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Sample records for additional therapeutic approaches

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

    PubMed Central

    Wei, Jianwen; Flaherty, Stephen; Karsenty, Gerard

    2016-01-01

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

  2. Pharmacogenetics approach to therapeutics.

    PubMed

    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. PMID:16700889

  3. [Hypercholesterolemia: a therapeutic approach].

    PubMed

    Moráis López, A; Lama More, R A; Dalmau Serra, J

    2009-05-01

    High blood cholesterol levels represent an important cardiovascular risk factor. Hypercholesterolemia is defined as levels of total cholesterol and low-density lipoprotein cholesterol above 95th percentile for age and gender. For the paediatric population, selective screening is recommended in children older than 2 years who are overweight, with a family history of early cardiovascular disease or whose parents have high cholesterol levels. Initial therapeutic approach includes diet therapy, appropriate physical activity and healthy lifestyle changes. Drug treatment should be considered in children from the age of 10 who, after having followed appropriate diet recommendations, still have very high LDL-cholesterol levels or moderately high levels with concomitant risk factors. In case of extremely high LDL-cholesterol levels, drug treatment should be taken into consideration at earlier ages (8 years old). Modest response is usually observed with bile acid-binding resins. Statins can be considered first-choice drugs, once evidence on their efficacy and safety has been shown. PMID:19427823

  4. Homocystinuria: Therapeutic approach.

    PubMed

    Kumar, Tarun; Sharma, Gurumayum Suraj; Singh, Laishram Rajendrakumar

    2016-07-01

    Homocystinuria is a disorder of sulfur metabolism pathway caused by deficiency of cystathionine β-synthase (CBS). It is characterized by increased accumulation of homocysteine (Hcy) in the cells and plasma. Increased homocysteine results in various vascular and neurological complications. Present strategies to lower cellular and plasma homocysteine levels include vitamin B6 intake, dietary methionine restriction, betaine supplementation, folate and vitamin B12 administration. However, these strategies are inefficient for treatment of homocystinuria. In recent years, advances have been made towards developing new strategies to treat homocystinuria. These mainly include functional restoration to mutant CBS, enhanced clearance of Hcy from the body, prevention of N-homocysteinylation-induced toxicity and inhibition of homocysteine-induced oxidative stress. In this review, we have exclusively discussed the recent advances that have been achieved towards the treatment of homocystinuria. The review is an attempt to help clinicians in developing effective therapeutic strategies and designing novel drugs against homocystinuria. PMID:27059523

  5. Therapeutic approaches for shankopathies.

    PubMed

    Wang, Xiaoming; Bey, Alexandra L; Chung, Leeyup; Krystal, Andrew D; Jiang, Yong-Hui

    2014-02-01

    Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANK as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article, we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function. PMID:23536326

  6. Therapeutic approaches for celiac disease

    PubMed Central

    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

  7. Therapeutic approach to sexual abuse.

    PubMed Central

    Furniss, T; Bingley-Miller, L; Bentovim, A

    1984-01-01

    An account is given of the development of a treatment project for sexually abused children and their families. We review incidence data which indicate that sexual abuse of children is likely to be a far more frequent problem than has been recognised and cause an appreciable degree of psychological damage. Professional responses to this are confused and treatment facilities limited. Sexual abuse is seen as an expression of severe relationship problems in the family and therapeutic provision is made, therefore, not only for the abused child but for other members of the family (including both parents). The method adopted is to offer group therapy to the child, mother, and father and regular family meetings with professionals in the community, concerned with care and protection of children. Clinical data on the first 56 children treated are discussed and our approach to treatment is evaluated. PMID:6486864

  8. Novel Therapeutic Approaches in Diabetes.

    PubMed

    Gallwitz, Baptist

    2016-01-01

    This chapter deals with novel therapeutic approaches, predominantly for type 2 diabetes. Incretin-based therapies utilize the effects of glucagon-like peptide-1 (GLP-1), which stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Incretin-based therapies comprise injectable GLP-1 receptor agonists and orally active dipeptidyl peptidase-IV inhibitors. Both have a low hypoglycaemia risk. GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide) reduce glycated haemoglobin levels more effectively than oral antidiabetic agents do and lead to weight loss as well as a slight decrease in systolic blood pressure. The most common side effects are nausea and fullness, especially during the start of therapy. Dipeptidyl peptidase-IV inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) are not inferior to sulfonylureas, causing significantly less hypoglycaemia and not inducing weight gain. Specific adverse effects have not been discovered yet, and cardiovascular safety has been demonstrated in respective studies. Sodium-glucose transporter-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) were introduced recently. They block the tubular reabsorption of glucose in the kidney and represent an insulin-independent mode of action, with low hypoglycaemia risk and allowing weight loss. The most common side effects are genital and urinary tract infections. Other novel drugs in development (G-protein-coupled receptor agonists, interleukin-1 antagonists) are also described. PMID:26824365

  9. Approaches for Therapeutic Temperature Management.

    PubMed

    Olson, DaiWai M; Hoffman, Jo

    2016-01-01

    In concert with an evolution toward an increased awareness of the need to tightly manage temperature, the methods used to monitor and manipulate temperature have evolved from mercury-filled glass thermometers, alcohol baths, and ice packs into a high technology-driven multidisciplinary activity. The purpose of this article is to provide a brief overview of the historical development of temperature management and the primary tenets of each of the 3 phases (induction, maintenance, and rewarming), which are now recognized as crucial steps to ensure the safe practice of therapeutic temperature management. PMID:26714116

  10. New therapeutic approaches in PV

    PubMed Central

    Falchi, Lorenzo; Newberry, Kate J.; Verstovsek, Srdan

    2015-01-01

    Polycytemia vera (PV) is one of the three Philadelphia-negative myeloproliferative neoplasms. Clinically, PV is an indolent disease but its course can be complicated by arterial and venous vascular accidents, evolution to myelofibrosis or leukemic transformation. Treatment of PV is, therefore, aimed at preventing such acute complications. The cornerstone of therapy of low-risk patients remains strict control of cardiovascular risk factors, the use of phlebotomy and low dose aspirin. Higher risk patients should also receive cytoreductive treatments. Hydroxyurea and interferon-α represent standard first-line options for newly diagnosed high-risk PV patients. Recommendations for patients who fail these therapies are less clearly defined. The discovery of a mutation in the Janus kinase 2 gene (V617F) in almost all cases of PV has prompted the development of molecularly targeted agents for the treatment of these patients. In this review we will discuss key clinical aspects, the current therapeutic armamentarium and data on the use of novel agents in patients with PV. PMID:26297275

  11. Topical and oral therapeutic approach to rosacea.

    PubMed

    Helfrich, Yolanda R; Maier, Lisa M

    2016-06-01

    Rosacea is an inflammatory condition of the skin, primarily affecting the central convexities of the face. Various topical and oral therapeutic approaches exist. Most have been developed to treat the papulopustular subtype of rosacea; however, other approaches can be used to treat the erythematotelangiectatic, ocular, and phymatous subtypes. This review provides a summary of available topical and oral approaches for the treatment of rosacea. PMID:27416312

  12. Therapeutic approaches to acquired von Willebrand syndrome.

    PubMed

    Federici, A B

    2000-02-01

    Acquired von Willebrand syndrome (AVWS) is a rare acquired bleeding disorder similar to the congenital von Willebrand disease (VWD) in terms of laboratory findings. Diagnosis of AVWS can be very difficult, with treatment normally taking an empirical form. Although more than 200 cases have been reported since 1968, no retrospective or prospective studies are available on AVWS. Recently, an International Registry on AVWS, gathering data directly from worldwide Departments of Haematology-Oncology and Haemophilia Centres, has been organised by a group working on behalf of the Subcommittee on VWF in the Scientific Standardisation Committee (SSC) of International Society on Thrombosis and Haemostasis (ISTH). Information about an additional 211 AVWS patients is now available, with more detailed data on demography, type of haemorrhage, diagnostic tests for AVWS and management of bleeding episodes. The additional 211 AVWS cases are associated with lymphoproliferative (47%) or myeloproliferative (19%) disorders, cardiovascular diseases, neoplasia (7%) and other miscellaneous diseases (14%). Bleeding episodes of AVWS patients were managed by different compounds including desmopressin (22%), FVIII/VWF concentrates (26%) and high-dose immunoglobulin (10%), plasmapheresis (2%), steroids (5%) and immunosuppressive drugs (20%). Based on complied data, we can conclude that none of the therapeutic approaches proposed are 100% effective in all AVWS cases. Therefore, treatment must be customized for each patient according to the underlying disorder, as well as to the type and the severity of bleeding episode and must be targeted to each specific case. PMID:11060681

  13. Therapeutic approach to "diabetic foot" complications.

    PubMed

    Calderini, Cristina; Cioni, Federico; Haddoub, Silvia; Maccanelli, Francesco; Magotti, Maria Grazia; Tardio, Sergio

    2014-01-01

    The series of ulcers of the lower extremities known as "diabetic foot" is a common complication of diabetes and the chief cause of admission to hospital. The causes may be numerous but the main ones are distal symmetric neuropathy and peripheral obliterative arteriopathy, often complicated by infection. In this review, the Authors, after having illustrated the main pathophysiological aspects of the diabetic foot, describe the clinical characteristics of the disease, focusing particularly on the risk of suprainfection and vascular problems. The clinical and therapeutic approach to diabetic foot is also investigated with particular reference to the antibiotic treatment of infections and the treatment of peripheral arterial disease. Poor tissue repair, persistent inflammation, the presence of deep abscesses, osteomyelitis and systemic involvement can lead to a very serious clinical picture of gangrene or necrosis, which is initially localised but which can extend widely, requiring minor or major amputation surgery, in order to radically remove the infected tissue. In conclusion, space for discussion is given to the rationale of hyperbaric oxygen therapy, negative pressure wound therapy and other advanced therapies that involve the use of dermoepidermal equivalents and skin substitutes in addition to gels made of platelet-derived growth factors and the epidermal growth factor. Nonetheless, prevention is, of course, of fundamental importance, based on an intensive treat-to-target approach for the treatment of diabetes, on regular examinations of the feet, on the stratification of risk and education of the patient, which has proved successful in reducing the onset of foot lesions in at least 50% of patients. PMID:25567455

  14. New Therapeutic Approaches for Advanced Gastrointestinal Stromal Tumors (GISTs)

    PubMed Central

    Somaiah, Neeta

    2010-01-01

    Synopsis The management of advanced GIST is increasingly complex due to imatinib refractory disease. Primary resistance to imatinib is uncommon, and most patients progress after development of additional genetic changes. This article reviews management strategies including surgical approaches, local modalities for progressive liver metastases, as well as novel therapeutic agents. PMID:19248977

  15. Biological plaque control: novel therapeutic approach to periodontal disease.

    PubMed

    Sugano, Naoyuki

    2012-03-01

    Despite its important role in the control of periodontal disease, mechanical plaque control is not properly practiced by most individuals. Therefore, adjunctive chemical plaque control using chlorhexidine and antibiotics has also been suggested as an additional therapeutic strategy to augment mechanical plaque control. However, the additional effects of adjunctive antibiotic therapy are small, and topical chlorhexidine therapy is not without side effects. Given current limitations, new approaches for the control of biofilm are required. The new therapeutic approaches discussed in this review are divided into two categories: probiotics and vaccines. Probiotics is an interesting new field of periodontology research that aims to achieve biological plaque control by eliminating pathogenic bacteria. In addition, passive immunization using egg yolk antibody raised against periodontal pathogens may be an effective approach for the treatment of periodontitis. Further study to evaluate the possible effects of these biological plaque control methods against periodontal disease is warranted. PMID:22466880

  16. Therapeutic approaches for spinal cord injury

    PubMed Central

    Cristante, Alexandre Fogaça; de Barros Filho, Tarcísio Eloy Pessoa; Marcon, Raphael Martus; Letaif, Olavo Biraghi; da Rocha, Ivan Dias

    2012-01-01

    This study reviews the literature concerning possible therapeutic approaches for spinal cord injury. Spinal cord injury is a disabling and irreversible condition that has high economic and social costs. There are both primary and secondary mechanisms of damage to the spinal cord. The primary lesion is the mechanical injury itself. The secondary lesion results from one or more biochemical and cellular processes that are triggered by the primary lesion. The frustration of health professionals in treating a severe spinal cord injury was described in 1700 BC in an Egyptian surgical papyrus that was translated by Edwin Smith; the papyrus reported spinal fractures as a “disease that should not be treated.” Over the last two decades, several studies have been performed to obtain more effective treatments for spinal cord injury. Most of these studies approach a patient with acute spinal cord injury in one of four manners: corrective surgery or a physical, biological or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at minimum, allow for partial functional recoveries for these patients, which could improve their quality of life. PMID:23070351

  17. Structurally Based Therapeutic Evaluation: A Therapeutic and Practical Approach to Teaching Medicinal Chemistry.

    ERIC Educational Resources Information Center

    Alsharif, Naser Z.; And Others

    1997-01-01

    Explains structurally based therapeutic evaluation of drugs, which uses seven therapeutic criteria in translating chemical and structural knowledge into therapeutic decision making in pharmaceutical care. In a Creighton University (Nebraska) medicinal chemistry course, students apply the approach to solve patient-related therapeutic problems in…

  18. Gene therapeutic approaches to inhibit hepatitis B virus replication

    PubMed Central

    Gebbing, Maren; Bergmann, Thorsten; Schulz, Eric; Ehrhardt, Anja

    2015-01-01

    Acute and chronic hepatitis B virus (HBV) infections remain to present a major global health problem. The infection can be associated with acute symptomatic or asymptomatic hepatitis which can cause chronic inflammation of the liver and over years this can lead to cirrhosis and the development of hepatocellular carcinomas. Currently available therapeutics for chronically infected individuals aim at reducing viral replication and to slow down or stop the progression of the disease. Therefore, novel treatment options are needed to efficiently combat and eradicate this disease. Here we provide a state of the art overview of gene therapeutic approaches to inhibit HBV replication. We discuss non-viral and viral approaches which were explored to deliver therapeutic nucleic acids aiming at reducing HBV replication. Types of delivered therapeutic nucleic acids which were studied since many years include antisense oligodeoxynucleotides and antisense RNA, ribozymes and DNAzymes, RNA interference, and external guide sequences. More recently designer nucleases gained increased attention and were exploited to destroy the HBV genome. In addition we mention other strategies to reduce HBV replication based on delivery of DNA encoding dominant negative mutants and DNA vaccination. In combination with available cell culture and animal models for HBV infection, in vitro and in vivo studies can be performed to test efficacy of gene therapeutic approaches. Recent progress but also challenges will be specified and future perspectives will be discussed. This is an exciting time to explore such approaches because recent successes of gene therapeutic strategies in the clinic to treat genetic diseases raise hope to find alternative treatment options for patients chronically infected with HBV. PMID:25729471

  19. [Benign thyroid nodules: diagnostic and therapeutic approach].

    PubMed

    Durante, Cosimo; Cava, Francesco; Paciaroni, Alessandra; Filetti, Sebastiano

    2008-05-01

    In the last years an increase in thyroid nodules detection has been reported from several epidemiological studies. This trend is largely due to the routine use of diagnostic sonography procedures in clinical practice. Thyroid nodules, both palpable or not palpable, rarely turn out to be malignant. Fine-needle aspiration cytology (FNAc) plays a central role in establishing the nature of the nodule. Excluded the presence of malignant lesions, which are generally treated with surgery, physicians are faced with a variety of therapeutic options, and choosing the optimal approach can be a difficult task. These include a periodic follow-up alone without treatment, the iodine supplementation, the thyroid-hormone suppressive therapy, the radioiodine administration, the percutaneous ethanol injections, and the new technique of laser photocoagulation. In all cases, decisions on the management of benign thyroid nodules should always be based on clinical target and a careful analysis of benefits and risks to the patient. PMID:18581970

  20. Therapeutic approaches to the modulation of apoptosis.

    PubMed

    Murphy, Finbarr J; Seery, Liam T; Hayes, Ian

    2003-01-01

    The appreciation of the role of apoptosis in the vast majority of diseases affecting humans has revolutionized the discovery and development of drugs targeting inflammation and oncology. Novel therapeutic approaches to modulate disease by regulating apoptosis are currently being tested in preclinical and clinical settings. Enthusiasm for some of these therapies is reflected in the fact that they have received U.S. Food and Drug Administration approval in record time. Approaches include the traditional use of small molecules to target specific players in the apoptosis cascade. They also include radical new approaches such as using antisense molecules to inhibit production of the Bcl-2 protein or antibodies that ligate either death receptors, such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), or the MHC (HLA-DR), resulting in the initiation of apoptosis of target cells. Antibodies targeting cell-specific antigens are being used in conjunction with radioactive isotopes to deliver a more specific chemotherapy, particularly in the case of B-cell lymphomas. Other therapies target mitochondria, a key organelle in the apoptosis cascade. This diverse range of therapies includes photodynamic therapy, retinoic acid and arsenic trioxide, all of which induce apoptosis by generating reactive oxygen species. As our understanding of apoptosis increases, further opportunities will arise for tailor-made therapies that will result in improved clinical outcome without the devastating side effects of current interventions. PMID:14585079

  1. Novel therapeutic approaches in multiple system atrophy.

    PubMed

    Palma, Jose-Alberto; Kaufmann, Horacio

    2015-02-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  2. New therapeutic approaches in type 2 diabetes.

    PubMed

    Scheen, A J

    2008-01-01

    Type 2 diabetes is a progressive chronic disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. New molecules have recently been launched and many others are under clinical investigation. Besides classical sulfonylureas and glinides, new insulin secretagogues are now available, which target the incretin gut hormone glucagon-like peptide-1 (GLP-1). Indeed, oral incretin enhancers acting as antagonists of the enzyme DPP-4 (dipeptidylpeptidase-4), which inactivates natural GLP-1,and injectable incretin mimetics (exenatide) or analogues (liraglutide), which reproduce the actions of GLP-1 while resisting to DPP-4, represent new opportunities to stimulate insulin secretion, without increasing the risk of hypoglycaemia and weight gain. Among insulin sensitizers, metformin remains unequivocally the first drug of choice for the treatment of type 2 diabetes, whereas promising drugs as thiazolidinediones (glitazones) were recently challenged because of various safety issues. When insulin is required, insulin analogues, both short-acting and basal ones, may offer some advantages regarding better control of postprandial hyperglycaemia, reduced risk of hypoglycaemia and/or lower weight gain in patients with type 2 diabetes. Emphasis should be put on early detection and intensive management of type 2 diabetes, individualized glucose lowering treatments and goals, stepwise pharmacological strategy avoiding therapeutic inertia, and multiple cardiovascular risk--targeted approach. PMID:19170358

  3. Childhood sleep disorders: diagnostic and therapeutic approaches.

    PubMed

    Pearl, Phillip L

    2002-03-01

    Pediatric sleep physiology begins with development of the sleep/wake cycle, and the origins of active versus quiet sleep. The 24-hour circadian cycle becomes established at 3 to 6 months. Sleep disorders are rationally approached in pediatrics as age-related. Disorders during infancy commonly include mild, usually self-limited conditions such as sleep-onset association disorder, excessive nighttime feedings, and poor limit-setting. These require behavioral management to avoid long-term deleterious sleep habits. In contrast, other sleep disorders are more ominous, including sudden infant death syndrome (SIDS), central congenital hypoventilation syndrome, and sleep apnea. Childhood is generally the golden age of sleep, with brief latency, high efficiency, and easy awakening. Parasomnias, sometimes stage specific, are manifest here. Adolescents have sleep requirements similar to preteens, posing a challenge for them to adapt to school schedules and lifestyles. Narcolepsy, usually diagnosed in adolescence or early adulthood, is a lifelong sleep disorder that has led to the identification of the hypocretin/orexin neurotransmitter system. This will lead to enhanced understanding of what regulates stage rapid eye movement, and to novel therapeutic advances for hypersomnolence. PMID:11898482

  4. [A therapeutic approach towards chronic granulomatous disease].

    PubMed

    Kawai, Toshinao

    2014-01-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID) characterized by the inability of phagocytes to produce reactive oxygen intermediates (ROIs) due to a defect in the NADPH oxidase complex. Recent studies have revealed that ROIs are involved in inflammatory signaling in phagocytes, illuminating the underlying mechanisms of hyper-inflammation in CGD. CGD patients frequently suffer from CGD-associated bowel inflammation, granuloma, and life-threatening infections. Based on the discovery of the regulatory function of ROIs in the immune response, therapeutic methods for excessive inflammation focusing on inflammatory cytokines are being developed for CGD. Although hematopoietic stem cell (HSC) transplantation (HSCT) is a curative therapy for CGD, successful transplants greatly depend on HSC source selection and the degree of matching of potential donors. Gene therapy trials for PID have been performed on over 120 patients with no HLA identical donor for HSCT, and have demonstrated clinical benefits. Genotoxicity in HSC gene therapy trials has expanded our knowledge on the mechanisms of vector-associated clonal expansion of gene-modified cells, which will advance gene therapy development using self-inactivating retrovirus and lentivirus vectors. We will discuss the complications of HSCT for CGD. We will then outline the status of gene therapy approaches in the treatment of CGD. PMID:25748127

  5. Pediatric narcolepsy: clinical and therapeutical approaches.

    PubMed

    Michel, Lecendreux

    2013-01-01

    Narcolepsy occurs during childhood in combination with cataplexy in one-third of the subjects. Symptoms may develop rapidly over a few weeks or months, with excessive daytime sleepiness and cataplexy being the most dramatic and observable symptoms. It can be secondary to brain tumors or several rare diseases, but in most cases narcolepsy with or without cataplexy is a primary condition, better explained by the selective loss of hypocretin neurons in posterolateral hypothalamus. A specific HLA allele, HLA-DQB1*0602, is involved and the disease is thought to be autoimmune. Tribbles 2-specific antibodies have been identified. Recent medications have greatly improved the symptoms and wellbeing of young patients. However, these treatments are delivered off-label in the pediatric population. There is an absolute necessity for well-conducted clinical trials in order to improve treatment in children and adolescents with narcolepsy and to evaluate clinical efficacy and good tolerance of medications. Nonpharmacological approaches are certainly helpful and should be promoted systematically, especially in very young children. Narcolepsy of recent onset in children or adolescents should be considered a therapeutic emergency, even though immunotherapy is still controversial. PMID:23622291

  6. Novel Therapeutic Approaches in Multiple System Atrophy

    PubMed Central

    Palma, Jose-Alberto; Kaufmann, Horacio

    2014-01-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  7. [Therapeutic approaches in autism spectrum disorders].

    PubMed

    Ruggieri, Víctor L; Arberas, Claudia L

    2015-02-25

    Autistic spectrum disorders affect one out of every 68 persons, with a 4:1 dominance in males. Since they are dysfunctions rather than irreversible injuries to the central nervous system, which can be attributed to deficits in the neuronal networks and synaptogenesis and are modifiable thanks to the plasticity of the brain, starting therapy as early as possible is essential for more favourable progress. Very few treatments are backed by solid scientific evidence. We will analyse the therapeutic approaches oriented towards improving autism spectrum disorders which showed a clinical improvement that can be related to neurophysiological or functional changes in the central nervous system. We will classify the behavioural educational treatments and those in the research phase into a hierarchy, highlighting the neurogenetic entities with a high prevalence of autism, in which their pathophysiology and molecular base are known, that attempt to modify the consequences of those alterations by means of pharmacological agents. These entities include fragile X syndrome (GABAergic and metabotropic glutamate receptor inhibitors), tuberous sclerosis (mTOR inhibitors), Phelan-McDermid syndrome and Rett syndrome (insulin-like growth factor 1 inhibitors). Oxytocin, which has been shown to improve social cognition in persons with autism spectrum disorders, is analysed separately. PMID:25726823

  8. Therapeutic approaches to age-associated neurocognitive disorders

    PubMed Central

    O'Hara, Ruth; Derouesné, Christian; Fountoulakis, Konstantinos N.; Yesavage, Jerome A.

    2001-01-01

    The United Nations projects that the number of individuals with dementia in developed countries alone will be approximately 36,7 million by the year 2050. International recognition of the significant emotional and economic burden of Alzheimer's disease has been matched by a dramatic increase in the development of pharmacological and nonpharmacological approaches to this illness in the past decade. Changing demographics have underscored the necessity to develop similar approaches for the remediation of the cognitive impairment associated with more benign syndromes, such as mild cognitive impairment (MCI) and age-associated cognitive decline (AACD). The present article aims to provide an overview of the most current therapeutic approaches to age-associated neurocognitive disorders. Additionally, it discusses the conceptual and methodological issues that surround the design, implementation, and interpretation of such approaches. PMID:22033831

  9. Autoimmune hemolytic anemia: classification and therapeutic approaches.

    PubMed

    Sève, Pascal; Philippe, Pierre; Dufour, Jean-François; Broussolle, Christiane; Michel, Marc

    2008-12-01

    Autoimmune hemolytic anemia (AIHA) is a relatively uncommon cause of anemia. Classifications of AIHA include warm AIHA, cold AIHA (including mainly chronic cold agglutinin disease and paroxysmal cold hemoglobinuria), mixed-type AIHA and drug-induced AIHA. AIHA may also be further subdivided on the basis of etiology. Management of AIHA is based mainly on empirical data and on small, retrospective, uncontrolled studies. The therapeutic options for treating AIHA are increasing with monoclonal antibodies and, potentially, complement inhibitory drugs. Based on data available in the literature and our experience, we propose algorithms for the treatment of warm AIHA and cold agglutinin disease in adults. Therapeutic trials are needed in order to better stratify treatment, taking into account the promising efficacy of rituximab. PMID:21082924

  10. Therapeutic approaches for muscle wasting disorders.

    PubMed

    Lynch, Gordon S; Schertzer, Jonathan D; Ryall, James G

    2007-03-01

    Muscle wasting and weakness are common in many disease states and conditions including aging, cancer cachexia, sepsis, denervation, disuse, inactivity, burns, HIV-acquired immunodeficiency syndrome (AIDS), chronic kidney or heart failure, unloading/microgravity, and muscular dystrophies. Although the maintenance of muscle mass is generally regarded as a simple balance between protein synthesis and protein degradation, these mechanisms are not strictly independent, but in fact they are coordinated by a number of different and sometimes complementary signaling pathways. Clearer details are now emerging about these different molecular pathways and the extent to which these pathways contribute to the etiology of various muscle wasting disorders. Therapeutic strategies for attenuating muscle wasting and improving muscle function vary in efficacy. Exercise and nutritional interventions have merit for slowing the rate of muscle atrophy in some muscle wasting conditions, but in most cases they cannot halt or reverse the wasting process. Hormonal and/or other drug strategies that can target key steps in the molecular pathways that regulate protein synthesis and protein degradation are needed. This review describes the signaling pathways that maintain muscle mass and provides an overview of some of the major conditions where muscle wasting and weakness are indicated. The review provides details on some therapeutic strategies that could potentially attenuate muscle atrophy, promote muscle growth, and ultimately improve muscle function. The emphasis is on therapies that can increase muscle mass and improve functional outcomes that will ultimately lead to improvement in the quality of life for affected patients. PMID:17258813

  11. [Pathophysiology and Therapeutic Approach of Pulmonary Aspiration].

    PubMed

    Uchida, Kanji

    2016-01-01

    Pulmonary aspiration is one of the serious adverse events in general anesthesia. Aspiration induced lung injury varies according to the nature of the contents of aspirates (acid or small particles in gastrointestinal tract, bile acid), amount of aspirates, and host-defense status. Early inflammatory responses to acid and small particles from gastrointestinal contents are categorized as aspiration pneumonitis causing rapid respiratory deterioration with early restoration of lung injury within a couple of days. Late phase lung injury is usually "aspiration pneumonia" caused by bacteria colonized in the aspirates. Treatment mainstream is to support respiratory function until the lung resolves from injury. Extracorporeal membrane oxygenation is another promising therapeutic option for cases with severe lung damage to keep the "lung rest" during fulminant lung injury, avoiding further lung damage by injurious ventilation. Empirical administration of antibiotics covering wide spectrum followed by meticulous bacteriological studies to either de-escalate or discontinue antibiotics is crucial. PMID:27004380

  12. Nanotechnology based approaches in cancer therapeutics

    NASA Astrophysics Data System (ADS)

    Kumer Biswas, Amit; Reazul Islam, Md; Sadek Choudhury, Zahid; Mostafa, Asif; Fahim Kadir, Mohammad

    2014-12-01

    The current decades are marked not by the development of new molecules for the cure of various diseases but rather the development of new delivery methods for optimum treatment outcome. Nanomedicine is perhaps playing the biggest role in this concern. Nanomedicine offers numerous advantages over conventional drug delivery approaches and is particularly the hot topic in anticancer research. Nanoparticles (NPs) have many unique criteria that enable them to be incorporated in anticancer therapy. This topical review aims to look at the properties and various forms of NPs and their use in anticancer treatment, recent development of the process of identifying new delivery approaches as well as progress in clinical trials with these newer approaches. Although the outcome of cancer therapy can be increased using nanomedicine there are still many disadvantages of using this approach. We aim to discuss all these issues in this review.

  13. Emerging Therapeutic Approaches to Mitochondrial Diseases

    ERIC Educational Resources Information Center

    Wenz, Tina; Williams, Sion L.; Bacman, Sandra R.; Moraes, Carlos T.

    2010-01-01

    Mitochondrial diseases are very heterogeneous and can affect different tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to…

  14. Novel therapeutic approaches for pulmonary fibrosis

    PubMed Central

    Datta, Arnab; Scotton, Chris J; Chambers, Rachel C

    2011-01-01

    Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis – median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial–mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair – including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways – modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21265830

  15. [CARDIORENAL SYNDROME: DIAGNOSTIC AND THERAPEUTIC APPROACHES].

