to iatrogenic injury is human error. The potential types of misadventure are infinite. Medication errors are a major part of this, being responsible for over 70% of cases that cause serious harm. However, many medication errors caused by slips, lapses, technical errors and mistakes are preventable; intentional violations of safe operating procedures are not. While medication errors were tolerated by society in the past, the readiness to institute criminal proceedings against health-care professionals has increased greatly in the UK over the last decade. The medication process consists of writing prescriptions, dispensing the product, administering it and monitoring its effects. Prescription errors arise owing to incomplete information, lack of appropriate labelling, environmental factors and human blunders. Even with a perfect prescription the right medication must be dispensed and appropriately labelled. Dispensing errors are not uncommon and may be compounded by non-clinical considerations. Administration of a drug by injection is one of the most dangerous aspects of the medication process, especially in inexperienced hands. The final component of medication supply is monitoring the effect of the medication. With short courses of medication such monitoring is easy, but with long-term medication, particularly with potent drugs where the margin between efficacy and toxicity is small, active procedures may be required to ensure toxicity does not ensue. Despite the endeavour of health-care professions to stick to the rule of 'first, do no harm', in reality this is difficult to achieve all of the time. When

  19. Mechanisms underpinning effective peer support: a qualitative analysis of interactions between expert peers and patients newly-diagnosed with bipolar disorder

    Directory of Open Access Journals (Sweden)

    Proudfoot Judith G

    2012-11-01

    Full Text Available Abstract Background The increasing burden on mental health services has led to the growing use of peer support in psychological interventions. Four theoretical mechanisms have been proposed to underpin effective peer support: advice grounded in experiential knowledge, social support, social comparison and the helper therapy principle. However, there has been a lack of studies examining whether these mechanisms are also evident in clinical populations in which interpersonal dysfunction is common, such as bipolar disorder. Method This qualitative study, conducted alongside a randomized controlled trial, examined whether the four mechanisms proposed to underpin effective peer support were expressed in the email exchange between 44 individuals newly-diagnosed with bipolar disorder and their Informed Supporters (n = 4, over the course of a supported online psychoeducation program for bipolar disorder. A total of 104 text segments were extracted and coded. The data were complemented by face-to-face interviews with three of the four Informed Supporters who participated in the study. Results Qualitative analyses of the email interchange and interview transcripts revealed rich examples of all four mechanisms. The data illustrated how the involvement of Informed Supporters resulted in numerous benefits for the newly-diagnosed individuals, including the provision of practical strategies for illness management as well as emotional support throughout the intervention. The Informed Supporters encouraged the development of positive relationships with mental health services, and acted as role models for treatment adherence. The Informed Supporters themselves reported gaining a number of benefits from helping, including a greater sense of connectedness with the mental health system, as well as a broader knowledge of illness management strategies. Conclusions Examples of the mechanisms underpinning effective peer support were found in the sample of emails from

  20. Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users.

    Science.gov (United States)

    Wesley, Michael J; Lohrenz, Terry; Koffarnus, Mikhail N; McClure, Samuel M; De La Garza, Richard; Salas, Ramiro; Thompson-Lake, Daisy G Y; Newton, Thomas F; Bickel, Warren K; Montague, P Read

    2014-01-01

    Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC.

  1. Essentials of Advocacy in Case Management: Part 1: Ethical Underpinnings of Advocacy-Theories, Principles, and Concepts.

    Science.gov (United States)

    Tahan, Hussein M

    2016-01-01

    This article describes the meaning and underpinnings of advocacy in the field of case management and shares essential principles and concepts for effective client advocacy. All practice settings across the continuum of health and human services and case managers of diverse professional backgrounds. Advocacy is vital to case management practice and a primary role of the professional case manager. It is rooted in ethical theory and principles. Successful case managers apply advocacy at every step of the case management process and in every action they take. Part I of this 2-part article explores the ethical theories and principles of advocacy, the perception of case management-related professional organizations of advocacy, and types of advocacy. Part II then presents a client advocacy model for case managers to apply in their practice, describes the role of advocacy in client engagement, and identifies important strategies and a set of essential competencies for effective case management advocacy. Acquiring foundational knowledge, skills, and competencies in what advocacy is equips case managers with the ability and confidence to enact advocacy-related behaviors in the provision of care to achieve desired outcomes for both the clients and health care agencies/providers alike. Case management leaders may use the knowledge shared in this article to develop advocacy training and competency programs for their case managers.

  2. Interventions and Strategies in Counseling and Psychotherapy.

    Science.gov (United States)

    Watts, Richard E., Ed.; Carlson, Jon, Ed.

    This book acknowledges the contributions of Alfred Adler and illustrates the many ways in which Adlerian ideas underpin and influence contemporary therapeutic approaches. It brings together today's leading thinkers to address the practice of counseling and psychotherapy from a social-cognitive perspective. Contributors apply the basic ideas of…

  3. Psicoterapia psicodinâmica breve: estratégia terapêutica e mudança no padrão de relacionamento conflituoso Brief psychodynamic therapy: therapeutic strategy and change in the conflictual relationship pattern

    Directory of Open Access Journals (Sweden)

    Elisa Medici Pizão Yoshida

    2009-12-01

    Full Text Available Examinaram-se possíveis relações entre mudanças no padrão de relacionamento conflituoso de paciente, de 48 anos, submetida a psicoterapia breve psicodinâmica, e a estratégia terapêutica adotada pela terapeuta. Foi também avaliada a "magnitude" da mudança em sintomas psicopatológicos ao final do processo e entrevistas de acompanhamento (3 e 6 meses, com instrumentos de autorrelato: Inventário Beck de Depressão (BDI, Escala de Alexitimia de Toronto (TAS, Escala de Avaliação de Sintomas-40 (EAS-40, Escala Fatorial de Ajustamento Emocional/ Neuroticismo (EFN. A avaliação do padrão relacional baseou-se no Tema Central de Relacionamento Conflituoso - CCRT e a estratégia terapêutica, no grau de "expressividade vs. apoio" das intervenções. Os resultados mostraram melhoras clinicamente significantes nos sintomas e mudança parcial do padrão central de relacionamento. As intervenções terapêuticas foram mais expressivas no início e mais suportivas à medida que mudanças positivas eram observadas. É necessária cautela na generalização dos resultados. A abordagem metodológica permite comparar diferentes indivíduos.This study aimed to evaluate possible association between change in the conflictual relationship pattern of a 48 year-old, woman, assisted on brief psychodynamic therapy, and the therapist's therapeutic strategy. Yet it was evaluated the magnitude of change of psychopathological symptoms at the end and follow-up interviews (3 and 6 months according to self-report measures: Beck Depression Inventory (BDI, Toronto Alexithymia Scale (TAS, Symptom Assessment Scale40 (EAS-40, Emotional Adjustment/ Neuroticism Factorial Scale (EFN. The relationship pattern was assessed based on the Core Conflictual Relationship Theme - CCRT method and the therapeutic strategy according to the degree of expressiveness vs supportiveness of the therapist's interventions. Results pointed out to clinically significant improvement on symptoms

  4. Development and Implementation of an Advanced Therapeutic Communication Course: An Interprofessional Collaboration.

    Science.gov (United States)

    Schwind, Jasna K; McCay, Elizabeth; Metersky, Kateryna; Martin, Jennifer

    2016-10-01

    Interprofessional education and practice have been gaining recognition during the past decade. However, little has been written on person-centered care (PCC) within interprofessional practice and how it could be taught to interprofessional learners. A key element of PCC is therapeutic communication. Consequently, a group of interprofessional faculty innovated a graduate-level elective course on advanced therapeutic communication where interprofessional learners together explore PCC within interprofessional care. The course curriculum is underpinned by mindfulness in education, nonviolent communication, and reflective writing. Various teaching- learning strategies, including creative self-expression, are also used. The created competencies and conceptual framework may be used by other educators in creating a similar interprofessional course. Interprofessional learners gained a deeper and broader understanding of PCC in interprofessional care. On the basis of this undertaking, the faculty gained a deeper appreciation for interprofessional collaboration in the development of innovative educational methodologies that advance interprofessional teamwork in education and professional practice. [J Nurs Educ. 2016;55(10):592-597.]. Copyright 2016, SLACK Incorporated.

  5. Targeting the endocannabinoid system : future therapeutic strategies

    NARCIS (Netherlands)

    Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-01-01

    The endocannabinoid system (ECS) is involved in many physiological regulation pathways in the human body, which makes this system the target of many drugs and therapies. In this review, we highlight the latest studies regarding the role of the ECS and the drugs that target it, with a particular

  6. Radon within therapeutic strategies of ankylosing spondylitis

    International Nuclear Information System (INIS)

    Herold, M.; Lind-Albrecht, G.

    2008-01-01

    For more than fifty years patients with rheumatic diseases have been treated in the thermal gallery of Bad Gastein, main indication is ankylosing spondylitis. Experiences of this kind of spa treatment on several hundred patients and randomised controlled clinical trials document the positive treatment effect of spa therapy with Radon which lasts for up to 40 weeks. (author) [de

  7. Optimization of Therapeutic Strategies for Organophosphate Poisoning

    Science.gov (United States)

    2008-03-01

    causes “mild to severe behavioral and cognitive changes, impaired consciousness or coma, seizures, or central apnea ” (Cannard, 2006:89). If the...2008:13). 21 “Severe symptoms include unconsciousness, convulsions, apnea , and flaccid paralysis” (CDC, 2008:13). For adults, first care...citing other 50 studies, the authors note that “disappointing results were found when … oxime administration was discontinued prematurely

  8. Presacral ganglioneuroma: diagnostic considerations and therapeutic strategy.

    Science.gov (United States)

    Vardas, Konstantinos; Manganas, Dimitrios; Papadimitriou, Georgios; Vougas, Vasileios; Bakalis, Athanasios; Chantziara, Maria; Exarhos, Dimitrios; Drakopoulos, Spiros

    2013-01-01

    Presacral ganglioneuroma is an extremely rare tumor of neural crest origin. To the best of our knowledge, less than 20 cases have been reported previously. The present study reports on a presacral ganglioneuroma, 10.5 × 8 × 4 cm in size, that was found incidentally in a 35-year-old man with prior history of diverticulitis. He was admitted to our hospital due to lower left abdominal pain. Abdominal computed tomography and magnetic resonance imaging confirmed the extension of the lesion from the S2 level to the coccyx. The mass had low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images with no intraspinal or rectal extension. T2-weighted images demonstrated a compartmentalized solid tumor with cystic components. Complete tumor resection with free surgical margins was achieved using an abdominal approach. The patient remains asymptomatic 2 years after surgery. We emphasize on clinical features, radiologic appearance and surgical treatment of this rare entity. The clinical and pathologic features of previously reported studies are also briefly reviewed.

  9. Presacral Ganglioneuroma: Diagnostic Considerations and Therapeutic Strategy

    Directory of Open Access Journals (Sweden)

    Konstantinos Vardas

    2013-11-01

    Full Text Available Presacral ganglioneuroma is an extremely rare tumor of neural crest origin. To the best of our knowledge, less than 20 cases have been reported previously. The present study reports on a presacral ganglioneuroma, 10.5 × 8 × 4 cm in size, that was found incidentally in a 35-year-old man with prior history of diverticulitis. He was admitted to our hospital due to lower left abdominal pain. Abdominal computed tomography and magnetic resonance imaging confirmed the extension of the lesion from the S2 level to the coccyx. The mass had low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images with no intraspinal or rectal extension. T2-weighted images demonstrated a compartmentalized solid tumor with cystic components. Complete tumor resection with free surgical margins was achieved using an abdominal approach. The patient remains asymptomatic 2 years after surgery. We emphasize on clinical features, radiologic appearance and surgical treatment of this rare entity. The clinical and pathologic features of previously reported studies are also briefly reviewed.

  10. Therapeutic angiogenesis for cardiovascular disease

    Directory of Open Access Journals (Sweden)

    D'Amore Patricia A

    2001-10-01

    Full Text Available Abstract The identification of angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor, has fueled interest in using such factors to induce therapeutic angiogenesis. The results of numerous animal studies and clinical trials have offered promise for new treatment strategies for various ischemic diseases. Increased understanding of the cellular and molecular biology of vessel growth has, however, prompted investigators and clinicians alike to reconsider the complexity of therapeutic angiogenesis. The realization that formation of a stable vessel is a complex, multistep process may provide useful insights into the design of the next generation of angiogenesis therapy.

  11. Optimal Strategy and Business Models

    DEFF Research Database (Denmark)

    Johnson, Peter; Foss, Nicolai Juul

    2016-01-01

    , it is possible to formalize useful notions of a business model, resources, and competitive advantage. The business model that underpins strategy may be seen as a set of constraints on resources that can be interpreted as controls in optimal control theory. Strategy then might be considered to be the control...... variable of firm path, suggesting in turn that the firm's business model is the codification of the application of investment resources used to control the strategic path of value realization....

  12. Identifying the latent failures underpinning medication administration errors: an exploratory study.

    Science.gov (United States)

    Lawton, Rebecca; Carruthers, Sam; Gardner, Peter; Wright, John; McEachan, Rosie R C

    2012-08-01

    The primary aim of this article was to identify the latent failures that are perceived to underpin medication errors. The study was conducted within three medical wards in a hospital in the United Kingdom. The study employed a cross-sectional qualitative design. Interviews were conducted with 12 nurses and eight managers. Interviews were transcribed and subject to thematic content analysis. A two-step inter-rater comparison tested the reliability of the themes. Ten latent failures were identified based on the analysis of the interviews. These were ward climate, local working environment, workload, human resources, team communication, routine procedures, bed management, written policies and procedures, supervision and leadership, and training. The discussion focuses on ward climate, the most prevalent theme, which is conceptualized here as interacting with failures in the nine other organizational structures and processes. This study is the first of its kind to identify the latent failures perceived to underpin medication errors in a systematic way. The findings can be used as a platform for researchers to test the impact of organization-level patient safety interventions and to design proactive error management tools and incident reporting systems in hospitals. © Health Research and Educational Trust.

  13. THE PERCEPTUAL COGNITIVE PROCESSES UNDERPINNING SKILLED PERFORMANCE IN VOLLEYBALL: EVIDENCE FROM EYE-MOVEMENTS AND VERBAL REPORTS OF THINKING INVOLVING AN IN SITU REPRESENTATIVE TASK

    Directory of Open Access Journals (Sweden)

    José Afonso

    2012-06-01

    Full Text Available An extensive body of work has focused on the processes underpinning perceptual-cognitive expertise. The majority of researchers have used film-based simulations to capture superior performance. We combined eye movement recording and verbal reports of thinking to explore the processes underpinning skilled performance in a complex, dynamic, and externally paced representative volleyball task involving in situ data collection. Altogether, 27 female volleyball players performed as centre backcourt defenders in simulated sessions while wearing an eye-tracking device. After each sequence, athletes were questioned concerning their perception of the situation. The visual search strategies employed by the highly-skilled players were more exploratory than those used by skilled players, involving more fixations to a greater number of locations. Highly-skilled participants spent more time fixating on functional spaces between two or more display areas, while the skilled participants fixated on the ball trajectory and specific players. Moreover, highly-skilled players generated more condition concepts with higher levels of sophistication than their skilled counterparts. Findings highlight the value of using representative task designs to capture performance in situ

  14. Therapeutic vaccines for leishmaniasis.

    Science.gov (United States)

    Khamesipour, Ali

    2014-11-01

    Numerous therapeutic strategies are used to treat leishmaniasis. The treatment of cutaneous leishmaniasis (CL) is solely depends on antimonate derivatives with safety issues and questionable efficacy and there is no fully effective modality to treat CL caused by Leishmania tropica and Leishmania braziliensis. There is no prophylactic vaccine available against any form of leishmaniasis. Immunotherapy for CL has a long history; immunotherapy trials of first and second generation vaccines showed promising results. The current article briefly covers the prophylactic vaccines and explains different immunotherapy strategies that have been used to treat leishmaniasis. This paper does not include experimental vaccines and only lays emphasis on human trials and those vaccines which reached human trials. Immunotherapy is currently used to successfully treat several disorders; Low cost, limited side effects and no possibility to develop resistance make immunotherapy a valuable choice especially for infectious disease with chemotherapy problems. Efforts are needed to explore the immunological surrogate marker(s) of cure and protection in leishmaniasis and overcome the difficulties in standardization of crude Leishmania vaccines. One of the reasons for anti-leishmaniasis vaccine failure is lack of an appropriate adjuvant. So far, not enough attention has been paid to develop vaccines for immunotherapy of leishmaniasis.

  15. High homogeneity of MAGE, BAGE, GAGE, tyrosinase and Melan-A/MART-1 gene expression in clusters of multiple simultaneous metastases of human melanoma: implications for protocol design of therapeutic antigen-specific vaccination strategies.

    Science.gov (United States)

    Dalerba, P; Ricci, A; Russo, V; Rigatti, D; Nicotra, M R; Mottolese, M; Bordignon, C; Natali, P G; Traversari, C

    1998-07-17

    Human melanoma cells express several antigens which are recognized by autologous and specific CTL clones in association with HLA-class-I molecules. Many of these antigens represent suitable targets for tumor immunotherapy, since their expression in human melanoma cells is common and highly specific. In order to achieve real clinical success with therapeutic vaccination strategies, one important requirement is the expression of the target antigen by all the tumor lesions of a patient. We have studied this issue by assessing, through an RT-PCR approach, the expression of MAGE-1, MAGE-2, MAGE-3, BAGE, GAGE-1/2, Tyrosinase and Melan-A/MART-1 genes in 17 clusters of simultaneous in-transit or regional lymph-node metastases collected from 15 stage-III and 1 stage-IV (AJCC/UICC pTNM system) melanoma patients. In 14 out of 17 clusters of simultaneous metastatic lesions (82%), the homogeneity in the pattern of gene expression within the cluster was complete. Heterogeneity within the same cluster was observed in only 3 out of 17 clusters (18%) and represented only minor features. Our data reveal that, in AJCC-stage-III melanoma patients, different but simultaneous metastatic lesions express the same pattern of antigen-coding genes. These observations have 2 main clinical implications: (i) the antigenic characterization of one single and easily accessible lesion allows identification of optimal targets for an active antigen-specific immunotherapy treatment; (ii) almost all the metastatic lesions are expected to be hit by the immune response eventually induced against the tumor antigen. Moreover, these data suggest that active specific immunotherapy directed against MAGE-1, MAGE-3, BAGE, GAGE-1/2, Melan-A/MART-1 and Tyrosinase antigens could be exploited as an adjuvant treatment to surgery in high-risk AJCC-stage-III-melanoma patients.

  16. Co-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy.

    Science.gov (United States)

    Islam, Shariful; Vick, Eric; Huber, Bryan; Morales, Carla; Spier, Catherine; Cooke, Laurence; Weterings, Eric; Mahadevan, Daruka

    2017-11-21

    Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate ∼30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4 + /CD8 + cells, we hypothesized that Program Death Ligand-1 (PD-L1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3Kα (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (∼9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-κB expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) ∼30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI >90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL.

  17. Unified underpinning of human mobility in the real world and cyberspace

    Science.gov (United States)

    Zhao, Yi-Ming; Zeng, An; Yan, Xiao-Yong; Wang, Wen-Xu; Lai, Ying-Cheng

    2016-05-01

    Human movements in the real world and in cyberspace affect not only dynamical processes such as epidemic spreading and information diffusion but also social and economical activities such as urban planning and personalized recommendation in online shopping. Despite recent efforts in characterizing and modeling human behaviors in both the real and cyber worlds, the fundamental dynamics underlying human mobility have not been well understood. We develop a minimal, memory-based random walk model in limited space for reproducing, with a single parameter, the key statistical behaviors characterizing human movements in both cases. The model is validated using relatively big data from mobile phone and online commerce, suggesting memory-based random walk dynamics as the unified underpinning for human mobility, regardless of whether it occurs in the real world or in cyberspace.

  18. The relational underpinnings of quality internal auditing in medical clinics in Israel.

    Science.gov (United States)

    Carmeli, Abraham; Zisu, Malka

    2009-03-01

    Internal auditing is a key mechanism in enhancing organizational reliability. However, research on the ways quality internal auditing is enabled through learning, deterrence, motivation and process improvement is scant. In particular, the relational underpinnings of internal auditing have been understudied. This study attempts to address this need by examining how organizational trust, perceived organizational support and psychological safety enable internal auditing. Data collected from employees in medical clinics of one of the largest healthcare organizations in Israel at two points in time six months apart. Our results show that organizational trust and perceived organizational support are positively related to psychological safety (measured at time 1), which, in turn, is associated with internal auditing (measured at time 2).

  19. Kolb's Experiential Learning Theory as a Theoretical Underpinning for Interprofessional Education.

    Science.gov (United States)

    Fewster-Thuente, Lori; Batteson, Tamzin J

    2018-01-01

    It is imperative to incorporate education on interprofessional competencies into the curriculum of healthcare provider students in order to meet the individual program accreditation standards. However, what is missing is a theoretical foundation for the education. The purpose of this paper was to examine if the qualitative data from a mixed-methods study using low-fidelity simulation of a case study that demonstrated changes in interprofessional attitudes and behaviors in healthcare provider students aligned with Kolb's Experiential Learning Theory (ELT). First-year students (n=515) from 8 professional healthcare programs participated in the 90-minute study which included a scripted scenario of the patient care rounding process. Using thematic analysis, the qualitative results demonstrated a significant alignment with the four stages of Kolb's ELT. Based on the results of this study, ELT appears to provide a solid theoretical underpinning for the education through which to teach interprofessional competencies to healthcare provider students.

  20. The Safe and Effective Use of Shared Data Underpinned by Stakeholder Engagement and Evaluation Practice.

    Science.gov (United States)

    Georgiou, Andrew; Magrabi, Farah; Hypponen, Hannele; Wong, Zoie Shui-Yee; Nykänen, Pirkko; Scott, Philip J; Ammenwerth, Elske; Rigby, Michael

    2018-04-22

     The paper draws attention to: i) key considerations involving the confidentiality, privacy, and security of shared data; and ii) the requirements needed to build collaborative arrangements encompassing all stakeholders with the goal of ensuring safe, secure, and quality use of shared data.  A narrative review of existing research and policy approaches along with expert perspectives drawn from the International Medical Informatics Association (IMIA) Working Group on Technology Assessment and Quality Development in Health Care and the European Federation for Medical Informatics (EFMI) Working Group for Assessment of Health Information Systems.  The technological ability to merge, link, re-use, and exchange data has outpaced the establishment of policies, procedures, and processes to monitor the ethics and legality of shared use of data. Questions remain about how to guarantee the security of shared data, and how to establish and maintain public trust across large-scale shared data enterprises. This paper identifies the importance of data governance frameworks (incorporating engagement with all stakeholders) to underpin the management of the ethics and legality of shared data use. The paper also provides some key considerations for the establishment of national approaches and measures to monitor compliance with best practice. Data sharing endeavours can help to underpin new collaborative models of health care which provide shared information, engagement, and accountability amongst all stakeholders. We believe that commitment to rigorous evaluation and stakeholder engagement will be critical to delivering health data benefits and the establishment of collaborative models of health care into the future. Georg Thieme Verlag KG Stuttgart.

  1. Identical genetic influences underpin behavior problems in adolescence and basic traits of personality.

    Science.gov (United States)

    Lewis, Gary J; Haworth, Claire M A; Plomin, Robert

    2014-08-01

    Understanding the etiology of adolescent problem behavior has been of enduring interest. Only relatively recently, however, has this issue been examined within a normal personality trait framework. Research suggests that problem behaviors in adolescence and beyond may be adequately explained by the taxonomy provided by the basic dimensions of normal personality: Such problem behaviors are suggested to be extreme points on a distribution of the full range of the underlying traits. We extend work in this field examining the extent to which genetic factors underlying the five-factor model of personality are common with genetic influences on adolescent behavior problems (namely, anxiety, peer problems, conduct, hyperactivity, and low prosociality). A nationally representative twin sample (Twins Early Development Study) from the general population of England and Wales, including 2031 pairs of twins aged 16 years old, was used to decompose variation into genetic and environmental components. Behavioral problems in adolescence were assessed by self-report with the Strengths and Difficulties Questionnaire. Adolescent behavior problems were moderately associated with normal personality: Specifically, a fifth to a third of phenotypic variance in problem behaviors was accounted for by five-factor model personality traits. Of central importance here, genetic influences underpinning personality were entirely overlapping with those genetic factors underlying adolescent behavior problems. These findings suggest that adolescent behavior problems can be understood, at least in part, within a model of normal personality trait variation, with the genetic bases of these behavior problems the same as those genetic influences underpinning normal personality. © 2013 The Authors. Journal of Child Psychology and Psychiatry. © 2013 Association for Child and Adolescent Mental Health.

  2. Systematic review of evidence underpinning non-pharmacological therapies in dementia.

    Science.gov (United States)

    Olley, Richard; Morales, Andrea

    2017-05-15

    underpin the use of these therapies. This report on a PRISMA systematic review of the available literature demonstrates that only two therapies have some evidence to underpin the use of these non-pharmaceutical therapies and that a significant research gap is exists. What are the implications for practitioners? The implications for practitioners is that significant research effort is required to determine the efficacy of many of the therapies that are currently deployed, and thus many of the therapies used lack an evidence base at this time.

  3. Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors.

    Science.gov (United States)

    Bhatia, Smita

    2015-03-01

    Subsequent malignant neoplasms (SMNs) are associated with significant morbidity and are a major cause of premature mortality among cancer survivors. Several large studies have demonstrated a strong association between the radiation and/or chemotherapy used to treat primary cancer and the risk of developing SMNs. However, for any given therapeutic exposure, the risk of developing an SMN varies between individuals. Genomic variation can potentially modify the association between therapeutic exposures and SMN risk and may explain the observed interindividual variability. In this review, the author provides a brief overview of the current knowledge regarding the role of genomic variation in the development of therapy-related SMNs and discusses the methodological challenges in undertaking an endeavor to develop a deeper understanding of the molecular underpinnings of therapy-related SMNs, such as an appropriate study design, the identification of an adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, clinical validation of the phenotype, and the selection of an appropriate approach or platform for genotyping. Understanding the factors that can modify the risk of treatment-related SMNs is critical to developing targeted intervention strategies and optimizing risk-based health care for cancer survivors. © 2014 American Cancer Society.

  4. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome.

    Science.gov (United States)

    Anderson, G; Berk, M; Maes, M

    2014-02-01

    Somatization is a symptom cluster characterized by 'psychosomatic' symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of 'psychosomatic' symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms. This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI). The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc. Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Memory underpinnings of future intentions: Would you like to see the sequel?