    PubMed

    Sens, Florence; Pouliquen, Éric; Lemoine, Sandrine; Bonnefoy-Cudraz, Éric; Juillard, Laurent

    2016-06-01

    Kidney dysfunction during congestive heart failure, although frequent, is often neglected. Yet, it represents a life-threatening condition, oven when the kidney dysfunction is moderate. The initial approach involvus strict application of recommendations, cardiologic and nephrologic joined management and close follow-up involving patient's general practitioner. Cases of true diuretics resistance are infrequent and late. Yet, it represents a significant turning point. Mortality is high, with a major individual unpredictability. A multidisciplinary approach is needed, which has to take into account patient's preferences. Several treatments may be discussed and are sometimes joined: cardiac transplantation, water and salt extraction (using ultrafiltration, hemodialysis or peritoneal dialysis), vasoconstrictive drugs, ventricular assistance devices and palliative care. Water and salt extraction techniques seem to space out hospitalizations and to provide symptomatic relief even though no benefit on patient survival has been demonstrated to date. The need for randomized clinical trials is mandatory. PMID:27538313

  16. Affinity approaches in RNAi-based therapeutics purification.

    PubMed

    Pereira, Patrícia; Queiroz, João A; Figueiras, Ana; Sousa, Fani

    2016-05-15

    The recent investigation on RNA interference (RNAi) related mechanisms and applications led to an increased awareness of the importance of RNA in biology. Nowadays, RNAi-based technology has emerged as a potentially powerful tool for silencing gene expression, being exploited to develop new therapeutics for treating a vast number of human disease conditions, as it is expected that this technology can be translated onto clinical applications in a near future. This approach makes use of a large number of small (namely short interfering RNAs, microRNAs and PIWI-interacting RNAs) and long non-coding RNAs (ncRNAs), which are likely to have a crucial role as the next generation therapeutics. The commercial and biomedical interest in these RNAi-based therapy applications have fostered the need to develop innovative procedures to easily and efficiently purify RNA, aiming to obtain the final product with high purity degree, good quality and biological activity. Recently, affinity chromatography has been applied to ncRNAs purification, in view of the high specificity. Therefore, this article intends to review the biogenesis pathways of regulatory ncRNAs and also to discuss the most significant and recent developments as well as applications of affinity chromatography in the challenging task of purifying ncRNAs. In addition, the importance of affinity chromatography in ncRNAs purification is addressed and prospects for what is forthcoming are presented. PMID:26830537

  17. A therapeutic approach for senile dementias: neuroangiogenesis.

    PubMed

    Ambrose, Charles T

    2015-01-01

    Alzheimer's disease (AD) and related senile dementias (SDs) represent a growing medical and economic crisis in this country. Apart from cautioning persons about risk factors, no practical, effective therapy is currently available. Much of the recent research in AD has been based on the amyloid cascade theory. Another approach assumes a vascular basis for SDs. This paper presents evidence from a score of studies that cerebral capillary density (CCD) declines during old age in animals and people as well as in AD. Neuroangiogenic (NAG) factors initiate and maintain capillaries in the brain. Thus a waning level of these factors and the ensuing declining CCD would lead to local areas of reduced oxygen and glucose and result in impaired synaptic and neuronal function. The NAG hypothesis developed here proposes that the age-linked decline in CCD is a terminal condition in SDs, including many cases of AD. This age-linked decline is independent of any other of the various pathologies proposed as causing AD and listed in Table 1. Waning NAG factors would render the SDs a deficiency condition, somewhat like falling androgen levels in aging males. A logical corollary of this hypothesis is that chronic replacement therapy with recombinant forms of NAG factors may arrest the age-linked decline in CCD and prevent further loss of memory and mental deterioration. A transnasal route of therapy seems the most practical one for general use in the large aging populations. PMID:25061056

  18. Chemical approaches to stem cell biology and therapeutics

    PubMed Central

    Li, Wenlin; Li, Ke; Wei, Wanguo; Ding, Sheng

    2013-01-01

    SUMMARY Small molecules that modulate stem cell fate and function offer significant opportunities that will allow the full realization of the therapeutic potential of stem cells. Rational design and screening for small molecules have identified useful compounds to probe fundamental mechanisms of stem cell self-renewal, differentiation, and reprogramming, and have facilitated the development of cell-based therapies and therapeutic drugs targeting endogenous stem and progenitor cells for repair and regeneration. Here, we will discuss recent scientific and therapeutic progress, as well as new perspectives and future challenges for using chemical approaches in stem cell biology and regenerative medicine. PMID:24012368

  19. New Therapeutic Approaches in Diabetic Retinopathy.

    PubMed

    Vaziri, Kamyar; Schwartz, Stephen G; Relhan, Nidhi; Kishor, Krishna S; Flynn, Harry W

    2015-01-01

    Diabetic retinopathy is a common microvascular complication of diabetes mellitus. It affects a substantial proportion of US adults over age 40. The condition is a leading cause of visual loss. Much attention has been given to expanding the role of current treatments along with investigating various novel therapies and drug delivery methods. In the treatment of diabetic macular edema (DME), intravitreal pharmacotherapies, especially anti-vascular endothelial growth factor (anti-VEGF) agents, have gained popularity. Currently, anti-VEGF agents are often used as first-line agents in center-involved DME, with recent data suggesting that among these agents, aflibercept leads to better visual outcomes in patients with worse baseline visual acuities. While photocoagulation remains the standard treatment for proliferative diabetic retinopathy (PDR), recent FDA approvals of ranibizumab and aflibercept in the management of diabetic retinopathy associated with DME may suggest a potential for pharmacologic treatments of PDR as well. Novel therapies, including small interfering RNAs, chemokines, kallikrein-kinin inhibitors, and various anti-angiogenic agents, are currently being evaluated for the management of diabetic retinopathy and DME. In addition to these strategies, novel drug delivery methods such as sustained-release implants and refillable reservoir implants are either under active evaluation or have recently gained FDA approval. This review provides an update on the novel developments in the treatment of diabetic retinopathy. PMID:26676668

  20. Therapeutic approaches to chronic hyperuricemia and gout.

    PubMed

    Grassi, Davide; Pontremoli, Roberto; Bocale, Raffaella; Ferri, Claudio; Desideri, Giovambattista

    2014-12-01

    Gout is currently one of the most common causes of inflammatory arthritis in most industrialised countries. Apart from its high frequency, gout is associated with disability, poor quality of life and increased mortality and therefore represents an ever increasing public health concern. Substantial experimental and epidemiological evidence exists supporting the link between elevated levels of serum uric acid and several comorbidities including cardiovascular and kidney diseases. The cornerstone of effective gout management is long-term serum urate lowering below saturation concentrations (<6 mg/dL or <360 μmol/L) in order to promote crystal dissolution and prevent monosodium urate crystals formation. The management of gout includes not only pharmacological approaches, but also a number of nonpharmacologic interventions aiming at lessening attack risk, lowering uric acid levels and promoting general health while preventing the development of comorbidities. It is of great address whether urate lowering strategies can also lower cardiovascular risk and some preliminary studies in both animal and human subjects suggest that they might. Patient education and appropriate lifestyle advice are core aspects of management of hyperuricemia and gout. The two xanthine oxidase inhibitors currently available are effective as long-term urate lowering therapy although the greater efficacy and good tolerability of febuxostat as urate lowering agent has to be adequately considered especially when the reduction of serum uric acid levels to achieve the target is particularly ambitious and/or the presence of comorbidities increases the risk of adverse effects. Associated comorbidities and cardiovascular risk factors should be also addressed as an important part of the management of chronic hyperuricemia and gout. PMID:24696068

  1. Herpes zoster: diagnostic, therapeutic, and preventive approaches.

    PubMed

    Bader, Mazen S

    2013-09-01

    Herpes zoster (Hz), which generally presents as a localized, painful cutaneous eruption, is a common clinical problem, particularly among adults ≥ 50 years of age and immunocompromised patients. The diagnosis of Hz is mainly made clinically, except in patients with atypical manifestations or certain complications, such as central nervous system involvement, in which laboratory virologic testing is required. In addition to having a higher mortality rate, immunocompromised individuals have atypical and severe clinical findings and are at greater risk for complications and recurrence of Hz. Treatment of Hz includes the use of antiviral agents, analgesics for control of acute zoster pain, good skin care for healing, and prevention of secondary bacterial infection. Antiviral agents, preferably valacyclovir or famciclovir, should be started within 72 hours of onset to reduce the severity of the infection, the duration of the eruptive phase, and the intensity of acute pain. Herpes zoster has been associated with several complications, of which post-herpetic neuralgia (PHN) is the most common and debilitating. Varicella-zoster virus vaccine and early treatment with either famciclovir or valacyclovir are the only measures proven to prevent PHN. The options for treating PHN include topical agents, such as lidocaine patches, and systemic agents, such as the anticonvulsants gabapentin and pregabalin. Measures for preventing Hz include infection control through routine hand hygiene and appropriate use of isolation precautions and personal protective equipment; immunoglobulins, such as the varicella-zoster virus immunoglobulin and vaccine; and antiviral agents. The zoster vaccine has been shown to be effective in reducing the incidence of Hz and PHN. The vaccine is recommended for all individuals aged ≥ 60 years who have no contraindications, including individuals who report a previous episode of Hz. PMID:24113666

  2. Therapeutic Approaches in the Stimulation of the Coronary Collateral Circulation

    PubMed Central

    Degen, Achim; Millenaar, Dominic; Schirmer, Stephan H.

    2014-01-01

    Arteriogenesis as a way to restore blood flow after arterial occlusion has been under investigation for the treatment of coronary artery disease (CAD) for decades. Therapeutic approaches so far have included delivery of cytokines and growth factors as well as mechanical stimulation such as external counterpulsation. As knowledge on the mechanisms of arteriogenesis expanded, new therapeutic approaches have emerged. This review summarizes recent attempts to stimulate the growth of the coronary vasculature and discusses their potential in clinical application. This article also delivers an overview of current studies and trials on coronary arteriogenesis. PMID:23721076

  3. Therapeutic Recreation in the Community: An Inclusive Approach. Second Edition

    ERIC Educational Resources Information Center

    Carter, Marcia Jean; LeConey, Stephen P.

    2004-01-01

    The second edition of Therapeutic Recreation in the Community: An Inclusive Approach reflects the changing and evolving nature of recreation and health care services. A number of social, economic, and political directives and technological advancements have fostered recreation in the community for all individuals. Due in part to a rising awareness…

  4. Smoking and atherosclerosis: mechanisms of disease and new therapeutic approaches.

    PubMed

    Siasos, Gerasimos; Tsigkou, Vasiliki; Kokkou, Eleni; Oikonomou, Evangelos; Vavuranakis, Manolis; Vlachopoulos, Charalambos; Verveniotis, Alexis; Limperi, Maria; Genimata, Vasiliki; Papavassiliou, Athanasios G; Stefanadis, Christodoulos; Tousoulis, Dimitris

    2014-01-01

    It has been clear that at least 1 billion adults worldwide are smokers and at least 700 million children are passive smokers at home. Smoking exerts a detrimental effect to many organ systems and is responsible for illnesses such as lung cancer, pneumonia, chronic obstructive pulmonary disease, cancer of head and neck, cancer of the urinary and gastrointestinal tract, periodontal disease, cataract and arthritis. Additionally, smoking is an important modifiable risk factor for the development of cardiovascular disease such as coronary artery disease, stable angina, acute coronary syndromes, sudden death, stroke, peripheral vascular disease, congestive heart failure, erectile dysfunction and aortic aneurysms via initiation and progression of atherosclerosis. A variety of studies has proved that cigarette smoking induces oxidative stress, vascular inflammation, platelet coagulation, vascular dysfunction and impairs serum lipid pro-file in both current and chronic smokers, active and passive smokers and results in detrimental effects on the cardiovascular system. The aim of this review is to depict the physical and biochemical properties of cigarette smoke and, furthermore, elucidate the main pathophysiological mechanisms of cigarette-induced atherosclerosis and overview the new therapeutic approaches for smoking cessation and augmentation of cardiovascular health. PMID:25174928

  5. Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy.

    PubMed

    Klein, A F; Dastidar, S; Furling, D; Chuah, M K

    2015-01-01

    Myotonic Dystrophy (DM), one of the most common neuromuscular disorders in adults, comprises two genetically distinct forms triggered by unstable expanded repeats in non-coding regions. The most common DM1 is caused by expanded CTG repeats in the 3'UTR of the DMPK gene, whereas DM2 is due to large expanded CCTG repeats in the first intron of the CNBP gene. Both mutations induce a pathogenic RNA gain-of-function mechanism. Mutant RNAs containing CUG or CCUG expanded repeats, which are retained in the nuclei as aggregates alter activities of alternative splicing regulators such as MBNL proteins and CELF1. As a consequence, alternative splicing misregulations of several pre-mRNAs are associated with DM clinical symptoms. Currently, there is no available cure for this dominant neuromuscular disease. Nevertheless, promising therapeutic strategies have been developed in the last decade. Preclinical progress in DM research prompted the first DM1 clinical trial based on antisense oligonucleotides promoting a RNase-H-mediated degradation of the expanded CUG transcripts. The ongoing Phase 1/2a clinical trial will hopefully give further insights into the quest to find a bona fide cure for DM1. In this review, we will provide an overview of the different strategies that were developed to neutralize the RNA toxicity in DM1. Different approaches including antisense oligonucleotide technologies, gene therapies or small molecules have been tested and validated in cellular and animal models. Remaining challenges and additional avenues to explore will be discussed. PMID:26122101

  6. Hyperuricaemia with deposition: latest evidence and therapeutic approach.

    PubMed

    Perez-Ruiz, Fernando; Marimon, Estibaliz; Chinchilla, Sandra P

    2015-12-01

    This article reviews recent evidence on urate deposition and the opportunity for a therapeutic approach. We reviewed Pubmed 2013-2015 literature using the search terms 'deposition' with 'hyperuricaemia', 'gout', 'ultrasonography', 'DECT' (dual-energy computed tomography), 'radiography', 'CT'(computed tomography), 'MRI' (magnetic resonance imaging), or 'cardiovascular', in addition to a digital bibliographic library compiled by the authors with 2072 papers on hyperuricaemia and gout. Relevant papers on the topic were selected. Recent evidence, mostly based on imaging studies, showed a continuum from hyperuricaemia to deposition and clinical manifestations. Chronic inflammation and structural damage may be present even in asymptomatic patients with crystal-proved deposition. The impact of early intervention in patients with asymptomatic deposition either on vascular outcomes or further structural joint damage has not been demonstrated yet. In conclusion, a worldwide definition of gout is still lacking, stages from hyperuricaemia to clinical gout not being definitively defined. Although there is increasing interest on the impact of early deposits on joint damage and cardiovascular outcomes, robust evidence is still lacking to fully support interventions. PMID:26622324

  7. Hyperuricaemia with deposition: latest evidence and therapeutic approach

    PubMed Central

    Perez-Ruiz, Fernando; Marimon, Estibaliz; Chinchilla, Sandra P.

    2015-01-01

    This article reviews recent evidence on urate deposition and the opportunity for a therapeutic approach. We reviewed Pubmed 2013–2015 literature using the search terms ‘deposition’ with ‘hyperuricaemia’, ‘gout’, ‘ultrasonography’, ‘DECT’ (dual-energy computed tomography), ‘radiography’, ‘CT’(computed tomography), ‘MRI’ (magnetic resonance imaging), or ‘cardiovascular’, in addition to a digital bibliographic library compiled by the authors with 2072 papers on hyperuricaemia and gout. Relevant papers on the topic were selected. Recent evidence, mostly based on imaging studies, showed a continuum from hyperuricaemia to deposition and clinical manifestations. Chronic inflammation and structural damage may be present even in asymptomatic patients with crystal-proved deposition. The impact of early intervention in patients with asymptomatic deposition either on vascular outcomes or further structural joint damage has not been demonstrated yet. In conclusion, a worldwide definition of gout is still lacking, stages from hyperuricaemia to clinical gout not being definitively defined. Although there is increasing interest on the impact of early deposits on joint damage and cardiovascular outcomes, robust evidence is still lacking to fully support interventions. PMID:26622324

  8. Therapeutic approach to IgG4-related disease

    PubMed Central

    Brito-Zerón, Pilar; Kostov, Belchin; Bosch, Xavier; Acar-Denizli, Nihan; Ramos-Casals, Manuel; Stone, John H.

    2016-01-01

    Abstract To review the reported evidence on the therapeutic management of IgG4-related disease (IgG4-RD) in clinical practice. A systematic search of the literature was conducted. The primary outcome measured was the rate of efficacy of first-line therapeutic approaches. Secondary outcomes measured included the rate of disease relapse, the outcome of untreated patients, the rate of patients without drug therapy at the end of follow-up, the rate of side effects, and mortality. The MOOSE, AHRQ, STROBE, and GRACE recommendations/statements were followed. The results of the systematic search strategy yielded 62 studies that included a total of 3034 patients. Complete information about first-line therapeutic regimens was detailed in 1952 patients, including glucocorticoid-based regimens in 1437 (74%), drug-free regimens in 213 (11%), and other therapies in 38 (2%). No therapy (wait and see management) was reported in 264 (13%) patients. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses treated with glucocorticoids, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases. Wide heterogeneity was observed with respect to the first-line therapeutic approaches used for the different organ-specific disease subsets, including significant differences in the mean dose of glucocorticoids used. Nearly 70% of reported IgG4-RD patients are treated with oral glucocorticoids in monotherapy. However, the therapeutic management is heavily influenced by geographical, epidemiological

  9. MicroRNA Targeted Therapeutic Approach for Pancreatic Cancer

    PubMed Central

    Li, Yiwei; Sarkar, Fazlul H.

    2016-01-01

    Pancreatic cancer remains the fourth leading cause of cancer-related death in the US and is expected to be the second leading cause of cancer-related death by 2030. Therefore, it is important to better understand the molecular pathogenesis, phenotypes and features of pancreatic cancer in order to design novel molecularly targeted therapies for achieving better therapeutic outcome of patients with pancreatic cancer. Recently, the roles of microRNAs (miRNAs) in the development and progression of pancreatic cancer became a hot topic in the scientific community of pancreatic cancer research. By conducting miRNA expression profiling, the aberrant expression of miRNAs was revealed in the serum and in cancer tissues from patients with pancreatic cancer. These aberrantly expressed miRNAs are critically correlated with the disease stage, drug resistance, and survival of pancreatic cancer patients. Hence, targeting these tiny molecules, the specific miRNAs, could provide an efficient and optimal approach in the therapy of pancreatic cancer. Indeed, the pre-clinical and in vivo experiments showed that nanoparticle delivery of synthetic oligonucleotides or treatment with natural agents could be useful to modulate the expression of miRNAs and thereby inhibit pancreatic cancer growth and progression, suggesting that targeting miRNAs combined with conventional anti-cancer therapeutics could be a novel therapeutic strategy for increasing drug sensitivity and achieving better therapeutic outcome of patients diagnosed with pancreatic cancer. PMID:26929739

  10. Therapeutic approaches to preventing cell death in Huntington disease

    PubMed Central

    Kaplan, Anna; Stockwell, Brent R.

    2012-01-01

    Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors—fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. PMID:22967354

  11. Therapeutic approaches to preventing cell death in Huntington disease.

    PubMed

    Kaplan, Anna; Stockwell, Brent R

    2012-12-01

    Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. PMID:22967354

  12. Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches.

    PubMed

    Tousoulis, Dimitris; Georgakis, Marios K; Oikonomou, Evangelos; Papageorgiou, Nikolaos; Zaromitidou, Marina; Latsios, George; Papaioannou, Spyridon; Siasos, Gerasimos

    2015-01-01

    Asymmetric dimethylarginine (ADMA) is a competitive endogenous inhibitor of nitric oxide synthase with a key role in the pathophysiology of endothelial dysfunction, in the progression of atherosclerosis and in cardiovascular diseases. Statins, renin-angiotensin-aldosterone system inhibitors, blood glucose lowering agents, insulin sensitizers, beta-blockers, estrogen replacement therapy, antioxidants, complex B vitamins, L-arginine and acetylsalicylic acid have been evaluated for their ability to reduce ADMA levels or inhibit its actions. Despite the major beneficial effects of these agents in cardiovascular disease, research has shown that their favorable actions are only partially mediated by reducing ADMA levels or by bypassing its effect in nitric oxide synthesis. Novel therapeutic approaches targeting selectively ADMA are encouraging, but have only been tested in vitro or in animal studies and further research is needed in order to conclude on how therapeutic strategies modulating ADMA actions can affect atherosclerosis progression and cardiovascular diseases. PMID:26112145

  13. siRNA Genome Screening Approaches to Therapeutic Drug Repositioning

    PubMed Central

    Perwitasari, Olivia; Bakre, Abhijeet; Tompkins, S. Mark; Tripp, Ralph A.

    2013-01-01

    Bridging high-throughput screening (HTS) with RNA interference (RNAi) has allowed for rapid discovery of the molecular basis of many diseases, and identification of potential pathways for developing safe and effective treatments. These features have identified new host gene targets for existing drugs paving the pathway for therapeutic drug repositioning. Using RNAi to discover and help validate new drug targets has also provided a means to filter and prioritize promising therapeutics. This review summarizes these approaches across a spectrum of methods and targets in the host response to pathogens. Particular attention is given to the utility of drug repurposing utilizing the promiscuous nature of some drugs that affect multiple molecules or pathways, and how these biological pathways can be targeted to regulate disease outcome. PMID:24275945

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

    SciTech Connect

    Not Available

    1983-10-01

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

  15. New therapeutic approaches for treatment of tularaemia: a review

    PubMed Central

    Boisset, Sandrine; Caspar, Yvan; Sutera, Vivien; Maurin, Max

    2014-01-01

    Antibiotic treatment of tularaemia is based on a few drugs, including the fluoroquinolones (e.g., ciprofloxacin), the tetracyclines (e.g., doxycycline), and the aminoglycosides (streptomycin and gentamicin). Because no effective and safe vaccine is currently available, tularaemia prophylaxis following proven exposure to F. tularensis also relies on administration of antibiotics. A number of reasons make it necessary to search for new therapeutic alternatives: the potential toxicity of first-line drugs, especially in children and pregnant women; a high rate of treatment relapses and failures, especially for severe and/or suppurated forms of the disease; and the possible use of antibiotic-resistant strains in the context of a biological threat. This review presents novel therapeutic approaches that have been explored in recent years to improve tularaemia patients' management and prognosis. These new strategies have been evaluated in vitro, in axenic media and cell culture systems and/or in animal models. First, the activities of newly available antibiotic compounds were evaluated against F. tularensis, including tigecycline (a glycylcycline), ketolides (telithromycin and cethromycin), and fluoroquinolones (moxifloxacin, gatifloxacin, trovafloxacin and grepafloxacin). The liposome delivery of some antibiotics was evaluated. The effect of antimicrobial peptides against F. tularensis was also considered. Other drugs were evaluated for their ability to suppress the intracellular multiplication of F. tularensis. The effects of the modulation of the innate immune response (especially via TLR receptors) on the course of F. tularensis infection was characterized. Another approach was the administration of specific antibodies to induce passive resistance to F. tularensis infection. All of these studies highlight the need to develop new therapeutic strategies to improve the management of patients with tularaemia. Many possibilities exist, some unexplored. Moreover, it is

  16. Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

    PubMed Central

    Farmer, Kevin L.; Li, Chengyuan

    2012-01-01

    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes that is associated with axonal atrophy, demyelination, blunted regenerative potential, and loss of peripheral nerve fibers. The development and progression of DPN is due in large part to hyperglycemia but is also affected by insulin deficiency and dyslipidemia. Although numerous biochemical mechanisms contribute to DPN, increased oxidative/nitrosative stress and mitochondrial dysfunction seem intimately associated with nerve dysfunction and diminished regenerative capacity. Despite advances in understanding the etiology of DPN, few approved therapies exist for the pharmacological management of painful or insensate DPN. Therefore, identifying novel therapeutic strategies remains paramount. Because DPN does not develop with either temporal or biochemical uniformity, its therapeutic management may benefit from a multifaceted approach that inhibits pathogenic mechanisms, manages inflammation, and increases cytoprotective responses. Finally, exercise has long been recognized as a part of the therapeutic management of diabetes, and exercise can delay and/or prevent the development of painful DPN. This review presents an overview of existing therapies that target both causal and symptomatic features of DPN and discusses the role of up-regulating cytoprotective pathways via modulating molecular chaperones. Overall, it may be unrealistic to expect that a single pharmacologic entity will suffice to ameliorate the multiple symptoms of human DPN. Thus, combinatorial therapies that target causal mechanisms and enhance endogenous reparative capacity may enhance nerve function and improve regeneration in DPN if they converge to decrease oxidative stress, improve mitochondrial bioenergetics, and increase response to trophic factors. PMID:22885705

  17. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension.

    PubMed

    Kim, Jun-Dae; Lee, Aram; Choi, Jihea; Park, Youngsook; Kang, Hyesoo; Chang, Woochul; Lee, Myeong-Sok; Kim, Jongmin

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID:26228095

  18. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension

    PubMed Central

    Kim, Jun-Dae; Lee, Aram; Choi, Jihea; Park, Youngsook; Kang, Hyesoo; Chang, Woochul; Lee, Myeong-Sok; Kim, Jongmin

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID:26228095

  19. Understanding Neuropathic Corneal Pain-Gaps and Current Therapeutic Approaches.

    PubMed

    Goyal, Sunali; Hamrah, Pedram

    2016-01-01

    The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain. PMID:26959131

  20. Immunologic therapeutic approaches in the management of food allergy.

    PubMed

    Wang, Julie; Sicherer, Scott H

    2009-05-01

    Food allergy affects up to 6% of children and 3-4% of adults in Westernized countries, and is the most common cause of outpatient anaphylaxis in most studies. The mainstay of treatment is strict avoidance of the offending allergens and education regarding the use of emergency medication in cases of accidental ingestions or exposures. While these approaches are generally effective, there are no definitive treatments that cure or provide long-term remission from food allergy. However, with recent advances in characterizing food allergens and understanding humoral and cellular immune responses in food allergy, several therapeutic strategies are being investigated. Potential treatments include allergen-specific immunotherapy as well as allergen-nonspecific approaches to downregulate the overall allergic response in food-allergic individuals. PMID:20477008

  1. Neprilysin gene transfer: A promising therapeutic approach for Alzheimer's disease.

    PubMed

    Li, Yuanli; Wang, Junqing; Zhang, Shenghao; Liu, Zhaohui

    2015-09-01

    Alzheimer's disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β (Aβ) in the neuropil and around blood vessels, and formation of neurofibrillary tangles. Aβ accumulation is considered the major pathological change in AD progression. In recent years, several therapeutic strategies for treating AD have focused on reducing the Aβ burden in the brain. Among these approaches, the expression of Aβ-degrading enzymes in the brain has been effective but, so far, impractical for treating patients. Neprilysin (NEP), the most prominent of the Aβ-degrading enzymes in vivo, has been successfully delivered intracranially by viral vectors and is a promising therapeutic approach for reducing Aβ accumulation and treating AD. However, some challenges are associated with the use of viral and nonviral vectors, including secondary toxicity, activation of the immune response, and low efficiency. Therefore, safe and efficient NEP delivery systems that could avoid the viral problems with minor injury and high transfection efficiency are required to deliver AD medical applications. This Mini-Review summarizes NEP gene transfer technologies that use viral and nonviral vectors and discusses the rationale and benefits of these delivery systems for AD treatment trials, providing a reference for basic and clinical studies on AD. PMID:26096375

  2. Cancer Terminator Viruses and Approaches for Enhancing Therapeutic Outcomes

    PubMed Central

    Das, Swadesh K.; Sarkar, Siddik; Dash, Rupesh; Dent, Paul; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B.

    2015-01-01

    No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy. PMID:23021240

  3. Growth hormone treatment in pediatric burns: a safe therapeutic approach.

    PubMed Central

    Ramirez, R J; Wolf, S E; Barrow, R E; Herndon, D N

    1998-01-01

    OBJECTIVE: To determine the safety and efficacy of recombinant human growth hormone (rhGH) in the treatment of children who are severely burned. SUMMARY BACKGROUND DATA: During the last decade, we have used recombinant human growth hormone (rhGH; 0.2 mg/kg/day s.q.) to successfully treat 130 children with more than 40% total body surface area (TBSA) burns to enhance wound healing and decrease protein loss. A significant increase in the mortality of adult patients in the intensive care unit who were given rhGH has recently been reported in two large European trials which questions the therapeutic safety of rhGH. METHODS: The records of 263 children who were burned were reviewed. Patients receiving either rhGH at 0.2 mg/kg/day subcutaneously as part of a randomized clinical trial (n = 48) or therapeutically (n = 82) were compared with randomized placebo-administered controls (n = 54), contiguous matched controls (n = 48), and matched patients admitted after August 1997, after which no patients were treated with rhGH (n = 31). Morbidity and mortality, which might be altered by rhGH therapy, were considered with specific attention to organ function or failure, infection, hemodynamics, and calcium, phosphorous, and albumin balance. RESULTS: A 2% mortality was observed in both rhGH and saline placebo groups in the controlled studies, with no differences in septic complications, organ dysfunction, or heart rate pressure product identified. In addition, no difference in mortality could be shown for those given rhGH therapeutically versus their controls. No patient deaths were attributed to rhGH in autopsies reviewed by observers blinded to treatment. Hyperglycemic episodes and exogenous insulin requirements were higher among rhGH recipients, whereas exogenous albumin requirements and the development of hypocalcemia was reduced. CONCLUSIONS: Data indicate that rhGH used in the treatment of children who were severely burned is safe and efficacious. PMID:9790334

  4. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  5. Immunopathogenesis and therapeutic approaches in pediatric celiac disease.

    PubMed

    Agarwal, Shreya; Kovilam, Oormila; Zach, Terence L; Agrawal, Devendra K

    2016-08-01

    Celiac Disease is an autoimmune enteropathy with increasing incidence worldwide in both adults and children. It occurs as an inflammatory condition with destruction of the normal architecture of villi on consumption of gluten and related protein products found in wheat, barley and rye. However, the exact pathogenesis is not yet fully understood. A gluten-free diet remains the main modality of therapy to date. While some patients continue to have symptoms even on a gluten-free diet, adherence to this diet is also difficult, especially for the children. Hence, there is continued interest in novel methods of therapy and the current research focus is on the promising novel non-dietary modalities of treatment. Here, we critically reviewed the existing literature regarding the pathogenesis of celiac disease in children including the role of in-utero exposure leading to neonatal and infant sensitization and its application for the development of new therapeutic approaches for these patients. PMID:26999328

  6. Novel therapeutic approaches targeting matrix metalloproteinases in cardiovascular disease.

    PubMed

    Briasoulis, Alexandros; Tousoulis, Dimitris; Papageorgiou, Nikolaos; Kampoli, Anna-Maria; Androulakis, Emmanuel; Antoniades, Charalambos; Tsiamis, Eleftherios; Latsios, George; Stefanadis, Christodoulos

    2012-01-01

    Matrix metalloproteinases (MMPs), are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in atherosclerotic plaque development, coronary artery disease and heart failure. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression, MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review discusses pharmacological approaches to MMP inhibition. PMID:22519451

  7. Control of Bovine Mastitis: Old and Recent Therapeutic Approaches.

    PubMed

    Gomes, Fernanda; Henriques, Mariana

    2016-04-01

    Mastitis is defined as the inflammatory response resulting of the infection of the udder tissue and it is reported in numerous species, namely in domestic dairy animals. This pathology is the most frequent disease of dairy cattle and can be potentially fatal. Mastitis is an economically important pathology associated with reduced milk production, changes in milk composition and quality, being considered one of the most costly to dairy industry. Therefore, the majority of research in the field has focused on control of bovine mastitis and many efforts are being made for the development of new and effective anti-mastitis drugs. Antibiotic treatment is an established component of mastitis control programs; however, the continuous search for new therapeutic alternatives, effective in the control and treatment of bovine mastitis, is urgent. This review will provide an overview of some conventional and emerging approaches in the management of bovine mastitis' infections. PMID:26687332

  8. Fetal stem cells and skeletal muscle regeneration: a therapeutic approach.

    PubMed

    Pozzobon, Michela; Franzin, Chiara; Piccoli, Martina; De Coppi, Paolo

    2014-01-01

    More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle-specific stem cells, namely satellite cells. Muscle diseases, in particular chronic degenerative states of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continuous cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is no definitive cure in particular for genetic muscle disease. Keeping this in mind, in this article, we will give special consideration to muscle diseases and the use of fetal derived stem cells as a new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immune-modulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies. PMID:25221507

  9. Suppression of Premature Termination Codons as a Therapeutic Approach

    PubMed Central

    Keeling, Kim M.; Wang, Dan; Conard, Sara E.; Bedwell, David M.

    2012-01-01

    In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach. PMID:22672057

  10. Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches

    PubMed Central

    Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D.

    2015-01-01

    The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis. PMID:26306443

  11. Therapeutic approaches to diabetic nephropathy--beyond the RAS.

    PubMed

    Fernandez-Fernandez, Beatriz; Ortiz, Alberto; Gomez-Guerrero, Carmen; Egido, Jesus

    2014-06-01

    Despite improvements in glycaemic and blood pressure control, and the efficacy of renin-angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway-further research into the potential nephroprotective effects of novel glucose-lowering agents is required. PMID:24802062

  12. Non-genetic therapeutic approaches to Canavan disease.

    PubMed

    Roscoe, Rebecca B; Elliott, Christina; Zarros, Apostolos; Baillie, George S

    2016-07-15

    Canavan disease (CD) is a rare leukodystrophy characterized by diffuse spongiform white matter degeneration, dysmyelination and intramyelinic oedema with consequent impairment of psychomotor development and early death. The molecular cause of CD has been identified as being mutations of the gene encoding the enzyme aspartoacylase (ASPA) leading to its functional deficiency. The physiological role of ASPA is to hydrolyse N-acetyl-l-aspartic acid (NAA), producing l-aspartic acid and acetate; as a result, its deficiency leads to abnormally high central nervous system NAA levels. The aim of this article is to review what is currently known regarding the aetiopathogenesis and treatment of CD, with emphasis on the non-genetic therapeutic strategies, both at an experimental and a clinical level, by highlighting: (a) major related hypotheses, (b) the results of the available experimental simulatory approaches, as well as (c) the relevance of the so far examined markers of CD neuropathology. The potential and the limitations of the current non-genetic neuroprotective approaches to the treatment of CD are particularly discussed in the current article, in a context that could be used to direct future experimental and (eventually) clinical work in the field. PMID:27288788

  13. Neoplastic Meningitis from Solid Tumors: New Diagnostic and Therapeutic Approaches

    PubMed Central

    Zustovich, Fable; Farina, Patrizia; Della Puppa, Alessandro; Manara, Renzo; Cecchin, Diego; Brunello, Antonella; Cappetta, Alessandro; Zagonel, Vittorina

    2011-01-01

    Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%–15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography–computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches. PMID:21795431

  14. A Novel Approach for Evaluating Carbamate Mixtures for Dose Additivity

    EPA Science Inventory

    Two mathematical approaches were used to test the hypothesis ofdose-addition for a binary and a seven-chemical mixture ofN-methyl carbamates, toxicologically similar chemicals that inhibit cholinesterase (ChE). In the more novel approach, mixture data were not included in the ana...

  15. [Molecular pathogenesis and therapeutic approach of GM2 gangliosidosis].