    Science.gov (United States)

    Stragà, Marta; Del Missier, Fabio; Marcatto, Francesco; Ferrante, Donatella

    2017-01-01

    In two studies, we investigated the memory underpinnings of future intentions related to past hedonic experiences. Preceding research did not make clear whether the specific memory processes supporting the expression of intentions about the future involve global judgments of the past experience (general affective evaluations formed on-line) or judgments derived from the episodic recollection of the past. Adapting a correlational paradigm previously employed to study future intentions, and applying it to the experience of watching a movie, we comparatively tested the influence of global retrospective evaluations vs. episodic-derived evaluations on future intentions. In Study 1, in which the intentions involved a future experience that was very similar to an overall past one (e.g., seeing the movie sequel), the findings showed that participants relied only on global judgments to form future intentions. In Study 2, in which the global judgment on the past was less diagnostic because the future intentions referred to specific parts of the past experience (e.g., watching a movie centered on a minor character in the previously seen movie), the results indicated that relevant episodic memories provided an essential contribution to the prediction of future intentions. These findings are in agreement with the predictions of the accessibility-diagnosticity framework and they show that global judgments and episodic memories of a past experience contribute differentially to diverse kinds of future intentions.

  6. An Ontology-Underpinned Emergency Response System for Water Pollution Accidents

    Directory of Open Access Journals (Sweden)

    Xiaoliang Meng

    2018-02-01

    Full Text Available With the unceasing development and maturation of environment geographic information system, the response to water pollution accidents has been digitalized through the combination of monitoring sensors, management servers, and application software. However, most of these systems only achieve the basic and general geospatial data management and functional process tasks by adopting mechanistic water-quality models. To satisfy the sustainable monitoring and real-time emergency response application demand of the government and public users, it is a hotspot to study how to make the water pollution information being semantic and make the referred applications intelligent. Thus, the architecture of the ontology-underpinned emergency response system for water pollution accidents is proposed in this paper. This paper also makes a case study for usability testing of the water ontology models, and emergency response rules through an online water pollution emergency response system. The system contributes scientifically to the safety and sustainability of drinking water by providing emergency response and decision-making to the government and public in a timely manner.

  7. Interpersonal factors associated with depression in adolescents: are these consistent with theories underpinning interpersonal psychotherapy?

    Science.gov (United States)

    O'Shea, Gabrielle; Spence, Susan H; Donovan, Caroline L

    2014-01-01

    The aim of this study was to investigate whether depressed adolescents differed from non-depressed adolescents in terms of constructs consistent with those that are proposed to underpin interpersonal psychotherapy. In particular, it was hypothesized that compared with non-depressed adolescents, depressed adolescents would demonstrate a greater number of negative life events associated with interpersonal loss and major life transitions, a more insecure attachment style and poorer communication skills, interpersonal relationships and social support. Thirty-one clinically diagnosed depressed adolescents were matched with 31 non-depressed adolescents on age, gender and socio-economic status. The 62 participants were aged between 12 and 19 years and comprised 18 male and 44 female adolescents. On a self-report questionnaire, depressed adolescents reported a greater number of negative interpersonal life events, a less secure attachment style and scored higher on all insecure attachment styles compared with the non-depressed adolescents. In addition, depressed adolescents demonstrated lower levels of social skill (on both adolescent and parent report), a poorer quality of relationship with parents (on both adolescent and parent report) and lower social competence (adolescent report only). Parents of depressed adolescents also reported more negative parental attitudes and behaviours towards their adolescent compared with parents of non-depressed adolescents. Thus, the results of this study are consistent with the constructs underlying interpersonal psychotherapy and suggest their usefulness in the assessment, conceptualization and treatment of adolescent depression. Clinical implications are discussed. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Harnessing the Toxocara Genome to Underpin Toxocariasis Research and New Interventions.

    Science.gov (United States)

    Gasser, Robin B; Korhonen, Pasi K; Zhu, Xing-Quan; Young, Neil D

    2016-01-01

    Parasitic worms, such as flatworms (platyhelminths) and roundworms (nematodes), cause substantial morbidity and mortality in animals and people globally. The ascaridoid nematode Toxocara canis is a zoonotic parasite of socioeconomic significance worldwide. In humans, this worm causes toxocariasis (disease) mainly in underprivileged communities in both the developed and developing worlds. While reasonably well studied from clinical and epidemiological perspectives, little is understood about the molecular biology of T. canis, its relationship with its hosts and the disease that it causes. However, a recent report of the draft genome and transcriptomes of T. canis should underpin many fundamental and applied research areas in the future. The present article gives a background on Toxocara and toxocariasis, a brief account of diagnostic approaches for specific identification and genetic analysis, and gives a perspective on the impact that the genome of T. canis and advanced molecular technologies could have on our understanding of the parasite and the diseases that it causes as well as the design of new and improved approaches for the diagnosis, treatment and control of toxocariasis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder.

    Science.gov (United States)

    Jogia, Jigar; Dima, Danai; Kumari, Veena; Frangou, Sophia

    2012-12-01

    Emotional dysregulation in bipolar disorder is thought to arise from dysfunction within prefrontal cortical regions involved in cognitive control coupled with increased or aberrant activation within regions engaged in emotional processing. The aim of this study was to determine the common and distinct patterns of functional brain abnormalities during reward and working memory processing in patients with bipolar disorder. Participants were 36 euthymic bipolar disorder patients and 37 healthy comparison subjects matched for age, sex and IQ. Functional magnetic resonance imaging (fMRI) was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task. During both tasks, patients with bipolar disorder demonstrated a pattern of inefficient engagement within the ventral frontopolar prefrontal cortex with evidence of segregation along the medial-lateral dimension for reward and working memory processing, respectively. Moreover, patients also showed greater activation in the anterior cingulate cortex during the Iowa Gambling Task and in the insula during the n-back task. Our data implicate ventral frontopolar dysfunction as a core abnormality underpinning bipolar disorder and confirm that overactivation in regions involved in emotional arousal is present even in tasks that do not typically engage emotional systems.

  10. Recent advances in exploring the neural underpinnings of auditory scene perception.

    Science.gov (United States)

    Snyder, Joel S; Elhilali, Mounya

    2017-05-01

    Studies of auditory scene analysis have traditionally relied on paradigms using artificial sounds-and conventional behavioral techniques-to elucidate how we perceptually segregate auditory objects or streams from each other. In the past few decades, however, there has been growing interest in uncovering the neural underpinnings of auditory segregation using human and animal neuroscience techniques, as well as computational modeling. This largely reflects the growth in the fields of cognitive neuroscience and computational neuroscience and has led to new theories of how the auditory system segregates sounds in complex arrays. The current review focuses on neural and computational studies of auditory scene perception published in the last few years. Following the progress that has been made in these studies, we describe (1) theoretical advances in our understanding of the most well-studied aspects of auditory scene perception, namely segregation of sequential patterns of sounds and concurrently presented sounds; (2) the diversification of topics and paradigms that have been investigated; and (3) how new neuroscience techniques (including invasive neurophysiology in awake humans, genotyping, and brain stimulation) have been used in this field. © 2017 New York Academy of Sciences.

  11. Neural underpinnings of divergent production of rules in numerical analogical reasoning.

    Science.gov (United States)

    Wu, Xiaofei; Jung, Rex E; Zhang, Hao

    2016-05-01

    Creativity plays an important role in numerical problem solving. Although the neural underpinnings of creativity have been studied over decades, very little is known about neural mechanisms of the creative process that relates to numerical problem solving. In the present study, we employed a numerical analogical reasoning task with functional Magnetic Resonance Imaging (fMRI) to investigate the neural correlates of divergent production of rules in numerical analogical reasoning. Participants performed two tasks: a multiple solution analogical reasoning task and a single solution analogical reasoning task. Results revealed that divergent production of rules involves significant activations at Brodmann area (BA) 10 in the right middle frontal cortex, BA 40 in the left inferior parietal lobule, and BA 8 in the superior frontal cortex. The results suggest that right BA 10 and left BA 40 are involved in the generation of novel rules, and BA 8 is associated with the inhibition of initial rules in numerical analogical reasoning. The findings shed light on the neural mechanisms of creativity in numerical processing. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. An Exploratory Qualitative Exploration of the Personal Values Underpinning Taiwanese and Malaysians’ Wine Consumption Behaviors

    Directory of Open Access Journals (Sweden)

    Miranda Mirosa

    2016-01-01

    Full Text Available Augmented buying power of East Asian consumers has resulted in increased interest in these markets. Wine is a particularly promising sector to target as the number of East Asians choosing to drink wine rises. In order to serve these markets, companies must understand factors influencing consumers’ choices. The objective of this research was to understand how Taiwanese and Malaysian consumers’ personal values influenced their consumption decisions about wine. The means–end chain framework and associated semi-structured interview technique, value laddering, was used to elicit consumers’ preferred product attributes, the consequences of these attributes and the values that underpin these consequences. Data collection involved intercepting foreign travelers from Malaysia and Taiwan in New Zealand (20 Taiwanese and 20 Malaysian to partake in a wine choice interview. The resulting findings are exploratory in nature. Analysis revealed the most preferred wine attributes for Taiwanese were “Price” and “Sensory Aspects”—that these attributes were linked to consequences “Financial Considerations” and “Satisfy Senses”—which in turn were linked to personal values “Self Direction” and “Achievement”. For the Malaysian participants, the attribute “Sensory Aspects” of wine was most important, as was the value “Hedonism”. This study adds to literature related to beverage consumption decision making by exploring cultural aspects. It also offers suggestions for practitioners interested in targeting these consumers.

  13. What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings?

    Science.gov (United States)

    Hughes, Daniel; Halliday, Mark

    2017-12-01

    The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrP Sc . Despite the identity of the molecular agent remaining the same, PrP Sc can cause a range of diseases with hereditary, spontaneous or iatrogenic aetiologies. However, the link between PrP Sc and toxicity is complex, with subclinical cases of prion disease discovered, and prion neurodegeneration without obvious PrP Sc deposition. The toxic mechanisms by which PrP Sc causes the extensive neuropathology are still poorly understood, although recent advances are beginning to unravel the molecular underpinnings, including oxidative stress, disruption of proteostasis and induction of the unfolded protein response. This review will discuss the diseases caused by PrP Sc toxicity, the nature of the toxicity of PrP Sc , and our current understanding of the downstream toxic signaling events triggered by the presence of PrP Sc .

  14. Levels of immunity parameters underpin bleaching and disease susceptibility of reef corals.

    Science.gov (United States)

    Palmer, Caroline V; Bythell, John C; Willis, Bette L

    2010-06-01

    Immunity is a key life history trait that may explain hierarchies in the susceptibility of corals to disease and thermal bleaching, two of the greatest current threats to coral health and the persistence of tropical reefs. Despite their ongoing and rapid global decline, there have been few investigations into the immunity mechanisms of reef-building corals. Variables commonly associated with invertebrate immunity, including the presence of melanin, size of melanin-containing granular cells, and phenoloxidase (PO) activity, as well as concentrations of fluorescent proteins (FPs), were investigated in hard (Scleractinia) and soft (Alcyonacea) corals spanning 10 families from the Great Barrier Reef. Detectable levels of these indicators were present in all corals investigated, although relative investment differed among coral taxa. Overall levels of investment were inversely correlated to thermal bleaching and disease susceptibility. In addition, PO activity, melanin-containing granular cell size, and FP concentration were each found to be significant predictors of susceptibility and thus may play key roles in coral immunity. Correlative evidence that taxonomic (family-level) variation in the levels of these constituent immunity parameters underpins susceptibility to both thermal bleaching and disease indicates that baseline immunity underlies the vulnerability of corals to these two threats. This reinforces the necessity of a holistic approach to understanding bleaching and disease in order to accurately determine the resilience of coral reefs.

  15. Associative learning mechanisms underpinning the transition from recreational drug use to addiction.

    Science.gov (United States)

    Hogarth, Lee; Balleine, Bernard W; Corbit, Laura H; Killcross, Simon

    2013-04-01

    Learning theory proposes that drug seeking is a synthesis of multiple controllers. Whereas goal-directed drug seeking is determined by the anticipated incentive value of the drug, habitual drug seeking is elicited by stimuli that have formed a direct association with the response. Moreover, drug-paired stimuli can transfer control over separately trained drug seeking responses by retrieving an expectation of the drug's identity (specific transfer) or incentive value (general transfer). This review covers outcome devaluation and transfer of stimulus-control procedures in humans and animals, which isolate the differential governance of drug seeking by these four controllers following various degrees of contingent and noncontingent drug exposure. The neural mechanisms underpinning these four controllers are also reviewed. These studies suggest that although initial drug seeking is goal-directed, chronic drug exposure confers a progressive loss of control over action selection by specific outcome representations (impaired outcome devaluation and specific transfer), and a concomitant increase in control over action selection by antecedent stimuli (enhanced habit and general transfer). The prefrontal cortex and mediodorsal thalamus may play a role in this drug-induced transition to behavioral autonomy. © 2012 New York Academy of Sciences.

  16. China's new oil import status underpins world's most dynamic petroleum scene

    International Nuclear Information System (INIS)

    Anon.