    PubMed

    Tsuji, Daisuke

    2013-01-01

    Tay-Sachs and Sandhoff diseases (GM2 gangliosidoses) are autosomal recessive lysosomal storage diseases caused by gene mutations in HEXA and HEXB, each encoding human lysosomal β-hexosaminidase α-subunits and β-subunits, respectively. In Tay-Sachs disease, excessive accumulation of GM2 ganglioside (GM2), mainly in the central nervous system, is caused by a deficiency of the HexA isozyme (αβ heterodimer), resulting in progressive neurologic disorders. In Sandhoff disease, combined deficiencies of HexA and HexB (ββ homodimer) cause not only the accumulation of GM2 but also of oligosaccharides carrying terminal N-acetylhexosamine residues (GlcNAc-oligosaccharides), resulting in systemic manifestations including hepatosplenomegaly as well as neurologic symptoms. Hence there is little clinically effective treatment for these GM2 gangliosidoses. Recent studies on the molecular pathogenesis in Sandhoff disease patients and disease model mice have shown the involvement of microglial activation and chemokine induction in neuroinflammation and neurodegeneration in this disease. Experimental and therapeutic approaches, including recombinant enzyme replacement, have been performed using Sandhoff disease model mice, suggesting the future application of novel techniques to treat GM2 gangliosidoses (Hex deficiencies), including Sandhoff disease as well as Tay-Sachs disease. In this study, we isolated astrocytes and microglia from the neonatal brain of Sandhoff disease model mice and demonstrated abnormalities of glial cells. Moreover, we demonstrated the therapeutic effect of an intracerebroventricular administration of novel recombinant human HexA carrying a high content of M6P residue in Sandhoff disease model mice. PMID:23370522

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

    PubMed

    van der Wal, P

    1982-02-01

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

  17. Targeting NF-κB in glioblastoma: A therapeutic approach

    PubMed Central

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)–binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

  18. The gut barrier: new acquisitions and therapeutic approaches.

    PubMed

    Scaldaferri, Franco; Pizzoferrato, Marco; Gerardi, Viviana; Lopetuso, Loris; Gasbarrini, Antonio

    2012-10-01

    The intestinal barrier serves 2 critical functions for the survival of the individual: first, it allows nutrient absorption and second, it defends the body from dangerous macromolecule penetration. It is a complex multilayer system, consisting of an external "anatomic" barrier and an inner "functional" immunological barrier. The interaction of these 2 barriers enables equilibrated permeability to be maintained. Many factors can alter this balance: gut microflora modifications, mucus layer alterations, and epithelial damage can increase intestinal permeability, allowing the translocation of luminal content to the inner layer of intestinal wall. Several techniques are now available that enable us to study gut permeability: "in vitro" models (Caco-2 and HT29-MTX cells) and "in vivo" not invasive tests (sugar tests and radioisotope scanning tests) are used to estimate permeability and to suggest molecular pathophysiological mechanisms of intestinal permeability in health and diseases. Many medicinal products used in the treatment of gastrointestinal diseases have also found to play an active role in modulate intestinal permeability: corticosteroids, 5-aminosalicylic acid, anti-tumor necrosis factor, probiotics, and mucosal protectors, like gelatin tannate. This review will particularly address the role of the gut barrier in maintaining intestinal permeability (microbiota, mucus, and epithelial cells), the techniques used for estimating intestinal permeability and the therapeutic approaches able to modify it. PMID:22955350

  19. Clinical Features of Oxaliplatin Induced Hypersensitivity Reactions and Therapeutic Approaches.

    PubMed

    Bano, Nusrat; Najam, Rahila; Qazi, Faaiza; Mateen, Ahmed

    2016-01-01

    Oxaliplatin, a third generation novel platinum compound is the most effective first line chemotherapeutic agent for colorectal cancer (CRC) in combination with 5FU and leucovorin. It is indicated for pancreatic, gastric and testicular cancers combined with bevacuzimab, capecitabine, irinotecan and other cytotoxic agents. However, moderate to severe hypersensitivity reactions (HSR) during or after oxaliplatin infusion usually require cessation of chemotherapy or substitution of the key therapeutic drug which largely interferes with improved patient prognosis. This mini- review showcases recent and accepted opinions/approaches in oxaliplatin induced HSR management. Physicians and oncologists have varying attitudes regarding the decision to rechallenge the patient after an HSR experience, efficacy of desensitization protocols, effectiveness and selection of drugs for premedication and possibilities of cross sensitivity to other platinum agents (e.g. carboplatin). A brief insight into underlying molecular mechanisms and clinical manifestations of oxaliplatin induced HSR is offered. We have also discussed the management of oxaliplatin induced HSR and risk stratification for a successful and complete chemotherapeutic plan. PMID:27221832

  20. Targeting NF-κB in glioblastoma: A therapeutic approach.

    PubMed

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

  1. Development of Nanoscale Approaches for Ovarian Cancer Therapeutics and Diagnostics

    PubMed Central

    Engelberth, Sarah A.; Hempel, Nadine; Bergkvist, Magnus

    2014-01-01

    Ovarian cancer is the deadliest of all gynecological cancers and the fifth leading cause of death due to cancer in women. This is largely due to late-stage diagnosis, poor prognosis related to advanced-stage disease, and the high recurrence rate associated with development of chemoresistance. Survival statistics have not improved significantly over the last three decades, highlighting the fact that improved therapeutic strategies and early detection require substantial improvements. Here, we review and highlight nanotechnology-based approaches that seek to address this need. The success of Doxil, a PEGylated liposomal nanoencapsulation of doxorubicin, which was approved by the FDA for use on recurrent ovarian cancer, has paved the way for the current wave of nanoparticle formulations in drug discovery and clinical trials. We discuss and summarize new nanoformulations that are currently moving into clinical trials and highlight novel nanotherapeutic strategies that have shown promising results in preclinical in vivo studies. Further, the potential for nanomaterials in diagnostic imaging techniques and the ability to leverage nanotechnology for early detection of ovarian cancer are also discussed. PMID:25271436

  2. Systems approaches to design of targeted therapeutic delivery.

    PubMed

    Myerson, Jacob W; Brenner, Jacob S; Greineder, Colin F; Muzykantov, Vladimir R

    2015-01-01

    Targeted drug delivery aims to improve therapeutic effects and enable mechanisms that are not feasible for untargeted agents (e.g., due to impermeable biological barriers). To achieve targeting, a drug or its carrier should possess properties providing specific accumulation from circulation at the desired site. There are several examples of systems-inspired approaches that have been applied to achieve this goal. First, proteomics analysis of plasma membrane fraction of the vascular endothelium has identified a series of target molecules and their ligands (e.g., antibodies) that deliver conjugated cargoes to well-defined vascular cells and subcellular compartments. Second, selection of ligands binding to cells of interest using phage display libraries in vitro and in vivo has provided peptides and polypeptides that bind to normal and pathologically altered cells. Finally, large-scale high-throughput combinatorial synthesis and selection of lipid- and polymer-based nanocarriers varying their chemical components has yielded a series of carriers accumulating in diverse organs and delivering RNA interference agents to diverse cells. Together, these approaches offer a basis for systems-based design and selection of targets, targeting molecules, and targeting vehicles. Current studies focus on expanding the arsenal of these and alternative targeting strategies, devising drug delivery systems capitalizing on these strategies and evaluation of their benefit/risk ratio in adequate animal models of human diseases. These efforts, combined with better understanding of mechanisms and unintended consequences of these targeted interventions, need to be ultimately translated into industrial development and the clinical domain. PMID:25946066

  3. Systems approaches to design of targeted therapeutic delivery

    PubMed Central

    Myerson, Jacob W.; Brenner, Jacob S.; Greineder, Colin F.; Muzykantov, Vladimir R.

    2016-01-01

    Targeted drug delivery aims to improve therapeutic effects and enable mechanisms that are not feasible for untargeted agents (e.g., due to impermeable biological barriers). To achieve targeting, a drug or its carrier should possess properties providing specific accumulation from circulation at the desired site. There are several examples of systems-inspired approaches that have been applied to achieve this goal. First, proteomics analysis of plasma membrane fraction of the vascular endothelium has identified a series of target molecules and their ligands (e.g., antibodies) that deliver conjugated cargoes to well-defined vascular cells and subcellular compartments. Second, selection of ligands binding to cells of interest using phage display libraries in vitro and in vivo has provided peptides and polypeptides that bind to normal and pathologically altered cells. Finally, large-scale high-throughput combinatorial synthesis and selection of lipid- and polymer-based nanocarriers varying their chemical components has yielded a series of carriers accumulating in diverse organs and delivering RNA interference agents to diverse cells. Together, these approaches offer a basis for systems-based design and selection of targets, targeting molecules, and targeting vehicles. Current studies focus on expanding the arsenal of these and alternative targeting strategies, devising drug delivery systems capitalizing on these strategies and evaluation of their benefit/risk ratio in adequate animal models of human diseases. These efforts, combined with better understanding of mechanisms and unintended consequences of these targeted interventions, need to be ultimately translated into industrial development and the clinical domain. PMID:25946066

  4. Atopic dermatitis: molecular mechanisms, clinical aspects and new therapeutical approaches.

    PubMed

    Galli, E; Cicconi, R; Rossi, P; Casati, A; Brunetti, E; Mancino, G

    2003-03-01

    Atopic dermatitis (AD) is a genetically determinated, chronic inflammatory skin disorder associated with cutaneous erythema and severe pruritus, affecting 10-15% of children with increasing incidence and socio-economical relevance. Frequently, AD is associated with development of allergic rhinitis and/or asthma later in childhood. In most of patients AD is associated with a sensitization to food and/or environmental allergens and increased serum-IgE, while only a fewer percentage missed links to the classical atopic diathesis. Currently investigated pathogenetic aspects of AD include imbalanced Th1/Th2 responses, altered prostaglandin metabolism, intrinsic defects in the keratinocyte function, delayed eosinophil apoptosis, and IgE-mediated facilitated antigen presentation by epidermal dendritic cells. An inflammatory response of the two-phase-type and the effects of staphylococcal superantigens (SAgs) are also reported. At present a standardized cure of AD and a consensus on therapeutical approach of the severe form of the disease have not been established. Current management of AD is directed to the reduction of cutaneous inflammation and infection, mainly by S. aureus, and to the elimination of exacerbating factors (irritants, allergens, emotional stresses). Since patient with AD show abnormalities in immunoregulation, therapy directed to adjustment of their immune function could represent an alternative approach, particularly in the severe form of the disease. In this review, we analyse the clinical and genetic aspects of AD, the related molecular mechanisms, and the immunobiology of the disease, focusing our attention on current treatments and future perspectives on this topic. PMID:12630559

  5. Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches.

    PubMed

    Pagano, Livio; Valentini, Caterina G; Grammatico, Sara; Pulsoni, Alessandro

    2016-07-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematological malignancy derived from the precursors of plamacytoid dendritic cells, with an aggressive clinical course and high frequency of cutaneous and bone marrow involvement. Neoplastic cells express CD4, CD43 (also termed SPN), CD45RA and CD56 (also termed NCAM1), as well as the plasmacytoid dendritic cell-associated antigens CD123 (also termed IL3RA), BDCA-2 (also termed CD303, CLEC4E) TCL1 and CTLA1 (also termed GZMB). The median survival is only a few months as the tumour exhibits a progressive course despite initial response to chemotherapy. The best modality of treatment remains to be defined. Generally, patients receive acute leukaemia-like induction, according to acute myeloid leukaemia (AML)-type or acute lymphoid leukaemia (ALL)-type regimens. The frequent neuromeningeal involvement indicates systematic pre-emptive intrathecal chemotherapy in addition to intensive chemotherapy. Allogeneic haematopoietic stem cell transplantation (HSCT), particularly when performed in first remission, may improve the survival. Preliminary data suggest a potential role for immunomodulatory agents and novel targeted drugs. Herein epidemiology, clinical manifestations, diagnosis and management of BPDCN will be presented. In detail, this review focuses on the therapeutic aspects of BPDCN, proposing a treatment algorithm for the management of the disease, including induction chemotherapy, allogeneic HSCT and intrathecal prophylaxis at different steps of treatment, according to compliance, biological and clinical characteristics of patients. PMID:27264021

  6. A Four-step Approach for Evaluation of Dose Additivity

    EPA Science Inventory

    A four step approach was developed for evaluating toxicity data on a chemical mixture for consistency with dose addition. Following the concepts in the U.S. EPA mixture guidance (EPA 2000), toxicologic interaction for a defined mixture (all components known) is departure from a c...

  7. Therapeutic Approach of Nanotechnology for Oxidative Stress Induced Ocular Neurodegenerative Diseases.

    PubMed

    Mitra, Rajendra N; Conley, Shannon M; Naash, Muna I

    2016-01-01

    Oxidative stress plays a role in many different forms of neurodegenerative ocular disease. The imbalance between the generation of endogenous reactive oxygen species (ROS) and their corresponding neutralization by endogenous antioxidant defense systems leads to cellular oxidative stress, oxidation of different bio-macromolecules, and eventually retinal disease. As a result, the administration of supplemental endogenous antioxidant materials or exogenous ROS scavengers is an interesting therapeutic approach for the treatment of forms of ocular disease associated with oxidative stress. Thus far, different dietary antioxidant supplements have been proven to be clinically reliable and effective, and different antioxidant gene therapy approaches are under investigation. In addition, various metal oxide nanoparticles were shown to be effective in defending against oxidative stress-associated injury. These benefits are due to free radical scavenging properties of the materials arising from non-stoichiometric crystal defects and oxygen deficiencies. Here we discuss the application of this approach to the protection of the retina. PMID:26427447

  8. Insulinoma After Bariatric Surgery: Diagnostic Dilemma and Therapeutic Approaches.

    PubMed

    Mulla, Christopher M; Storino, Alessandra; Yee, Eric U; Lautz, David; Sawnhey, Mandeep S; Moser, A James; Patti, Mary-Elizabeth

    2016-04-01

    Hypoglycemia is increasingly recognized as a complication of bariatric surgery. Typically, hypoglycemia does not appear immediately postoperatively, but rather more than 1 year later, and usually occurs 1-3 h after meals. While rare, insulinoma has been reported after bariatric surgery. Clinical factors which should raise suspicion for insulinoma and the need for comprehensive clinical and biochemical evaluation include hypoglycemia occurring in the fasting state, predating bariatric surgery, and/or worsening immediately postoperatively, and lack of response to conservative therapy. Localization and successful resection of insulinoma can be achieved using novel endoscopic ultrasound and surgical approaches. In summary, hypoglycemia presenting shortly after gastric bypass or with a dominant fasting pattern should be fully evaluated to exclude insulinoma. Additionally, evaluation prior to gastric bypass should include screening for history of hypoglycemia symptoms. PMID:26846121

  9. Approaches to improve development methods for therapeutic cancer vaccines.

    PubMed

    Ogi, Chizuru; Aruga, Atsushi

    2015-04-01

    Therapeutic cancer vaccines are an immunotherapy that amplify or induce an active immune response against tumors. Notably, limitations in the methodology for existing anti-cancer drugs may subsist while applying them to cancer vaccine therapy. A retrospective analysis was performed using information obtained from ClinicalTrials.gov, PubMed, and published articles. Our research evaluated the optimal methodologies for therapeutic cancer vaccines based on (1) patient populations, (2) immune monitoring, (3) tumor response evaluation, and (4) supplementary therapies. Failure to optimize these methodologies at an early phase may impact development at later stages; thus, we have proposed some points to be considered during the early phase. Moreover, we compared our proposal with the guidance for industry issued by the US Food and Drug Administration in October 2011 entitled "Clinical Considerations for Therapeutic Cancer Vaccines". Consequently, while our research was aligned with the guidance, we hope it provides further insights in order to predict the risks and benefits and facilitate decisions for a new technology. We identified the following points for consideration: (1) include in the selection criteria the immunological stage with a prognostic value, which is as important as the tumor stage; (2) select immunological assays such as phenotype analysis of lymphocytes, based on their features and standardize assay methods; (3) utilize optimal response criteria for immunotherapy in therapeutic cancer vaccine trials; and (4) consider supplementary therapies, including immune checkpoint inhibitors, for future therapeutic cancer vaccines. PMID:25746315

  10. Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

    PubMed Central

    2011-01-01

    Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic

  11. Adipobiology for novel therapeutic approaches in metabolic syndrome.

    PubMed

    Malagón, María M; Díaz-Ruiz, Alberto; Guzmán-Ruiz, Rocío; Jiménez-Gómez, Yolanda; Moreno, Natalia R; García-Navarro, Socorro; Vázquez-Martínez, Rafael; Peinado, Juan R

    2013-11-01

    Obesity is dramatically increasing virtually worldwide, which has been linked to the rising prevalence of metabolic syndrome. Excess fat accumulation causes severe alterations in adipose tissue function. Actually, adipose tissue is now recognized as a major endocrine and secretory organ that releases a wide variety of signaling molecules (hormones, growth factors, cytokines, chemokines, etc.), the adipokines, which play central roles in the regulation of energy metabolism and homeostasis, immunity and inflammation. In addition, adipose tissue is no longer regarded as a passive lipid storage site but as a highly dynamic energy depot which stores excess energy during periods of positive energy balance and mobilizes it in periods of nutrient deficiency in a tightly regulated manner. Altered lipid release and adipokine production and signaling, as occurs in obesity, are linked to insulin resistance and the associated comorbidities of metabolic syndrome (dyslipidemia, hypertension), which confer an increased risk for the development of type 2 diabetes and cardiovascular disease. Here we summarize current knowledge on adipose tissue and review the contribution of novel techniques and experimental approaches in adipobiology to the identification of novel biomarkers and potential targets for dietary or pharmacological intervention to prevent and treat adipose tissue-associated diseases. PMID:24168446

  12. Clinical decision-making and therapeutic approaches in osteopathy - a qualitative grounded theory study.

    PubMed

    Thomson, Oliver P; Petty, Nicola J; Moore, Ann P

    2014-02-01

    There is limited understanding of how osteopaths make decisions in relation to clinical practice. The aim of this research was to construct an explanatory theory of the clinical decision-making and therapeutic approaches of experienced osteopaths in the UK. Twelve UK registered osteopaths participated in this constructivist grounded theory qualitative study. Purposive and theoretical sampling was used to select participants. Data was collected using semi-structured interviews which were audio-recorded and transcribed. As the study approached theoretical sufficiency, participants were observed and video-recorded during a patient appointment, which was followed by a video-prompted interview. Constant comparative analysis was used to analyse and code data. Data analysis resulted in the construction of three qualitatively different therapeutic approaches which characterised participants and their clinical practice, termed; Treater, Communicator and Educator. Participants' therapeutic approach influenced their approach to clinical decision-making, the level of patient involvement, their interaction with patients, and therapeutic goals. Participants' overall conception of practice lay on a continuum ranging from technical rationality to professional artistry, and contributed to their therapeutic approach. A range of factors were identified which influenced participants' conception of practice. The findings indicate that there is variation in osteopaths' therapeutic approaches to practice and clinical decision-making, which are influenced by their overall conception of practice. This study provides the first explanatory theory of the clinical decision-making and therapeutic approaches of osteopaths. PMID:23932101

  13. Aptamer-Based Therapeutics: New Approaches to Combat Human Viral Diseases

    PubMed Central

    Shum, Ka-To; Zhou, Jiehua; Rossi, John J.

    2013-01-01

    Viruses replicate inside the cells of an organism and continuously evolve to contend with an ever-changing environment. Many life-threatening diseases, such as AIDS, SARS, hepatitis and some cancers, are caused by viruses. Because viruses have small genome sizes and high mutability, there is currently a lack of and an urgent need for effective treatment for many viral pathogens. One approach that has recently received much attention is aptamer-based therapeutics. Aptamer technology has high target specificity and versatility, i.e., any viral proteins could potentially be targeted. Consequently, new aptamer-based therapeutics have the potential to lead a revolution in the development of anti-infective drugs. Additionally, aptamers can potentially bind any targets and any pathogen that is theoretically amenable to rapid targeting, making aptamers invaluable tools for treating a wide range of diseases. This review will provide a broad, comprehensive overview of viral therapies that use aptamers. The aptamer selection process will be described, followed by an explanation of the potential for treating virus infection by aptamers. Recent progress and prospective use of aptamers against a large variety of human viruses, such as HIV-1, HCV, HBV, SCoV, Rabies virus, HPV, HSV and influenza virus, with particular focus on clinical development of aptamers will also be described. Finally, we will discuss the challenges of advancing antiviral aptamer therapeutics and prospects for future success. PMID:24287493

  14. Understanding the Mechanism of Hepatic Fibrosis and Potential Therapeutic Approaches

    PubMed Central

    Ahmad, Areeba; Ahmad, Riaz

    2012-01-01

    Hepatic fibrosis (HF) is a progressive condition with serious clinical complications arising from abnormal proliferation and amassing of tough fibrous scar tissue. This defiance of collagen fibers becomes fatal due to ultimate failure of liver functions. Participation of various cell types, interlinked cellular events, and large number of mediator molecules make the fibrotic process enormously complex and dynamic. However, with better appreciation of underlying cellular and molecular mechanisms of fibrosis, the assumption that HF cannot be cured is gradually changing. Recent findings have underlined the therapeutic potential of a number of synthetic compounds as well as plant derivatives for cessation or even the reversal of the processes that transforms the liver into fibrotic tissue. It is expected that future inputs will provide a conceptual framework to develop more specific strategies that would facilitate the assessment of risk factors, shortlist early diagnosis biomarkers, and eventually guide development of effective therapeutic alternatives. PMID:22626794

  15. Allergen-specific immunotherapy: from therapeutic vaccines to prophylactic approaches

    PubMed Central

    Valenta, R.; Campana, R.; Marth, K.; van Hage, M.

    2015-01-01

    Immunoglobulin E-mediated allergies affect more than 25% of the population. Allergen exposure induces a variety of symptoms in allergic patients, which include rhinitis, conjunctivitis, asthma, dermatitis, food allergy and life-threatening systemic anaphylaxis. At present, allergen-specific immunotherapy (SIT), which is based on the administration of the disease-causing allergens, is the only disease-modifying treatment for allergy. Current therapeutic allergy vaccines are still prepared from relatively poorly defined allergen extracts. However, with the availability of the structures of the most common allergen molecules, it has become possible to produce well-defined recombinant and synthetic allergy vaccines that allow specific targeting of the mechanisms of allergic disease. Here we provide a summary of the development and mechanisms of SIT, and then review new forms of therapeutic vaccines that are based on recombinant and synthetic molecules. Finally, we discuss possible allergen-specific strategies for prevention of allergic disease. PMID:22640224

  16. Today Prospects for Tissue Engineering Therapeutic Approach in Dentistry

    PubMed Central

    Bossù, Maurizio; Pacifici, Andrea; Carbone, Daniele; Tenore, Gianluca; Ierardo, Gaetano; Pacifici, Luciano; Polimeni, Antonella

    2014-01-01

    In dental practice there is an increasing need for predictable therapeutic protocols able to regenerate tissues that, due to inflammatory or traumatic events, may suffer from loss of their function. One of the topics arising major interest in the research applied to regenerative medicine is represented by tissue engineering and, in particular, by stem cells. The study of stem cells in dentistry over the years has shown an exponential increase in literature. Adult mesenchymal stem cells have recently been isolated and characterized from tooth-related tissues and they might represent, in the near future, a new gold standard in the regeneration of all oral tissues. The aim of our review is to provide an overview on the topic reporting the current knowledge for each class of dental stem cells and to identify their potential clinical applications as therapeutic tool in various branches of dentistry. PMID:25379516

  17. Exploiting Base Excision Repair to Improve Therapeutic Approaches for Pancreatic Cancer

    PubMed Central

    Sharbeen, George; McCarroll, Joshua; Goldstein, David; Phillips, Phoebe A.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDA) is a highly chemoresistant and metastatic disease with a dismal 5-year survival rate of 6%. More effective therapeutic targets and approaches are urgently needed to tackle this devastating disease. The base excision repair (BER) pathway has been identified as a predictor of therapeutic response, prognostic factor, and therapeutic target in a variety of cancers. This review will discuss our current understanding of BER in PDA and its potential to improve PDA treatment. PMID:25988138

  18. Vectorization of Nucleic Acids for Therapeutic Approach: Tutorial Review.

    PubMed

    Geinguenaud, Frederic; Guenin, Erwann; Lalatonne, Yoann; Motte, Laurence

    2016-05-20

    Oligonucleotides present a high therapeutic potential for a wide variety of diseases. However, their clinical development is limited by their degradation by nucleases and their poor blood circulation time. Depending on the administration mode and the cellular target, these macromolecules will have to cross the vascular endothelium, to diffuse through the extracellular matrix, to be transported through the cell membrane, and finally to reach the cytoplasm. To overcome these physiological barriers, many strategies have been developed. Here, we review different methods of DNA vectorization, discuss limitations and advantages of the various vectors, and provide new perspectives for future development. PMID:26950048

  19. Additional approaches to solving the phase problem in optics.

    PubMed

    Zenkova, C Yu; Gorsky, M P; Ryabiy, P A; Angelskaya, A O

    2016-04-20

    The paper presents principal approaches to diagnosing the structure-forming skeleton of a complex optical field. Analysis of optical field singularity algorithms, depending on intensity discretization and image resolution, has been carried out. An optimal approach is chosen, which allows us to get much closer to the solution of the phase problem of localization speckle-field special points. The use of a "window" 2D Hilbert transform for reconstruction of the phase distribution of the intensity of a speckle field is proposed. It is shown that the advantage of this approach consists in the invariance of a phase map to a position change of the kernel of transformation and in a possibility to reconstruct the structure-forming elements of the skeleton of an optical field, including singular points and saddle points. We demonstrate the possibility to reconstruct the equi-phase lines within a narrow confidence interval and introduce an additional algorithm for solving the phase problem for random 2D intensity distributions. PMID:27140136

  20. Classification and therapeutic approaches in autoimmune hemolytic anemia: an update.

    PubMed

    Michel, Marc

    2011-12-01

    Autoimmune hemolytic anemia (AIHA) is an uncommon autoantibody-mediated immune disorder that affects both children and adults. The diagnosis of AIHA relies mainly on the direct antiglobulin test, which is a highly sensitive and relatively specific test. The classification of AIHA is based on the pattern of the direct antiglobulin test and on the immunochemical properties of the autoantibody (warm or cold type), but also on the presence or absence of an underlying condition or disease (secondary vs primary AIHAs) that may have an impact on treatment and outcome. The distinction between AIHAs due to warm antibody (wAIHA) and AIHAs due to cold antibody is a crucial step of the diagnostic procedure as it influences the therapeutic strategy. Whereas corticosteroids are the cornerstone of treatment in wAIHA, they have no or little efficacy in cold AIHA. In wAIHA that is refractory or dependent to corticosteroids, splenectomy and rituximab are both good alternatives and the benefit?risk ratio of each option must be discussed on an individual basis. In chronic agglutinin disease, the most common variety of cold AIHA in adults, beyond supportive measures, rituximab given either alone or in combination with chemotherapy may be helpful. In this article, the classification of AIHA and the recent progress in therapeutics are discussed. PMID:22077525

  1. Molecular subtyping of breast cancer: opportunities for new therapeutic approaches.

    PubMed

    Mullan, P B; Millikan, R C

    2007-12-01

    Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review). PMID:17957336

  2. Tourette's syndrome: clinical features, pathophysiology, and therapeutic approaches.

    PubMed

    Müller, Norbert

    2007-01-01

    Tourette's syndrome (TS) is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive symptoms. Its onset occurs before the age of 21. Typically, TS shows a waxing and waning course, but a chronification of the tics, even during later life, is often observed. TS mainly occurs in boys, and shows genetic heritability with differing penetrance. The pathological mechanism is still unclear Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS. Several possibly causative mechanisms of the disturbed dopaminergic neurotransmission are discussed, with the main emphasis on the-infection-triggered-inflammatory immune process. Extrapyramidal movement disorders are known to occur as a symptom of poststreptococcal disease, such as in Sydenham's chorea. Cases of childhood TS are proposed to be caused by such a poststreptococcal mechanism, being part of a spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented. The therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic natures of different infections, but also an autoimmune process. Moreover, therapeutic strategies using typical and atypical antipsychotics, and also experimental therapies such as repetitive transcranial magnetic stimulation and deep brain stimulation, are critically discussed. PMID:17726915

  3. Therapeutic Approaches to Histone Reprogramming in Retinal Degeneration

    PubMed Central

    Kleinman, Mark E.

    2016-01-01

    Recent data have revealed epigenetic derangements and subsequent chromatin remodeling as a potent biologic switch for chronic inflammation and cell survival which are important therapeutic targets in the pathogenesis of several retinal degenerations. Histone deacetylases (HDACs) are a major component of this system and serve as a unique control of the chromatin remodeling process. With a multitude of targeted HDAC inhibitors now available, their use in both basic science and clinical studies has widened substantially. In the field of ocular biology, there are data to suggest that HDAC inhibition may suppress neovascularization and may be a possible treatment for retinitis pigmentosa and dry age-related macular degeneration (AMD). However, the effects of these inhibitors on cell survival and chemokine expression in the chorioretinal tissues remain very unclear. Here, we review the multifaceted biology of HDAC activity and pharmacologic inhibition while offering further insight into the importance of this epigenetic pathway in retinal degenerations. Our laboratory investigations aim to open translational avenues to advance dry AMD therapeutics while exploring the role of acetylation on inflammatory gene expression in the aging and degenerating retina. PMID:26427391

  4. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    PubMed

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  5. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches

    PubMed Central

    Akram, Khondoker M.; Patel, Neil; Spiteri, Monica A.; Forsyth, Nicholas R.

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  6. Animal Models of Polyglutamine Diseases and Therapeutic Approaches*

    PubMed Central

    Marsh, J. Lawrence; Lukacsovich, Tamas; Thompson, Leslie Michels

    2009-01-01

    The dominant gain-of-function polyglutamine repeat diseases, in which the initiating mutation is known, allow development of models that recapitulate many aspects of human disease. To the extent that pathology is a consequence of disrupted fundamental cellular activities, one can effectively study strategies to ameliorate or protect against these cellular insults. Model organisms allow one to identify pathways that affect disease onset and progression, to test and screen for pharmacological agents that affect pathogenic processes, and to validate potential targets genetically as well as pharmacologically. Here, we describe polyglutamine repeat diseases that have been modeled in a variety of organisms, including worms, flies, mice, and non-human primates, and discuss examples of how they have broadened the therapeutic landscape. PMID:18957429

  7. [Limitation of therapeutic effort: Approach to a combined view].

    PubMed

    Bueno Muñoz, M J

    2013-01-01

    Over the past few decades, we have been witnessing that increasing fewer people pass away at home and increasing more do so within the hospital. More specifically, 20% of deaths now occur in an intensive care unit (ICU). However, death in the ICU has become a highly technical process. This sometimes originates excesses because the resources used are not proportionate related to the purposes pursued (futility). It may create situations that do not respect the person's dignity throughout the death process. It is within this context that the situation of the clinical procedure called "limitation of the therapeutic effort" (LTE) is reviewed. This has become a true bridge between Intensive Care and Palliative Care. Its final goal is to guarantee a dignified and painless death for the terminally ill. PMID:24112828

  8. A systematic MEDLINE analysis of therapeutic approaches in ankylosing spondylitis.

    PubMed

    Goh, L; Samanta, A

    2009-08-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disorder involving the sacroiliac joints (SIJs), spine and less frequently the peripheral joints. Traditionally, it is well recognised that AS is a challenging disease to manage due to the lack of effective therapeutic options. Current evidence would suggest this has changed and there are now a number of therapies available that provide persistent control of inflammatory symptoms with improvement in daily function. NSAIDs remain the first step in patient treatment. Sulphasalazine may be effective in peripheral arthritis and there are emerging data to support its use in early inflammatory back pain. Studies have shown that pamidronate and steroid injection into SIJ have a symptom-modifying effect in AS. Current data suggest that anti-TNF treatment promises early benefit which is likely to continue in the longer term. Treatment with biologics should be considered sooner rather than later in the management of AS. PMID:19562344

  9. Amyotrophic Lateral Sclerosis and Metabolomics: Clinical Implication and Therapeutic Approach

    PubMed Central

    Kumar, Alok; Ghosh, Devlina; Singh, R. L.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is one of the most common motor neurodegenerative disorders, primarily affecting upper and lower motor neurons in the brain, brainstem, and spinal cord, resulting in paralysis due to muscle weakness and atrophy. The majority of patients die within 3–5 years of symptom onset as a consequence of respiratory failure. Due to relatively fast progression of the disease, early diagnosis is essential. Metabolomics offer a unique opportunity to understand the spatiotemporal metabolic crosstalks through the assessment of body fluids and tissue. So far, one of the most challenging issues related to ALS is to understand the variation of metabolites in body fluids and CNS with the progression of disease. In this paper we will review the changes in metabolic profile in response to disease progression condition and also see the therapeutic implication of various drugs in ALS patients. PMID:26317018

  10. Osteitis pubis in elite athletes: Diagnostic and therapeutic approach.

    PubMed

    Angoules, Antonios G

    2015-10-18

    Osteitis pubis (OP) is a debilitating overuse syndrome characterizing by pelvic pain and local tenderness over the pubic symphysis commonly encountered in athletes often involved in kicking, twisting and cutting activities in sports such as soccer and rugby and to a lesser degree distance running. It is a common source of groin pain in elite athletes attributable to pubis sympysis instability as the result of microtrauma caused by repetitive muscle strains on pubic bones. Diagnosis is based mainly on detailed sports history and a meticulous clinical examination, although occasionally is difficult to distinguish this nosological entity from other pathologies affecting the involved area which may occur concomitantly in the same patient. Radiologic examinations such as plain radiographs, magnetic resonance imaging and 3 phase bone isotope scanning may be helpful to differentiate from other clinical entities with similar clinical presentation. Most cases respond well to conservative treatment which includes several physical modalities and especially a progressive rehabilitation programmed individualized to each one of patients diagnosed with OP. Local injection therapies have been also been proposed as a non-operative therapeutic option for the efficient management of these patients. In refractory cases, surgical therapeutic strategies are warranted. These include several open or minimally invasive surgical interventions such as arthroscopic or open symphysis curettage, wedge or total resection of pubic sympysis, polypropylene mesh placement and pubic fusion. In this review a critical analysis of OP in elite athletes is performed with special focus on current concepts of diagnosis and management of this source of athletic groin pain. PMID:26495244

  11. Osteitis pubis in elite athletes: Diagnostic and therapeutic approach

    PubMed Central

    Angoules, Antonios G

    2015-01-01

    Osteitis pubis (OP) is a debilitating overuse syndrome characterizing by pelvic pain and local tenderness over the pubic symphysis commonly encountered in athletes often involved in kicking, twisting and cutting activities in sports such as soccer and rugby and to a lesser degree distance running. It is a common source of groin pain in elite athletes attributable to pubis sympysis instability as the result of microtrauma caused by repetitive muscle strains on pubic bones. Diagnosis is based mainly on detailed sports history and a meticulous clinical examination, although occasionally is difficult to distinguish this nosological entity from other pathologies affecting the involved area which may occur concomitantly in the same patient. Radiologic examinations such as plain radiographs, magnetic resonance imaging and 3 phase bone isotope scanning may be helpful to differentiate from other clinical entities with similar clinical presentation. Most cases respond well to conservative treatment which includes several physical modalities and especially a progressive rehabilitation programmed individualized to each one of patients diagnosed with OP. Local injection therapies have been also been proposed as a non-operative therapeutic option for the efficient management of these patients. In refractory cases, surgical therapeutic strategies are warranted. These include several open or minimally invasive surgical interventions such as arthroscopic or open symphysis curettage, wedge or total resection of pubic sympysis, polypropylene mesh placement and pubic fusion. In this review a critical analysis of OP in elite athletes is performed with special focus on current concepts of diagnosis and management of this source of athletic groin pain. PMID:26495244

  12. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    PubMed

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. PMID:27131224

  13. Plasma Kallikrein Inhibitors in Cardiovascular Disease: An Innovative Therapeutic Approach.

    PubMed

    Kolte, Dhaval; Shariat-Madar, Zia

    2016-01-01

    Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolylcarboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system, and the complement pathways. As such, plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation. Under physiological conditions, plasma kallikrein serves as a cardioprotective enzyme. However, its increased plasma concentration or hyperactivity perpetuates cardiovascular disease (CVD). In this article, we review the biochemistry and cell biology of plasma kallikrein and summarize data from preclinical and clinical studies that have established important functions of this serine protease in CVD states. Finally, we propose plasma kallikrein inhibitors as a novel class of drugs with potential therapeutic applications in the treatment of CVDs. PMID:25853524

  14. [Idiopatic pulmonary fibrosis - news in multidisciplinary diagnostic and therapeutic approaches].