    1994-01-01

    China is poised to become a net importer of oil in 1994--95. That sets the stage for China importing more than 1 million b/d of crude oil and refined products on a net basis by the turn of the century. That development underpins a bigger story -- arguably the biggest story on the petroleum scene today. The turnabout that is seeing the world's fifth biggest oil producer go from significant oil exporter in recent years to major oil importer by the turn of the century points to several other truisms in the petroleum industry: That an oil demand surge in the Asia-Pacific region led by China will fuel overall world oil demand growth for years to come; that a refining and petrochemical boom in a country that accounts for about one fifth of the world's population has dramatic implications for those two industries; that privatization has gathered so much momentum in the global petroleum industry that even Communist China has embraced some form of it; that China's domestic crude supply shortfall is creating unprecedented opportunities for foreign upstream investors in one of the world's most prospective yet underexplored and underexploited regions; and that the same new openness that is distinguishing China's petroleum industry today is turning some of its state owned companies into major competitors to be reckoned with on the international scene, upstream and downstream. The paper discusses China's oil export/import balance, supply/demand outlook, policy changes, and new regulations governing export of crude oil and products

  17. Contact networks structured by sex underpin sex-specific epidemiology of infection.

    Science.gov (United States)

    Silk, Matthew J; Weber, Nicola L; Steward, Lucy C; Hodgson, David J; Boots, Mike; Croft, Darren P; Delahay, Richard J; McDonald, Robbie A

    2018-02-01

    Contact networks are fundamental to the transmission of infection and host sex often affects the acquisition and progression of infection. However, the epidemiological impacts of sex-related variation in animal contact networks have rarely been investigated. We test the hypothesis that sex-biases in infection are related to variation in multilayer contact networks structured by sex in a population of European badgers Meles meles naturally infected with Mycobacterium bovis. Our key results are that male-male and between-sex networks are structured at broader spatial scales than female-female networks and that in male-male and between-sex contact networks, but not female-female networks, there is a significant relationship between infection and contacts with individuals in other groups. These sex differences in social behaviour may underpin male-biased acquisition of infection and may result in males being responsible for more between-group transmission. This highlights the importance of sex-related variation in host behaviour when managing animal diseases. © 2017 The Authors. Ecology Letters published by CNRS and John Wiley & Sons Ltd.

  18. Warfarin therapeutic monitoring: is 70% time in the therapeutic range the best we can do?

    Science.gov (United States)

    Lader, E; Martin, N; Cohen, G; Meyer, M; Reiter, P; Dimova, A; Parikh, D

    2012-08-01

    Warfarin, an oral anticoagulant, which has been in clinical use for over sixty years, remains a challenge for clinicians to utilize, given the multiplicity of items which can limit its efficacy. Our objective is to review the evidence and comment on whether INR control can be better than has been currently reported in various studies. The duration of time a patient's international normalized ratio (INR) is maintained within the therapeutic range (time in the therapeutic range, TTR) for his or her particular indication for the drug impacts the effectiveness and safety of warfarin therapy. Maintaining a therapeutic INR while on warfarin is difficult, and numerous studies employing various strategies confirm the challenge, but not the impossibility of achieving a TTR above 70%. Maintaining a therapeutic INR requires a dedicated multi-faceted approach. With diligence, skill and various therapeutic strategies, a TTR >70% can be achieved. © 2011 Blackwell Publishing Ltd.

  19. The perceptual cognitive processes underpinning skilled performance in volleyball: evidence from eye-movements and verbal reports of thinking involving an in situ representative task.

    Science.gov (United States)

    Afonso, José; Garganta, Jêlio; McRobert, Allistair; Williams, Andrew M; Mesquita, Isabel

    2012-01-01

    An extensive body of work has focused on the processes underpinning perceptual-cognitive expertise. The majority of researchers have used film-based simulations to capture superior performance. We combined eye movement recording and verbal reports of thinking to explore the processes underpinning skilled performance in a complex, dynamic, and externally paced representative volleyball task involving in situ data collection. Altogether, 27 female volleyball players performed as centre backcourt defenders in simulated sessions while wearing an eye-tracking device. After each sequence, athletes were questioned concerning their perception of the situation. The visual search strategies employed by the highly-skilled players were more exploratory than those used by skilled players, involving more fixations to a greater number of locations. Highly-skilled participants spent more time fixating on functional spaces between two or more display areas, while the skilled participants fixated on the ball trajectory and specific players. Moreover, highly-skilled players generated more condition concepts with higher levels of sophistication than their skilled counterparts. Findings highlight the value of using representative task designs to capture performance in situ. Key pointsDecision-making in complex sports relies deeply on perceptual-cognitive expertise. In turn, the effect of expertise is highly dependent on the nature and complexity of the task.Nonetheless, most researchers use simple tasks in their research designs, risking not capturing performance in a meaningful way. We proposed to use a live action setting with a complex task design, representative of real world situations.We combined eye movement registration with collection of immediate retrospective verbal reports. Although the two data sets are not directly comparable, they may be used in a complementary manner, providing a deeper and fuller understanding of the processes underpinning superior performance

  20. Therapeutic approaches for celiac disease

    Science.gov (United States)

    Plugis, Nicholas M.; Khosla, Chaitan

    2015-01-01

    Celiac disease is a common, lifelong autoimmune disorder for which dietary control is the only accepted form of therapy. A strict gluten-free diet is burdensome to patients and can be limited in efficacy, indicating there is an unmet need for novel therapeutic approaches to supplement or supplant dietary therapy. Many molecular events required for disease pathogenesis have been recently characterized and inspire most current and emerging drug-discovery efforts. Genome-wide association studies (GWAS) confirm the importance of human leukocyte antigen genes in our pathogenic model and identify a number of new risk loci in this complex disease. Here, we review the status of both emerging and potential therapeutic strategies in the context of disease pathophysiology. We conclude with a discussion of how genes identified during GWAS and follow-up studies that enhance susceptibility may offer insight into developing novel therapies. PMID:26060114

  1. On the inference of agency in operant action : an examination of the cognitive and neural underpinnings in health and schizophrenia

    NARCIS (Netherlands)

    Renes, R.A.

    2016-01-01

    This dissertation elucidates cognitive and neural underpinnings of the sense of agency, which is the feeling that we are in control of our actions and the subsequent consequences. This consciously accessible sensation of control is pervasive, sometimes subtle, and can even be illusory in nature.

  2. From Chicken Breath to the Killers Lake of Cameroon: Uniting Seven Interesting Phenomena with a Single Chemical Underpinning

    Science.gov (United States)

    Delorenzo, Ron

    2001-02-01

    By using a single equation prototype, seven interesting mysteries and phenomena can be seen as sharing a common chemical underpinning. The applications discussed are the Killer Lakes of Cameroon, chicken breath, the Permian Ocean, the snow line, boiler scale, the Fizz Keeper, and stalactites and stalagmites.

  3. Chains of (dis)trust : Exploring the underpinnings of knowledge-sharing and quality care across mental health services

    NARCIS (Netherlands)

    Brown, P.R.; Calnan, M.W.

    Quality and safety in healthcare settings are underpinned by organisational cultures, which facilitate or impede the refinement, sharing and application of knowledge. Avoiding the use of the term culture as a residual category, we focus specifically on describing chains of (dis)trust, analysing

  4. Free and Open Source Software underpinning the European Forest Data Centre

    Science.gov (United States)

    Rodriguez Aseretto, Dario; Di Leo, Margherita; de Rigo, Daniele; Corti, Paolo; McInerney, Daniel; Camia, Andrea; San-Miguel-Ayanz, Jesús

    2013-04-01

    Worldwide, governments are growingly focusing [1] on free and open source software (FOSS) as a move toward transparency and the freedom to run, copy, study, change and improve the software [2]. The European Commission (EC) is also supporting the development of FOSS (see e.g., [3]). In addition to the financial savings, FOSS contributes to scientific knowledge freedom in computational science (CS) [4] and is increasingly rewarded in the science-policy interface within the emerging paradigm of open science [5-8]. Since complex computational science applications may be affected by software uncertainty [4,9-11], FOSS may help to mitigate part of the impact of software errors by CS community-driven open review, correction and evolution of scientific code [10,12-15]. The continental scale of EC science-based policy support implies wide networks of scientific collaboration. Thematic information systems also may benefit from this approach within reproducible [16] integrated modelling [4]. This is supported by the EC strategy on FOSS: "for the development of new information systems, where deployment is foreseen by parties outside of the EC infrastructure, [F]OSS will be the preferred choice and in any case used whenever possible" [17]. The aim of this contribution is to highlight how a continental scale information system may exploit and integrate FOSS technologies within the transdisciplinary research underpinning such a complex system. A European example is discussed where FOSS innervates both the structure of the information system itself and the inherent transdisciplinary research for modelling the data and information which constitute the system content. The information system. The European Forest Data Centre (EFDAC, http://forest.jrc.ec.europa.eu/efdac/) has been established at the EC Joint Research Centre (JRC) as the focal point for forest data and information in Europe to supply European decision-makers with processed, quality checked and timely policy relevant

  5. The Medicinal Chemistry of Therapeutic Oligonucleotides.

    Science.gov (United States)

    Wan, W Brad; Seth, Punit P

    2016-11-10

    Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and conjugation strategies which can improve the nuclease stability, RNA-binding affinity, and pharmacokinetic properties of oligonucleotides for therapeutic applications. In this perspective, we present a summary of the most commonly used nucleobase, sugar and backbone modification, and conjugation strategies used in oligonucleotide medicinal chemistry.

  6. Novel Therapeutics for Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Lowery, Maeve A; O'Reilly, Eileen M

    2015-08-01

    The last decade has seen significant developments in the use of combination systemic therapy for advanced pancreatic ductal adenocarcinoma (PDAC), with median survival approaching 1 year for select patients treated with FOLFIRINOX in the metastatic setting. However, it is sobering that these developments have been achieved with the use of traditional cytotoxics rather than from successes in the more modern fields of molecularly targeted therapies or immunotherapy. This article highlights several promising therapeutic approaches to PDAC currently under clinical evaluation, including immune therapies, molecularly targeted therapies, strategies for stromal depletion, and targeted therapy for genetically selected patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. [Self-regulation and virtual reality in forensic psychiatry: An emphasis on theoretical underpinnings].

    Science.gov (United States)

    Benbouriche, M; Renaud, P; Pelletier, J-F; De Loor, P

    2016-12-01

    Forensic psychiatry is the field whose expertise is the assessment and treatment of offending behaviours, in particular when offenses are related to mental illness. An underlying question for all etiological models concerns the manner in which an individual's behaviours are organized. Specifically, it becomes crucial to understand how certain individuals come to display maladaptive behaviours in a given environment, especially when considering issues such as offenders' responsibility and their ability to change their behaviours. Thanks to its ability to generate specific environments, associated with a high experimental control on generated simulations, virtual reality is gaining recognition in forensic psychiatry. Virtual reality has generated promising research data and may turn out to be a remarkable clinical tool in the near future. While research has increased, a conceptual work about its theoretical underpinnings is still lacking. However, no important benefit should be expected from the introduction of a new tool (as innovative as virtual reality) without an explicit and heuristic theoretical framework capable of clarifying its benefits in forensic psychiatry. Our paper introduces self-regulation perspective as the most suitable theoretical framework for virtual reality in forensic psychiatry. It will be argued that virtual reality does not solely help to increase ecological validity. However, it does allow one to grant access to an improved understanding of violent offending behaviours by probing into the underlying mechanisms involved in the self-regulation of behaviours in a dynamical environment. Illustrations are given as well as a discussion regarding perspectives in the use of virtual reality in forensic psychiatry. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  8. Lung eQTLs to help reveal the molecular underpinnings of asthma.

    Directory of Open Access Journals (Sweden)

    Ke Hao

    Full Text Available Genome-wide association studies (GWAS have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151. The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.

  9. A model for the molecular underpinnings of tooth defects in Axenfeld–Rieger syndrome

    Science.gov (United States)

    Li, Xiao; Venugopalan, Shankar R.; Cao, Huojun; Pinho, Flavia O.; Paine, Michael L.; Snead, Malcolm L.; Semina, Elena V.; Amendt, Brad A.

    2014-01-01

    Patients with Axenfeld–Rieger Syndrome (ARS) present various dental abnormalities, including hypodontia, and enamel hypoplasia. ARS is genetically associated with mutations in the PITX2 gene, which encodes one of the earliest transcription factors to initiate tooth development. Thus, Pitx2 has long been considered as an upstream regulator of the transcriptional hierarchy in early tooth development. However, because Pitx2 is also a major regulator of later stages of tooth development, especially during amelogenesis, it is unclear how mutant forms cause ARS dental anomalies. In this report, we outline the transcriptional mechanism that is defective in ARS. We demonstrate that during normal tooth development Pitx2 activates Amelogenin (Amel) expression, whose product is required for enamel formation, and that this regulation is perturbed by missense PITX2 mutations found in ARS patients. We further show that Pitx2-mediated Amel activation is controlled by chromatin-associated factor Hmgn2, and that Hmgn2 prevents Pitx2 from efficiently binding to and activating the Amel promoter. Consistent with a physiological significance to this interaction, we show that K14-Hmgn2 transgenic mice display a severe loss of Amel expression on the labial side of the lower incisors, as well as enamel hypoplasia—consistent with the human ARS phenotype. Collectively, these findings define transcriptional mechanisms involved in normal tooth development and shed light on the molecular underpinnings of the enamel defect observed in ARS patients who carry PITX2 mutations. Moreover, our findings validate the etiology of the enamel defect in a novel mouse model of ARS. PMID:23975681

  10. Matrix Expansion and Syncytial Aggregation of Syndecan-1+ Cells Underpin Villous Atrophy in Coeliac Disease

    Science.gov (United States)

    Salvestrini, Camilla; Lucas, Mark; Lionetti, Paolo; Torrente, Franco; James, Sean; Phillips, Alan D.; Murch, Simon H.