    PubMed

    Vašáková, Martina; Matěj, Radoslav

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a primary fibrosing pulmonary process. Due to the ineffectiveness of current therapeutic strategies and unfavorable prognosis, IPF is the most serious example of idiopathic interstitial lung diseases (ILD). Etiology and pathogenesis of this disorder have not been fully clarified yet; but it is anticipated, that the fibroproliferation is caused by the imbalance of reparative and immunologic processes in the genetically predisposed patients. Radiologically and histopathologically, IPF is characterized by specific pattern called usual interstitial pneumonia (UIP), however, this pattern is not fully typical in all cases, and, moreover, it could be seen in other ILD´s, e.g. chronic hypersensitivity pneumonitis, asbestosis, autoimmune connective tissue diseases and many others as well. The final diagnosis of IPF is a consensual result of multidisciplinary team composed of pulmologist, pathologist and radiologist. IPF was an incurable disease with prognosis worse than cancer till the year 2011, when antifibrotic drugs decelerating a progression of this disease have been introduced. Earlier and correct diagnosis of IPF is the most important issue for the patients because they could be effectively treated and thus, prolonging their survival as much as possible. PMID:27223586

  15. Impact of epigenetic mechanisms on therapeutic approaches of hemoglobinopathies.

    PubMed

    Costa, Dario; Capuano, Maria; Sommese, Linda; Napoli, Claudio

    2015-08-01

    Hemoglobinopathies are inherited disorders characterized by anomalies of structure, function or production of globin chains. From conception to adulthood, the different expressions over time of the various globin chains depend on the activation/deactivation of different globin genes through methylation and chromatin remodeling processes. The most significant clinical disorders are β-thalassemia and sickle cell disease. The clinical management of these disorders engages regular blood transfusions. Another therapy is represented by allogeneic hematopoietic cells transplantation. There are several studies based on the innovative therapeutic strategies that involve some epigenetic mechanisms focused on the reactivation of γ-globin gene expression. The induction of fetal hemoglobin expression in adulthood is an effective therapy for these disorders. Particularly interesting are the recent data on miRNAs showing the interaction of these molecules with different transcription factors such as MYB, KLF, BCL11A and SOX6. The aim of this review was to report an update on the dynamic epigenetic modifications as targets for therapy in hemoglobinopathies. PMID:26142322

  16. Seizures and gliomas - towards a single therapeutic approach.

    PubMed

    Huberfeld, Gilles; Vecht, Charles J

    2016-04-01

    Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions. PMID:26965673

  17. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.

    PubMed

    Xiao, Yun; Tang, Juan; Guo, Hui; Zhao, Yixia; Tang, Rong; Ouyang, Song; Zeng, Qiuming; Rappleye, Chad A; Rajaram, Murugesan V S; Schlesinger, Larry S; Tao, Lijian; Brown, Gordon D; Langdon, Wallace Y; Li, Belinda T; Zhang, Jian

    2016-08-01

    Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis. PMID:27428899

  18. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes.

    PubMed

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK-STAT, hedgehog, PI3K-Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  19. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes

    PubMed Central

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2V617F a decade ago led to optimism for a rapidly developing treatment revolution in Ph− myeloproliferative neoplasms. Unlike BCR–ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK–STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK–STAT, hedgehog, PI3K–Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  20. New therapeutic approaches for the prevention and treatment of migraine.

    PubMed

    Diener, Hans-Christoph; Charles, Andrew; Goadsby, Peter J; Holle, Dagny

    2015-10-01

    The management of patients with migraine is often unsatisfactory because available acute and preventive therapies are either ineffective or poorly tolerated. The acute treatment of migraine attacks has been limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines, and the triptans. Successful new approaches for the treatment of acute migraine target calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine, 5-HT1F) receptors. Other approaches targeting the transient receptor potential vanilloid (TRPV1) receptor, glutamate, GABAA receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide synthesis have been investigated but have not been successful in clinical trials thus far. In migraine prevention, the most promising new approaches are humanised antibodies against CGRP or the CGRP receptor. Non-invasive and invasive neuromodulation approaches also show promise as both acute and preventive therapies, although further studies are needed to define appropriate candidates for these therapies and optimum protocols for their use. PMID:26376968

  1. Counselling Refugee Young People: An Exploration of Therapeutic Approaches

    ERIC Educational Resources Information Center

    Warr, Sally

    2010-01-01

    This paper presents and discusses the key findings from a study that considered significant issues that affect refugees and asylum-seekers, and explored beneficial counselling approaches relevant to this group. In-depth narrative interviews were conducted with three counsellors and three specialist children's support advisors. Data were analysed…

  2. Medications, youth therapeutic cultures and performance consumptions: A sociological approach.

    PubMed

    Lopes, Noémia; Clamote, Telmo; Raposo, Hélder; Pegado, Elsa; Rodrigues, Carla

    2015-07-01

    This article analyses performance consumptions among young people. The theme is explored along two main axes. The first concerns the social heterogeneity in this field, considered on two levels: the different purposes for those investments - cognitive/mental and physical performance; and the different social contexts - university and work - where performance practices and dispositions may be fostered. The second axis explores the roles of pharmacological and natural consumptions, and their interrelationship, in the dissemination of these practices. The empirical data for this analysis were drawn from an ongoing research project on performance consumptions among young people (aged 18-29 years) in Portugal, including both university students and young workers without university education. The results correspond to the stage of extensive research, for which a questionnaire was organised at a national level, using non-proportional quota sampling. On the one hand, they show that (a) there is a hierarchy of acceptance of consumptions according to their purposes, with cognitive/mental performance showing higher acceptance and (b) both pharmaceuticals and natural products are consumed for every type of performance investment. On the other, the comparison between students and workers introduces a certain heterogeneity in this general backdrop, both in terms of the purposes for their consumptions and their opting for natural or pharmacological resources. These threads of heterogeneity will prompt a discussion of the dynamics of pharmaceuticalisation within the field of performance, in particular how therapeutic cultures may be changing in terms of the way individuals relate to medications, expanding their uses in social life. PMID:25331645

  3. Are Macrophages in Tumors Good Targets for Novel Therapeutic Approaches?

    PubMed Central

    Alahari, Samthosh V; Dong, Shengli; Alahari, Suresh K

    2015-01-01

    The development of cancer has been an extensively researched topic over the past few decades. Although great strides have been made in cancer prevention, diagnosis, and treatment, there is still much to be learned about cancer’s micro-environmental mechanisms that contribute to cancer formation and aggressiveness. Macrophages, lymphocytes which originate from monocytes, are involved in the inflammatory response and often dispersed to areas of infection to fight harmful antigens and mutated cells in tissues. Macrophages have a plethora of roles including tissue development and repair, immune system functions, and inflammation. We discuss various pathways by which macrophages get activated, various approaches that can regulate the function of macrophages, and how these approaches can be helpful in developing new cancer therapies.

  4. Integration of therapeutic approaches in working with children

    PubMed Central

    Cordell, Antoinette S.; Allen, Susan F.

    1997-01-01

    Child treatment and family therapy have developed divergent theories and methods, yet each contributes concepts that benefit children and families presenting with clinical problems. The authors discuss the theories and methods for both forms of treatment and review the literature on efforts to combine these approaches. They then describe a model, illustrated with case examples, in which careful assessment and planning throughout the treatment process are used to flexibly combine individual and family therapy techniques. PMID:9058560

  5. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update

    PubMed Central

    Tiwari, Pragya

    2015-01-01

    Diabetes highlights a growing epidemic imposing serious social economic crisis to the countries around the globe. Despite scientific breakthroughs, better healthcare facilities, and improved literacy rate, the disease continues to burden several sections, especially middle and low income countries. The present trends indicate the rise in premature death, posing a major threat to global development. Scientific and technological advances have witnessed the development of newer generation of drugs like sulphonylureas, biguanides, alpha glucosidase inhibitors, and thiazolidinediones with significant efficacy in reducing hyperglycemia. Recent approaches in drug discovery have contributed to the development of new class of therapeutics like Incretin mimetics, Amylin analogues, GIP analogs, Peroxisome proliferator activated receptors, and dipeptidyl peptidase-4 inhibitor as targets for potential drugs in diabetes treatment. Subsequently, the identification and clinical investigation of bioactive substances from plants have revolutionized the research on drug discovery and lead identification for diabetes management. With a focus on the emerging trends, the review article explores the current statistical prevalence of the disease, discussing the benefits and limitations of the commercially available drugs. Additionally, the critical areas in clinical diabetology are discussed, with respect to prospects of statins, nanotechnology, and stem cell technology as next generation therapeutics and why the herbal formulations are consistently popular choice for diabetes medication and management. PMID:26273667

  6. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update.

    PubMed

    Tiwari, Pragya

    2015-01-01

    Diabetes highlights a growing epidemic imposing serious social economic crisis to the countries around the globe. Despite scientific breakthroughs, better healthcare facilities, and improved literacy rate, the disease continues to burden several sections, especially middle and low income countries. The present trends indicate the rise in premature death, posing a major threat to global development. Scientific and technological advances have witnessed the development of newer generation of drugs like sulphonylureas, biguanides, alpha glucosidase inhibitors, and thiazolidinediones with significant efficacy in reducing hyperglycemia. Recent approaches in drug discovery have contributed to the development of new class of therapeutics like Incretin mimetics, Amylin analogues, GIP analogs, Peroxisome proliferator activated receptors, and dipeptidyl peptidase-4 inhibitor as targets for potential drugs in diabetes treatment. Subsequently, the identification and clinical investigation of bioactive substances from plants have revolutionized the research on drug discovery and lead identification for diabetes management. With a focus on the emerging trends, the review article explores the current statistical prevalence of the disease, discussing the benefits and limitations of the commercially available drugs. Additionally, the critical areas in clinical diabetology are discussed, with respect to prospects of statins, nanotechnology, and stem cell technology as next generation therapeutics and why the herbal formulations are consistently popular choice for diabetes medication and management. PMID:26273667

  7. Therapeutic approaches to neonatal jaundice: an international survey.

    PubMed

    Hansen, T W

    1996-06-01

    Jaundice is one of the most common clinical phenomena in the neonatal period and a frequent indication for treatment with phototherapy, exchange transfusion, or drugs. The present study documents the variability in approaches to the treatment of this condition. A mail questionnaire was sent to neonatal units worldwide. One hundred and eight answers (49% response rate) were received from Europe (n = 72), North America (n = 28), Africa (n = 7), and Asia (n = 1). The neonatal intensive care units represented by the respondents had 31 +/- 18 beds [mean +/- SD], and 638 +/- 519 admissions per year. All units offered phototherapy, 106/108 performed exchange transfusion, while 44/108 used some form of drug therapy. There was considerable variability among the units in their approaches to the jaundiced neonate. This applied to all aspects of care, including type of phototherapy lights used, practical implementation of phototherapy, use of fluid supplementation, and use of prophylactic phototherapy. The majority used written protocols for investigation and treatment of neonatal jaundice and would let their decision on whether to treat be influenced by the infant's clinical state. There was great variability between units in the level of serum bilirubin that would trigger therapy. This applied across weight groups and to phototherapy as well as exchange transfusion. The significant heterogeneity in our approach to the treatment of jaundiced neonates suggests that our understanding of the biology of neonatal jaundice is inadequate and that further research will be necessary in order to provide a more solid biological foundation for therapy. PMID:8782955

  8. Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

    PubMed Central

    Ando, Kosei; Heymann, Marie-Françoise; Stresing, Verena; Mori, Kanji; Rédini, Françoise; Heymann, Dominique

    2013-01-01

    Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies. PMID:24216993

  9. Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

    PubMed Central

    Clemente-Casares, Xavier; Tsai, Sue; Huang, Carol; Santamaria, Pere

    2012-01-01

    Development of strategies capable of specifically curbing pathogenic autoimmune responses in a disease- and organ-specific manner without impairing foreign or tumor antigen-specific immune responses represents a long sought-after goal in autoimmune disease research. Unfortunately, our current understanding of the intricate details of the different autoimmune diseases that affect mankind, including type 1 diabetes, is rudimentary. As a result, progress in the development of the so-called “antigen-specific” therapies for autoimmunity has been slow and fraught with limitations that interfere with bench-to-bedside translation. Absent or incomplete understanding of mechanisms of action and lack of adequate immunological biomarkers, for example, preclude the rational design of effective drug development programs. Here, we provide an overview of antigen-specific approaches that have been tested in preclinical models of T1D and, in some cases, human subjects. The evidence suggests that effective translation of these approaches through clinical trials and into patients will continue to meet with failure unless detailed mechanisms of action at the level of the organism are defined. PMID:22355799

  10. [Spinal and spinal cord injuries. Therapeutic approach in Gabon].

    PubMed

    Loembe, P M; Bouger, D; Dukuly, L; Ndong-Launay, M

    1991-01-01

    The authors present their experience with 81 cases (66.4%) of acute cervical spine injuries (C.S.I.) and 41 cases (33.6%) of acute thoracolumbar spine injuries (T.L.S.I.) treated by a multidisciplinary approach, at Jeanne Ebori Hospital (Libreville, Gabon) between the years 1981 and 1987. Traffic accidents were the leading cause of injury. The largest group consisted of patients in their third decade. The anatomic localizations were: upper cervical spine: 22 cases (27%); lower cervical spine: 56 (69%); upper thoracic spine: 11 (26.8%); lower thoracic spine or thoracolumbar area: 19 (46.3%); lumbar spine: 7 (17%). There were osteoligamental lesions in 3 cases (3.7%) of C.S.I. and 4 (9.7%) of T.L.S.I. Clinically, 44 patients (54.3%) with C.S.I. and 37 (90.2%) with T.L.S.I. had neurological deficits. Surgical indications depended upon the osseous as well as neurologic lesions. There were five important steps in the treatment of spinal injuries associated with neurological deficit: (1) immobilization, (2) medical stabilization, (3) spinal alignment (skeletal traction), (4) operative decompression if there was proven cord compression, and (5) spinal stabilization. Twenty patients (24.6%) with cervical injuries were treated conservatively (traction, collar, kinesitherapy); 53 (65.4%) underwent a surgical intervention (anterior approach - 21, posterior fusion - 30, combined approach - 2); and in 8 patients (9.8%) refraining from surgery seemed the best alternative. After lengthy multidisciplinary discussion, the authors elected not to operate on tetraplegic patients with respiratory problems that necessitated assisted ventilation, because of its fatal outcome. Of injuries to the thoracolumbar spine, 13 (31.7%) were treated conservatively (bedrest, orthopedic treatment). Twenty-eight patients (68.2%) with unstable thoracic and lumbar fractures associated with neurologic deficit required acute surgical intervention (stabilization with or without decompression of the neural

  11. Emerging innovative therapeutic approaches targeting PCSK9 to lower lipids.

    PubMed

    Shantha, G P S; Robinson, J G

    2016-01-01

    Statins are established therapies for cardiovascular disease prevention and ezetimibe has recently been shown to modestly reduce cardiovascular events when added to background statin therapy. Yet here remains a clear unmet need for additional therapies aimed at lowering low density lipoprotein cholesterol (LDL-C) to further reduce cardiovascular risk. Multiple strategies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have emerged as effective modalities for LDL-C lowering. PCSK9 monoclonal antibodies are the farthest along in clinical development and alirocumab and evolocumab were approved for clinical use by regulatory agencies in 2015. In addition to robust LDL-C lowering (nearly 50-65% from baseline), they improve other lipid parameters as well. Adverse events associated with these medications are minimal. Importantly, they improve clinical cardiovascular disease outcomes, although long-term study results are awaited. Cost may be an important limiting factor in their use and we propose two possible solutions which can potentially curtail cost. PMID:26492546

  12. Overview of current therapeutic approaches for pulmonary hypertension

    PubMed Central

    Stamm, Jason A.; Risbano, Michael G.; Mathier, Michael A.

    2011-01-01

    There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension. PMID:22034603

  13. Alternative Therapeutic Approach in the Treatment of Oral Pyogenic Granuloma

    PubMed Central

    Bugshan, Amr; Patel, Harsh; Garber, Karen; Meiller, Timothy F.

    2015-01-01

    Pyogenic granulomas (PGs) in the oral cavity present as an inflammatory hyperplasia usually caused by trauma, hormonal imbalance, chronic irritation, or as the response to a wide variety of drugs. PGs with atypical presentation and behavior may clinically mimic malignant tumors. Thus, histological examination is required to rule out cancer development. Lesions in the oral cavity have been described to be either an isolated entity or present in multiple forms and with multiple recurrences. Conservative surgical excision is the standard choice of treatment in almost every scenario. However, the severity of the lesions and the affected sites often challenge surgical treatment. In this report, we describe the clinical scenario of a recurrent PG, where surgical excision of the lesion was questioned. As an alternative, we describe a noninvasive approach with lesional steroid injections. PMID:26668570

  14. Therapeutic Approach of Wrist Ganglion Using Electroacupuncture: Two Case Reports

    PubMed Central

    Kim, Kyoung Min; Lee, Sung Hoon; Jung, A Young; Nam, Doo Hyoun; Cheon, Ji Hwan

    2014-01-01

    A ganglion cyst is a relatively common benign tumor on the wrist. Conservative and surgical approaches have been used for its treatment. Various conservative treatment methods have been suggested such as reassurance, aspiration, sclerosant injection, and direct compression. But, there is no acceptable treatment of choice yet because each suggested method has a relatively high recurrence rate. We want to report two cases in which the size of the wrist ganglion was decreased by using electroacupuncture. One patient presented with a chronic ganglion for six years and the other patient presented with a recently occurred acute ganglion. We applied electroacupuncture for 20 minutes once a week for eight weeks to both of them. Afterwards, the size of the wrist ganglion diminished in the follow-up sonography and the accompanying pain was also relieved. Herein we report both cases along with a review of the relevant literature. PMID:25024969

  15. A Multi-scale Approach to Designing Therapeutics for Tuberculosis

    PubMed Central

    Linderman, Jennifer J.; Cilfone, Nicholas A.; Pienaar, Elsje; Gong, Chang; Kirschner, Denise E.

    2015-01-01

    Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi-compartment view of the in vivo immune response to M. tuberculosis. We describe computational models that can be used to study (a) immunomodulation with the cytokines tumor necrosis factor and interleukin 10, (b) oral and inhaled antibiotics, and (c) the effect of vaccination. PMID:25924949

  16. Receptor modification as a therapeutic approach against viral diseases

    PubMed Central

    Farid, Rabia; Khan, Mohammad Haroon; Rashid, Hamid

    2012-01-01

    Poliovirus causes flaccid paralysis through the destruction of motor neurons in the CNS. Susceptibility to its infection is mainly due to the interaction in between the surface capsid proteins and its receptors on the host cell surface, important for binding, penetration and other necessary events during early infection. Receptor modification is a new approach to treat viral diseases by the modification of target proteins structure. Binding domains are modified in an effective way to make it difficult for the virus to recognize it. In this study, tolerant and intolerant induced mutations in the poliovirus receptor, VP1 and VP2 were identified and substituted in the seed sequence to get the modified versions. Substitutions causing changes in initial folding were short listed and further analyzed for high level folding, physiochemical properties and interactions. Highest RMSD values were observed in between the seed and the mutant K90F (3.265 Å) and Q130W (3.270Å) respectively. The proposed substitutions were found to have low functional impact and thus can be further tested and validated by the experimental researchers. Interactions analyses proved most of the substitutions having decreased affinity for both the VP1 and VP2 and thus are of significant importance against poliovirus. This study will play an important role for bridging computational biology to other fields of applied biology and also will provide an insight to develop resistance against viral diseases. It is also expected that same approach can also be applicable against other viruses like HCV, HIV and other in near future. PMID:22553391

  17. A Molecular Approach to Epilepsy Management: from Current Therapeutic Methods to Preconditioning Efforts.

    PubMed

    Amini, Elham; Rezaei, Mohsen; Mohamed Ibrahim, Norlinah; Golpich, Mojtaba; Ghasemi, Rasoul; Mohamed, Zahurin; Raymond, Azman Ali; Dargahi, Leila; Ahmadiani, Abolhassan

    2015-08-01

    Epilepsy is the most common and chronic neurological disorder characterized by recurrent unprovoked seizures. The key aim in treating patients with epilepsy is the suppression of seizures. An understanding of focal changes that are involved in epileptogenesis may therefore provide novel approaches for optimal treatment of the seizure. Although the actual pathogenesis of epilepsy is still uncertain, recently growing lines of evidence declare that microglia and astrocyte activation, oxidative stress and reactive oxygen species (ROS) production, mitochondria dysfunction, and damage of blood-brain barrier (BBB) are involved in its pathogenesis. Impaired GABAergic function in the brain is probably the most accepted hypothesis regarding the pathogenesis of epilepsy. Clinical neuroimaging of patients and experimental modeling have demonstrated that seizures may induce neuronal apoptosis. Apoptosis signaling pathways are involved in the pathogenesis of several types of epilepsy such as temporal lobe epilepsy (TLE). The quality of life of patients is seriously affected by treatment-related problems and also by unpredictability of epileptic seizures. Moreover, the available antiepileptic drugs (AED) are not significantly effective to prevent epileptogenesis. Thus, novel therapies that are proficient to control seizure in people who are suffering from epilepsy are needed. The preconditioning method promises to serve as an alternative therapeutic approach because this strategy has demonstrated the capability to curtail epileptogenesis. For this reason, understanding of molecular mechanisms underlying brain tolerance induced by preconditioning is crucial to delineate new neuroprotective ways against seizure damage and epileptogenesis. In this review, we summarize the work to date on the pathogenesis of epilepsy and discuss recent therapeutic strategies in the treatment of epilepsy. We will highlight that novel therapy targeting such as preconditioning process holds great

  18. New therapeutic approaches for ANCA-associated vasculitides.

    PubMed

    Chaigne, Benjamin; Guillevin, Loïc

    2016-06-01

    For many years, despite severe side effects, vasculitides have been managed with high doses of corticosteroids and long-lasting intensive immunosuppression. Recent, innovative approaches have improved our knowledge of the disease pathophysiologies leading to novel treatments that are transforming the standard of care, at least for antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs) and again providing new elements to further understanding of the disease mechanisms. Although this could seem to be a virtuous circle of enhanced comprehension and innovation, many questions regarding patient care remain unsolved and a closer look at the past could temper this exciting race to new drug discovery. In this review, we describe the different evidence-based medicine strategies, the drugs that are being tested in AAV patients and novel strategies that should improve AAV treatment. However, the costs and benefits of the development of new treatment strategies are also considered in light of 20 years of clinical trial experience in the field of AAVs. PMID:27256972

  19. Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities.

    PubMed

    Szabo, Attila

    2015-01-01

    Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer's disease. PMID:26236313

  20. Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

    PubMed Central

    Gorini, Giorgio; Adron Harris, R; Dayne Mayfield, R

    2014-01-01

    Recent studies have shown that gene regulation is far more complex than previously believed and does not completely explain changes at the protein level. Therefore, the direct study of the proteome, considerably different in both complexity and dynamicity to the genome/transcriptome, has provided unique insights to an increasing number of researchers. During the past decade, extraordinary advances in proteomic techniques have changed the way we can analyze the composition, regulation, and function of protein complexes and pathways underlying altered neurobiological conditions. When combined with complementary approaches, these advances provide the contextual information for decoding large data sets into meaningful biologically adaptive processes. Neuroproteomics offers potential breakthroughs in the field of alcohol research by leading to a deeper understanding of how alcohol globally affects protein structure, function, interactions, and networks. The wealth of information gained from these advances can help pinpoint relevant biomarkers for early diagnosis and improved prognosis of alcoholism and identify future pharmacological targets for the treatment of this addiction. PMID:23900301

  1. Advancement in contemporary diagnostic and therapeutic approaches for rheumatoid arthritis.

    PubMed

    Kumar, L Dinesh; Karthik, R; Gayathri, N; Sivasudha, T

    2016-04-01

    This review is intended to provide a summary of the pathogenesis, diagnosis and therapies for rheumatoid arthritis. Rheumatoid arthritis (RA) is a common form of inflammatory autoimmune disease with unknown aetiology. Bone degradation, cartilage and synovial destruction are three major pathways of RA pathology. Sentinel cells includes dendritic cells, macrophages and mast cells bound with the auto antigens and initiate the inflammation of the joints. Those cells further activates the immune cells on synovial membrane by releasing inflammatory cytokines Interleukin 1, 6, 17, etc., Diagnosis of this disease is a combinational approach comprises radiological imaging, blood and serology markers assessment. The treatment of RA still remain inadequate due to the lack of knowledge in disease development. Non-steroidal anti-inflammatory drugs, disease modifying anti rheumatic drugs and corticosteroid are the commercial drugs to reduce pain, swelling and suppressing several disease factors. Arthroscopy will be an useful method while severe degradation of joint tissues. Gene therapy is a major advancement in RA. Suppressor gene locus of inflammatory mediators and matrix degrading enzymes were inserted into the affected area to reduce the disease progression. To overcome the issues aroused from those therapies like side effects and expenses, phytocompounds have been investigated and certain compounds are proved for their anti-arthritic potential. Furthermore certain complementary alternative therapies like yoga, acupuncture, massage therapy and tai chi have also been proved for their capability in RA treatment. PMID:27044812

  2. [Cormorbidity in multiple sclerosis and its therapeutic approach].

    PubMed

    Estruch, Bonaventura Casanova

    2014-12-01

    Multiple sclerosis (MS) is a long-term chronic disease, in which intercurrent processes develop three times more frequently in affected individuals than in persons without MS. Knowledge of the comorbidity of MS, its definition and measurement (Charlson index) improves patient management. Acting on comorbid conditions delays the progression of disability, which is intimately linked to the number of concurrent processes and with health states and habits. Moreover, the presence of comorbidities delays the diagnosis of MS, which in turn delays the start of treatment. The main comorbidity found in MS includes other autoimmune diseases (thyroiditis, systemic lupus erythematosus, or pemphigus) but can also include general diseases, such as asthma or osteomuscular alterations, and, in particular, psychiatric disturbances. All these alterations should be evaluated with multidimensional scales (Disability Expectancy Table, DET), which allow more accurate determination of the patient's real clinical course and quality of life. These scales also allow identification of how MS, concurrent and intercurrent processes occurring during the clinical course, and the treatment provided affect patients with MS. An overall approach to patients' health status helps to improve quality of life. PMID:25732944

  3. [FUNCTIONAL ANALYTIC PSYCHOTHERAPY: APPROACHES AND SCOPE OF BEHAVIOR THERAPY BASED ON CHANGES IN THE THERAPEUTIC CONTEXT].

    PubMed

    Muñoz-Martínez, Amanda M; Coletti, Juan Pablo

    2015-01-01

    Abstract Functional Analytic Psychotherapy (FAP) is a therapeutic approach developed in context. FAP is characterized by use therapeutic relationship and the behaviors emit into it to improve clients daily life functioning. This therapeutic model is supported in behavior analysis principles and contextual functionalism philosophy. FAP proposes that clients behavior in session are functional equivalent with those out of session; therefore, when therapists respond to clients behaviors in session contingently, they promote and increase improvements in the natural setting. This article poses main features of FAP, its philosophical roots, achievements and research challenges to establish FAP as an independent treatment based on the evidence. PMID:26323113

  4. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

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

  5. Fullerenols as a New Therapeutic Approach in Nanomedicine

    PubMed Central

    2013-01-01

    Recently, much attention has been paid to the bioactive properties of water-soluble fullerene derivatives: fullerenols, with emphasis on their pro- and antioxidative properties. Due to their hydrophilic properties and the ability to scavenge free radicals, fullerenols may, in the future, provide a serious alternative to the currently used pharmacological methods in chemotherapy, treatment of neurodegenerative diseases, and radiobiology. Some of the most widely used drugs in chemotherapy are anthracycline antibiotics. Anthracycline therapy, in spite of its effective antitumor activity, induces systemic oxidative stress, which interferes with the effectiveness of the treatment and results in serious side effects. Fullerenols may counteract the harmful effects of anthracyclines by scavenging free radicals and thereby improve the effects of chemotherapy. Additionally, due to the hollow spherical shape, fullerenols may be used as drug carriers. Moreover, because of the existence of the currently ineffective ways for neurodegenerative diseases treatment, alternative compounds, which could prevent the negative effects of oxidative stress in the brain, are still sought. In the search of alternative methods of treatment and diagnosis, today's science is increasingly reaching for tools in the field of nanomedicine, for example, fullerenes and their water-soluble derivatives, which is addressed in the present paper. PMID:24222914

  6. Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

    PubMed Central

    Szabo, Attila

    2015-01-01

    Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease. PMID:26236313

  7. A therapeutic approach to treat cardiovascular dysfunction of diabetes.

    PubMed

    Bhatt, L K; Veeranjaneyulu, A

    2012-11-01

    Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10(-5) M) and relaxation responses to acetylcholine (10(-9)-10(-4) M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt(max) and dp/dt(min) were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment. PMID:21474293

  8. Endovascular Therapeutic Approaches for Acute Superior Mesenteric Artery Occlusion

    SciTech Connect

    Acosta, S. Sonesson, B.; Resch, T.

    2009-09-15

    The purpose of this study was to characterize the outcome of attempted endovascular intervention in patients with acute embolic or thrombotic superior mesenteric artery (SMA) occlusion. The records of 21 patients during a 3-year period between 2005 and 2008 were retrieved from the in-hospital registry. The first group included 10 patients (6 women and 4 men; median age 78 years) with acute embolic occlusion of the SMA. The median duration of symptoms from symptom onset to angiography was 30 hours (range 6 to 120). Synchronous emboli (n = 12) occurred in 6 patients. Embolus aspiration was performed in 9 patients, and 7 of these had satisfactory results. Complementary local thrombolysis was successful in 2 of 3 patients. Residual emboli were present at completion angiography in all 7 patients who underwent successful aspiration embolectomy, and bowel resection was necessary in only 1 of these patients. One serious complication occurred because of a long SMA dissection. The in-hospital survival rate was 90% (9 of 10 patients). The second group included 11 patients (10 women and 1 man; median age 68 years) with atherosclerotic acute SMA occlusions. The median time of symptom duration before intervention was 97 hours (range 17 to 384). The brachial, femoral, and SMA routes were used in 6, 7, and 5 patients, respectively. SMA stenting was performed through an antegrade (n = 7) or retrograde (n = 3) approach. Bowel resection was necessary in 4 patients. No major complications occurred. The in-hospital survival rate was 82% (9 of 11 patients). Endovascular therapy of acute SMA occlusion provides a good alternative to open surgery.

  9. Therapeutic Targeting of Siglecs using Antibody- and Glycan-Based Approaches.

    PubMed

    Angata, Takashi; Nycholat, Corwin M; Macauley, Matthew S

    2015-10-01

    The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of immunomodulatory receptors whose functions are regulated by their glycan ligands. Siglecs are attractive therapeutic targets because of their cell type-specific expression pattern, endocytic properties, high expression on certain lymphomas/leukemias, and ability to modulate receptor signaling. Siglec-targeting approaches with therapeutic potential encompass antibody- and glycan-based strategies. Several antibody-based therapies are in clinical trials and continue to be developed for the treatment of lymphoma/leukemia and autoimmune disease, while the therapeutic potential of glycan-based strategies for cargo delivery and immunomodulation is a promising new approach. Here we review these strategies with special emphasis on emerging approaches and disease areas that may benefit from targeting the Siglec family. PMID:26435210

  10. Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery

    PubMed Central

    Imbrici, Paola; Liantonio, Antonella; Camerino, Giulia M.; De Bellis, Michela; Camerino, Claudia; Mele, Antonietta; Giustino, Arcangela; Pierno, Sabata; De Luca, Annamaria; Tricarico, Domenico; Desaphy, Jean-Francois; Conte, Diana

    2016-01-01

    In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets. PMID:27242528

  11. Targeting Neuropilin-1 to Inhibit VEGF Signaling in Cancer: Comparison of Therapeutic Approaches

    PubMed Central

    Gabhann, Feilim Mac; Popel, Aleksander S

    2006-01-01

    Angiogenesis (neovascularization) plays a crucial role in a variety of physiological and pathological conditions including cancer, cardiovascular disease, and wound healing. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Multiple VEGF receptors are expressed on endothelial cells, including signaling receptor tyrosine kinases (VEGFR1 and VEGFR2) and the nonsignaling co-receptor Neuropilin-1. Neuropilin-1 binds only the isoform of VEGF responsible for pathological angiogenesis (VEGF165), and is thus a potential target for inhibiting VEGF signaling. Using the first molecularly detailed computational model of VEGF and its receptors, we have shown previously that the VEGFR–Neuropilin interactions explain the observed differential effects of VEGF isoforms on VEGF signaling in vitro, and demonstrated potent VEGF inhibition by an antibody to Neuropilin-1 that does not block ligand binding but blocks subsequent receptor coupling. In the present study, we extend that computational model to simulation of in vivo VEGF transport and binding, and predict the in vivo efficacy of several Neuropilin-targeted therapies in inhibiting VEGF signaling: (a) blocking Neuropilin-1 expression; (b) blocking VEGF binding to Neuropilin-1; (c) blocking Neuropilin–VEGFR coupling. The model predicts that blockade of Neuropilin–VEGFR coupling is significantly more effective than other approaches in decreasing VEGF–VEGFR2 signaling. In addition, tumor types with different receptor expression levels respond differently to each of these treatments. In designing human therapeutics, the mechanism of attacking the target plays a significant role in the outcome: of the strategies tested here, drugs with similar properties to the Neuropilin-1 antibody are predicted to be most effective. The tumor type and the microenvironment of the target tissue are also significant in determining therapeutic efficacy of each of the treatments studied. PMID:17196035

  12. Chemical Mixture Risk Assessment Additivity-Based Approaches

    EPA Science Inventory

    Powerpoint presentation includes additivity-based chemical mixture risk assessment methods. Basic concepts, theory and example calculations are included. Several slides discuss the use of "common adverse outcomes" in analyzing phthalate mixtures.

  13. The Miniature Job Training and Evaluation Approach: Additional Findings.

    ERIC Educational Resources Information Center

    Siegel, Arthur I.

    1983-01-01

    Describes miniature job training and evaluation situations administered to 1,034 "low aptitude" Navy recruits. Checklist criterion data describing the on-the-job performance of the sample were collected after the recruits were on their fleet assignments. The results confirmed the predictive validity of the miniature job training approach.…

  14. Mitochondrial Reactive Oxygen Species at the Heart of the Matter: New Therapeutic Approaches for Cardiovascular Diseases

    PubMed Central

    Kornfeld, Opher S.; Hwang, Sunhee; Disatnik, Marie-Hélène; Chen, Che-Hong; Qvit, Nir; Mochly-Rosen, Daria

    2015-01-01

    Reactive oxygen species (ROS) have been implicated in a variety of age-related diseases including multiple cardiovascular disorders. However, translation of ROS scavengers (anti-oxidants) into the clinic has not been successful. These anti-oxidants grossly reduce total levels of cellular ROS including ROS that participate in physiological signaling. In this review, we challenge the traditional anti-oxidant therapeutic approach that targets ROS directly with novel approaches that improve mitochondrial functions to more effectively treat cardiovascular diseases. PMID:25999419

  15. Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches

    PubMed Central

    NEGREI, CAROLINA; BOJINCA, VIOLETA; BALANESCU, ANDRA; BOJINCA, MIHAI; BACONI, DANIELA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.; STAN, MIRIANA

    2016-01-01

    Rheumatic diseases are highly prevalent chronic disorders and the leading cause of physical disability worldwide, with a marked socio-economic impact. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology with an autoimmune pathogenesis, characterised by arthropathy with chronic, deforming, destructive evolution and multiple systemic manifestations. The management of RA has undergone significant changes as far as objectives and approaches are concerned, ending in the current strategy known as ‘treat to target’. The therapeutic array of RA includes several categories of medicinal products, of varying potential. There are several criteria for the classification of medicinal products used against this disease, one of the most important and modern of which divides such substances according to their effects on the progress of the disease: symptom-modifying antirheumatic drugs (including non-steroidal anti-inflammatory drugs and corticoids), disease-modifying antirheumatic drugs (including various substances, such as gold salts, antimalarials, sulfasalazine, D-penicillamine; non-specific immunosuppressive medication, such as methotrexate, cyclophosphamide, azathioprine and leflunomide) and biological therapy is a recent addition, providing new insight into the treatment of this disease. The selection of the optimal therapy for RA should be based on guidelines and recommendations, but also on clinical particular aspects and patient preferences. PMID:27073419

  16. Therapeutic Approaches to Limit Hemolysis-Driven Endothelial Dysfunction: Scavenging Free Heme to Preserve Vasculature Homeostasis

    PubMed Central

    Tolosano, Emanuela

    2013-01-01

    Hemolysis results in the release of hemoglobin and heme into the bloodstream and is associated with the development of several pathologic conditions of different etiology, including hemoglobinopathies, hemolytic anemias, bacterial infections, malaria, and trauma. In addition, hemolysis is associated with surgical procedures, hemodialysis, blood transfusion, and other conditions in which mechanical forces can lead to red blood cell rupture. Free plasma hemoglobin and heme are toxic for the vascular endothelium since heme iron promotes oxidative stress that causes endothelial activation responsible for vasoocclusive events and thrombus formation. Moreover, free hemoglobin scavenges nitric oxide, reducing its bioavailability, and heme favours ROS production, thus causing oxidative nitric oxide consumption. This results in the dysregulation of the endothelium vasodilator:vasoconstrictor balance, leading to severe vasoconstriction and hypertension. Thus, endothelial dysfunction and impairment of cardiovascular function represent a common feature of pathologic conditions associated with hemolysis. In this review, we discuss how hemoglobin/heme released following hemolysis may affect vascular function and summarise the therapeutic approaches available to limit hemolysis-driven endothelial dysfunction. Particular emphasis is put on recent data showing the beneficial effects obtained through the use of the plasma heme scavenger hemopexin in counteracting heme-mediated endothelial damage in mouse models of hemolytic diseases. PMID:23781294

  17. The management of a sexually charged clinical problem: social structural and psychoanalytic functionalist approaches in a therapeutic community.

    PubMed

    James, O W

    1986-03-01

    An event in a therapeutic community is examined from the perspectives of the structuralism of Durkheim and the functionalism of psychoanalysis. Although these two approaches might appear theoretically contradictory, analysis of the evidence shows them to be clinically complementary. The role of social structure in therapeutic communities requires deliberate conceptualization if such communities are to be demonstrably therapeutic. PMID:3964583

  18. Lentiviral-based approach for the validation of cancer therapeutic targets in vivo.

    PubMed

    Ambrogio, Chiara; Stern, Patrick; Scuoppo, Claudio; Kranz, Harald; Barbacid, Mariano; Santamaría, David

    2014-10-01

    Despite the pressing need for novel cancer treatments, our improved understanding of tumor biology is not being successfully translated into better therapies. Here we present a lentiviral vector that enables in vivo validation of cancer therapeutic targets when combined with existing cancer animal models that faithfully reproduce the natural history of human disease. Unlike the conventional genetic approaches with targeted alleles, the outlined experimental strategy could be used to assess the preclinical efficacy of a growing number of putative therapeutic hits in a rapid and cost-effective manner. PMID:25312087

  19. Human iPSC for Therapeutic Approaches to the Nervous System: Present and Future Applications

    PubMed Central

    Cefalo, Maria Giuseppina; Carai, Andrea; Po, Agnese; Ferretti, Elisabetta; Mastronuzzi, Angela; Germano, Isabelle M.

    2016-01-01

    Many central nervous system (CNS) diseases including stroke, spinal cord injury (SCI), and brain tumors are a significant cause of worldwide morbidity/mortality and yet do not have satisfying treatments. Cell-based therapy to restore lost function or to carry new therapeutic genes is a promising new therapeutic approach, particularly after human iPSCs became available. However, efficient generation of footprint-free and xeno-free human iPSC is a prerequisite for their clinical use. In this paper, we will first summarize the current methodology to obtain footprint- and xeno-free human iPSC. We will then review the current iPSC applications in therapeutic approaches for CNS regeneration and their use as vectors to carry proapoptotic genes for brain tumors and review their applications for modelling of neurological diseases and formulating new therapeutic approaches. Available results will be summarized and compared. Finally, we will discuss current limitations precluding iPSC from being used on large scale for clinical applications and provide an overview of future areas of improvement. In conclusion, significant progress has occurred in deriving iPSC suitable for clinical use in the field of neurological diseases. Current efforts to overcome technical challenges, including reducing labour and cost, will hopefully expedite the integration of this technology in the clinical setting. PMID:26697076

  20. Exploration of developmental approaches to companion animal antimicrobials: providing for the unmet therapeutic needs of dogs and cats.

    PubMed

    Apley, M; Claxton, R; Davis, C; DeVeau, I; Donecker, J; Lucas, A; Neal, A; Papich, M

    2010-04-01

    The American Academy of Veterinary Pharmacology and Therapeutics (AAVPT) and the United States Pharmacopeia (USP) co-sponsored a workshop to explore approaches for developing companion animal antimicrobials. This workshop was developed in response to the shortage of antimicrobials labeled for dogs and cats, as there is a shortage of approved antimicrobials for the range of infectious diseases commonly treated in small animal practice. The objective of the workshop was to identify alternative approaches to data development to support new indications consistent with the unmet therapeutic needs of dogs and cats. The indications for currently approved antimicrobials do not reflect the broader range of infectious diseases that are commonly diagnosed and treated by the veterinarian. Therefore, the labels for these approved antimicrobials provide limited information to the veterinarian for appropriate therapeutic decision-making beyond the few indications listed. Industry, veterinary practice, and regulatory challenges to the development of new antimicrobial indications were discussed. The workshop resulted in short- and long-term recommendations. Short-term recommendations focus on the use of additional data considerations for product labeling. Long-term recommendations center on legislative or regulatory legal initiatives. The workshop recommendations will need collaboration from industry, academia, and regulatory authorities and a legal shift in the drug approval and availability processes. PMID:20444045

  1. From substance dependence to addiction: impact of a conceptual shift on therapeutic approaches?

    PubMed

    Reynaud, Michel; Karila, Laurent

    2011-01-01

    Switching from the concept of substance or alcohol dependence to that of addiction has profoundly modified our ways of approaching, treating and organizing the care of this disease. This more complex and subtle approach gives less importance to the substance and its effects and focuses more on the initiation of pathological behavior. It is important to keep in mind that the addictive process associates a substance (more or less addictive), an individual (more or less vulnerable) and an environment (more or less condoning). Today, it is no longer possible to consider that a drug acts on only one receptor or one system. Current understanding of inner regulation mechanisms integrates the interactions between the various stimulated brain pathways. Addiction treatments which should benefit from advances in genetics, neuropsychology and neuroimaging could be increasingly individualized in the years to come. The "addictology" approach has triggered thinking about other therapeutic approaches such as modification of therapeutic objectives toward "risk reductions" or applying this model to behavioral addictions (food, sex, sport, gaming...). This conceptual shift seems to enrich clinical analysis, the therapeutic possibilities and the avenues for research. PMID:21524269

  2. Novel activity-dependent approaches to therapeutic hypnosis and psychotherapy: the general waking trance.

    PubMed

    Rossi, Ernest; Erickson-Klein, Roxanna; Rossi, Kathryn

    2008-10-01

    This paper presents a highly edited version of a videotape made in 1980 by Marion Moore, M.D., showing Milton H. Erickson and Moore demonstrating novel, activity-dependent approaches to hand-levitation and therapeutic hypnosis on their subject, Ernest Rossi. Erickson's naturalistic and utilization approach is described in his very direct and surprising induction in a trance challenged patient. These novel, and surprising inductions are examples of how Erickson was prescient in developing activity-dependent approaches to therapeutic hypnosis and psychotherapy several generations before modern neuroscience documented the activity-dependent molecular-genomic mechanisms of memory, learning, and behavior change. Erickson describes a case where he utilized what he called, "The General Waking Trance" when he "dared" not use an obvious hypnotic induction. It is proposed that the states of intense mental absorption and response attentiveness that are facilitated by the general waking trance are functionally related to the three conditions neuroscientists have identified as novelty, enrichment, and exercise (both mental and physical), which can turn on activity-dependent gene expression and activity-dependent brain plasticity, that are the molecular-genomic and neural basis ofmemory, learning, consciousness, and behavior change. We recommend that the next step in investigating the efficacy of therapeutic hypnosis will be in partnering with neuroscientists to explore the possibilities and limitations of utilizing the activity-dependent approaches to hypnotic induction and the general waking trance in facilitating activity-dependent gene expression and brain plasticity. PMID:18998388

  3. She will give birth easily: therapeutic approaches to childbirth in 1st millennium BCE cuneiform sources.

    PubMed

    Couto-Ferreira M Erica

    2014-01-01

    This article offers, in the first place, an overview on women's healthcare in relation to childbirth in ancient Mesopotamia, as an introduction that helps to evaluate the meaning of the 7th century Assur text BAM 248 within therapeutic cuneiform texts on childbirth. We proceed to analyse the variety of therapeutic approaches to childbirth present in BAM 248, which brings together various healing devices to help a woman give birth quickly and safely. We analyse the text in its entirety as an example of intersection between different medical approaches to childbirth, given the number of differences in the complexity of remedies, in the materia medica employed, in the methods of preparation and application, even in the technical knowledge required and also, most probably, in the social origin and/or use of the remedies in question. PMID:25481964

  4. She will givebirth easily: therapeutic approaches to childbirth in 1st millennium BCE cuneiform sources.

    PubMed

    Couto-Ferreira M Erica

    2014-01-01

    This article offers, in the first place, an overview on women's healthcare in relation to childbirth in ancient Mesopotamia, as an introduction that helps to evaluate the meaning of the 7th century Assur text BAM 248 within therapeutic cuneiform texts on childbirth. We proceed to analyse the variety of therapeutic approaches to childbirth present in BAM 248, which brings together various healing devices to help a woman give birth quickly and safely. We analyse the text in its entirety as an example of intersection between different medical approaches to childbirth, given the number of differences in the complexity of remedies, in the materia medica employed, in the methods of preparation and application, even in the technical knowledge required and also, most probably, in the social origin and/or use of the remedies in question. PMID:25508816

  5. Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: from discovery to clinical trials

    PubMed Central

    Shimizu-Motohashi, Yuko; Miyatake, Shouta; Komaki, Hirofumi; Takeda, Shin’ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder caused by the absence of dystrophin. There is no curative therapy, although innovative therapeutic approaches have been aggressively investigated over recent years. Currently, the international clinical trial registry platform for this disease has been constructed and clinical trials for innovative therapeutic approaches are underway. Among these, exon skipping and read-through of nonsense mutations are in the most advanced stages, with exon skipping theoretically applicable to a larger number of patients. To date, exon skipping that targets exons 51, 44, 45, and 53 is being globally investigated including in USA, EU, and Japan. The latest announcement from Japan was made, demonstrating successful dystrophin production in muscles of patients with DMD after treating with exon 53 skipping antisense oligonucleotides (ASOs). However, the innovative therapeutic approaches have demonstrated limited efficacy. To address this issue in exon skipping, studies to unveil the mechanism underlying gymnotic delivery of ASO uptake in living cells have been conducted in an effort to improve in vivo delivery. Further, establishing the infrastructures to integrate multi-institutional clinical trials are needed to facilitate the development of successful therapies for DMD, which ultimately is applicable to other myopathies and neurodegenerative diseases, including spinal muscular atrophy and motor neuron diseases. PMID:27398133

  6. Neoadjuvant Therapy in Patients with Pancreatic Cancer: A Disappointing Therapeutic Approach?

    PubMed Central

    Zimmermann, Carolin; Folprecht, Gunnar; Zips, Daniel; Pilarsky, Christian; Saeger, Hans Detlev; Grutzmann, Robert

    2011-01-01

    Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed. PMID:24212810

  7. Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach.

    PubMed

    Epner, Elliot M; Saroya, Bikramajit Singh; Hasanali, Zainul S; Loughran, Thomas P

    2016-03-01

    We recently reported that addition of epigenetic agents could overcome resistance of leukemic cells to monoclonal antibody-mediated anti-tumor effects in T-cell prolymphocytic leukemia. We also reported that epigenetic agents could induce expression of the CD30 gene, thus providing a therapeutic target for the antibody drug conjugate brentuximab vedotin. Here we discuss these findings and their generality to treatment of other hematologic and solid malignancies. PMID:26802532

  8. Therapeutic approach to IgG4-related disease: A systematic review.

    PubMed

    Brito-Zerón, Pilar; Kostov, Belchin; Bosch, Xavier; Acar-Denizli, Nihan; Ramos-Casals, Manuel; Stone, John H

    2016-06-01

    To review the reported evidence on the therapeutic management of IgG4-related disease (IgG4-RD) in clinical practice.A systematic search of the literature was conducted. The primary outcome measured was the rate of efficacy of first-line therapeutic approaches. Secondary outcomes measured included the rate of disease relapse, the outcome of untreated patients, the rate of patients without drug therapy at the end of follow-up, the rate of side effects, and mortality. The MOOSE, AHRQ, STROBE, and GRACE recommendations/statements were followed.The results of the systematic search strategy yielded 62 studies that included a total of 3034 patients. Complete information about first-line therapeutic regimens was detailed in 1952 patients, including glucocorticoid-based regimens in 1437 (74%), drug-free regimens in 213 (11%), and other therapies in 38 (2%). No therapy (wait and see management) was reported in 264 (13%) patients. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses treated with glucocorticoids, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases. Wide heterogeneity was observed with respect to the first-line therapeutic approaches used for the different organ-specific disease subsets, including significant differences in the mean dose of glucocorticoids used.Nearly 70% of reported IgG4-RD patients are treated with oral glucocorticoids in monotherapy. However, the therapeutic management is heavily influenced by geographical, epidemiological, and clinical

  9. Therapeutic elements in a self-management approach: experiences from group participation among people suffering from chronic pain

    PubMed Central

    Furnes, Bodil; Natvig, Gerd Karin; Dysvik, Elin

    2014-01-01

    Objective Chronic pain is a complex, multifaceted subjective experience that involves the whole person. Self-management is the dynamic and continuous process of adapting one’s situation to the cognitive, behavioral, and emotional responses necessary to maintain a satisfactory quality of life. Approaches based on cognitive behavioral therapy (CBT) are described as appropriate in assisting people suffering from chronic pain because they challenge maladaptive beliefs and behaviors in relation to pain. This study aimed to explore patients’ experiences of therapeutic elements from group participation in a chronic pain management program. Methods A qualitative research design with a phenomenological hermeneutic approach was used. Six months after participation in the 8-week course, 34 participants formulated and submitted written reports based on open-ended questions related to their group participation and self-help achievement. These reports were analyzed by elements of qualitative content analysis. Results The analysis resulted in two subthemes: “The significance of active involvement in gaining new insight” and “The significance of community and group support.” These were abstracted in the main theme: “Successful self-management is related to several significant contributions in the group.” Conclusion An active role with writing, self-revelation, and exchanges of thoughts and feelings in the group seemed to be the key tools for success. In addition, group support and access to other group members’ experiences were significant therapeutic elements. We suggest that successful self-management requires knowledge of essential therapeutic elements. In a CBT-based group approach, such elements may offer an important health care contribution. PMID:25170253

  10. Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases.

    PubMed

    Mesentier-Louro, Louise A; Zaverucha-do-Valle, Camila; Rosado-de-Castro, Paulo H; Silva-Junior, Almir J; Pimentel-Coelho, Pedro M; Mendez-Otero, Rosalia; Santiago, Marcelo F

    2016-01-01

    Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized. PMID:26649049

  11. Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

    PubMed Central

    Mesentier-Louro, Louise A.; Zaverucha-do-Valle, Camila; Rosado-de-Castro, Paulo H.; Silva-Junior, Almir J.; Pimentel-Coelho, Pedro M.; Mendez-Otero, Rosalia; Santiago, Marcelo F.

    2016-01-01

    Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized. PMID:26649049

  12. Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

    PubMed Central

    Nonami, Atsushi; Sattler, Martin; Weisberg, Ellen; Liu, Qingsong; Zhang, Jianming; Patricelli, Matthew P.; Christie, Amanda L.; Saur, Amy M.; Kohl, Nancy E.; Kung, Andrew L.; Yoon, Hojong; Sim, Taebo; Griffin, James D.

    2015-01-01

    Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes. PMID:25833960

  13. Teaching communication and therapeutic relationship skills to baccalaureate nursing students: a peer mentorship simulation approach.

    PubMed

    Miles, Leslie W; Mabey, Linda; Leggett, Sarah; Stansfield, Katie

    2014-10-01

    The literature on techniques for improving student competency in therapeutic communication and interpersonal skills is limited. A simulation approach to enhance the learning of communication skills was developed to address these issues. Second-semester and senior nursing students participated in videorecorded standardized patient simulations, with senior students portraying the patient. Following simulated interactions, senior students provided feedback to junior students on their use of communication skills and other therapeutic factors. To integrate the learning experience, junior students completed a written assignment, in which they identified effective and noneffective communication; personal strengths and weaknesses; and use of genuineness, empathy, and positive regard. A videorecording of each student interaction gave faculty the opportunity to provide formative feedback to students. Student evaluations have been positive. Themes identified in student evaluations include the impact of seeing oneself, significance of practicing, getting below the surface in communication, and moving from insight to goal setting. PMID:25207556

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

    PubMed Central

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

    2013-01-01

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

  15. Plant derived edible nanoparticles as a new therapeutic approach against diseases.

    PubMed

    Zhang, Mingzhen; Viennois, Emilie; Xu, Changlong; Merlin, Didier

    2016-01-01

    In plant cells, nanoparticles containing miRNA, bioactive lipids and proteins serve as extracellular messengers to mediate cell-cell communication in a manner similar to the exosomes secreted by mammalian cells. Notably, such nanoparticles are edible. Moreover, given the proper origin and cargo, plant derived edible nanoparticles could function in interspecies communication and may serve as natural therapeutics against a variety of diseases. In addition, nanoparticles made of plant-derived lipids may be used to efficiently deliver specific drugs. Plant derived edible nanoparticles could be more easily scaled up for mass production, compared to synthetic nanoparticles. In this review, we discuss recent significant developments pertaining to plant derived edible nanoparticles and provide insight into the use of plants as a bio-renewable, sustainable, diversified platform for the production of therapeutic nanoparticles. PMID:27358751

  16. Advanced oropharyngeal squamous cell carcinoma: Pathogenesis, treatment, and novel therapeutic approaches

    PubMed Central

    Swiecicki, Paul L; Malloy, Kelly M; Worden, Francis P

    2016-01-01

    Oropharyngeal cancer accounts for approximately 2.8% of newly cancer cases. Although classically a tobacco related disease, most cases today are related to infection with human papilloma virus (HPV) and present with locally advanced tumors. HPV related tumors have been recognized as a molecularly distinct entity with higher response rates to therapy, lower rates of relapse, and improved overall survival. Treatment of oropharyngeal cancer entails a multi-disciplinary approach with concomitant chemoradiation. The role of induction chemotherapy in locally advanced tumors continues to be controversial however large studies have demonstrated no difference in survival or time to treatment failure. Surgical approaches may be employed with low volume oropharyngeal cancers and with development new endoscopic tools, more tumors are able to be resected via an endoscopic approach. Given advances in the understanding of HPV related oropharyngeal cancer, ongoing research is looking at ways to minimize toxicities via de-intensification of therapy. Unfortunately, some patients develop recurrent or metastatic disease. Novel therapeutics are currently being investigated for this patient population including immunotherapeutics. This review discusses the current understanding of the pathogenesis of oropharyngeal cancer and treatment. We also discuss emerging areas of research as it pertains to de-intensification as well novel therapeutics for the management of metastatic disease. PMID:26862488

  17. Metabolic Modification in Gastrointestinal Cancer Stem Cells: Characteristics and Therapeutic Approaches.

    PubMed

    Di Francesco, Angela Maria; Toesca, Amelia; Cenciarelli, Carlo; Giordano, Antonio; Gasbarrini, Antonio; Puglisi, Maria Ausiliatrice

    2016-10-01

    Currently, there is much interest in the characterization of metabolic profiling of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal capacity. Indeed, ever-growing evidence indicate that metabolism and stemness are highly intertwined processes in tumor tissue. In this review, we analyze the potential metabolic targeting strategies for eradicating CSCs that could help to develop a more effective therapeutic approach for gastrointestinal cancers. Indeed, the successful elimination of a tumor requires an anticancer therapy that affects both cancer cells and CSCs. The observation that gastrointestinal CSCs possess higher inducible nitric oxide sinthase (iNOS) expression, lower reactive oxygen species (ROS) production, and a different metabolism respect to no-CSCs tumor cells has paved the way to develop drugs targeting CSC specific signaling. In particular, several studies have highlighted that metformin, aldehyde dehydrogenase 1, and iNOS inhibitors selectively suppressed CSC growth and that combinatorial therapy of them with standard chemotherapeutic drugs had a synergistic effect resulting in reduced tumor burden and delayed tumor recurrence. Thus, the possibility of combining specific CSC metabolism inhibitors with existing therapeutic approaches could have profound anticancer effects, changing the conventional treatment approaches to gastrointestinal cancers. J. Cell. Physiol. 231: 2081-2087, 2016. © 2016 Wiley Periodicals, Inc. PMID:26791139

  18. A Therapeutic Approach to Teaching Poetry: Individual Development, Psychology, and Social Reparation. Psychoanalysis, Education and Social Transformation

    ERIC Educational Resources Information Center

    Williams, Todd O.

    2012-01-01

    A Therapeutic Approach to Teaching Poetry develops a poetry pedagogy that offers significant benefits to students by helping them to achieve a sense of renewal (a deeper awareness of self and potentials) and reparation (a realistic, but positive and proactive worldview). Todd O. Williams offers a thorough examination of the therapeutic potential…

  19. The skin microbiome: potential for novel diagnostic and therapeutic approaches to cutaneous disease

    PubMed Central

    Grice, Elizabeth A.

    2015-01-01

    A vast diversity of microorganisms, including bacteria, fungi, viruses, and arthropods, colonize the human skin. Culture-independent genomic approaches for identifying and characterizing microbial communities have provided glimpses into the topographical, temporal, and interpersonal complexity that defines the skin microbiome. Identification of changes associated with cutaneous disease, including acne, atopic dermatitis, rosacea, and psoriasis, are being established. In this review, our current knowledge of the skin microbiome in health and disease is discussed, with particular attention to potential opportunities to leverage the skin microbiome as a diagnostic, prognostic, and/or therapeutic tool. PMID:25085669

  20. Polymorphonuclear neutrophils in periodontitis and their possible modulation as a therapeutic approach.

    PubMed

    Nicu, Elena A; Loos, Bruno G

    2016-06-01

    The main focus of this review is polymorphonuclear neutrophilic granulocytes. Polymorphonuclear neutrophils play a pivotal role in normal host resistance to subgingival dental-plaque biofilm. Both hyper- and hypo-responsiveness of the immune system toward the microbial challenge in periodontitis have been described. We review polymorphonuclear neutrophil physiology with emphasis on the role of neutrophil functions and dysfunctions in periodontitis. Text boxes are given at the end of each subsection, which present the current knowledge on neutrophil-modulating agents as a potential therapeutic approach in periodontitis. PMID:27045435

  1. The use of canine models of inherited retinal degeneration to test novel therapeutic approaches

    PubMed Central

    Beltran, William A.

    2011-01-01

    Inherited retinal degenerations (RDs) are a common cause of blindness in dogs and in humans. Over the past two decades numerous genes causally associated with these diseases have been identified and several canine models have been used to improve our understanding of the molecular mechanisms of RDs, as well as to test the proof of principle and safety of novel therapies. This review briefly summarizes the drug delivery approaches and therapeutic strategies that have been and are currently tested in dogs, with a particular emphasis on corrective gene therapy, and retinal neuroprotection. PMID:19392879

  2. Corticobasal degeneration: clinical characteristics and multidisciplinary therapeutic approach in 26 patients.

    PubMed

    Shehata, Hatem S; Shalaby, Nevin M; Esmail, Eman H; Fahmy, Ebtesam

    2015-09-01

    Corticobasal syndrome (CBS) is a sporadic tauopathy that manifests by a various combination of motor and cognitive deficits, which makes its diagnosis challenging. Treatment of CBS is symptomatic and based on evidence from other similar disorders due to the lack of studies on CBS. The aim of the study was to investigate low-frequency repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool in CBS. Twenty-six patients with clinically evident CBS according to Cambridge criteria were followed for 12-18 months while receiving low-frequency rTMS combined with pharmacological, rehabilitation treatment and botulinum toxin injection. The majority of patients are manifested with akinetic-rigid syndrome and cognitive dysfunction. There was improvement of the UPDRS and quality of life after 3 months of therapeutic interventions (P < 0.001 and <0.05, respectively). No significant deterioration in cognitive functions was detected over the study period. There was a significant reduction of caregiver burden after 3 months of interventions (P < 0.01); this improvement was maintained up to 18 months. Cognitive dysfunction is a frequent manifestation of CBS. CBS patients can benefit from multidisciplinary therapeutic approach employing low-frequency rTMS. PMID:25917399

  3. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

    PubMed Central

    2012-01-01

    Objective Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments. PMID:23351279

  4. Cell- and gene-based therapeutic approaches for neurological deficits in Mucopolysaccharidoses

    PubMed Central

    Pan, Dao

    2014-01-01

    Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases that are resulted from abnormal accumulation of glycosaminoglycans. Among the progressive multi-organ abnormalities often associated with MPS diseases, the deterioration of central nervous system (CNS) is the most challenging manifestations to be tackled, due to the impermeability of the blood-brain-barrier (BBB). Evolved with recent development in stem cell biotechnology and gene therapy, several novel experimental approaches have been investigated in animal models. In this review, we will address different approaches attempting to bypass the BBB for neuropathic MPS treatment using cell- and gene-based therapies. Several neurological findings in CNS pathophysiology emerged with therapeutic investigation will also be discussed. PMID:21235445

  5. Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers, and therapeutic approaches

    PubMed Central

    Sahu, Praveen K.; Satpathi, Sanghamitra; Behera, Prativa K.; Mishra, Saroj K.; Mohanty, Sanjib; Wassmer, Samuel Crocodile

    2015-01-01

    Cerebral malaria is a severe neuropathological complication of Plasmodium falciparum infection. It results in high mortality and post-recovery neuro-cognitive disorders in children, even after appropriate treatment with effective anti-parasitic drugs. While the complete landscape of the pathogenesis of cerebral malaria still remains to be elucidated, numerous innovative approaches have been developed in recent years in order to improve the early detection of this neurological syndrome and, subsequently, the clinical care of affected patients. In this review, we briefly summarize the current understanding of cerebral malaria pathogenesis, compile the array of new biomarkers and tools available for diagnosis and research, and describe the emerging therapeutic approaches to tackle this pathology effectively. PMID:26579500

  6. ERα-Negative and Triple Negative Breast Cancer: Molecular Features and Potential Therapeutic Approaches

    PubMed Central

    Chen, Jin-Qiang; Russo, Jose

    2010-01-01

    Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E2/ERβ – mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC. PMID:19527773

  7. The use of nanoparticles as a promising therapeutic approach in cancer immunotherapy.

    PubMed

    Hosseini, Maryam; Haji-Fatahaliha, Mostafa; Jadidi-Niaragh, Farhad; Majidi, Jafar; Yousefi, Mehdi

    2016-06-01

    Cancer is one of the most important causes of death all over the world, which has not yet been treated efficiently. Although several therapeutic approaches have been used, some side effects such as toxicity and drug resistance have been observed in patients, particularly with chemotherapy. The nanoparticle-mediated drug delivery systems (DDS) have a great potential to improve cancer treatment by transferring therapeutic factors directly to the tumor site. Such a treatment significantly decreases the adverse effects associated with cancer therapy on healthy tissues. Two main strategies, including passive and active methods, have been considered to be effective techniques which can target the drugs to the tumor sites. The current review sheds some light on the place of nanotechnology in cancer drug delivery, and introduces nanomaterials and their specific characteristics that can be used in tumor therapy. Moreover, passive and active targeting approaches focus on antibodies, particularly single chain variable fragments (scFv), as a novel and important ligand in a drug delivery system. PMID:25612903

  8. Variant fatty acid-like molecules Conjugation, novel approaches for extending the stability of therapeutic peptides

    PubMed Central

    Li, Ying; Wang, Yuli; Wei, Qunchao; Zheng, Xuemin; Tang, Lida; Kong, Dexin; Gong, Min

    2015-01-01

    The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides. PMID:26658631

  9. Variant fatty acid-like molecules Conjugation, novel approaches for extending the stability of therapeutic peptides.

    PubMed

    Li, Ying; Wang, Yuli; Wei, Qunchao; Zheng, Xuemin; Tang, Lida; Kong, Dexin; Gong, Min

    2015-01-01

    The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides. PMID:26658631

  10. Isolated blunt lingual artery injury secondary to a road traffic accident: diagnostic and therapeutic approach.

    PubMed

    Mawaddah, Azman; Goh, Bee See; Kew, Thean Yean; Rozman, Zakaria

    2012-04-01

    Neurologic and airway compromise as a result of traumatic vascular injuries to the neck region often lead to more severe complications and thus require special consideration. Furthermore, these cases pose diagnostic and therapeutic challenges to healthcare providers. Here, we report a case of a 28-year-old motorcyclist presenting with progressively enlarged Zone 2 neck swelling on the left side following a high impact collision. There were no symptoms or signs suggesting neurologic or laryngeal injury. Computed tomography angiogram of the neck revealed signs of an active arterial bleed. The apparent vascular injury was managed by close observation for signs of airway compromise, urgent angiogram, and selective catheter embolisation of the left lingual artery. The patient subsequently recovered without further operative exploration of the neck. At 6 months post-trauma, the neck swelling fully subsided with no complications from angioembolisation. This case illustrates the individualised treatment and multidisciplinary approach in managing such cases. We review our rationale for this diagnostic and therapeutic approach. PMID:22973141

  11. New therapeutic approach to corrosive burns of the upper gastrointestinal tract.

    PubMed Central

    Di Costanzo, J; Noirclerc, M; Jouglard, J; Escoffier, J M; Cano, N; Martin, J; Gauthier, A

    1980-01-01

    The therapeutic approach to the management of corrosive burns of the upper gastrointestinal tract leaves a considerable morbidity and a heavy mortality rate. This work evaluates the effectiveness of a new therapeutic approach given to 94 consecutive patients. The management has been based on three major points: (1) the definition of extent of upper gastrointestinal lesions by immediate fibroendoscopy; (2) immediate protection of the upper gastrointestinal tract by total parenteral nutrition in cases with serious burns (41 cases), normal oral nutrition being allowed for minor burns (35 cases); (3) reparative surgical procedures for any of the sequelae of such burns during the fibrosing phase. The results were as follows: (a) healing, depending upon the degree of burn, occurred between eight to 90 days; (b) the frequency of subsequent local complications was small with total parenteral nutrition started a few hours after ingestion of the corrosive product; (c) after reconstructive surgery no serious complications occurred; (d) the overall morbidity stayed at a very low level (four patients). We conclude that the general prognosis of a severe burn of the upper gastrointestinal tract, without other trauma, is appreciably improved by the very early institution of total parenteral nutrition. PMID:6776011

  12. A Prodrug Approach to the Use of Coumarins as Potential Therapeutics for Superficial Mycoses

    PubMed Central

    Mercer, Derry K.; Robertson, Jennifer; Wright, Kristine; Miller, Lorna; Smith, Shane; Stewart, Colin S.; O′Neil, Deborah A.