    2014-01-01

    Background We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy. Methods We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls. Results In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1+ plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6+ mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19. Conclusions Matrix expansion, through syndecan-1+ cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1+ cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders

  11. Cis-regulatory underpinnings of human GLI3 expression in embryonic craniofacial structures and internal organs.

    Science.gov (United States)

    Abbasi, Amir A; Minhas, Rashid; Schmidt, Ansgar; Koch, Sabine; Grzeschik, Karl-Heinz

    2013-10-01

    The zinc finger transcription factor Gli3 is an important mediator of Sonic hedgehog (Shh) signaling. During early embryonic development Gli3 participates in patterning and growth of the central nervous system, face, skeleton, limb, tooth and gut. Precise regulation of the temporal and spatial expression of Gli3 is crucial for the proper specification of these structures in mammals and other vertebrates. Previously we reported a set of human intronic cis-regulators controlling almost the entire known repertoire of endogenous Gli3 expression in mouse neural tube and limbs. However, the genetic underpinning of GLI3 expression in other embryonic domains such as craniofacial structures and internal organs remain elusive. Here we demonstrate in a transgenic mice assay the potential of a subset of human/fish conserved non-coding sequences (CNEs) residing within GLI3 intronic intervals to induce reporter gene expression at known regions of endogenous Gli3 transcription in embryonic domains other than central nervous system (CNS) and limbs. Highly specific reporter expression was observed in craniofacial structures, eye, gut, and genitourinary system. Moreover, the comparison of expression patterns directed by these intronic cis-acting regulatory elements in mouse and zebrafish embryos suggests that in accordance with sequence conservation, the target site specificity of a subset of these elements remains preserved among these two lineages. Taken together with our recent investigations, it is proposed here that during vertebrate evolution the Gli3 expression control acquired multiple, independently acting, intronic enhancers for spatiotemporal patterning of CNS, limbs, craniofacial structures and internal organs. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

  12. Digital games for type 1 and type 2 diabetes: underpinning theory with three illustrative examples.

    Science.gov (United States)

    Kamel Boulos, Maged N; Gammon, Shauna; Dixon, Mavis C; MacRury, Sandra M; Fergusson, Michael J; Miranda Rodrigues, Francisco; Mourinho Baptista, Telmo; Yang, Stephen P

    2015-03-18

    Digital games are an important class of eHealth interventions in diabetes, made possible by the Internet and a good range of affordable mobile devices (eg, mobile phones and tablets) available to consumers these days. Gamifying disease management can help children, adolescents, and adults with diabetes to better cope with their lifelong condition. Gamification and social in-game components are used to motivate players/patients and positively change their behavior and lifestyle. In this paper, we start by presenting the main challenges facing people with diabetes-children/adolescents and adults-from a clinical perspective, followed by three short illustrative examples of mobile and desktop game apps and platforms designed by Ayogo Health, Inc. (Vancouver, BC, Canada) for type 1 diabetes (one example) and type 2 diabetes (two examples). The games target different age groups with different needs-children with type 1 diabetes versus adults with type 2 diabetes. The paper is not meant to be an exhaustive review of all digital game offerings available for people with type 1 and type 2 diabetes, but rather to serve as a taster of a few of the game genres on offer today for both types of diabetes, with a brief discussion of (1) some of the underpinning psychological mechanisms of gamified digital interventions and platforms as self-management adherence tools, and more, in diabetes, and (2) some of the hypothesized potential benefits that might be gained from their routine use by people with diabetes. More research evidence from full-scale evaluation studies is needed and expected in the near future that will quantify, qualify, and establish the evidence base concerning this gamification potential, such as what works in each age group/patient type, what does not, and under which settings and criteria.

  13. The importance of professional skills alongside scientific and technical excellence to underpin ethical geoscience practice

    Science.gov (United States)

    Allington, Ruth; Fernandez-Fuentes, Isabel

    2013-04-01

    There is consensus that reliable ground models, based on a sound understanding of the geology and surface processes are vital as a basis for natural hazard identification and risk assessment, and there is a great deal of skill and experience in the geoscience community with mapping, modelling and predicting natural hazards and their likely impacts. This presentation will highlight the contributions of geology and geomorphology in the identification of natural hazards and mitigation of their impacts. It will then consider a range of "professional skills" that are needed by geoscientists working with other specialists and non-specialists (e.g. engineers, emergency services, land-use planners, architects responsible for building codes, politicians, regulators, the public etc) alongside technical and scientific excellence. It will argue that development and application of both scientific/technical and professional skills is essential to ensure that the maps, models and other data relevant to natural hazards and environmental change are used to provide effective public protection through communication, land-use planning and planning for resilience. The professional skills of particular importance include interdisciplinary collaboration; project management; cost-benefit analysis; effective communication with specialists and non specialists (especially the public); and facilitative skills. All the technical, scientific and professional skills need to be applied competently and with the highest standards of ethical underpinning. The contribution will consider how this can be achieved (or at least facilitated) through professional training, award of professional titles, licensure etc, drawing on international examples of best practice in professional codes of conduct and regulation directed to the protection of the public.

  14. Does legume nitrogen fixation underpin host quality for the hemiparasitic plant Rhinanthus minor?

    Science.gov (United States)

    Jiang, Fan; Jeschke, W Dieter; Hartung, Wolfram; Cameron, Duncan D

    2008-01-01

    The high quality of leguminous hosts for the parasitic plant Rhinanthus minor (in terms of growth and fecundity), compared with forbs (non-leguminous dicots) has long been assumed to be a function of the legume's ability to fix atmospheric nitrogen (N) from the air and the potential for direct transfer of compatible amino compounds to the parasite. Using associations between Rhinanthus minor and Vicia faba (Fabaceae) that receive N either exclusively via symbiotic associations with rhizobia supplying organic N fixed from N(2) or exclusively through the supply of inorganic nitrate to the substrate, the underlying reasons for the quality of legumes as hosts for this parasite are unravelled. It is shown that sole dependence of the host, V. faba, on N fixation results in lower growth of the attached parasite than when the host is grown in a substrate supplied exclusively with inorganic N. In contrast, the host plants themselves achieved a similar biomass irrespective of their N source. The physiological basis for this is investigated in terms of N and abscisic acid (ABA) partitioning, haustorial penetration, and xylem sap amino acid profiles. It is concluded that legume N fixation does not underpin the quality of legumes as hosts for Rhinanthus but rather the well-developed haustorium formed by the parasite, coupled with the lack of defensive response of the host tissues to the invading haustorium and the presence of sufficient nitrogenous compounds in the xylem sap accessible to the parasite haustoria, would appear to be the primary factors influencing host quality of the legumes.

  15. Digital Games for Type 1 and Type 2 Diabetes: Underpinning Theory With Three Illustrative Examples

    Science.gov (United States)

    Gammon, Shauna; Dixon, Mavis C; MacRury, Sandra M; Fergusson, Michael J; Miranda Rodrigues, Francisco; Mourinho Baptista, Telmo; Yang, Stephen P

    2015-01-01

    Digital games are an important class of eHealth interventions in diabetes, made possible by the Internet and a good range of affordable mobile devices (eg, mobile phones and tablets) available to consumers these days. Gamifying disease management can help children, adolescents, and adults with diabetes to better cope with their lifelong condition. Gamification and social in-game components are used to motivate players/patients and positively change their behavior and lifestyle. In this paper, we start by presenting the main challenges facing people with diabetes—children/adolescents and adults—from a clinical perspective, followed by three short illustrative examples of mobile and desktop game apps and platforms designed by Ayogo Health, Inc. (Vancouver, BC, Canada) for type 1 diabetes (one example) and type 2 diabetes (two examples). The games target different age groups with different needs—children with type 1 diabetes versus adults with type 2 diabetes. The paper is not meant to be an exhaustive review of all digital game offerings available for people with type 1 and type 2 diabetes, but rather to serve as a taster of a few of the game genres on offer today for both types of diabetes, with a brief discussion of (1) some of the underpinning psychological mechanisms of gamified digital interventions and platforms as self-management adherence tools, and more, in diabetes, and (2) some of the hypothesized potential benefits that might be gained from their routine use by people with diabetes. More research evidence from full-scale evaluation studies is needed and expected in the near future that will quantify, qualify, and establish the evidence base concerning this gamification potential, such as what works in each age group/patient type, what does not, and under which settings and criteria. PMID:25791276

  16. Neural underpinnings of distortions in the experience of time across senses.

    Science.gov (United States)

    Harrington, Deborah L; Castillo, Gabriel N; Fong, Christopher H; Reed, Jason D

    2011-01-01

    Auditory signals (A) are perceived as lasting longer than visual signals (V) of the same physical duration when they are compared together. Despite considerable debate about how this illusion arises psychologically, the neural underpinnings have not been studied. We used functional magnetic resonance imaging (fMRI) to investigate the neural bases of audiovisual temporal distortions and more generally, intersensory timing. Adults underwent fMRI while judging the relative duration of successively presented standard interval-comparison interval (CI) pairs, which were unimodal (A-A, V-V) or crossmodal (V-A, A-V). Mechanisms of time dilation and compression were identified by comparing the two crossmodal pairs. Mechanisms of intersensory timing were identified by comparing the unimodal and crossmodal conditions. The behavioral results showed that auditory CIs were perceived as lasting longer than visual CIs. There were three novel fMRI results. First, time dilation and compression were distinguished by differential activation of higher-sensory areas (superior temporal, posterior insula, middle occipital), which typically showed stronger effective connectivity when time was dilated (V-A). Second, when time was compressed (A-V) activation was greater in frontal cognitive-control centers, which guide decision making. These areas did not exhibit effective connectivity. Third, intrasensory timing was distinguished from intersensory timing partly by decreased striatal and increased superior parietal activation. These regions showed stronger connectivity with visual, memory, and cognitive-control centers during intersensory timing. Altogether, the results indicate that time dilation and compression arise from the connectivity strength of higher-sensory systems with other areas. Conversely, more extensive network interactions are needed with core timing (striatum) and attention (superior parietal) centers to integrate time codes for intersensory signals.

  17. Partial diel migration: A facultative migration underpinned by long-term inter-individual variation.

    Science.gov (United States)

    Harrison, Philip M; Gutowsky, Lee F G; Martins, Eduardo G; Patterson, David A; Cooke, Steven J; Power, Michael

    2017-09-01

    The variations in migration that comprise partial diel migrations, putatively occur entirely as a consequence of behavioural flexibility. However, seasonal partial migrations are increasingly recognised to be mediated by a combination of reversible plasticity in response to environmental variation and individual variation due to genetic and environmental effects. Here, we test the hypothesis that while partial diel migration heterogeneity occurs primarily due to short-term within-individual flexibility in behaviour, long-term individual differences in migratory behaviour also underpin this migration variation. Specifically, we use a hierarchical behavioural reaction norm approach to partition within- and among-individual variation in depth use and diel plasticity in depth use, across short- and long-term time-scales, in a group of 47 burbot (Lota lota) tagged with depth-sensing acoustic telemetry transmitters. We found that within-individual variation at the among-dates-within-seasons and among-seasons scale, explained the dominant proportion of phenotypic variation. However, individuals also repeatedly differed in their expression of migration behaviour over the 2 year study duration. These results reveal that diel migration variation occurs primarily due to short-term within-individual flexibility in depth use and diel migration behaviour. However, repeatable individual differences also played a key role in mediating partial diel migration. These findings represent a significant advancement of our understanding of the mechanisms generating the important, yet poorly understood phenomena of partial diel migration. Moreover, given the pervasive occurrence of diel migrations across aquatic taxa, these findings indicate that individual differences have an important, yet previously unacknowledged role in structuring the temporal and vertical dynamics of aquatic ecosystems. © 2017 The Authors. Journal of Animal Ecology © 2017 British Ecological Society.

  18. Antiretroviral therapeutic drug monitoring

    African Journals Online (AJOL)

    Winnie

    A narrow therapeutic window. □ Good correlation between drug ... Antiretroviral therapeutic drug monitoring (TDM) is an additional monitoring tool to assist in the management of HIV-infected patients. Antiretroviral TDM is ... Antiretroviral TDM could play an important adjunctive role in our area. Clearly this will be a limited ...

  19. Elucidating the atomistic mechanisms underpinning plasticity in Li-Si nanostructures

    Science.gov (United States)

    Yan, Xin; Gouissem, Afif; Guduru, Pradeep R.; Sharma, Pradeep

    2017-10-01

    Amorphous lithium-silicon (a-Li-Si), especially in nanostructure form, is an attractive high-capacity anode material for next-generation Li-ion batteries. During cycles of charging and discharging, a-Li-Si undergoes substantive inelastic deformation and exhibits microcracking. The mechanical response to repeated lithiation-delithiation eventually results in the loss of electrical contact and consequent decrease of capacity, thus underscoring the importance of studying the plasticity of a-Li-Si nanostructures. In recent years, a variety of phenomenological continuum theories have been introduced that purport to model plasticity and the electro-chemo-mechanical behavior of a-Li-Si. Unfortunately, the micromechanisms and atomistic considerations underlying plasticity in Li-Si material are not yet fully understood and this impedes the development of physics-based constitutive models. Conventional molecular dynamics, although extensively used to study this material, is grossly inadequate to resolve this matter. As is well known, conventional molecular dynamics simulations can only address phenomena with characteristic time scales of (at most) a microsecond. Accordingly, in such simulations, the mechanical behavior is deduced under conditions of very high strain rates (usually, 108s-1 or even higher). This limitation severely impacts a realistic assessment of rate-dependent effects. In this work, we attempt to circumvent the time-scale bottleneck of conventional molecular dynamics and provide novel insights into the mechanisms underpinning plastic deformation of Li-Si nanostructures. We utilize an approach that allows imposition of slow strain rates and involves the employment of a new and recently developed potential energy surface sampling method—the so-called autonomous basin climbing—to identify the local minima in the potential energy surface. Combined with other techniques, such as nudged elastic band, kinetic Monte Carlo and transition state theory, we assess

  20. GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth.

    Science.gov (United States)

    Esquerré, Michaël; Momot, Marie; Goubier, Anne; Gonindard, Christophe; Leung-Theung-Long, Stéphane; Misseri, Yolande; Bissery, Marie-Christine

    2017-03-13

    GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8 + T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8 + T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Applications to the design of human therapeutics

    Indian Academy of Sciences (India)

    Administrator

    Strategies for multi-target therapeutics and network analysis with a focus on cancer and HIV are dis- cussed. Methods for gene and siRNA delivery are .... sis for cancer treatment. Most of the current anticancer drugs have low thera- ...... Colorectal Cancer 6 29. 37. Sidhu S S, Li B, Chen Y, Fellouse F A, Eigenbrot C and Fuh ...