    2013-01-01

    Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20–25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones. PMID:24260474

  13. SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin

    PubMed Central

    Seufert, Jochen

    2015-01-01

    Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These “concomitant effects” are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program

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

    PubMed

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

    2013-10-15

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

  15. The Role of Insulin-Like Growth Factor System in Soft Tissue Sarcomas: From Physiopathology to Targeted Therapeutic Approaches

    PubMed Central

    1998-01-01

    Purpose/Results. Although surgical, chemo- and radiotherapeutic treatment regimens in patients with soft tissue sarcomas have constantly been refined over the past two decades, the survival rate for these patients is rather low. Discussion. There is a great need to investigate the mechanisms for oncogenesis and to identify the factors involved in malignant transformation in sarcomas. Among these factors, IGFs are thought to play a pivotal role as progression factors in various types of sarcomas. The dysregulation of the IGF-II synthesis, e.g. by loss of imprinting which occurs in most types of sarcomas, is a permissive effect through the suppression of cell death. In addition, cells that overexpress the type I IGF receptors are more susceptible to transformation by oncogenes. As TP53 suppresses the activity of IGF-II P3 and P4, as well as the type I IGF receptor promoter, mutations of TP53 in sarcomas may alternatively lead to the activation of these factors. Finally, the phenomenon of non-islet cell tumour hypoglycaemia that occurs in patients with sarcomas, and which is related to the secretion of IGF-II prohormones, is discussed. Future therapeutic strategies may be based upon the application of antibodies or antisense oligonucleotides directed against the type I IGF receptors, with the common goal of inducing apoptosis in sarcoma cells. Ultimately, these and other therapeutic approaches may lead to a better outcome in patients suffering from sarcoma. PMID:18521237

  16. Synergy of Homocysteine, MicroRNA, and Epigenetics: A Novel Therapeutic Approach for Stroke

    PubMed Central

    Kalani, Anuradha; Kamat, Pradeep K.; Tyagi, Suresh C.

    2013-01-01

    Homocysteine (Hcy) is a thiol-containing amino acid formed during methionine metabolism. Elevated level of Hcy is known as hyperhomocysteinemia (HHcy). HHcy is an independent risk factor for cerebrovascular diseases such as stroke, dementia, Alzheimer’s disease, etc. Stroke, which is caused by interruption of blood supply to the brain, is one of the leading causes of death and disability in a number of people worldwide. The HHcy causes an increased carotid artery plaque that may lead to ischemic stroke but the mechanism is currently not well understood. Though mutations or polymorphisms in the key genes of Hcy metabolism pathway have been well elucidated in stroke, emerging evidences suggested epigenetic mechanisms equally play an important role in stroke development such as DNA methylation, chromatin remodeling, RNA editing, noncoding RNAs (ncRNAs), and microRNAs (miRNAs). However, there is no review available yet that describes the role of genetics and epigenetics during HHcy in stroke. The current review highlights the role of genetics and epigenetics in stroke during HHcy and the role of epigenetics in its therapeutics. The review also highlights possible epigenetic mechanisms, potential therapeutic molecules, putative challenges, and approaches to deal with stroke during HHcy. PMID:23430482

  17. New therapeutic approaches for malignant glioma: in search of the Rosetta stone

    PubMed Central

    Auffinger, Brenda; Thaci, Bart; Nigam, Pragati; Rincon, Esther; Cheng, Yu

    2012-01-01

    Malignant gliomas are heterogeneous, diffuse and highly infiltrating by nature. Despite wide surgical resection and improvements in radio- and chemotherapies, the prognosis of patients with glioblastoma multiforme remains extremely poor, with a median survival time of only 14.5 months from diagnosis to death. Particular challenges for glioblastoma multiforme therapy are posed by limitations in the extent of feasible surgical resections, distinct tumor heterogeneity, difficulties in drug delivery across the blood-brain barrier and low drug distribution within the tumor. Therefore, new paradigms permitting tumor-specific targeting and extensive intratumoral distribution must be developed to allow an efficient therapeutic delivery. This review highlights the latest advances in the treatment of glioblastoma multiforme and the recent developments that have resulted from the interchange between preclinical and clinical efforts. We also summarize and discuss novel therapies for malignant glioma, focusing on advances in the following main topics of glioblastoma multiforme therapy: immunotherapy, gene therapy, stem cell-based therapies and nanotechnology. We discuss strategies and outcomes of emerging therapeutic approaches in these fields, and the main challenges associated with the integration of discoveries that occur in the laboratory into clinical practice. PMID:22991580

  18. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163

    PubMed Central

    Hashizume, Rintaro; Ozawa, Tomoko; Gryaznov, Sergei M.; Bollen, Andrew W.; Lamborn, Kathleen R.; Frey, William H.; Deen, Dennis F.

    2008-01-01

    The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xeno-grafts intranasally with GRN163, an oligonucleotide N3′→P5′thio-phosphoramidate telomerase inhibitor. 3′-Fuorescein isothiocyanate (FITC)–labeled GRN163 was administered intranasally every 2 min as 6 μl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients. PMID:18287341

  19. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163.

    PubMed

    Hashizume, Rintaro; Ozawa, Tomoko; Gryaznov, Sergei M; Bollen, Andrew W; Lamborn, Kathleen R; Frey, William H; Deen, Dennis F

    2008-04-01

    The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-->P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 microl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients. PMID:18287341

  20. Mind-mapping for lung cancer: Towards a personalized therapeutics approach

    PubMed Central

    Mollberg, N; Surati, M; Demchuk, C; Fathi, R; Salama, AK; Husain, AN; Hensing, T; Salgia, R

    2011-01-01

    There will be over 220,000 people diagnosed with lung cancer and over 160,000 dying of lung cancer this year alone in the United States. In order to arrive at better control, prevention, diagnosis, and therapeutics for lung cancer, we must be able to personalize the approach towards lung cancer. Mind-mapping has existed for centuries for physicians to properly think about various “flows” of personalized medicine. We include here the epidemiology, diagnosis, histology, and treatment of lung cancer—specifically, non-small cell lung cancer. As we have new molecular signatures for lung cancer, this is further detailed. This review is not meant to be a comprehensive review, but rather its purpose is to highlight important aspects of lung cancer diagnosis, management, and personalized treatment options. PMID:21337123

  1. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches

    PubMed Central

    Rosenbaum, Anton I.; Maxfield, Frederick R.

    2010-01-01

    Cholesterol is an important lipid of mammalian cells. Its unique physicochemical properties modulate membrane behavior and it serves as the precursor for steroid hormones, oxysterols and vitamin D. Cholesterol is effluxed from the late endosomes/lysosomes via the concerted action of at least two distinct proteins: Niemann-Pick C1 and Niemann-Pick C2. Mutations in these two proteins manifest as Niemann-Pick type C disease – a very rare, usually fatal, autosomal, recessive, neurovisceral, lysosomal storage disorder. In this review we discuss the possible mechanisms of action for NPC1 and NPC2 in mediating cholesterol efflux, as well as the different therapeutic approaches being pursued for the treatment of this lipid storage disorder. PMID:20807315

  2. Alcohol liver disease: A review of current therapeutic approaches to achieve long-term abstinence

    PubMed Central

    García, María Luisa Gutiérrez; Blasco-Algora, Sara; Fernández-Rodríguez, Conrado M

    2015-01-01

    Harmful alcohol drinking may lead to significant damage on any organ or system of the body. Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe. In ALD, only alcohol abstinence was associated with a better long-term survival. Therefore, current effective therapeutic strategy should be oriented towards achieving alcohol abstinence or a significant reduction in alcohol consumption. Screening all primary care patients to detect those cases with alcohol abuse has been proposed as population-wide preventive intervention in primary care. It has been suggested that in patients with mild alcohol use disorder the best approach is brief intervention in the primary care setting with the ultimate goal being abstinence, whereas patients with moderate-to-severe alcohol use disorder must be referred to specialized care where detoxification and medical treatment of alcohol dependence must be undertaken. PMID:26229395

  3. Use of Integrated Computational Approaches in the Search for New Therapeutic Agents.

    PubMed

    Persico, Marco; Di Dato, Antonio; Orteca, Nausicaa; Cimino, Paola; Novellino, Ettore; Fattorusso, Caterina

    2016-09-01

    Computer-aided drug discovery plays a strategic role in the development of new potential therapeutic agents. Nevertheless, the modeling of biological systems still represents a challenge for computational chemists and at present a single computational method able to face such challenge is not available. This prompted us, as computational medicinal chemists, to develop in-house methodologies by mixing various bioinformatics and computational tools. Importantly, thanks to multi-disciplinary collaborations, our computational studies were integrated and validated by experimental data in an iterative process. In this review, we describe some recent applications of such integrated approaches and how they were successfully applied in i) the search of new allosteric inhibitors of protein-protein interactions and ii) the development of new redox-active antimalarials from natural leads. PMID:27546035

  4. Targeting autophagy as a potential therapeutic approach for immune thrombocytopenia therapy.

    PubMed

    Shan, Ning-Ning; Dong, Li-Li; Zhang, Xiao-Mei; Liu, Xin; Li, Ying

    2016-04-01

    Autophagy involves the sequestration and lysosomal degradation of various cytoplasmic structures, including damaged organelles and invading microorganisms. Autophagy is not only an essential cell-intrinsic mechanism for protecting against internal and external stress conditions but is also key in the cellular response against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. In recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Immune thrombocytopenia (ITP) is a multifactorial disease characterized by autoimmune responses to self-platelet membrane proteins. Recently, our unpublished original data demonstrated aberrant expression of molecules in the autophagy pathway in ITP patients compared with controls, and we found a close correlation between the pathogenesis of ITP and the autophagy pathway. The potential of targeting the autophagy pathway in ITP as a novel therapeutic approach has been discussed. PMID:26830007

  5. Pharmacological targeting of redox regulation systems as new therapeutic approach for psychiatric disorders: A literature overview.

    PubMed

    Schiavone, Stefania; Trabace, Luigia

    2016-05-01

    Redox dysregulation occurs following a disequilibrium between reactive oxygen species (ROS) producing and degrading systems, i.e. mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and nitric oxide synthase (NOS) on one hand and the principal antioxidant system, the glutathione, on the other hand. Increasing recent evidence points towards a pathogenetic role of an altered redox state in the development of several mental disorders, such as anxiety, bipolar disorders, depression, psychosis, autism and post-traumaticstress disorders (PTSD). In this regard, pharmacological targeting of the redox state regulating systems in the brain has been proposed as an innovative and promising therapeutic approach for the treatment of these mental diseases. This review will summarize current knowledge obtained from both pre-clinical and clinical studies in order to descant "lights and shadows" of targeting pharmacologically both the producing and degrading reactive oxygen species (ROS) systems in psychiatric disorders. PMID:26995306

  6. Antihypertensive therapy versus alternative therapeutic options for prehypertension: an evidence-based approach.

    PubMed

    Gaddam, Krishna K; Ventura, Hector; Lavie, Carl J

    2012-01-01

    The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) defines hypertension as systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg. The JNC-7 defines 'prehypertension' to include systolic BP values between 120 and 139 mmHg and diastolic BP values between 80 and 89 mmHg. Individuals with blood pressure in the prehypertension range are clearly at increased risk of developing hypertension in the future and have an increased risk of cardiovascular morbidity and mortality, compared with those with normal BP. However, there is paucity of evidence to intervene in these patients. In this article we discuss an evidence-based approach to therapeutic options in patients with prehypertension. PMID:22185450

  7. Alcohol liver disease: A review of current therapeutic approaches to achieve long-term abstinence.

    PubMed

    García, María Luisa Gutiérrez; Blasco-Algora, Sara; Fernández-Rodríguez, Conrado M

    2015-07-28

    Harmful alcohol drinking may lead to significant damage on any organ or system of the body. Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe. In ALD, only alcohol abstinence was associated with a better long-term survival. Therefore, current effective therapeutic strategy should be oriented towards achieving alcohol abstinence or a significant reduction in alcohol consumption. Screening all primary care patients to detect those cases with alcohol abuse has been proposed as population-wide preventive intervention in primary care. It has been suggested that in patients with mild alcohol use disorder the best approach is brief intervention in the primary care setting with the ultimate goal being abstinence, whereas patients with moderate-to-severe alcohol use disorder must be referred to specialized care where detoxification and medical treatment of alcohol dependence must be undertaken. PMID:26229395

  8. The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach.

    PubMed

    Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D; Gripp, Karen W; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum A; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A; Roberts, Amy; Silva, Alcino J; Sittampalam, Sitta G; Zhang, Chao; Schoyer, Lisa

    2015-08-01

    "The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. PMID:25900621

  9. Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease.

    PubMed

    Takahashi, Kou; Kong, Qiongman; Lin, Yuchen; Stouffer, Nathan; Schulte, Delanie A; Lai, Liching; Liu, Qibing; Chang, Ling-Chu; Dominguez, Sky; Xing, Xuechao; Cuny, Gregory D; Hodgetts, Kevin J; Glicksman, Marcie A; Lin, Chien-Liang Glenn

    2015-03-01

    Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD. PMID:25711212

  10. New trends in breast cancer surgery: a therapeutic approach increasingly efficacy and respectful of the patient

    PubMed Central

    FRANCESCHINI, G.; SANCHEZ, A. MARTIN; DI LEONE, A.; MAGNO, S.; MOSCHELLA, F.; ACCETTA, C.; MASETTI, R.

    2015-01-01

    The surgical management of breast cancer has undergone continuous and profound changes over the last 40 years. The evolution from aggressive and mutilating treatment to conservative approach has been long, but constant, despite the controversies that appeared every time a new procedure came to light. Today, the aesthetic satisfaction of breast cancer patients coupled with the oncological safety is the goal of the modern breast surgeon. Breast-conserving surgery with adjuvant radiotherapy is considered the gold standard approach for patients with early stage breast cancer and the recent introduction of “oncoplastic techniques” has furtherly increased the use of breast-conserving procedures. Mastectomy remains a valid surgical alternative in selected cases and is usually associated with immediate reconstructive procedures. New surgical procedures called “conservative mastectomies” are emerging as techniques that combine oncological safety and cosmesis by entirely removing the breast parenchyma sparing the breast skin and nipple-areola complex. Staging of the axilla has also gradually evolved toward less aggressive approaches with the adoption of sentinel node biopsy and new therapeutic strategies are emerging in patients with a pathological positivity in sentinel lymph node biopsy. The present work will highlight the new surgical treatment options increasingly efficacy and respectful of breast cancer patients. PMID:26712068

  11. Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach.

    PubMed

    Martínez, Jorge; Besa, Santiago; Arab, Juan P; Quintana, Juan C; Regonesi, Carlos; Huete, Alvaro; Jarufe, Nicolás; Guerra, Juan F; Benítez, Carlos; Arrese, Marco

    2015-01-01

    Gastrointestinal neuroendocrine tumors (NET) frequently present with unresectable hepatic metastases, which poses a barrier for curative treatment. Resection of the primary tumor and subsequent orthotopic liver transplantation (OLT) has been proposed as a treatment approach but available data in this regard is limited. We present a clinical case of an otherwise asymptomatic 44-yo man complaining of abdominal pain and dyspepsia that was diagnosed of a 10 cm duodenal tumor with multiple hepatic metastases. A CT-guided biopsy confirmed a NET. He underwent first a Whipple's procedure, and then was listed for liver transplantation. During the waiting time a multimodal therapeutic approach was used including the use of radioactive 177lutetium-labeled somatostatin analogues, long-acting somastostatin analogues and antiangiogenic antibodies (bevacizumab) in order to keep neoplastic disease under control. Two years after Whipple's procedure and given disease stability he underwent OLT with an uneventful postoperative evolution. Patient condition and graft function are optimal after a 4-year follow-up period with no evidence of recurrence. This case report underscores how a multimodal approach involving careful patient selection, resective surgery as well as use of somatostatin analogues and antiangiogenic biological therapy followed by liver transplantation can achieve excellent long-term results in this difficult patient population. PMID:26256906

  12. Targeting Importin-α7 as a Therapeutic Approach against Pandemic Influenza Viruses

    PubMed Central

    Resa-Infante, Patricia; Paterson, Duncan; Bonet, Jaume; Otte, Anna; Oliva, Baldo; Fodor, Ervin

    2015-01-01

    ABSTRACT Viral drug resistance is believed to be less likely to occur if compounds are directed against cellular rather than viral proteins. In this study, we analyzed the feasibility of a crucial viral replication factor, namely, importin-α7, as a cellular drug target to combat pandemic influenza viruses. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7−/− mice that otherwise are resistant. Viral escape from importin-α7 requirement was mediated by five mutations in the viral ribonucleoprotein complex and the surface glycoproteins. Moreover, the importin-α7−/− mouse-adapted strain became even more virulent for wild-type mice than the parental strain. These studies show that targeting host proteins may still result in viral escape by alternative pathways, eventually giving rise to even more virulent virus strains. Thus, therapeutic intervention strategies should consider a multitarget approach to reduce viral drug resistance. IMPORTANCE Here, we investigated the long-standing hypothesis based on in vitro studies that viral drug resistance occurrence is less likely if compounds are directed against cellular rather than viral proteins. Here, we challenged this hypothesis by analyzing, in an in vivo animal model, the feasibility of targeting the cellular factor importin-α7, which is crucial for human influenza virus replication and pathogenesis, as an efficient antiviral strategy against pandemic influenza viruses. In summary, our studies suggest that resistance against cellular factors is possible in vivo, and the emergence of even more virulent viral escape variants calls for particular caution. Thus, therapeutic intervention strategies should consider a multitarget approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence. PMID:26085167

  13. Mechanistic Evidence in Support of Alpha1-Antitrypsin as a Therapeutic Approach for Type 1 Diabetes

    PubMed Central

    Fleixo-Lima, Gabriella; Ventura, Hilla; Medini, Michal; Bar, Liliana; Strauss, Pnina

    2014-01-01

    Utilizing endogenous molecules as a therapeutic approach is almost unequivocally superior to engineered or synthetic molecules. However, one rarely encounters an anti-inflammatory, cytoprotective, immunomodulatory and wound-healing molecule that has been available for use for decades. α1-antitrypsin (AAT), a circulating protein that rises more than 4-fold during acute-phase responses, has been administered for a rare genetic deficiency at large doses, for life. Aside from advances in insulin therapy, medical research in type 1 diabetes (T1D) has predominantly focused on autoimmunity—controlling the adaptive immune response. However, it is now appreciated that one may need to extend therapeutic targets to incorporate immune responses to cellular injury, as well as promote selective control over excessive inflammation and early tissue repair. Recent data suggest that tissue damage related to lung and renal ischemia-reperfusion injury, stroke, and ischemic heart disease is markedly reduced by AAT. AAT was also shown to protect pancreatic islet β cells at multiple levels. Unlike classic immunosuppressive and anti-inflammatory approaches, AAT exerts some antiviral and antibacterial activities. Based on these and other reports, AAT is under evaluation for treatment of T1D patients in multiple clinical trials. Initial results suggest that AAT therapy could potentially improve insulin production without adverse effects. Up to 50% of individuals displayed improved islet function. It is a rare occurrence in T1D research that a therapy is offered that holds a safety profile equal or superior to that of insulin alone. While placebo-controlled trials are ongoing, the mechanism(s) behind these favorable activities of AAT are still being explored. PMID:25155845

  14. A retrosynthetic biology approach to metabolic pathway design for therapeutic production

    PubMed Central

    2011-01-01

    Background Synthetic biology is used to develop cell factories for production of chemicals by constructively importing heterologous pathways into industrial microorganisms. In this work we present a retrosynthetic approach to the production of therapeutics with the goal of developing an in situ drug delivery device in host cells. Retrosynthesis, a concept originally proposed for synthetic chemistry, iteratively applies reversed chemical transformations (reversed enzyme-catalyzed reactions in the metabolic space) starting from a target product to reach precursors that are endogenous to the chassis. So far, a wider adoption of retrosynthesis into the manufacturing pipeline has been hindered by the complexity of enumerating all feasible biosynthetic pathways for a given compound. Results In our method, we efficiently address the complexity problem by coding substrates, products and reactions into molecular signatures. Metabolic maps are represented using hypergraphs and the complexity is controlled by varying the specificity of the molecular signature. Furthermore, our method enables candidate pathways to be ranked to determine which ones are best to engineer. The proposed ranking function can integrate data from different sources such as host compatibility for inserted genes, the estimation of steady-state fluxes from the genome-wide reconstruction of the organism's metabolism, or the estimation of metabolite toxicity from experimental assays. We use several machine-learning tools in order to estimate enzyme activity and reaction efficiency at each step of the identified pathways. Examples of production in bacteria and yeast for two antibiotics and for one antitumor agent, as well as for several essential metabolites are outlined. Conclusions We present here a unified framework that integrates diverse techniques involved in the design of heterologous biosynthetic pathways through a retrosynthetic approach in the reaction signature space. Our engineering methodology

  15. Targeting Importin-α7 as a Therapeutic Approach against Pandemic Influenza Viruses.

    PubMed

    Resa-Infante, Patricia; Paterson, Duncan; Bonet, Jaume; Otte, Anna; Oliva, Baldo; Fodor, Ervin; Gabriel, Gülsah

    2015-09-01

    Viral drug resistance is believed to be less likely to occur if compounds are directed against cellular rather than viral proteins. In this study, we analyzed the feasibility of a crucial viral replication factor, namely, importin-α7, as a cellular drug target to combat pandemic influenza viruses. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7⁻/⁻ mice that otherwise are resistant. Viral escape from importin-α7 requirement was mediated by five mutations in the viral ribonucleoprotein complex and the surface glycoproteins. Moreover, the importin-α7⁻/⁻ mouse-adapted strain became even more virulent for wild-type mice than the parental strain. These studies show that targeting host proteins may still result in viral escape by alternative pathways, eventually giving rise to even more virulent virus strains. Thus, therapeutic intervention strategies should consider a multitarget approach to reduce viral drug resistance. IMPORTANCE Here, we investigated the long-standing hypothesis based on in vitro studies that viral drug resistance occurrence is less likely if compounds are directed against cellular rather than viral proteins. Here, we challenged this hypothesis by analyzing, in an in vivo animal model, the feasibility of targeting the cellular factor importin-α7, which is crucial for human influenza virus replication and pathogenesis, as an efficient antiviral strategy against pandemic influenza viruses. In summary, our studies suggest that resistance against cellular factors is possible in vivo, and the emergence of even more virulent viral escape variants calls for particular caution. Thus, therapeutic intervention strategies should consider a multitarget approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence. PMID:26085167

  16. Systems biology approach to developing S(2)RM-based "systems therapeutics" and naturally induced pluripotent stem cells.

    PubMed

    Maguire, Greg; Friedman, Peter

    2015-05-26

    The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell's power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely "systems therapeutic", can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called "systems therapeutics". A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S(2)RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S(2)RM technology, to develop a new class of therapeutics called "systems therapeutics." Given the ubiquitous and powerful nature of innate S(2)RM-based healing in the human body, this "systems therapeutic" approach using S(2)RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications. PMID:26029345

  17. Dissecting the role of microRNAs in prostate cancer metastasis: implications for the design of novel therapeutic approaches.

    PubMed

    Doldi, Valentina; Pennati, Marzia; Forte, Barbara; Gandellini, Paolo; Zaffaroni, Nadia

    2016-07-01

    Metastatic prostate cancer is a lethal disease that remains incurable despite the recent approval of new drugs, thus making the development of alternative treatment approaches urgently needed. A more precise understanding of the molecular mechanisms underlying prostate cancer dissemination could lead to the identification of novel therapeutic targets for the design of efficient anti-metastatic strategies. MicroRNA (miRNAs) are endogenous, small non-coding RNA molecules acting as key regulators of gene expression at post-transcriptional level. It has been clearly established that altered miRNA expression is a common hallmark of cancer. In addition, emerging evidence suggests their direct involvement in the metastatic cascade. In this review, we present a comprehensive overview of the data generated in experimental tumor models indicating that specific miRNAs may impinge on the different stages of prostate cancer metastasis, including (i) the regulation of epithelial-to-mesenchymal transition and cell migration/invasion, (ii) the interplay between cancer cells and the surrounding stroma, (iii) the control of angiogenesis, (iv) the regulation of anoikis, and (v) the colonization of distant organs. Moreover, we show preliminary evidence of the clinical relevance of some of these miRNAs, in terms of association with tumor aggressiveness/dissemination and clinical outcome, as emerged from translation studies carried out in prostate cancer patient cohorts. We also discuss the potential and the current limitations of manipulating metastasis-related miRNAs, by mimicking or inhibiting them, as a strategy for the development of novel therapeutic approaches for the advanced disease. PMID:26970978

  18. A multidisciplinary approach to therapeutic risk management of the suicidal patient

    PubMed Central

    Grant, Cynthia L; Lusk, Jaimie L

    2015-01-01

    As health care trends toward a system of care approach, providers from various disciplines strive to collaborate to provide optimal care for their patients. While a multidisciplinary approach to suicide risk assessment and management has been identified as important for reducing suicidality, standardized clinical guidelines for such an approach do not yet exist. In this article, the authors propose the adoption of the therapeutic risk management of the suicidal patient (TRMSP) to improve suicide risk assessment and management within multidisciplinary systems of care. The TRMSP, which has been fully articulated in previous articles, involves augmenting clinical risk assessment with structured instruments, stratifying risk in terms of both severity and temporality, and developing and documenting a safety plan. Augmenting clinical risk assessments with reliable and valid structured instruments serves several functions, including ensuring important aspects of suicide are addressed, establishing a baseline for suicidal thoughts and behaviors, facilitating interprofessional communication, and mitigating risk. Similarly, a two-dimensional risk stratification qualifying suicide risk in terms of both severity and temporality can enhance communication across providers and settings and improve understanding of acute crises in the context of chronic risk. Finally, safety planning interventions allow providers and patients to collaboratively create a personally meaningful plan for managing a suicidal crisis that can be continually modified across time with multiple providers in different care settings. In a busy care environment, the TRMSP can provide concrete guidance on conducting clinically and medicolegally sound suicide risk assessment and management. This collaborative and comprehensive process would potentially improve care of patients with suicidality, optimize clinical resources, decrease unnecessary and costly admissions, and mitigate medicolegal risk. The TRMSP may

  19. National Heart, Lung, and Blood Institute and the translation of cardiovascular discoveries into therapeutic approaches.

    PubMed

    Galis, Zorina S; Black, Jodi B; Skarlatos, Sonia I

    2013-04-26

    The molecular causes of ≈4000 medical conditions have been described, yet only 5% have associated therapies. For decades, the average time for drug development through approval has taken 10 to 20 years. In recent years, the serious challenges that confront the private sector have made it difficult to capitalize on new opportunities presented by advances in genomics and cellular therapies. Current trends are disturbing. Pharmaceutical companies are reducing their investments in research, and biotechnology companies are struggling to obtain venture funds. To support early-stage translation of the discoveries in basic science, the National Institutes of Health and the National Heart, Lung, and Blood Institute have developed new approaches to facilitating the translation of basic discoveries into clinical applications and will continue to develop a variety of programs that create teams of academic investigators and industry partners. The goal of these programs is to maximize the public benefit of investment of taxpayer dollars in biomedical research and to lessen the risk required for industry partners to make substantial investments. This article highlights several examples of National Heart, Lung, and Blood Institute-initiated translational programs and National Institutes of Health translational resources designed to catalyze and enable the earliest stages of the biomedical product development process. The translation of latest discoveries into therapeutic approaches depends on continued federal funding to enhance the early stages of the product development process and to stimulate and catalyze partnerships between academia, industry, and other sources of capital. PMID:23620235

  20. Nitric oxide scavengers as a therapeutic approach to nitric oxide mediated disease.

    PubMed

    Fricker, S P

    1999-08-01

    The essential role of nitric oxide (NO) in normal physiology and its involvement in the pathophysiology of a variety of diseases render the compound an attractive therapeutic target. NO donor drugs are used in the treatment of hypotension and angina where abnormalities in the L-arginine-nitric oxide pathway have been implicated. Overproduction of NO has been associated with a number of disease states including septic shock, inflammatory diseases, diabetes, ischaemia-reperfusion injury, adult respiratory distress syndrome, neurodegenerative diseases and allograft rejection. NO is produced by a group of enzymes, the nitric oxide synthases. Selective inhibition of the inducible isoform is one approach to the treatment of diseases where there is an overproduction of NO; an alternative approach is to scavenge or remove excess NO. A number of NO scavenger molecules have demonstrated pharmacological activity in disease models, particularly models of septic shock. These include organic molecules such as PTIO (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), haemoglobin derivatives such as the pyridoxalated haemoglobin polyoxyethylene conjugate (PHP), low molecular weight iron compounds of diethylenetriaminepentaacetic acid and diethyldithiocarbamate and ruthenium polyaminocarboxylate complexes. The data suggest a potential role for NO scavengers in the treatment of NO mediated disease. PMID:15992146

  1. Implications of current therapeutic approaches in colorectal cancer for other gastrointestinal malignancies.

    PubMed

    Lembersky, B C

    1991-02-01

    Novel immunotherapeutic strategies for combating colon cancer are also being explored in pancreatic, hepatic, and esophageal cancers. Preliminary clinical trials in patients with pancreatic cancer suggest a therapeutic role for anti-idiotypic antibodies against tumor-specific monoclonal antibodies (MoAbs)--eg, CO17-1A, BW 494/32--but not for MoAbs when used alone. Adding low doses of interferon gamma to CO17-1A enhances in vitro antibody-dependent cellular cytotoxicity against pancreatic tumor cells; CO17-1A plus a regimen of 5-FU/doxorubicin/mitomycin has resulted in beneficial therapeutic effect. Treatments with immunotoxins, radiolabeled MoAbs, and adoptive immunotherapy are still being tested preclinically. In 105 patients with unresectable hepatocellular cancer, a 7% complete and 41% partial regression rate with 131I-labeled antiferritin has been reported. In several patients, radiolabeled antiferritin caused sufficient shrinkage of lesions to permit curative resection. Pretreatment with low-dose doxorubicin may improve the efficacy of low-dose radiolabeled antiferritin antibody therapy. Chemoembolization of primary hepatocellular carcinoma, based on the concept of regional therapy for metastatic colorectal cancer, has shown considerable palliative and survival benefit in patients with unresectable disease. Although adoptive immunotherapy has been used to treat hepatocellular carcinoma, the results have been disappointing. The development of immunotherapeutic approaches to esophageal cancer is less advanced than that for other gastrointestinal malignancies. Paralleling the successful use of 5-FU/interferon alfa-2a in colon cancer are two phase II studies that have evaluated this combination in patients with locally advanced esophageal cancer. The objective response rate (27%) was encouraging. PMID:1992529

  2. Bacteriophage--a common divergent therapeutic approach for Alzheimer's disease and type II diabetes mellitus.

    PubMed

    Sohrab, Sayed S; Karim, Sajjad; Kamal, Mohammad A; Abuzenadah, Adel M; Chaudhary, Adeel G; Al-Qahtani, Mohammed H; Mirza, Zeenat

    2014-04-01

    Alzheimer's disease, the most important neurodegenerative disorder, is an irreversible, age-dependent disease of the brain characterized by problems in progressive impairments in memory, language, reasoning, behavior and visuospatial skills. It is characterized by the deposition of amyloid beta peptide, forming compact fibrillar plaques and neurofibrillary tau tangles. Another major and much more prevalent cause of morbidity and mortality in world is diabetes especially type 2 diabetes mellitus. It is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic wounds caused by antibiotic resistant bacterial infections that fail to heal are a common complication of diabetes mellitus and the most frequent reason for nontraumatic lower limb amputation. Holistically, these two diseases are linked at molecular level but the exact mechanism is a topic of debate. Bacteriophages are viruses infecting bacteria and lack ability to infect mammalian cells. They are neither causative agent for Alzheimer's disease or type 2 diabetes mellitus nor involved in their pathogenicity but promises for a novel divergent therapeutic approach. The great versatility of the phage system has led to the development of improved phage delivery vectors, as well as immunomodulation of anti-amyloid beta peptide response. Phages could also constitute valuable prophylaxis against bacterial infections, especially in immunocompromised patients like in the case of diabetes. Patients having diabetes have a high risk of developing foot ulcers which are difficult to be treated by antibiotics alone due to ever increasing antibiotic resistance strains. Combination therapy based on multiple phage and broad spectrum antibiotics holds great promise. The potential therapeutic phage therapy arises from its lack of natural tropism for mammalian cells, resulting in no adverse effects. PMID:24059304

  3. Differences in the Therapeutic Approach to Colorectal Cancer in Young and Elderly Patients

    PubMed Central

    Jimenez, Ana B.; García-Alhambra, María A.; Pla, Rosa; Vidán, Maite; Rodríguez, Paz; Ortiz, Javier; García-Alfonso, Pilar; Martín, Miguel

    2012-01-01

    Purpose. To analyze differences in the therapeutic approach to and tumor-related mortality of young and elderly colorectal cancer (CRC) patients. Patients and Methods. This was a descriptive study of a retrospective cohort, based on administrative databases, of all patients with CRC diagnosed or treated in our institution. We extracted data on sociodemographic characteristics, comorbidity, type of cancer, type of treatment received, survival time, and cause of death. We compared differences between a young group (YG) (age <75 years) and an older group (OG) (age ≥75 years) and assessed the variables associated with receiving different therapeutic options (multivariate analysis) and with survival time (Cox proportional hazards models). Results. The study included 503 patients (YG, 320; OG, 183), with mean ages of 63.1 years in the YG and 81.8 years in the OG. No differences were observed between the groups in degree of differentiation, extension, tumor stage, or comorbidity. After adjustment for gender, comorbidity, and tumor localization and extension, YG patients were more likely than OG patients to receive surgery, radiotherapy, and chemotherapy and less likely to receive palliative care. After a median follow-up of 36.5 months, YG patients had a longer tumor-specific survival time than OG patients (36.41 months vs 26.05 months). After further adjustment, the YG had a lower tumor-specific mortality risk (hazard ratio, 0.66) than the OG. Conclusion. In comparison with younger patients, elderly CRC patients are undertreated, mainly because of their age and not because of their tumor type or comorbidity. Elderly patients have a significantly shorter tumor-specific survival time, partially because of this undertreatment. PMID:22923453

  4. Transglutaminase inhibition as a possible therapeutical approach to protect cells from death in neurodegenerative diseases.