  2. Humor: A Therapeutic Intervention for Child Counseling

    Science.gov (United States)

    Berg, Rachelle G.; Parr, Gerald; Bradley, Loretta J.; Berry, Jeremy J.

    2009-01-01

    Counselors utilize many strategies, techniques, and tools when building a therapeutic alliance or addressing children's issues. Due to the serious nature of discussing problems or perhaps because of the fear of seeming insensitive, counselors often overlook humor as a means to enhance therapy. Whether deliberate or spontaneous, humor can add…

  3. Therapeutic opportunities in biological responses of ultrasound.

    Science.gov (United States)

    Paliwal, Sumit; Mitragotri, Samir

    2008-08-01

    The therapeutic benefits of several existing ultrasound-based therapies such as facilitated drug delivery, tumor ablation and thrombolysis derive largely from physical or mechanical effects. In contrast, ultrasound can also trigger various time-dependent biochemical responses in the exposed biological milieu. Several biological responses to ultrasound exposure have been previously described in the literature but only a handful of these provide therapeutic opportunities. These include the use of ultrasound for healing of soft tissues and bones, the use of ultrasound for inducing non-necrotic tumor atrophy as well as for potentiation of chemotherapeutic drugs, activation of the immune system, angiogenesis and suppression of phagocytosis. A review of these therapeutic opportunities is presented with particular emphasis on their mechanisms. Overall, this review presents the increasing importance of ultrasound's role as a biological sensitizer enabling novel therapeutic strategies.

  4. Binge-eating disorder: Clinical and therapeutic advances.

    Science.gov (United States)

    Hutson, Peter H; Balodis, Iris M; Potenza, Marc N

    2018-02-01

    Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2-5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment. Here we review the current state of binge-eating neurobiology and pharmacology, drawing from clinical therapeutic, neuroimaging, cognitive, human genetic and animal model studies. These studies, which are still in their infancy, indicate that while there are many gaps in our knowledge, several key neural substrates appear to underpin binge-eating and may be conserved between human and animals. This observation suggests that behavioral intermediate phenotypes or endophenotypes relevant to BED may be modeled in animals, facilitating the identification and testing of novel pharmacological targets. The development of novel, safe and effective pharmacological therapies for the treatment of BED will enhance the ability of clinicians to provide optimal care for people with BED. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Associations among the Five Components within COSO Internal Control-Integrated Framework as the Underpinning of Quality Corporate Governance

    OpenAIRE

    Kirsten Rae; John Sands; Nava Subramaniam

    2017-01-01

    This paper examines the associations among COSO components and how they affect the monitoring function of organisations. Five components of an effective internal control system are described using the framework designed by COSO (1992) and have been selected because they have been identified as underpinning quality corporate governance. Structural equation modelling (SEM) was used first to run confirmatory factor analysis to determine the measurement models for the five COSO compon...

  6. Feel, Think, Teach--Emotional Underpinnings of Approaches to Teaching in Higher Education

    Science.gov (United States)

    Kordts-Freudinger, Robert

    2017-01-01

    The paper investigates relations between higher education teachers' approaches to teaching and their emotions during teaching, as well as their emotion regulation strategies. Based on the assumption that the approaches hinge on emotional experiences with higher education teaching and learning, three studies assessed teachers' emotions, their…

  7. Therapeutic enhancement: nursing intervention category for patients diagnosed with Readiness for Therapeutic Regimen Management.

    Science.gov (United States)

    Kelly, Cynthia W

    2008-04-01

    To present a new nursing intervention category called therapeutic enhancement. Fewer than half of North Americans follow their physician's recommendations for diet and exercise, even when such are crucial to their health or recovery. It is imperative that nurses consider new ways to promote healthy behaviours. Therapeutic enhancement is intended to provide such a fresh approach. Traditional intervention techniques focusing on education, contracts, social support and more frequent interaction with physicians appear not to be effective when used alone. Successful strategies have been multidisciplinary; and have included interventions by professional nurses who assist patients to understand their disease and the disease process and that helps them to develop disease-management and self-management skills. Therapeutic enhancement incorporates The Stages of Change Theory, Commitment to Health Theory, Motivational Interviewing techniques and instrumentation specifically designed for process evaluation of health-promoting interventions. This is a critical review of approaches that, heretofore, have not been synthesised in a single published article. Based on the commonly used Stages of Change model, therapeutic enhancement is useful for patients who are at the action stage of change. Using therapeutic enhancement as well as therapeutic strategies identified in Stages of Change Theory, such as contingency management, helping relationships, counterconditioning, stimulus control and Motivational Interviewing techniques, nursing professionals can significantly increase the chances of patients moving from action to the maintenance stage of change for a specific health behaviour. Using the nursing intervention category, therapeutic enhancement can increase caregivers' success in helping patients maintain healthy behaviours.

  8. Intentional attunement: mirror neurons and the neural underpinnings of interpersonal relations.

    Science.gov (United States)

    Gallese, Vittorio; Eagle, Morris N; Migone, Paolo

    2007-01-01

    The neural circuits activated in a person carrying out actions, expressing emotions, and experiencing sensations are activated also, automatically via a mirror neuron system, in the observer of those actions, emotions, and sensations. It is proposed that this finding of shared activation suggests a functional mechanism of "embodied simulation" that consists of the automatic, unconscious, and noninferential simulation in the observer of actions, emotions, and sensations carried out and experienced by the observed. It is proposed also that the shared neural activation pattern and the accompanying embodied simulation constitute a fundamental biological basis for understanding another's mind. The implications of this perspective for psychoanalysis are discussed, particularly regarding unconscious communication, projective identification, attunement, empathy, autism, therapeutic action, and transference-countertransference interactions.

  9. Specialized stomatal humidity responses underpin ecological diversity in C3 bromeliads.

    Science.gov (United States)

    Males, Jamie; Griffiths, Howard

    2017-12-01

    The Neotropical Bromeliaceae display an extraordinary level of ecological variety, with species differing widely in habit, photosynthetic pathway and growth form. Divergences in stomatal structure and function, hitherto understudied in treatments of bromeliad evolutionary physiology, could have been critical to the generation of variety in ecophysiological strategies among the bromeliads. Because humidity is a key factor in bromeliad niches, we focussed on stomatal responses to vapour pressure deficit (VPD). We measured the sensitivity of stomatal conductance and assimilation rate to VPD in eight C 3 bromeliad species of contrasting growth forms and ecophysiological strategies and parameterised the kinetics of stomatal responses to a step change in VPD. Notably, three tank-epiphyte species displayed low conductance, high sensitivity and fast kinetics relative to the lithophytes, while three xeromorphic terrestrial species showed high conductance and sensitivity but slow stomatal kinetics. An apparent feedforward response of transpiration to VPD occurred in the tank epiphytes, while water-use efficiency was differentially impacted by stomatal closure depending on photosynthetic responses. Differences in stomatal responses to VPD between species of different ecophysiological strategies are closely linked to modifications of stomatal morphology, which we argue has been a pivotal component of the evolution of high diversity in this important plant family. © 2017 The Authors Plant, Cell & Environment Published by John Wiley & Sons Ltd.

  10. Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

    NARCIS (Netherlands)

    Rizzo, L.Y.; Theek, B.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

    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-)

  11. Theranostics Using Antibodies and Antibody-Related Therapeutics

    NARCIS (Netherlands)

    Moek, Kirsten L; Giesen, Danique; Kok, Iris C; de Groot, Derk Jan A; Jalving, Mathilde; Fehrmann, Rudolf S N; Lub-de Hooge, Marjolijn N; Brouwers, Adrienne H; de Vries, Elisabeth G E

    In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these

  12. Recent novel tumor gatekeepers and potential therapeutic approaches

    African Journals Online (AJOL)

    In this review, efforts have been made to present some of the latest knowledge about novel tumor gatekeepers and new therapeutic strategies to improve the efficacy of chemotherapy and give new hope to cancer patients to fight against cancer. Keywords: Cancer, Potent inhibitors, Gatekeepers, Therapeutic approaches, ...

  13. Inferring the Impact of Regulatory Mechanisms that Underpin CD8+ T Cell Control of B16 Tumor GrowthIn vivoUsing Mechanistic Models and Simulation.

    Science.gov (United States)

    Klinke, David J; Wang, Qing

    2016-01-01

    A major barrier for broadening the efficacy of immunotherapies for cancer is identifying key mechanisms that limit the efficacy of tumor infiltrating lymphocytes. Yet, identifying these mechanisms using human samples and mouse models for cancer remains a challenge. While interactions between cancer and the immune system are dynamic and non-linear, identifying the relative roles that biological components play in regulating anti-tumor immunity commonly relies on human intuition alone, which can be limited by cognitive biases. To assist natural intuition, modeling and simulation play an emerging role in identifying therapeutic mechanisms. To illustrate the approach, we developed a multi-scale mechanistic model to describe the control of tumor growth by a primary response of CD8+ T cells against defined tumor antigens using the B16 C57Bl/6 mouse model for malignant melanoma. The mechanistic model was calibrated to data obtained following adenovirus-based immunization and validated to data obtained following adoptive transfer of transgenic CD8+ T cells. More importantly, we use simulation to test whether the postulated network topology, that is the modeled biological components and their associated interactions, is sufficient to capture the observed anti-tumor immune response. Given the available data, the simulation results also provided a statistical basis for quantifying the relative importance of different mechanisms that underpin CD8+ T cell control of B16F10 growth. By identifying conditions where the postulated network topology is incomplete, we illustrate how this approach can be used as part of an iterative design-build-test cycle to expand the predictive power of the model.

  14. Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation.

    Science.gov (United States)

    Guenin-Macé, Laure; Veyron-Churlet, Romain; Thoulouze, Maria-Isabel; Romet-Lemonne, Guillaume; Hong, Hui; Leadlay, Peter F; Danckaert, Anne; Ruf, Marie-Thérèse; Mostowy, Serge; Zurzolo, Chiara; Bousso, Philippe; Chrétien, Fabrice; Carlier, Marie-France; Demangel, Caroline

    2013-04-01

    Mycolactone is a diffusible lipid secreted by the human pathogen Mycobacterium ulcerans, which induces the formation of open skin lesions referred to as Buruli ulcers. Here, we show that mycolactone operates by hijacking the Wiskott-Aldrich syndrome protein (WASP) family of actin-nucleating factors. By disrupting WASP autoinhibition, mycolactone leads to uncontrolled activation of ARP2/3-mediated assembly of actin in the cytoplasm. In epithelial cells, mycolactone-induced stimulation of ARP2/3 concentrated in the perinuclear region, resulting in defective cell adhesion and directional migration. In vivo injection of mycolactone into mouse ears consistently altered the junctional organization and stratification of keratinocytes, leading to epidermal thinning, followed by rupture. This degradation process was efficiently suppressed by coadministration of the N-WASP inhibitor wiskostatin. These results elucidate the molecular basis of mycolactone activity and provide a mechanism for Buruli ulcer pathogenesis. Our findings should allow for the rationale design of competitive inhibitors of mycolactone binding to N-WASP, with anti-Buruli ulcer therapeutic potential.

  15. Timing underpins the benefits associated with injectable collagen biomaterial therapy for the treatment of myocardial infarction.

    Science.gov (United States)

    Blackburn, Nick J R; Sofrenovic, Tanja; Kuraitis, Drew; Ahmadi, Ali; McNeill, Brian; Deng, Chao; Rayner, Katey J; Zhong, Zhiyuan; Ruel, Marc; Suuronen, Erik J

    2015-01-01

    Injectable hydrogel biomaterials are promising therapies to promote repair and regeneration post-myocardial infarction (MI). However, the timing of delivery and the mechanisms through which biomaterial treatments confer their benefits are translational issues that remain to be addressed. We assessed the efficacy of an injectable collagen matrix at 3 different delivery time points post-MI. Infarcted mice received the matrix or control (saline) treatment at 3 h, 1 week or 2 weeks after MI. The earlier treatment delivery better prevented negative ventricular remodeling and long-term deterioration of cardiac function (up to 3 months), whereas waiting longer to administer the matrix (1 and 2 weeks post-MI) reduced the therapeutic effects. Collagen matrix delivery did not stimulate an inflammatory response acutely and favorably modulated inflammation in the myocardium long-term. We found that the matrix interacts with the host tissue to alter the myocardial cytokine profile, promote angiogenesis, and reduce fibrosis and cell death. This work highlights that the timing of delivery can significantly affect the ability of an injectable hydrogel to protect the post-MI environment, which will be an important consideration in the clinical translation of cardiac biomaterial therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Levodopa: History and Therapeutic Applications.

    Science.gov (United States)

    Ovallath, Sujith; Sulthana, Bahiya

    2017-01-01

    Levodopa - the aromatic amino acid L-3,4-dihydroxy phenylalanine has held the attention of neurologists and pharmacologists alike for more than half a century. Even though extensive research has been done across the globe in treatment of Parkinson's disease, with different molecules, none could replace the gold standard treatment or provide complete relief for the debilitated. Although research brought us better tips and tricks to modulate the dopamine blood levels to balance between the desired and deleterious effects, it could never replace the basic substrate. From simple oral preparation to more advanced treatment like duodenal dopa administration for better efficacy and compliance, L-dopa has sure undergone scrutiny and stayed strong as the fundamental neurotransmitter replacement therapy to pave path for many more new therapeutic strategies. So as a token of gratitude to the revolutionary agent and pioneers behind it, a trip down the memory lane is in order.