    PubMed

    Iannaccone, Martina; Serretiello, Enrica; De Vivo, Giulia; Martin, Antonio; Stefanile, Alessandro; Titta, Federica; Gentile, Vittorio

    2013-08-01

    Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, "tissue" transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates to cysteamine and derivatives. PMID:23688272

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

    PubMed

    Dalamagkas, Kyriakos; Tsintou, Magdalini; Seifalian, Alexander

    2016-08-01

    Peripheral nerve injury is a very common medical condition with varying clinical severity but always great impact on the patients' productivity and the quality of life. Even the current 1st-choice surgical therapeutic approach or the "gold standard" as frequently called in clinical practice, is not addressing the problem efficiently and cost-effectively, increasing the mortality through the need of a second surgical intervention, while it does not take into account the several different types of nerves involved in peripheral nerve injuries. Neural tissue engineering approaches could potentially offer a very promising and attractive tool for the efficient peripheral nerve injury management, not only by mechanically building the gap, but also by inducing neuroregenerative mechanisms in a well-regulated microenvironment which would mimic the natural environment of the specific nerve type involved in the injury to obtain an optimum clinical outcome. There is still room for a lot of optimizations in regard to the conduits which have been developed with the help of neural engineering since many parameters affect the clinical outcome and the underlying mechanisms are still not well understood. Especially the intraluminal cues controlling the microenvironment of the conduits are in an infantile stage but there is profound potential in the application of the scaffolds. The aim of our review is to provide a quick reference to the recent advances in the field, focusing on the parameters that can significantly affect the clinical potentials of each approach, with suggestions for future improvements that could take the current work from bench to bedside. Thus, further research could shed light to those questions and it might hold the key to discover new more efficient and cost-effective therapies. PMID:27157770

  6. [Immunosuppressive treatment of rheumatic diseases. Experimental bases of a rational concept of therapeutic approach (author's transl)].

    PubMed

    Lemmel, E M; Botzenhardt, U

    1976-01-01

    For treatment of diseases such as rheumatoid arthritis or systemic lupus erythematodes, which are initiated or sustained by immune-pathological mechanisms, various "immunosuppressive" drugs are used. There are conflicting data as to the benefit of this type of therapy. In this paper it is attempted to define a base for a more differentiated application of available drugs, since the present therapeutic approach seems rather empiric or is deducted from analogy to selected animal experiments. The investigations presented focus primarily on the behaviour of the small and medium lymphocytes of the organism, the adopted carriers of immunological (as well as autoimmune) reactivity, under conventional conditions (and under the influence of suitable drugs) as a biological supposition for the activity of "immunosuppressives". In rabbits, and mice, number and rate of proliferation of lymphoid cells is determined in untreated controls and animals treated with 6-mercaptopurine (6-MP) and cyclophosphamide (Cy), two immunosuppressive agents representing different types of pharmacological action. The elucidation why in rabbits both substances are equally immunosuppressive, whereas in mice only Cy has significant immunosuppressive activity, yields the base for a therapeutic concept of clinical immunosuppression. This species dependent activity of 6-MP can be explained by different proliferation kinetics of lymphoid cells in mouse and rabbit. Lymphocytes of the rabbit, compared to those of mice, are short-lived and have a distinctly higher proliferation rate. Thus, 6-MP, as an antiproliferative agent, leads, in the rabbit (under long-term as well as single-dose therapy) to a significant reduction of the number of small lymphocytes, whereas it reduces the long-lived lymphocytes of the mouse only marginally, thus explaining the good immunosuppressive potency in the rabbit and failure in the mouse. Cy leads, in both species, to a marked reduction of small lymphocytes and affects the

  7. Targeting surface-layer proteins with single-domain antibodies: a potential therapeutic approach against Clostridium difficile-associated disease.

    PubMed

    Kandalaft, Hiba; Hussack, Greg; Aubry, Annie; van Faassen, Henk; Guan, Yonghong; Arbabi-Ghahroudi, Mehdi; MacKenzie, Roger; Logan, Susan M; Tanha, Jamshid

    2015-10-01

    Clostridium difficile is a leading cause of death from gastrointestinal infections in North America. Antibiotic therapy is effective, but the high incidence of relapse and the rise in hypervirulent strains warrant the search for novel treatments. Surface layer proteins (SLPs) cover the entire C. difficile bacterial surface, are composed of high-molecular-weight (HMW) and low-molecular-weight (LMW) subunits, and mediate adherence to host cells. Passive and active immunization against SLPs has enhanced hamster survival, suggesting that antibody-mediated neutralization may be an effective therapeutic strategy. Here, we isolated a panel of SLP-specific single-domain antibodies (VHHs) using an immune llama phage display library and SLPs isolated from C. difficile hypervirulent strain QCD-32g58 (027 ribotype) as a target antigen. Binding studies revealed a number of VHHs that bound QCD-32g58 SLPs with high affinity (K D = 3-6 nM) and targeted epitopes located on the LMW subunit of the SLP. The VHHs demonstrated melting temperatures as high as 75 °C, and a few were resistant to the gastrointestinal protease pepsin at physiologically relevant concentrations. In addition, we demonstrated the binding specificity of the VHHs to the major C. difficile ribotypes by whole cell ELISA, where all VHHs were found to bind 001 and 027 ribotypes, and a subset of antibodies were found to be broadly cross-reactive in binding cells representative of 012, 017, 023, and 078 ribotypes. Finally, we showed that several of the VHHs inhibited C. difficile QCD-32g58 motility in vitro. Targeting SLPs with VHHs may be a viable therapeutic approach against C. difficile-associated disease. PMID:25936376

  8. An in silico approach for identification of novel inhibitors as a potential therapeutics targeting HIV-1 viral infectivity factor.

    PubMed

    Sinha, Chanda; Nischal, Anuradha; Bandaru, Srinivas; Kasera, Priyadarshani; Rajput, Ashish; Nayarisseri, Anuraj; Khattri, Sanjay

    2015-01-01

    Currently available antiviral drugs target the pol-encoded retroviral enzymes or integrases, in addition, inhibitors that target HIV-1 envelope-receptor interactions have also been recently approved. Recent understanding of the interactions between HIV-1 and host restriction factors has provided fresh avenues for development of novel antiviral drugs. For example, viral infectivity factor (Vif) now surfaced as an important therapeutic target in treatment of HIV infection. Vif suppresses A3G antiviral activity by targeting these proteins for polyubiquitination and proteasomal degradation. In the present study we analyzed the inhibitory potential of VEC5 and RN18 to inhibit the Vif-A3G interaction through protein- protein docking studies. Perusal of the study showed that, VEC5 and RN18 though inhibits the interaction however showed sub optimal potential. To overcome this set back, we identified 35 structural analogues of VEC5 and 18 analogues of RN18 through virtual screening approach. Analogue with PubCID 71624757 and 55358204 (AKOS006479723) -structurally akin to VEC5 and RN18 respectively showed much appreciable interaction than their respective parent compound. Evident from Vif-A3G; protein - protein docking studies, analogue PubCID 71624757 demonstrated 1.08 folds better inhibitory potential than its parent compound VEC5 while analogue PubCID 55358204 was 1.15 folds better than RN18. Further these analogues passed drug likeness filters and predicted to be non- toxic. We expect these analogues can be put to pharmacodynamic studies that can pave way the breakthrough in HIV therapeutics. PMID:25579575

  9. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches.

    PubMed

    Di Meo, Ivano; Lamperti, Costanza; Tiranti, Valeria

    2015-10-01

    Mitochondrial disorders are a group of highly invalidating human conditions for which effective treatment is currently unavailable and characterized by faulty energy supply due to defective oxidative phosphorylation (OXPHOS). Given the complexity of mitochondrial genetics and biochemistry, mitochondrial inherited diseases may present with a vast range of symptoms, organ involvement, severity, age of onset, and outcome. Despite the wide spectrum of clinical signs and biochemical underpinnings of this group of dis-orders, some common traits can be identified, based on both pathogenic mechanisms and potential therapeutic approaches. Here, we will review two peculiar mitochondrial disorders, ethylmalonic encephalopathy (EE) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), caused by mutations in the ETHE1 and TYMP nuclear genes, respectively. ETHE1 encodes for a mitochondrial enzyme involved in sulfide detoxification and TYMP for a cytosolic enzyme involved in the thymidine/deoxyuridine catabolic pathway. We will discuss these two clinical entities as a paradigm of mitochondrial diseases caused by the accumulation of compounds normally present in traces, which exerts a toxic and inhibitory effect on the OXPHOS system. PMID:26194912

  10. HSP90 and HSP70: Implication in Inflammation Processes and Therapeutic Approaches for Myeloproliferative Neoplasms

    PubMed Central

    Sevin, Margaux; Girodon, François; Garrido, Carmen; de Thonel, Aurélie

    2015-01-01

    Myeloproliferative neoplasms (MPN) are clonal stem cell disorders that lead to the excessive production of one or more blood cell lineages. It has been reported that, in most MPN, inflammatory cytokines are frequently increased, indicating that inflammation plays a crucial role in these disorders. Heat shock proteins (HSP) are induced in response to many stressful conditions from heat shock to hypoxia and inflammation. Besides their chaperone and cytoprotective functions, HSPs are key players during inflammation, hence the term “chaperokine.” Through their chaperone activity, HSP90, a stabilizer of many oncogenes (e.g., JAK2), and HSP70, a powerful antiapoptotic chaperone, tightly regulate Nuclear Factor-kappa B signalling, a critical pathway in mediating inflammatory responses. In light of this potential, several HSP90 inhibitors have been generated as anticancer agents able to degrade oncogenes. As it turns out, however, these drugs are also potent inhibitors of the inflammatory response in various diseases. Given the chaperone potential of HSP70 and the fact that HSP90 inhibitors induce HSP70, interest in HSP70 inhibitors is also increasing. Here, we focus on the implication of HSP90 and HSP70 in inflammatory responses and on the emergence of new therapeutic approaches in MPN based on HSP inhibitors. PMID:26549943

  11. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches

    PubMed Central

    Di Meo, Ivano; Lamperti, Costanza; Tiranti, Valeria

    2015-01-01

    Mitochondrial disorders are a group of highly invalidating human conditions for which effective treatment is currently unavailable and characterized by faulty energy supply due to defective oxidative phosphorylation (OXPHOS). Given the complexity of mitochondrial genetics and biochemistry, mitochondrial inherited diseases may present with a vast range of symptoms, organ involvement, severity, age of onset, and outcome. Despite the wide spectrum of clinical signs and biochemical underpinnings of this group of dis-orders, some common traits can be identified, based on both pathogenic mechanisms and potential therapeutic approaches. Here, we will review two peculiar mitochondrial disorders, ethylmalonic encephalopathy (EE) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), caused by mutations in the ETHE1 and TYMP nuclear genes, respectively. ETHE1 encodes for a mitochondrial enzyme involved in sulfide detoxification and TYMP for a cytosolic enzyme involved in the thymidine/deoxyuridine catabolic pathway. We will discuss these two clinical entities as a paradigm of mitochondrial diseases caused by the accumulation of compounds normally present in traces, which exerts a toxic and inhibitory effect on the OXPHOS system. PMID:26194912

  12. A new therapeutic approach using a schizophyllan-based drug delivery system for inflammatory bowel disease.

    PubMed

    Takedatsu, Hidetoshi; Mitsuyama, Keiichi; Mochizuki, Shinichi; Kobayashi, Teppei; Sakurai, Kazuo; Takeda, Hiroshi; Fujiyama, Yoshihide; Koyama, Yoshikazu; Nishihira, Jun; Sata, Michio

    2012-06-01

    Antisense technologies for the targeted inhibition of gene expression could provide an effective strategy for the suppression of inflammation. However, the effective use of antisense oligonucleotides (ODN) has been limited because of several problems. Therefore, a delivery system for antisense ODNs that enhances antisense stability, while maintaining the specificity of antisense for its target RNA or DNA is needed. We have developed a delivery system for antisense ODN using schizophyllan (SPG), a polysaccharide that belongs to the β-(1-3) glucan family. This system has several advantages enabling the effective suppression of targeted RNA or DNA: the SPG complex is stable in vivo and does not dissolve in the presence of deoxyribonuclease, and the SPG complex is effectively taken up into macrophages by phagocytosis through Dectin-1. Macrophage-migration inhibitory factor (MIF), which is mainly produced by macrophages has been shown to have a pathogenetic role in inflammatory bowel disease (IBD). We developed a technique to create an SPG complex that highly conformed to the antisense MIF. The administration of antisense MIF/SPG complex effectively suppressed MIF production and significantly ameliorated intestinal inflammation. Our result demonstrated a possible new therapeutic approach, i.e., the administration of antisense MIF/SPG complex, for the treatment of IBD. PMID:22334022

  13. A New Therapeutic Approach Using a Schizophyllan-based Drug Delivery System for Inflammatory Bowel Disease

    PubMed Central

    Takedatsu, Hidetoshi; Mitsuyama, Keiichi; Mochizuki, Shinichi; Kobayashi, Teppei; Sakurai, Kazuo; Takeda, Hiroshi; Fujiyama, Yoshihide; Koyama, Yoshikazu; Nishihira, Jun; Sata, Michio

    2012-01-01

    Antisense technologies for the targeted inhibition of gene expression could provide an effective strategy for the suppression of inflammation. However, the effective use of antisense oligonucleotides (ODN) has been limited because of several problems. Therefore, a delivery system for antisense ODNs that enhances antisense stability, while maintaining the specificity of antisense for its target RNA or DNA is needed. We have developed a delivery system for antisense ODN using schizophyllan (SPG), a polysaccharide that belongs to the β-(1-3) glucan family. This system has several advantages enabling the effective suppression of targeted RNA or DNA: the SPG complex is stable in vivo and does not dissolve in the presence of deoxyribonuclease, and the SPG complex is effectively taken up into macrophages by phagocytosis through Dectin-1. Macrophage-migration inhibitory factor (MIF), which is mainly produced by macrophages has been shown to have a pathogenetic role in inflammatory bowel disease (IBD). We developed a technique to create an SPG complex that highly conformed to the antisense MIF. The administration of antisense MIF/SPG complex effectively suppressed MIF production and significantly ameliorated intestinal inflammation. Our result demonstrated a possible new therapeutic approach, i.e., the administration of antisense MIF/SPG complex, for the treatment of IBD. PMID:22334022

  14. Acute respiratory distress syndrome following cardiovascular surgery: current concepts and novel therapeutic approaches

    PubMed Central

    Hoegl, Sandra; Zwissler, Bernhard; Eltzschig, Holger K.; Vohwinkel, Christine

    2015-01-01

    Purpose of review This review gives an update on current treatment options and novel concepts on the prevention and treatment of the acute respiratory distress syndrome (ARDS) in cardiovascular surgery patients. Recent findings The only proven beneficial therapeutic options in ARDS are those that help to prevent further ventilator-induced lung injury, such as prone position, use of lung-protective ventilation strategies, and extracorporeal membrane oxygenation. In the future also new approaches like mesenchymal cell therapy, activation of hypoxia-elicited transcription factors or targeting of purinergic signaling may be successful outside the experimental setting. Owing to the so far limited treatment options, it is of great importance to determine patients at risk for developing ARDS already perioperatively. In this context, serum biomarkers and lung injury prediction scores could be useful. Summary Preventing ARDS as a severe complication in the cardiovascular surgery setting may help to reduce morbidity and mortality. As cardiovascular surgery patients are of greater risk to develop ARDS, preventive interventions should be implemented early on. Especially, use of low tidal volumes, avoiding of fluid overload and restrictive blood transfusion regimes may help to prevent ARDS. PMID:26598954

  15. Acupuncture Points Stimulation for Meniere's Disease/Syndrome: A Promising Therapeutic Approach

    PubMed Central

    He, Jiaojun; Jiang, Liyuan; Peng, Tianqiang; Xia, Meixia

    2016-01-01

    Objective. This study aims to explore evidence for acupuncture points stimulation (APS) in treatment of Meniere's disease (MD). Method. A literature search was conducted in seven databases including EMBASE, Medline, Cochrane Library, Web of Science, CBM, CNKI, and WangFang database and the data analysis was performed by using the RevMan version 5.3. Results. 12 RCTs with 993 participants were acquired after the search. The quality of most eligible studies was very low which limited the value of the meta-analysis. Compared with western medicine comprehensive treatment (WMCT), the APS alone or in combination with WMCT had a significant positive effect in controlling vertigo; however, the result was negative in hearing improvement and DHI. No adverse events were reported in the studies. Conclusion. The APS might be a promising therapeutic approach for MD. However, the currently available evidence is insufficient to make a definitive conclusion for the poor quality of included studies. More high-quality researches with larger sample size are urgently needed to assess the effectiveness and safety. PMID:27547229

  16. Novel therapeutics for primary biliary cholangitis: Toward a disease-stage-based approach.

    PubMed

    Mousa, Hani S; Carbone, Marco; Malinverno, Federica; Ronca, Vincenzo; Gershwin, M Eric; Invernizzi, Pietro

    2016-09-01

    Primary biliary cholangitis (PBC; previously "primary biliary cirrhosis") is a cholestatic, putatively autoimmune-mediated liver disease with a clear female preponderance affecting the intrahepatic small and medium-size bile ducts and resulting in bile duct destruction, ductopenia and portal fibrosis that progresses slowly to biliary cirrhosis. Despite suboptimal response in one third of patients treated with ursodeoxycholic acid (UDCA), this remains the only FDA-approved agent for this disease. In this review, we cover recent advances in research that have yielded numerous agents currently at different stages of the drug pipeline, some of which are expected to be approved in the near future. We also discuss accumulating evidence supporting the use of older agents (fibrates and glucocorticoids) as an adjunctive therapy to UDCA in non-responsive patients. We suggest that with the imminent expansion of the therapeutic armamentarium for PBC, a more comprehensive approach - ideally taking into account not only biochemical markers of disease stage - is needed to better select patients in whom these strategies might be most useful. Studies are also needed to compare the relative efficacy of different proposed second-line treatments not only against UDCA monotherapy. PMID:27393766

  17. Acute encephalitis with refractory, repetitive partial seizures: Pathological findings and a new therapeutic approach using tacrolimus.

    PubMed

    Sato, Yuko; Numata-Uematsu, Yurika; Uematsu, Mitsugu; Kikuchi, Atsuo; Nakayama, Tojo; Kakisaka, Yosuke; Kobayashi, Tomoko; Hino-Fukuyo, Naomi; Suzuki, Hiroyoshi; Takahashi, Yukitoshi; Saito, Yoshiaki; Tanuma, Naoyuki; Hayashi, Masaharu; Iwasaki, Masaki; Haginoya, Kazuhiro; Kure, Shigeo

    2016-09-01

    Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by prolonged severe seizures and a high-grade fever. We experienced a boy with severe AERRPS with frequent partial seizures that exhibited right-side predominance. The patient required the continuous intravenous administration of many antiepileptic drugs and respirator management for several months. Methylprednisolone pulse therapy and intravenous immunoglobulin administration were only temporarily effective. The MRI and EEG showed the abnormality in the left occipital lobe. Although occipital lobectomy was performed, his seizures continued. His cerebrospinal fluid exhibited elevated protein and proinflammatory cytokine levels, and was positive for anti-glutamate receptor ε2 antibodies. Pathological examination showed infiltration of many neutrophilic leukocytes, T cells, and microglia in the area exhibiting severe spongiosis. We thought that the exaggerated microglia and T-cell responses were related to the pathogenesis of the patient's seizures, and we therefore initiated treatment with tacrolimus. As a result, many of the daily seizure clusters were ameliorated, and the patient was discharged. We attempted to discontinue the tacrolimus twice, but the patient's seizure clusters recurred each time. This is the first case report of the pathological findings of AERRPS and showing an effective therapeutic approach using tacrolimus. Tacrolimus may be an effective immunosuppressant, especially for patients with severe AERRPS. PMID:26906012

  18. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases.

    PubMed

    Cuenca, Nicolás; Fernández-Sánchez, Laura; Campello, Laura; Maneu, Victoria; De la Villa, Pedro; Lax, Pedro; Pinilla, Isabel

    2014-11-01

    Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies. PMID:25038518

  19. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation.

    PubMed

    Langdon, Amy; Crook, Nathan; Dantas, Gautam

    2016-01-01

    The widespread use of antibiotics in the past 80 years has saved millions of human lives, facilitated technological progress and killed incalculable numbers of microbes, both pathogenic and commensal. Human-associated microbes perform an array of important functions, and we are now just beginning to understand the ways in which antibiotics have reshaped their ecology and the functional consequences of these changes. Mounting evidence shows that antibiotics influence the function of the immune system, our ability to resist infection, and our capacity for processing food. Therefore, it is now more important than ever to revisit how we use antibiotics. This review summarizes current research on the short-term and long-term consequences of antibiotic use on the human microbiome, from early life to adulthood, and its effect on diseases such as malnutrition, obesity, diabetes, and Clostridium difficile infection. Motivated by the consequences of inappropriate antibiotic use, we explore recent progress in the development of antivirulence approaches for resisting infection while minimizing resistance to therapy. We close the article by discussing probiotics and fecal microbiota transplants, which promise to restore the microbiota after damage of the microbiome. Together, the results of studies in this field emphasize the importance of developing a mechanistic understanding of gut ecology to enable the development of new therapeutic strategies and to rationally limit the use of antibiotic compounds. PMID:27074706

  20. Non-Clear Cell Renal Cancer: Disease-Based Management and Opportunities for Targeted Therapeutic Approaches

    PubMed Central

    Linehan, W. Marston; Srinivasan, Ramaprasad; Garcia, Jorge A.

    2014-01-01

    A better understanding of the biology of renal cell carcinoma (RCC) has significantly changed the treatment paradigm of the disease. Several novel VEGF and TORC inhibitors have bee recently FDA-approved. Unfortunately, the vast majority of clinical trials conducted today have been aimed to include patients with clear-cell RCC which remains the most common histologic subtype of the disease. Non-clear cell RCC represents approximately 20 to 25% of all RCC patients. Non-clear RCC is made up of multiple histologic subtypes each with a different molecular printing profile. Although VEGF and TORC inhibitors are commonly used in the management of this cohort of patients, non-clear cell histologies do not appear to be related to VHL. As such the clinical efficacy of the existing agents is quite limited. There is a need to develop more rational therapeutic approaches that specifically target the biology off each of the different subtypes of non-clear RCC. In this review, we discuss molecular and clinical characteristics of each of the non-clear cell RCC subtypes and describe ongoing efforts to develop novel agents for this subset of patients. PMID:23972715

  1. Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma.

    PubMed

    Sourbier, Carole; Valera-Romero, Vladimir; Giubellino, Alessio; Yang, Youfeng; Sudarshan, Sunil; Neckers, Len; Linehan, W Marston

    2010-10-15

    Hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated renal tumors are aggressive and tend to metastasize early. There are currently no effective forms of therapy for patients with advanced HLRCC-associated kidney cancer. We have previously shown that HLRCC cells express a high level of reactive oxygen species (ROS). In the present study we investigated the cytotoxic effects of increasing ROS level using bortezomib in combination with cisplatin on HLRCC cells in vitro and in an in vivo xenograft model. The cytotoxic effect of several ROS inducers on FH-deficient cells was assessed by synthetic lethality. ROS inducers had a pronounced impact on the viability of FH-deficient cells. Because of its high potency, the proteasome inhibitor bortezomib was further investigated. Bortezomib induced apoptosis in vitro in HLRCC cells and inhibited HLRCC tumour growth in vivo. Bortezomib-associated cytotoxicity was highly correlated with cellular ROS level: combining bortezomib with other ROS inducers enhanced cytotoxicity, while combining bortezomib with a ROS scavenger inhibited its cytotoxic effect. Finally, HLRCC murine xenografts were treated with bortezomib and cisplatin, another ROS inducer. This regimen induced HLRCC tumour regression in vivo. These findings suggest that increasing ROS level in HLRCC above a certain threshold can induce HLRCC-tumor cell death. Increasing tumor ROS with bortezomib in combination with cisplatin represents a novel targeted therapeutic approach to treat advanced HLRCC-associated renal tumors. PMID:20953139

  2. Ion channel remodeling in vascular smooth muscle during hypertension: Implications for novel therapeutic approaches

    PubMed Central

    Joseph, Biny K.; Thakali, Keshari M.; Moore, Christopher L.; Rhee, Sung W.

    2013-01-01

    Ion channels are multimeric, transmembrane proteins that selectively mediate ion flux across the plasma membrane in a variety of cells including vascular smooth muscle cells (VSMCs). The dynamic interplay of Ca2+ and K+ channels on the plasma membrane of VSMCs plays a pivotal role in modulating the vascular tone of small arteries and arterioles. The abnormally-elevated arterial tone observed in hypertension thus points to an aberrant expression and function of Ca2+ and K+ channels in the VSMCs. In this short review, we focus on the three well-studied ion channels in VSMCs, namely the L-type Ca2+ (CaV1.2) channels, the voltage-gated K+ (KV) channels, and the large-conductance Ca2+-activated K+ (BK) channels. First, we provide a brief overview on the physiological role of vascular CaV1.2, KV and BK channels in regulating arterial tone. Second, we discuss the current understanding of the expression changes and regulation of CaV1.2, KV and BK channels in the vasculature during hypertension. Third, based on available proof-of-concept studies, we describe the potential therapeutic approaches targeting these vascular ion channels in order to restore blood pressure to normotensive levels. PMID:23376354

  3. ARB-based single-pill platform to guide a practical therapeutic approach to hypertensive patients.

    PubMed

    Volpe, Massimo; de la Sierra, Alejandro; Kreutz, Reinhold; Laurent, Stéphane; Manolis, Athanasios J

    2014-06-01

    Hypertension is a major modifiable risk for the development of cardiovascular, cerebrovascular and renal diseases. Thus, effective treatment of high blood pressure is an important strategy for reducing disease burden; however, in spite of the availability of numerous effective therapies only 30-40 % of patients with hypertension achieve the recommended blood pressure goals of <140/90 mmHg. Lack of adherence to therapy and reluctance to intensify therapy are cited frequently to explain the discrepancy between potential and attained outcomes. Adherence is closely related to the tolerability, effectiveness and complexity of therapy. Therapeutic inertia may be influenced by concerns over tolerability, as well as the lack of clear preferences for therapies when managing patients with risk factors and comorbidities. Effective and well-tolerated single pill combination therapies are now available that improve adherence and simplify treatment. The combination of a renin-angiotensin system blocker with a calcium channel blocker and a diuretic improves adherence to therapy. We have devised a practical tool for orienting the application of well-tolerated single pill 2/3 drug fixed dose combination therapies in clinical situations commonly encountered when treating hypertensive patients. This approach employs the angiotensin receptor blocker olmesartan alone or in combinations with amlodipine and/or hydrochlorothiazide. This platform is based on clinical evidence, guidelines, best practice, and clinical experience where none of these is available. We believe it will increase the percentage of hypertensive patients who achieve blood pressure control when applied as part of an integrative approach that includes regular follow-up and instruction on lifestyle changes. PMID:24532183

  4. Disease course and therapeutic approach in dermatomyositis: A four-center retrospective study of 100 patients.

    PubMed

    Johnson, Nicholas E; Arnold, W David; Hebert, Donald; Gwathmey, Kelly; Dimachkie, Mazen M; Barohn, Richard J; McVey, April L; Pasnoor, Mamatha; Amato, Anthony A; McDermott, Michael P; Kissel, John; Heatwole, Chad R

    2015-08-01

    Dermatomyositis is a life-altering inflammatory disorder of skin and muscle. Details regarding the natural course of this disorder, the effects of specific therapies on its progression, and the optimal therapeutic dosage and duration of prednisone are limited. We performed a retrospective medical record review of dermatomyositis patients at four medical centers. All patients were over the age of 21 and had a clinical diagnosis of dermatomyositis with pathological confirmation. We reviewed average muscle strength, corticosteroid use, creatine kinase levels, and supplemental immunosuppressant use during the 36-month period following each patient's initial assessment. One hundred patients participated with an average age of 50.1 years. Average muscle strength improved and prednisone requirements lessened six months after initial assessment. There was no difference in the mean change in muscle strength or cumulative corticosteroid use over 36 months among those initially treated with methotrexate, mycophenolate mofetil, pulse IVIG, or azathioprine. There was a 5% mortality rate in dermatomyositis patients due to infections. Treated dermatomyositis patients demonstrate the most significant improvement in strength during the first six-to-twelve months following their initial clinical assessment. Additional prospective studies are needed to determine the relative benefit of select immunosuppressant agents in preserving strength and reducing corticosteroid use in dermatomyositis. PMID:26022999

  5. Pegylated arginase I: a potential therapeutic approach in T-ALL

    PubMed Central

    Hernandez, Claudia P.; Morrow, Kevin; Lopez-Barcons, Lluis A.; Zabaleta, Jovanny; Sierra, Rosa; Velasco, Cruz; Cole, John

    2010-01-01

    Adult patients with acute lymphoblastic T cell leukemia (T-ALL) have a very poor prognosis and few effective therapeutic options. Therefore, novel therapies that increase the efficacy of the treatments and that prolong T-ALL patient survival are needed. Malignant T cells require high concentrations of nutrients to sustain their increased rate of proliferation. In this study, we determined whether L-Arginine depletion by the pegylated form of the L-Arginine-metabolizing enzyme arginase I (peg-Arg I) impairs the proliferation of malignant T cells. Our results show that peg-Arg I depleted L-Arginine levels in vitro and in vivo. In addition, treatment of malignant T-cell lines with peg-Arg I significantly impaired their proliferation, which correlated with a decreased progression into the cell cycle, followed by the induction of apoptosis. Furthermore, peg-Arg I impaired the expression of cyclin D3, a fundamental protein in T-ALL proliferation, through a global arrest in protein synthesis. Injection of peg-Arg I plus chemotherapy agent Cytarabine prolonged survival in mice bearing T-ALL tumors. This antitumoral effect correlated with an inhibition of T-ALL proliferation in vivo, a decreased expression of cyclin D3, and T-ALL apoptosis. The results suggest the potential benefit of L-Arginine depletion by peg-Arg I in the treatment of T-cell malignancies. PMID:20407034

  6. Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: the advances continue.

    PubMed

    Khan, Imtiaz; Ibrar, Aliya; Ahmed, Waqas; Saeed, Aamer

    2015-01-27

    The presence of N-heterocycles as an essential structural motif in a variety of biologically active substances has stimulated the development of new strategies and technologies for their synthesis. Among the various N-heterocyclic scaffolds, quinazolines and quinazolinones form a privileged class of compounds with their diverse spectrum of therapeutic potential. The easy generation of complex molecular diversity through broadly applicable, cost-effective, practical and sustainable synthetic methods in a straightforward fashion along with the importance of these motifs in medicinal chemistry, received significant attention from researchers engaged in drug design and heterocyclic methodology development. In this perspective, the current review article is an effort to recapitulate recent developments in the eco-friendly and green procedures for the construction of highly challenging and potentially bioactive quinazoline and quinazolinone compounds in order to help medicinal chemists in designing and synthesizing novel and potent compounds for the treatment of different disorders. The key mechanistic insights for the synthesis of these heterocycles along with potential applications and manipulations of the products have also been conferred. This article also aims to highlight the promising future directions for the easy access to these frameworks in addition to the identification of more potent and specific products for numerous biological targets. PMID:25461317

  7. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease

    PubMed Central

    Ferolla, Silvia Marinho; Armiliato, Geyza Nogueira de Almeida; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditions that include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients. PMID:25848479

  8. A Review of Therapeutic Aptamer Conjugates with Emphasis on New Approaches

    PubMed Central

    Bruno, John G.