  17. Antiviral Polymer Therapeutics

    DEFF Research Database (Denmark)

    Smith, Anton Allen Abbotsford

    2014-01-01

    The field of drug delivery is in essence an exercise in engineered pharmacokinetics. Methods of doing so have been developed through the introduction of a vehicle carrying the drug, either by encapsulation or covalent attachment. The emergence of polymer therapeutics in anticancer therapy has...... garnered a great deal of interest due to the substantial room for improvement inherent to conventional chemotherapeutic agents. Chemotherapeutic agents and antiviral agents have a lot of features in common due to both of them typically targeting endogenous targets, unlike antibacterial compounds, though...... the examples of polymer therapeutics being applied as an antiviral treatment are few and far in-between. This work aims to explore antiviral therapeutics, specifically in context of hepatitis virus C (HCV) and HIV. The current treatment of hepatitis C consists of a combination of drugs, of which ribavirin...

  18. Therapeutic HIV Peptide Vaccine

    DEFF Research Database (Denmark)

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

  19. Home Care of Children With Diarrhea in Bangui's Therapeutic Landscape (Central African Republic).

    Science.gov (United States)

    Giles-Vernick, Tamara; Bainilago, Louis; Fofana, Moussa; Bata, Petulla; Vray, Muriel

    2016-01-01

    We explore how the therapeutic landscape of Bangui, capital of the Central African Republic, shaped and reflected caregivers' home care of childhood diarrhea. Using interviews, group discussions, and participant observation, we found that caregivers described several categories of diarrhea, but in practice, adopted an experimental approach to home diarrheal care. Many managed incertitude by initially dosing children with street medicines and herbal infusions; they delayed seeking professional medical care to avoid expenses, observed their children's symptoms, consulted social networks, and used therapeutic foods. The logics underpinning these practices emerged from caregivers' conviction that diarrhea necessitated medical therapy and restricted choices within Bangui's therapeutic landscape, a consequence of lengthy political economic crisis. This crisis impoverished Bangui populations, eroded formal health care, and sharpened religious differences, discouraging care seeking from traditional healers. Analyses of therapeutic landscapes illuminate why caregivers embraced specific practices and logics and should guide the elaboration of more effective public health interventions. © The Author(s) 2015.

  20. Environmental context affects microbial ecophysiological mechanisms underpinning soil carbon storage under different land use

    Science.gov (United States)

    Malik, A. A.; Puissant, J.; Buckeridge, K. M.; Goodall, T.; Jehmlich, N.; Chowdhury, S.; Gleixner, G.; Griffiths, R.

    2017-12-01

    Soil microorganisms act as gatekeepers for soil-atmosphere carbon exchange by balancing the accumulation and release of organic matter in soil. Increasing evidence now exists to suggest that microbial biomass contributes significantly to soil organic carbon formation. However, we do not fully understand the microbial mechanisms of organic matter processing and this hinders the development of effective land management strategies to enhance soil carbon storage. Here we empirically link key microbial ecophysiological traits to soil carbon storage in temperate grassland habitats ranging in land use from pristine species-rich grasslands to intensive croplands in 56 different soils across Britain. Physiological mechanisms of soil microorganisms were assessed using stable carbon isotope tracing and soil proteomics. Through spatial patterns and path analysis of structural equation modeling we discern two distinct pH-related mechanisms of soil carbon storage and highlight that the response of these mechanistic indicators is shaped by the environmental context. Land use intensification in low pH soils that increases soil pH above a threshold value ( 6.2) leads to loss of carbon due to increased microbial degradation as a result of lower acid retardation of organic matter decomposition. On the contrary, the loss of carbon through intensification in high pH (> 6.2) soils was linked to decreased microbial biomass and reduced carbon use efficiency that was linked to tradeoffs with stress alleviation and resource acquisition. We conclude that land use intensification-induced changes in soil pH can be used as a proxy to determine the effect of land management strategies on microbial soil carbon cycling processes and emphasize that more extensive land management practices at higher soil pH have greater potential for soil carbon storage through increased microbial metabolic efficiency, whereas in acidic soils abiotic factors exert a greater influence on the fate of soil carbon.

  1. Therapeutic neutrality reconsidered.

    Science.gov (United States)

    Humphries, R H

    1982-06-01

    This paper suggests that therapists' tendency to ignore the impact of their own religious beliefs on their patients constitutes an area of potential abuse of psychotherapy. The author reviews the religious stance of the founders of psychotherapy, as well as recent criticisms of the therapeutic process, and proposes steps to safeguard against the inadvertent fostering of therapists' religious views on the patient.

  2. Therapeutic Angiogenesis for Treating Cardiovascular Diseases

    Science.gov (United States)

    Deveza, Lorenzo; Choi, Jeffrey; Yang, Fan

    2012-01-01

    Cardiovascular disease is the leading cause of death worldwide and is often associated with partial or full occlusion of the blood vessel network in the affected organs. Restoring blood supply is critical for the successful treatment of cardiovascular diseases. Therapeutic angiogenesis provides a valuable tool for treating cardiovascular diseases by stimulating the growth of new blood vessels from pre-existing vessels. In this review, we discuss strategies developed for therapeutic angiogenesis using single or combinations of biological signals, cells and polymeric biomaterials. Compared to direct delivery of growth factors or cells alone, polymeric biomaterials provide a three-dimensional drug-releasing depot that is capable of facilitating temporally and spatially controlled release. Biomimetic signals can also be incorporated into polymeric scaffolds to allow environmentally-responsive or cell-triggered release of biological signals for targeted angiogenesis. Recent progress in exploiting genetically engineered stem cells and endogenous cell homing mechanisms for therapeutic angiogenesis is also discussed. PMID:22916079

  3. Therapeutic targets in liver fibrosis.

    Science.gov (United States)

    Fallowfield, Jonathan A

    2011-05-01

    Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

  4. Rett syndrome: genes, synapses, circuits and therapeutics

    Directory of Open Access Journals (Sweden)

    Abhishek eBanerjee

    2012-05-01

    Full Text Available Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT is a postnatal neurological disorder of genetic origin, caused by mutations in the X-linked gene MECP2. It features neuropsychiatric abnormalities like motor dysfunctions and mild to severe cognitive impairment. This review discusses several key questions and attempts to evaluate recently developed animal models, cell-type specific function of MeCP2, defects in neural circuit plasticity and possible therapeutic strategies. Finally, we also discuss how genes, proteins and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies.

  5. Therapeutic Vaccination for HPV Induced Cervical Cancers

    OpenAIRE

    Brinkman, Joeli A.; Hughes, Sarah H.; Stone, Pamela; Caffrey, Angela S.; Muderspach, Laila I.; Roman, Lynda D.; Weber, Jeffrey S.; Kast, W. Martin

    2007-01-01

    Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining th...

  6. Therapeutic Vaccination for HPV Induced Cervical Cancers

    Directory of Open Access Journals (Sweden)

    Joeli A. Brinkman

    2007-01-01

    Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

  7. Therapeutic vaccination for HPV induced cervical cancers.

    Science.gov (United States)

    Brinkman, Joeli A; Hughes, Sarah H; Stone, Pamela; Caffrey, Angela S; Muderspach, Laila I; Roman, Lynda D; Weber, Jeffrey S; Kast, W Martin

    2007-01-01

    Cervical Cancer is the second leading cause of cancer-related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

  8. RNAi Therapeutic Platforms for Lung Diseases

    Directory of Open Access Journals (Sweden)

    Kazuyoshi Kuwano

    2013-02-01

    Full Text Available RNA interference (RNAi is rapidly becoming an important method for analyzing gene functions in many eukaryotes and holds promise for the development of therapeutic gene silencing. The induction of RNAi relies on small silencing RNAs, which affect specific messenger RNA (mRNA degradation. Two types of small RNA molecules, i.e. small interfering RNAs (siRNAs and microRNAs (miRNAs, are central to RNAi. Drug discovery studies and novel treatments of siRNAs are currently targeting a wide range of diseases, including various viral infections and cancers. Lung diseases in general are attractive targets for siRNA therapeutics because of their lethality and prevalence. In addition, the lung is anatomically accessible to therapeutic agents via the intrapulmonary route. Recently, increasing evidence indicates that miRNAs play an important role in lung abnormalities, such as inflammation and oncogenesis. Therefore, miRNAs are being targeted for therapeutic purposes. In this review, we present strategies for RNAi delivery and discuss the current state-of-the-art RNAi-based therapeutics for various lung diseases.

  9. Nuclear and isotopic techniques underpinning probabilistic ecological risk analysis in coastal marine systems

    International Nuclear Information System (INIS)

    Szymczak, R.; Twining, J.; Hollins, S.; Hughes, C.; Mazumder, D.; Alquezar, R.

    2006-01-01

    strategy

  10. Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Rui Lu

    2017-10-01

    Full Text Available Acute myeloid leukemia (AML, a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently “hit” genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event. Increasing body of evidence demonstrates that chromatin modification aberrations underlying the formation of blood cancer can be reversed by pharmacological targeting of the responsible epigenetic modulators, thus providing new mechanism-based treatment strategies. Here, we summarize recent advances in development of small-molecule inhibitors specific to chromatin factors and their potential applications in the treatment of genetically defined AMLs. These compounds selectively inhibit various subclasses of “epigenetic writers” (such as histone methyltransferases MLL/KMT2A, G9A/KMT1C, EZH2/KMT6A, DOT1L/KMT4, and PRMT1, “epigenetic readers” (such as BRD4 and plant homeodomain finger proteins, and “epigenetic erasers” (such as histone demethylases LSD1/KDM1A and JMJD2C/KDM4C. We also discuss about the molecular mechanisms underpinning therapeutic effect of these epigenetic compounds in AML and favor their potential usage for combinational therapy and treatment of pre-leukemia diseases.

  11. A pervasive denigration of natural history misconstrues how biodiversity inventories and taxonomy underpin scientific knowledge.

    Science.gov (United States)

    Cotterill, Fenton P D; Foissner, Wilhelm

    2010-01-01

    of its intricacies. Beyond weakening research capacities and outputs across comparative biology, this Denigration of Natural History impacts on the integrity of knowledge itself, undermining progress and pedagogy throughout science. Unprecedented advances in knowledge are set to follow on consummate inventories of biodiversity, including the protists. These opportunities challenge us to survey biodiversity representatively-detailing the natural history of species. Research strategies cannot continue to ignore arguments for such an unprecedented investment in idiographic natural history. Idiographic shortcuts to general (nomothetic) insights simply do not exist. The biodiversity sciences face a stark choice. No matter how charismatic its portrayed species, an incomplete 'Brochure of Life' cannot match the scientific integrity of the 'Encyclopedia of Life'.

  12. Reversible G Protein βγ9 Distribution-Based Assay Reveals Molecular Underpinnings in Subcellular, Single-Cell, and Multicellular GPCR and G Protein Activity.

    Science.gov (United States)

    Senarath, Kanishka; Ratnayake, Kasun; Siripurapu, Praneeth; Payton, John L; Karunarathne, Ajith

    2016-12-06

    Current assays to measure the activation of G protein coupled receptors (GPCRs) and G proteins are time-consuming, indirect, and expensive. Therefore, an efficient method which directly measures the ability of a ligand to govern GPCR-G protein interactions can help to understand the molecular underpinnings of the associated signaling. A live cell imaging-based approach is presented here to directly measure ligand-induced GPCR and G protein activity in real time. The number of active GPCRs governs G protein heterotrimer (αβγ) dissociation, thereby controlling the concentration of free βγ subunits. The described γ9 assay measures the GPCR activation-induced extent of the reversible βγ9 subunit exchange between the plasma membrane (PM) and internal membranes (IMs). Confocal microscopy-based γ9 assay quantitatively determines the concentration dependency of ligands on GPCR activation. Demonstrating the high-throughput screening (HTS) adaptability, the γ9 assay performed using an imaging plate reader measures the ligand-induced GPCR activation. This suggests that the γ9 assay can be employed to screen libraries of compounds for their ability to activate GPCRs. Together with subcellular optogenetics, the spatiotemporal sensitivity of the γ9 assay permits experimental determination of the limits of spatially restricted activation of GPCRs and G proteins in subcellular regions of single cells. This assay works effectively for GPCRs coupled to αi/o and αs heterotrimers, including light-sensitive GPCRs. In addition, computational modeling of experimental data from the assay is used to decipher intricate molecular details of the GPCR-G protein activation process. Overall, the γ9 assay provides a robust strategy for quantitative as well as qualitative determination of GPCR and G protein function on a single-cell, multicell, and subcellular level. This assay not only provides information about the inner workings of the signaling pathway, but it also strengthens

  13. Discourses and values underpin public debate on fracking in Spain: A case study at the crossroad

    Science.gov (United States)

    Hermelinda Lopera Pareja, Emilia; García Laso, Ana; Martín Sánchez, Domingo Alfonso

    2015-04-01

    In the EU context extraction of shale and oil gas by hydraulic fracturing (fracking) differs from country to country in terms of legislation and implementation. While fossil fuel extraction using this technology is currently taking place in the UK, Germany and France have adopted respective moratoria. In between is the Spanish case, where hydrocarbon extraction projects through fracking have to undergo mandatory and routine environmental assessment in accordance with the last changes to environmental regulations. Nowadays Spain is at the crossroad with respect to the future of this technology. We presume a social conflictt in our country since the position and strategy of the involved and confronted social actors -national, regional and local authorities, energy companies, scientists, NGO and other social organization- are going to play key and likely divergent roles in its industrial implementation and public acceptance. In order to improve knowledge on how to address these controverted situations from the own engineering context, the affiliated units from the Higher Technical School of Mines and Energy Engineering at UPM have been working on a transversal program to teach values and ethics. Over the past seven years, this pioneering experience has shown the usefulness of applying a consequentialist ethics, based on a case-by-case approach and costs-benefits analysis both for action and inaction. As a result of this initiative a theoretical concept has arisen and crystallized in this field: it is named Inter-ethics. This theoretical perspective can be very helpful in complex situations, with multi-stakeholders and plurality of interests, when ethical management requires the interaction between the respective ethics of each group; professional ethics of a single group is not enough. Under this inter-ethics theoretical framework and applying content analysis techniques, this paper explores the articulation of the discourse in favour and against fracking technology

  14. Innovative therapeutic strategies against chemo and radio-resistant cancers: hydrogenated nano-diamonds and metal organic frameworks. An in vitro study in 2D and 3D systems

    International Nuclear Information System (INIS)

    Grall, Romain

    2015-01-01

    The present work focuses on nanoparticles and their great skills for oncology therapies. Two kinds of nanoparticles have been studied in order to biologically validate and characterize their features. The use of hydrogenated Nano-diamonds (H-NDs) as radio sensitizer is based on a physic-chemical postulate where they act as oxidative stress generator through interaction with irradiation. Thus we validated this hypothesis in radio resistant kidney and breast cancer cell lines and identify senescence as the main pathway after co-treatment with H-NDs and irradiation. Metal organic frameworks are also of particular interest for drug delivery because of their very important loading capacities. Here we demonstrate the biocompatibility of the empty compounds in four lung and hepatic cancer cell lines, a main point before their involvement in drug delivery strategies. Finally, following international guidelines encouraging to make animal testing more ethic, we developed a new 3D cell culture mimicking mucinous lung adenocarcinoma. This well characterized model will be used for the study of cancer development and drug screening. (author) [fr

  15. Practice as ‘Research’ Within The Context of Art and Design Academia: A Brief Excursion Into Its Philosophical Underpinnings

    Directory of Open Access Journals (Sweden)

    Dominique Rio Adiwijaya

    2015-07-01

    Full Text Available Integration of many fields of human endeavor including art and design into academic system is not at all surprising in our modern world that continues to modernize itself in the quest for ever increasing welfare of humanity. The backbone of modern welfare is unmistakably techno-scientific academic research, explaining current expansion of its ‘standardized’ paradigm, regulation and infrastructure without exception into the field of art and design. This is where the problem precisely arises, since their own nature, art and design as ‘creative’ fields, are incompatible with scientific paradigm which emphasizes a uniform reproducibility of research findings. ‘The heart of the arts’, in contrast, is its singularities. The industry actually has recognized the difference by assigning ‘patents’ to technological invention and ‘copyright’ to singular artworks. The question is then how to incorporate such creatively plural fields into uniform academic research system. Fortunately within the past 20 years, there were developments within international art and design academia that came up with a keystone principle called practice-based research. It relies upon philosophical underpinnings of phenomenology and hermeneutics which has been critically acclaimed in showing inadequacies of positivistic (natural science-based paradigm in understanding cultural phenomena exemplified by art and design. It is the intention of this article to briefly explain this new principle and its philosophical underpinnings in order to let us appreciate its positive contribution for our understanding of art and design. This understanding in turn would allow us to cultivate those creative fields within academic context in a more appropriate way. 

  16. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. [Achievement of therapeutic objectives].

    Science.gov (United States)

    Mantilla, Teresa

    2014-07-01

    Therapeutic objectives for patients with atherogenic dyslipidemia are achieved by improving patient compliance and adherence. Clinical practice guidelines address the importance of treatment compliance for achieving objectives. The combination of a fixed dose of pravastatin and fenofibrate increases the adherence by simplifying the drug regimen and reducing the number of daily doses. The good tolerance, the cost of the combination and the possibility of adjusting the administration to the patient's lifestyle helps achieve the objectives for these patients with high cardiovascular risk. Copyright © 2014 Sociedad Española de Arteriosclerosis y Elsevier España, S.L. All rights reserved.

  18. Therapeutic approaches to cellulite.

    Science.gov (United States)

    Green, Jeremy B; Cohen, Joel L; Kaufman, Joely; Metelitsa, Andrei I; Kaminer, Michael S

    2015-09-01

    Cellulite is a condition that affects the vast majority of women. Although it is of no danger to one's overall health, cellulite can be psychosocially debilitating. Consequently, much research has been devoted to understanding cellulite and its etiopathogenesis. With additional insights into the underlying causes of its clinical presentation, therapeutic modalities have been developed that offer hope to cellulite sufferers. This review examines evidence for topical treatments, noninvasive energy-based devices, and recently developed minimally invasive interventions that may finally provide a solution. ©2015 Frontline Medical Communications.

  19. Revitalizing Psychiatric Therapeutics

    Science.gov (United States)

    Hyman, Steven E

    2014-01-01

    Despite high prevalence and enormous unmet medical need, the pharmaceutical industry has recently de-emphasized neuropsychiatric disorders as ‘too difficult' a challenge to warrant major investment. Here I describe major obstacles to drug discovery and development including a lack of new molecular targets, shortcomings of current animal models, and the lack of biomarkers for clinical trials. My major focus, however, is on new technologies and scientific approaches to neuropsychiatric disorders that give promise for revitalizing therapeutics and may thus answer industry's concerns. PMID:24317307

  20. Rethinking Therapeutic Misconception in Biobanking

    DEFF Research Database (Denmark)

    Tupasela, Aaro; Snell, Karoliina; Cañada, Jose

    2017-01-01

    Some authors have noted that in biobank research participants may be guided by what is called therapeutic misconception, whereby participants attribute therapeutic intent to research procedures.This article argues that the notion of therapeutic misconception is increasingly less justified when ev...

  1. Integrating school-based and therapeutic conflict management models at schools.

    Science.gov (United States)

    D'Oosterlinck, Franky; Broekaert, Eric

    2003-08-01

    Including children with emotional and behavioral needs in mainstream school systems leads to growing concern about the increasing number of violent and nonviolent conflicts. Schools must adapt to this evolution and adopt a more therapeutic dimension. This paper explores the possibility of integrating school-based and therapeutic conflict management models and compares two management models: a school-based conflict management program. Teaching Students To Be Peacemakers; and a therapeutic conflict management program, Life Space Crisis Intervention. The authors conclude that integration might be possible, but depends on establishing a positive school atmosphere, the central position of the teacher, and collaborative and social learning for pupils. Further implementation of integrated conflict management models can be considered but must be underpinned by appropriate scientific research.

  2. Mechanisms of Plasma Therapeutics

    Science.gov (United States)

    Graves, David

    2015-09-01

    In this talk, I address research directed towards biomedical applications of atmospheric pressure plasma such as sterilization, surgery, wound healing and anti-cancer therapy. The field has seen remarkable growth in the last 3-5 years, but the mechanisms responsible for the biomedical effects have remained mysterious. It is known that plasmas readily create reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS (or RONS), in addition to a suite of other radical and non-radical reactive species, are essential actors in an important sub-field of aerobic biology termed ``redox'' (or oxidation-reduction) biology. It is postulated that cold atmospheric plasma (CAP) can trigger a therapeutic shielding response in tissue in part by creating a time- and space-localized, burst-like form of oxy-nitrosative stress on near-surface exposed cells through the flux of plasma-generated RONS. RONS-exposed surface layers of cells communicate to the deeper levels of tissue via a form of the ``bystander effect,'' similar to responses to other forms of cell stress. In this proposed model of CAP therapeutics, the plasma stimulates a cellular survival mechanism through which aerobic organisms shield themselves from infection and other challenges.

  3. Therapeutic nuclear medicine

    Energy Technology Data Exchange (ETDEWEB)

    Baum, Richard P. (ed.) [ENETS Center of Excellence, Bad Berka (Germany). THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging

    2014-07-01

    Discusses all aspects of radionuclide therapy, including basic principles, newly available treatments, regulatory requirements, and future trends. Provides the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Explains the role of the therapeutic nuclear physician in effectively coordinating a diverse multidisciplinary team. Written by leading experts. The recent revolution in molecular biology offers exciting new opportunities for targeted radionuclide therapy. The selective irradiation of tumor cells through molecular biological mechanisms is now permitting the radiopharmaceutical control of tumors that are unresectable and unresponsive to either chemotherapy or conventional radiotherapy. In this up-to-date, comprehensive book, world-renowned experts discuss the basic principles of radionuclide therapy, explore in detail the available treatments, explain the regulatory requirements, and examine likely future developments. The full range of clinical applications is considered, including thyroid cancer, hematological malignancies, brain tumors, liver cancer, bone and joint disease, and neuroendocrine tumors. The combination of theoretical background and practical information will provide the reader with all the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Careful attention is also paid to the important role of the therapeutic nuclear physician in delivering the effective coordination of a diverse multidisciplinary team that is essential to the safe provision of treatment.

  4. Therapeutic nuclear medicine

    International Nuclear Information System (INIS)

    Baum, Richard P.

    2014-01-01

    Discusses all aspects of radionuclide therapy, including basic principles, newly available treatments, regulatory requirements, and future trends. Provides the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Explains the role of the therapeutic nuclear physician in effectively coordinating a diverse multidisciplinary team. Written by leading experts. The recent revolution in molecular biology offers exciting new opportunities for targeted radionuclide therapy. The selective irradiation of tumor cells through molecular biological mechanisms is now permitting the radiopharmaceutical control of tumors that are unresectable and unresponsive to either chemotherapy or conventional radiotherapy. In this up-to-date, comprehensive book, world-renowned experts discuss the basic principles of radionuclide therapy, explore in detail the available treatments, explain the regulatory requirements, and examine likely future developments. The full range of clinical applications is considered, including thyroid cancer, hematological malignancies, brain tumors, liver cancer, bone and joint disease, and neuroendocrine tumors. The combination of theoretical background and practical information will provide the reader with all the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Careful attention is also paid to the important role of the therapeutic nuclear physician in delivering the effective coordination of a diverse multidisciplinary team that is essential to the safe provision of treatment.

  5. [Hemoglobinopathies. Current therapeutic possibilities].

    Science.gov (United States)

    Birgens, H S; Karle, H

    1995-05-29

    In recent years, the number of immigrants has increased considerably in Denmark. Consequently, a series of new clinical pictures has appeared in the Danish health care system. Typical examples are the genetic diseases, the haemoglobinopathies. Most of the immigrants come from areas, where the gene frequency of these disorders is widely distributed, for instance the Mediterranean countries, the Middle East, Southeast Asia and Africa. Most frequent are the heterozygous thalassaemias, but also the number of patients with severe thalassaemia and other clinically important haemoglobinopathies such as sickle cell anaemia has also increased in recent years. The clinical problems concerning these patients focus on two important topics, namely genetic counselling of heterozygous individuals (in some cases combined with prenatal diagnostics) and the treatment of patients with clinically severe haemoglobinopathy. The only curative treatment of the haemoglobinopathies is allogeneic bone marrow transplantation, but this treatment can only be offered to a few of these patients. However, a variety of therapeutic options exist which can improve their prognosis and quality of life. Since the number of patients with these diseases will probably increase over the next years we find it relevant, based on typical case stories, to give a review of the present therapeutic possibilities for these disorders.

  6. Pharmacogenetics approach to therapeutics.

    Science.gov (United States)

    Koo, Seok Hwee; Lee, Edmund Jon Deoon

    2006-01-01

    1. Pharmacogenetics refers to the study of genetically controlled variations in drug response. Functional variants caused by single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolising enzymes, transporters, ion channels and drug receptors have been known to be associated with interindividual and interethnic variation in drug response. Genetic variations in these genes play a role in influencing the efficacy and toxicity of medications. 2. Rapid, precise and cost-effective high-throughput technological platforms are essential for performing large-scale mutational analysis of genetic markers involved in the aetiology of variable responses to drug therapy. 3. The application of a pharmacogenetics approach to therapeutics in general clinical practice is still far from being achieved today owing to various constraints, such as limited accessibility of technology, inadequate knowledge, ambiguity of the role of variants and ethical concerns. 4. Drug actions are determined by the interplay of several genes encoding different proteins involved in various biochemical pathways. With rapidly emerging SNP discovery technological platforms and widespread knowledge on the role of SNPs in disease susceptibility and variability in drug response, the pharmacogenetics approach to therapeutics is anticipated to take off in the not-too-distant future. This will present profound clinical, economic and social implications for health care.

  7. Therapeutic touch and agitation in individuals with Alzheimer's disease.

    Science.gov (United States)

    Hawranik, Pamela; Johnston, Pat; Deatrich, Judith

    2008-06-01

    Limited effective strategies exist to alleviate or treat disruptive behaviors in people with Alzheimer's disease. Fifty-one residents of a long-term care facility with Alzheimer's disease were randomly assigned to one of three intervention groups. A multiple time series, blinded, experimental design was used to compare the effectiveness of therapeutic touch, simulated therapeutic touch, and usual care on disruptive behavior. Three forms of disruptive behavior comprised the dependent variables: physical aggression, physical nonaggression, and verbal agitation. Physical nonaggressive behaviors decreased significantly in those residents who received therapeutic touch compared with those who received the simulated version and the usual care. No significant differences in physically aggressive and verbally agitated behaviors were observed across the three study groups. The study provided preliminary evidence for the potential for therapeutic touch in dealing with agitated behaviors by people with dementia. Researchers and practitioners must consider a broad array of strategies to deal with these behaviors.

  8. Inhibiting DNA Polymerases as a Therapeutic Int