    2013-01-01

    The potential to emulate or enhance antibodies with nucleic acid aptamers while lowering costs has prompted development of new aptamer-protein, siRNA, drug, and nanoparticle conjugates. Specific focal points of this review discuss DNA aptamers covalently bound at their 3' ends to various proteins for enhanced stability and greater pharmacokinetic lifetimes in vivo. The proteins can include Fc tails of IgG for opsonization, and the first component of complement (C1q) to trigger complement-mediated lysis of antibiotic-resistant Gram negative bacteria, cancer cells and possibly some parasites during vulnerable stages. In addition, the 3' protein adduct may be a biotoxin, enzyme, or may simply be human serum albumin (HSA) or a drug known to bind HSA, thereby retarding kidney and other organ clearance and inhibiting serum exonucleases. In this review, the author summarizes existing therapeutic aptamer conjugate categories and describes his patented concept for PCR-based amplification of double-stranded aptamers followed by covalent attachment of proteins or other agents to the chemically vulnerable overhanging 3' adenine added by Taq polymerase. PCR amplification of aptamers could dramatically lower the current $2,000/gram cost of parallel chemical oligonucleotide synthesis, thereby enabling mass production of aptamer-3'-protein or drug conjugates to better compete against expensive humanized monoclonal antibodies. PMID:24276022

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

    PubMed

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

    2014-03-01

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

  10. A Four Step Approach to Evaluate Mixtures for Consistency with Dose Addition

    EPA Science Inventory

    We developed a four step approach for evaluating chemical mixture data for consistency with dose addition for use in environmental health risk assessment. Following the concepts in the U.S. EPA mixture risk guidance (EPA 2000a,b), toxicological interaction for a defined mixture (...

  11. Glucagon-like peptide-1 (GLP-1) and protective effects in cardiovascular disease: a new therapeutic approach for myocardial protection

    PubMed Central

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family implicated in the control of appetite and satiety. GLP-1 has insulinotropic, insulinomimetic, and glucagonostatic effects, thereby exerting multiple complementary actions to lower blood glucose in subjects with type 2 diabetes mellitus. A major advantage over conventional insulin is the fact that the insulinotropic actions of GLP-1 are dependent upon ambient glucose concentration, mitigating the risks of hypoglycemia. Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested in both preclinical and clinical studies. The experimental data indicate GLP-1 and its analogs to have direct effects on the cardiovascular system, in addition to their classic glucoregulatory actions. Clinically, beneficial effects of GLP-1 have also been demonstrated in patients with myocardial ischemia and heart failure. GLP-1 has recently been demonstrated to be a more effective alternative in treating myocardial injury. This paper provides a review on the current evidence supporting the use of GLP-1 in experimental animal models and human trials with the ischemic and non-ischemic heart and discusses their molecular mechanisms and potential as a new therapeutic approach. PMID:23777457

  12. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches?

    PubMed

    Holgate, Stephen T

    2011-09-01

    Current asthma therapy is based on the use of adrenergic bronchodilator and anti-inflammatory drugs the specificity, efficacy, duration of action, and safety of which have been derived through classical pharmacology and medicinal chemistry. That asthma is a T(H)2-type inflammatory disorder frequently associated with atopy and allergic comorbidities has led to a concentrated effort to find treatments that act selectively on this pathway. A systematic literature review was undertaken, as well as a review of the Web site Clinicaltrials.gov for ongoing trials. Targets have included T cells themselves and their associated cytokines, chemokines, and receptors mostly targeted with biological agents. With the exception of anti-human IgE, none of these have met the expectations predicted from animal models and human in vitro tests. For most of these new therapies, only a very small subpopulation appears to respond. A case is made for a different approach to drug discovery based on acquiring a greater understanding of asthma stratification, the relevant pathways involved, and the development of appropriate diagnostic tests enabling the targeting of selective treatments to those asthmatic phenotypes most likely to respond. The recognition that asthma is more than allergy mandates improved predictive animal models and an appreciation that many of the environmental insults that initiate, consolidate, and exacerbate asthma operate through an epithelium functioning in a disorderly fashion. An integrated model that places the epithelium at the forefront of asthma pathogenesis suggests that greater emphasis should be placed on therapeutics that increase the airways' resistance against the inhaled environment rather than focusing only on suppression of inflammation. PMID:21807404

  13. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

    PubMed Central

    Kostich, Walter; Hamman, Brian D.; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V.; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K.; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M.; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O’Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H.; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E.; Lentz, Kimberley A.; Santone, Kenneth S.; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K.; Nara, Susheel J.; Dzierba, Carolyn; Bronson, Joanne; Macor, John E.; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M.

    2016-01-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  14. A novel approach to investigate the effect of methionine oxidation on pharmacokinetic properties of therapeutic antibodies

    PubMed Central

    Stracke, Jan; Emrich, Thomas; Rueger, Petra; Schlothauer, Tilman; Kling, Lothar; Knaupp, Alexander; Hertenberger, Hubert; Wolfert, Andreas; Spick, Christian; Lau, Wilma; Drabner, Georg; Reiff, Ulrike; Koll, Hans; Papadimitriou, Apollon

    2014-01-01

    Preserving the chemical and structural integrity of therapeutic antibodies during manufacturing and storage is a major challenge during pharmaceutical development. Oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels. Because oxidation occurs in both positions simultaneously, their individual contribution to the concomitant changes in pharmacokinetic properties has not been clearly established. A novel pH-gradient FcRn affinity chromatography method was applied to isolate three antibody oxidation variants from an oxidized IgG1 preparation based on their FcRn binding properties. Physico-chemical characterization revealed that the three oxidation variants differed predominantly in the number of oxMet252 per IgG (0, 1, or 2), but not significantly in the content of oxMet428. Corresponding to the increase in oxMet252 content, stepwise reduction of FcRn affinity in vitro, as well as faster clearance and shorter terminal half-life, in huFcRn-transgenic mice were observed. A single Met252 oxidation per antibody had no significant effect on pharmacokinetics (PK) compared with unmodified IgG. Importantly, only molecules with both heavy chains oxidized at Met252 exhibited significantly faster clearance. In contrast, Met428 oxidation had no apparent negative effect on PK and even led to somewhat improved FcRn binding and slower clearance. This minor effect, however, seemed to be abrogated by the dominant effect of Met252 oxidation. The novel approach of functional chromatographic separation of IgG oxidation variants followed by physico-chemical and biological characterization has yielded the first experimentally-backed explanation for the unaltered PK properties of antibody preparations containing relatively high Met252 and Met428 oxidation levels. PMID:25517308

  15. Biological computational approaches: new hopes to improve (re)programming robustness, regenerative medicine and cancer therapeutics.

    PubMed

    Ebrahimi, Behnam

    2016-01-01

    Hundreds of transcription factors (TFs) are expressed and work in each cell type, but the identity of the cells is defined and maintained through the activity of a small number of core TFs. Existing reprogramming strategies predominantly focus on the ectopic expression of core TFs of an intended fate in a given cell type regardless of the state of native/somatic gene regulatory networks (GRNs) of the starting cells. Interestingly, an important point is that how much products of the reprogramming, transdifferentiation and differentiation (programming) are identical to their in vivo counterparts. There is evidence that shows that direct fate conversions of somatic cells are not complete, with target cell identity not fully achieved. Manipulation of core TFs provides a powerful tool for engineering cell fate in terms of extinguishment of native GRNs, the establishment of a new GRN, and preventing installation of aberrant GRNs. Conventionally, core TFs are selected to convert one cell type into another mostly based on literature and the experimental identification of genes that are differentially expressed in one cell type compared to the specific cell types. Currently, there is not a universal standard strategy for identifying candidate core TFs. Remarkably, several biological computational platforms are developed, which are capable of evaluating the fidelity of reprogramming methods and refining existing protocols. The current review discusses some deficiencies of reprogramming technologies in the production of a pure population of authentic target cells. Furthermore, it reviews the role of computational approaches (e.g. CellNet, KeyGenes, Mogrify, etc.) in improving (re)programming methods and consequently in regenerative medicine and cancer therapeutics. PMID:27056282

  16. Mucocutaneous warts in Middle Anatolia, Turkey: clinical presentations and therapeutic approaches

    PubMed Central

    Gönül, Müzeyyen; Iyidal, Ayşegül Yalçınkaya; Çakmak, Seray; Kılıç, Arzu; Gul, Ulker; Doner, Pinar

    2015-01-01

    Introduction Viral warts are common skin condition caused by the human papilloma virus. Aim To determine the clinical features of warts and therapeutic approaches to warts and compare them with the literature. Material and methods A cross-sectional survey was conducted on 362 consecutive patients presenting to a dermatology clinic in Ankara, Middle Anatolia, Turkey. Age, gender, anatomic localization, clinical types, number of warts, and medical therapy histories were recorded. Results In our study 139 (38.4%) children and 223 (61.6%) adults had warts. Warts were seen in 191 men, and 171 women. The mean age was 24.7 ±13.5. In all groups the incidence and the number of warts were higher in men. Clinical types of warts were vulgar, anogenital, plantar, verruca plana, filiform, and mosaic. Thirty-six (9.9%) of 362 cases had more than one type. The locations of warts were as follows extremities (n = 233, 64.4%), anogenital (n = 86, 23.7%) and head and neck (n = 73, 20.2%). The incidence of anogenital warts was statistically higher in men than women (p < 0.05). Topical medical treatment was the first choice (n = 60, 57.1%). Conclusions In our study, the incidence and the number of warts were higher in men, which is different than in previous reports. The anogenital wart (AW) was ranked second in all types of warts. According to this finding, we can say that the frequency of AW has been increased in Turkey. To our knowledge recently there have been no studies investigating the clinical features of viral warts in all ages in the literature. PMID:26161058

  17. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.

    PubMed

    Kostich, Walter; Hamman, Brian D; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O'Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E; Lentz, Kimberley A; Santone, Kenneth S; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K; Nara, Susheel J; Dzierba, Carolyn; Bronson, Joanne; Macor, John E; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M; Zambrowicz, Brian; Albright, Charles F

    2016-09-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  18. New developments for antibody-drug conjugate-based therapeutic approaches.

    PubMed

    de Goeij, Bart Ecg; Lambert, John M

    2016-06-01

    The clinical success of Adcetris(®) (brentuximab vedotin) and Kadcyla(®) (ado-trastuzumab emtansine) has sparked clinical development of novel ADCs. These powerful anti-cancer agents are designed to allow specific targeting of highly potent cytotoxic agents to tumor cells while sparing healthy tissues. Despite the use of tumor-specific antibodies, the emerging clinical data with ADCs indicates that adverse effects frequently occur before ADCs have reached their optimal therapeutic dose, resulting in a relatively narrow therapeutic window. This review summarizes the therapeutic window of ADCs currently in clinical development, along with some strategies that may help to widen the window. PMID:26963132

  19. Evaluation and management of ischiofemoral impingement: a pathophysiologic, radiologic, and therapeutic approach to a complex diagnosis.

    PubMed

    Hernando, Moisés Fernández; Cerezal, Luis; Pérez-Carro, Luis; Canga, Ana; González, Raquel Prada

    2016-06-01

    Ischiofemoral impingement syndrome (IFI) is an underrecognized form of atypical, extra-articular hip impingement defined by hip pain related to narrowing of the space between the ischial tuberosity and the femur. The etiology of IFI is multifactorial and potential sources of ischiofemoral engagement include anatomic variants of the proximal femur or pelvis, functional disorders as hip instability, pelvic/spinal instability, or abductor/adductor imbalance, ischial tuberosity enthesopathies, trauma/overuse or extreme hip motion, iatrogenic conditions, tumors and other pathologies. Magnetic resonance imaging (MRI) is the diagnostic procedure of choice for assessing IFI and may substantially influence patient management. The injection test of the ischiofemoral space (IFS) has both a diagnostic and therapeutic function. Endoscopic decompression of the IFS appears useful in improving function and diminishing hip pain in patients with IFI but conservative treatment is always the first step in the treatment algorithm. Because of the ever-increasing use of advanced MRI techniques, the frequent response to conservative treatment, and the excellent outcomes of new endoscopic treatment, radiologists must be aware of factors that predispose or cause IFI. In addition, focused treatment in these conditions is often more important than in secondary impingement. In this article, we briefly describe the anatomy of the IFS, review the clinical examination and symptoms, assess the diagnostic imaging criteria and pathophysiological mechanisms, and develop an understandable classification of IFI, with particular focus on its etiology, predisposing factors, and associated musculoskeletal abnormalities. We also assess the role of the radiologist in the diagnosis, treatment, and preoperative evaluation of both primary and secondary IFI. PMID:26940209

  20. Soteria Berne: an innovative milieu therapeutic approach to acute schizophrenia based on the concept of affect-logic

    PubMed Central

    Ciompi, Luc; Hoffmann, Holger

    2004-01-01

    The name "Soteria" stands for an alternative low-drug milieu-therapeutic approach to acute schizophrenia that was first implemented by Mosher and Menn in San Francisco, and since 1984 further developed by Ciompi and co-workers in Berne, on the basis of their concept of affect-logic, that emphasizes the often neglected influence of emotional factors in schizophrenia. In both settings, equal and even partly better therapeutic results, compared with traditional methods, were obtained with much lower doses of antipsychotics and comparable daily costs. Basic concepts, practical proceedings and empirical findings of Soteria Berne are reported, and their theoretical and practical implications for mainstream psychiatry are discussed. They support the hypothesis of a crucial pathogenetic and therapeutic-preventive role played by emotional factors not only in the so-called affective psychoses, but also in schizophrenia. PMID:16633478

  1. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches.

    PubMed

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-01-01

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders. PMID:26123042

  2. Obesity and hypertension: mechanisms, cardio-renal consequences, and therapeutic approaches.

    PubMed

    Reisin, Efrain; Jack, Avanelle V

    2009-05-01

    The increasing prevalence of obesity in the industrialized world is causing an alarming epidemic. Almost 70% of American adults are overweight or obese. The link between increasing body weight and hypertension is well established. Obesity hypertension through metabolic, endocrinic, and systemic hemodynamic alteration causes structural vascular and cardiac adaptations that trigger concentric, eccentric left ventricular hypertrophy and electrophysiological changes, which may increase the risk for congestive heart failure and sudden cardiac death as a result of arrhythmias. The increased renal blood flow in conjunction with a decreased renal vascular resistance causes renal hyperperfusion and hyperfiltration. Such changes lead to glomerulomegaly, focal segmental glomerulosclerosis, tubulointerstitial inflammation, and fibrosis that characterize the renal damage in obese hypertensive subjects. We propose that weight reduction, with the addition of other nonpharmacological approaches that included exercise and reduction in alcohol intake, should be the first choice to treat obesity hypertension. Salt restriction may be helpful only in salt-sensitive patients. The benefits of diet in obese patients include improvement of insulin sensitivity, reduction in sympathetic nervous and renin angiotensin system activities, and restoration of leptin sensitivity. As a consequence of these and other metabolic changes, the previously described systemic and renal hemodynamic alterations improved and the cardiovascular and renal morphological changes induced by obesity were lessened. After reviewing the medications available, we believe that owing to the cardiovascular and renal morbidity and mortality that characterized obesity hypertension, the ACEI or ARBs offer the best cardio-renal protection and should be the pharmacologic treatment of choice. If these alone do not control BP adequately, then a low-dose diuretic should be added as a second approach. Although we strongly believe

  3. Integrated therapeutic approaches in head and neck cancer: the importance of multidisciplinary team management.

    PubMed

    Perri, Francesco; Muto, Paolo; Aversa, Corrado; Daponte, Antonio; Della Vittoria, Giuseppina; Pepe, Stefano; Caponigro, Francesco

    2013-07-01

    Multidisciplinary team (MDT) is of paramount importance in the approach to patients with head and neck cancer. Its aim is to provide the best diagnostic work-up, tumor staging, and treatment. Furthermore, the prognosis of patients who are managed by MDT is usually better. MDT has a great value in all presentation settings. The role of the pathologist in the team is of utmost importance, in particular with regards to information provided on Human Papilloma Virus (HPV) status, which has a well acknowledged independent prognostic value mainly in oropharyngeal carcinoma. In early stage disease, namely in T1-2 N0 M0 patients, the meetings within the MDT mainly involve surgeons and radiation therapists. Surgery represents the mainstay of treatment, while radiation therapy is a suitable alternative, in particular in patients with advanced age, poor performance status and comorbidities. In locally advanced disease, surgeons, medical oncologists and radiotherapists are the key people, since different approaches have been carried out. In operable patients, adjuvant chemoradiation is indicated when resection margins are involved or close, or in presence of extracapsular nodal spread. Concurrent chemoradiotherapy, preceded or not by induction chemotherapy, is the favourite approach in this setting when surgery is strictly not indicated. In recurrent/metastatic disease chemotherapy and best supportive care are the main options, although local treatments, such as reirradiation and salvage surgery, are also worth considering. The standard chemotherapy treatment has finally evolved after about 30 years, and strong efforts are being pursued to further improve the outcome, mainly with the addition of new drugs. PMID:23194421

  4. Anaphylaxis in referred pediatric patients: demographic and clinical features, triggers, and therapeutic approach.

    PubMed

    De Swert, Liliane F A; Bullens, Dominique; Raes, Marc; Dermaux, Anna-Maria

    2008-11-01

    Anaphylaxis remains under-diagnosed and under-treated. A better knowledge of patterns and triggers of anaphylaxis might contribute to a better management. In this study we evaluated the demographic and clinical features of anaphylaxis in pediatric patients, as well as its triggers and therapeutic approach. From May 1st 2004 until April 30th 2006 we prospectively collected data on all patients referred for investigation of anaphylaxis to the pediatric department of the University Hospital Gasthuisberg Leuven and to two private pediatric practices. Data were stored in a MYSQL database by use of an online encrypted web form. Sixty-four cases of anaphylaxis occurred in 48 children, aged 6 months to 14.8 years. Twenty-seven episodes (42.2%) occurred at home. The symptoms were dermatologic in 62 (96.9%) episodes, respiratory in 57 (89.1%), gastrointestinal in 19 (29.7%), cardiovascular in 14 (21.8%), and neurological or behavioural in 19 (29.7%). Antihistamines were administered in 41/57 (71.9%) cases, corticosteroids in 26/57 (45.6%), beta-2-mimetics in 14/57 (24.6%), and adrenaline in 11/57 (19.3%). Out of nine cases where Epipen was available at the moment of anaphylaxis, it was administered in one case only. Food was the cause of anaphylaxis in 42/55 (76.4%) cases with identified trigger, while medication, insect stings, latex, and birch pollen triggered 5 (9.1%), 4 (7.3%), 3 (5.5%), and 1 (1.8%) case(s), respectively. Allergy to the trigger was known prior to anaphylaxis in 19/55 (34.5%) cases. In conclusion, anaphylaxis in pediatric patients generally presents with dermatologic and respiratory symptoms, while in 1/5 episodes cardiovascular symptoms occur. Food is by far the most frequent trigger. Allergy to the trigger is known in 1/3 cases only. Anaphylaxis is under-treated, even when appropriate medication is available. PMID:18204859

  5. Fitting additive hazards models for case-cohort studies: a multiple imputation approach.

    PubMed

    Jung, Jinhyouk; Harel, Ofer; Kang, Sangwook

    2016-07-30

    In this paper, we consider fitting semiparametric additive hazards models for case-cohort studies using a multiple imputation approach. In a case-cohort study, main exposure variables are measured only on some selected subjects, but other covariates are often available for the whole cohort. We consider this as a special case of a missing covariate by design. We propose to employ a popular incomplete data method, multiple imputation, for estimation of the regression parameters in additive hazards models. For imputation models, an imputation modeling procedure based on a rejection sampling is developed. A simple imputation modeling that can naturally be applied to a general missing-at-random situation is also considered and compared with the rejection sampling method via extensive simulation studies. In addition, a misspecification aspect in imputation modeling is investigated. The proposed procedures are illustrated using a cancer data example. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26194861

  6. Control of asymmetry in the radical addition approach to chiral amine synthesis.

    PubMed

    Friestad, Gregory K

    2014-01-01

    The state-of-the-science in asymmetric free radical additions to imino compounds is presented, beginning with an overview of methods involving stereocontrol by various chiral auxiliary approaches. Chiral N-acylhydrazones are discussed with respect to their use as radical acceptors for Mn-mediated intermolecular additions, from design to scope surveys to applications to biologically active targets. A variety of aldehydes and ketones serve as viable precursors for the chiral hydrazones, and a variety of alkyl iodides may be employed as radical precursors, as discussed in a critical review of the functional group compatibility of the reaction. Applications to amino acid and alkaloid synthesis are presented to illustrate the synthetic potential of these versatile stereocontrolled carbon-carbon bond construction reactions. Asymmetric catalysis is discussed, from seminal work on the stereocontrol of radical addition to imino compounds by non-covalent interactions with stoichiometric amounts of catalysts, to more recent examples demonstrating catalyst turnover. PMID:24085561

  7. Control of Asymmetry in the Radical Addition Approach to Chiral Amine Synthesis

    PubMed Central

    Friestad, Gregory K.

    2014-01-01

    The state-of-the-science in asymmetric free radical additions to imino compounds is presented, beginning with an overview of methods involving stereocontrol by various chiral auxiliary approaches. Chiral N-acylhydrazones are discussed with respect to their use as radical acceptors for Mn-mediated intermolecular additions, from design to scope surveys to applications to biologically active targets. A variety of aldehydes and ketones serve as viable precursors for the chiral hydrazones, and a variety of alkyl iodides may be employed as radical precursors, as discussed in a critical review of the functional group compatibility of the reaction. Applications to amino acid and alkaloid synthesis are presented to illustrate the synthetic potential of these versatile stereocontrolled carbon–carbon bond construction reactions. Asymmetric catalysis is discussed, from seminal work on the stereocontrol of radical addition to imino compounds by non-covalent interactions with stoichiometric amounts of catalysts, to more recent examples demonstrating catalyst turnover. PMID:24085561

  8. "Am I going crazy, doc?": a self psychology approach to therapeutic assessment.

    PubMed

    Peters, Eric J; Handler, Leonard; White, Kathryn G; Winkel, Justin D

    2008-09-01

    In this case study, we explore the effectiveness of Therapeutic Assessment with a severely disturbed 25-year-old man, referred by his therapist, following Finn's (2007; Finn & Tonsager, 1992, 1997) model. This patient-therapist pair had been working together for approximately 2 months, but the therapy had ceased to progress. The therapist requested a clearer picture of his patient's affective functioning, interpersonal functioning, and self-functioning that might facilitate more effective treatment. Through a collaborative assessment process informed by the principles of Kohutian self psychology, the evaluator and patient slowly formed a working alliance that proved useful for the eventual communication to the patient of his psychologically tenuous reality. This case illustrates the utility of a collaborative, multimethod Therapeutic Assessment with a severely ill patient and the use of Therapeutic Assessment by a less experienced clinician. PMID:18704801

  9. Novel therapeutic approaches for chronic kidney disease due to glomerular disorders.

    PubMed

    Del Nogal-Avila, Maria; Donoro-Blazquez, Hector; Saha, Manish K; Marshall, Caroline B; Clement, Lionel C; Macé, Camille E A; Chugh, Sumant S

    2016-07-01

    Improved understanding of glomerular disease mechanisms over the past decade has led to the emergence of new and targeted therapeutic strategies for chronic kidney disease (CKD). Most promising among these are the administration of recombinant mutated human angiopoietin-like 4, sialic acid-related sugars that induce sialylation in vivo, compounds related to Bis-T-23, and immune depletion of the soluble urokinase receptor from the circulation. Taking these therapeutic strategies into clinical trials will be the first step away from repurposed and relatively toxic drugs currently used for treating kidney disease. PMID:27147672

  10. A four-step approach to evaluate mixtures for consistency with dose addition.

    PubMed

    Hertzberg, Richard C; Pan, Yi; Li, Ruosha; Haber, Lynne T; Lyles, Robert H; Herr, David W; Moser, Virginia C; Simmons, Jane Ellen

    2013-11-16

    Mixture risk assessment is often hampered by the lack of dose-response information on the mixture being assessed, forcing reliance on component formulas such as dose addition. We present a four-step approach for evaluating chemical mixture data for consistency with dose addition for use in supporting a component based mixture risk assessment. Following the concepts in the U.S. EPA mixture risk guidance (U.S. EPA, 2000a,b), toxicological interaction for a defined mixture (all components known) is departure from a clearly articulated definition of component additivity. For the common approach of dose additivity, the EPA guidance identifies three desirable characteristics, foremost of which is that the component chemicals are toxicologically similar. The other two characteristics are empirical: the mixture components have toxic potencies that are fixed proportions of each other (throughout the dose range of interest), and the mixture dose term in the dose additive prediction formula, which we call the combined prediction model (CPM), can be represented by a linear combination of the component doses. A consequent property of the proportional toxic potencies is that the component chemicals must share a common dose-response model, where only the dose coefficients depend on the chemical components. A further consequence is that the mixture data must be described by the same mathematical function ("mixture model") as the components, but with a distinct coefficient for the total mixture dose. The mixture response is predicted from the component dose-response curves by using the dose additive CPM and the prediction is then compared with the observed mixture results. The four steps are to evaluate: (1) toxic proportionality by determining how well the CPM matches the single chemical models regarding mean and variance; (2) fit of the mixture model to the mixture data; (3) agreement between the mixture data and the CPM prediction; and (4) consistency between the CPM and the

  11. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells.

    PubMed

    Justilien, Verline; Fields, Alan P

    2015-02-01

    The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy. PMID:25646180

  12. Teaching Therapeutic Reasoning through the Case-Study Approach: Adding the Probabilistic Dimension.

    ERIC Educational Resources Information Center

    Hartzema, Abraham G.

    1994-01-01

    It is proposed that clinical decision making in pharmacy should integrate principles of pharmacoepidemiology, economics, and medical decision making, and that case studies provide an opportunity to use these principles in probabilistic reasoning, thereby improving self-learning, critical thinking, and therapeutic and monitoring skills. Steps in…

  13. Phase-dependent modulation as a novel approach for therapeutic brain stimulation

    PubMed Central

    Azodi-Avval, Ramin; Gharabaghi, Alireza

    2015-01-01

    Closed-loop paradigms provide us with the opportunity to optimize stimulation protocols for perturbation of pathological oscillatory activity in brain-related disorders. In this vein, spiking activity of motor cortex neurons and beta activity of local field potentials in the subthalamic nucleus have both been used independently of each other as neuronal signals to trigger deep brain stimulation for alleviating Parkinsonism. These approaches were superior to the standard continuous high-frequency stimulation protocols used in daily practice. However, they achieved their effects by bursts of stimulation that were applied at high-frequency as well, i.e., independent of the phase information in the stimulated region. In this context, we propose that, by timing stimulation pulses relative to the ongoing oscillation, an alternative approach, namely the targeted perturbation of pathological rhythms, could be obtained. In this modeling study, we first captured the underlying dynamics of neuronal oscillations in the human subthalamic nucleus by phased coupled neuronal oscillators. We then quantified the nature of the interaction between these coupled oscillators by obtaining a physiologically informed phase response curve from local field potentials. Reconstruction of the phase response curve predicted the sensitivity of the phase oscillator to external stimuli, revealing phase intervals that optimally maximized the degree of perturbation. We conclude that our specifically timed intervention based on the coupled oscillator concept will enable us to identify personalized ways of delivering stimulation pulses in closed-loop paradigms triggered by the phase of pathological oscillations. This will pave the way for novel physiological insights and substantial clinical benefits. In addition, this precisely phased modulation may be capable of modifying the effective interactions between oscillators in an entirely new manner. PMID:25767446

  14. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches.

    PubMed

    Federici, A B; Stabile, F; Castaman, G; Canciani, M T; Mannucci, P M

    1998-10-15

    Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10 patients with MGUS and AvWS: 8 had IgGkappa (3) or lambda (5) MGUS and 2 IgM-kappa MGUS. Three therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor (FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS, DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently. IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS associated with IgG-MGUS, but not with IgM-MGUS. PMID:9763553

  15. A new approach to handle additive and multiplicative uncertainties in the measurement for ? LPV filtering

    NASA Astrophysics Data System (ADS)

    Lacerda, Márcio J.; Tognetti, Eduardo S.; Oliveira, Ricardo C. L. F.; Peres, Pedro L. D.

    2016-04-01

    This paper presents a general framework to cope with full-order ? linear parameter-varying (LPV) filter design subject to inexactly measured parameters. The main novelty is the ability of handling additive and multiplicative uncertainties in the measurements, for both continuous and discrete-time LPV systems, in a unified approach. By conveniently modelling scheduling parameters and uncertainties affecting the measurements, the ? filter design problem can be expressed in terms of robust matrix inequalities that become linear when two scalar parameters are fixed. Therefore, the proposed conditions can be efficiently solved through linear matrix inequality relaxations based on polynomial solutions. Numerical examples are presented to illustrate the improved efficiency of the proposed approach when compared to other methods and, more important, its capability to deal with scenarios where the available strategies in the literature cannot be used.

  16. Identification of Xenoestrogens in Food Additives by an Integrated in Silico and in Vitro Approach

    PubMed Central

    Amadasi, Alessio; Mozzarelli, Andrea; Meda, Clara; Maggi, Adriana; Cozzini, Pietro

    2009-01-01

    In the search for xenoestrogens within food additives, we have analyzed the Joint FAO-WHO expert committee database, containing 1500 compounds, using an integrated in silico and in vitro approach. This analysis identified 31 potential estrogen receptor α ligands that were reduced to 13 upon applying a stringent filter based on ligand volume and binding mode. Among the 13 potential xenoestrogens, four were already known to exhibit an estrogenic activity, and the other nine were assayed in vitro, determining the binding affinity to the receptor and biological effects. Propyl gallate was found to act as an antagonist, and 4-hexylresorcinol was found to act as a potent transactivator; both ligands were active at nanomolar concentrations, as predicted by the in silico analysis. Some caution should be issued for the use of propyl gallate and 4-hexylresorcinol as food additives. PMID:19063592

  17. Folic Acid and Creatine as Therapeutic Approaches to Lower Blood Arsenic: A Randomized Controlled Trial

    PubMed Central

    Peters, Brandilyn A.; Hall, Megan N.; Liu, Xinhua; Parvez, Faruque; Sanchez, Tiffany R.; van Geen, Alexander; Mey, Jacob L.; Siddique, Abu B.; Shahriar, Hasan; Uddin, Mohammad Nasir; Islam, Tariqul; Balac, Olgica; Ilievski, Vesna; Factor-Litvak, Pam; Graziano, Joseph H.

    2015-01-01

    Peters BA, Hall MN, Liu X, Parvez F, Sanchez TR, van Geen A, Mey JL, Siddique AB, Shahriar H, Uddin MN, Islam T, Balac O, Ilievski V, Factor-Litvak P, Graziano JH, Gamble MV. 2015. Folic acid and creatine as therapeutic approaches to lower blood arsenic: a randomized controlled trial. Environ Health Perspect 123:1294–1301; http://dx.doi.org/10.1289/ehp.1409396 PMID:25978852

  18. Cystathionine β-Synthase Inhibition Is a Potential Therapeutic Approach to Treatment of Ischemic Injury

    PubMed Central

    Chan, Su Jing; Chai, Chou; Lim, Tze Wei; Yamamoto, Mie; Lo, Eng H; Lai, Mitchell Kim Peng

    2015-01-01

    Hydrogen sulfide (H2S) has been reported to exacerbate stroke outcome in experimental models. Cystathionine β-synthase (CBS) has been implicated as the predominant H2S-producing enzyme in central nervous system. When SH-SY5Y cells were transfected to overexpress CBS, these cells were able to synthesize H2S when exposed to high levels of enzyme substrates but not substrate concentrations that may reflect normal physiological conditions. At the same time, these cells demonstrated exacerbated cell death when subjected to oxygen and glucose deprivation (OGD) together with high substrate concentrations, indicating that H2S production has a detrimental effect on cell survival. This effect could be abolished by CBS inhibition. The same effect was observed with primary astrocytes exposed to OGD and high substrates or sodium hydrosulfide. In addition, CBS was upregulated and activated by truncation in primary astrocytes subjected to OGD. When rats were subjected to permanent middle cerebral artery occlusion, CBS activation was also observed. These results imply that in acute ischemic conditions, CBS is upregulated and activated by truncation causing an increased production of H2S, which exacerbate the ischemic injuries. Therefore, CBS inhibition may be a viable approach to stroke treatment. PMID:25873304

  19. ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer.

    PubMed

    Hasanabady, Maryam Hosseini; Kalalinia, Fatemeh

    2016-06-01

    Breast cancer resistance protein (BCRP, ABCP or MXR)/ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a selfdefence mechanism for the organism; it enhances eliminating of toxic xenobiotic substances and harmful agents in the intestine, as well as through the blood-brain barrier and placenta. ABCG2 recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and new targeted small therapeutic molecules in clinical usage. Development of ABCG2 inhibitors for clinical usage may allow increased penetration of therapeutic agents into sanctuary sites and increases their intestinal absorption. Here we review the mechanisms that modulate MDR mediated by the ABC transporter ABCG2 in normal and cancer cells by different levels including, epigenetic modifications, transcriptional, post-transcriptional, translation and post-translational regulation. Some clinical applications of ABCG2 inhibitors are also explained. PMID:27240991

  20. Computational approaches for designing potent and selective analogs of peptide toxins as novel therapeutics

    PubMed Central

    Kuyucak, Serdar; Norton, Raymond S

    2015-01-01

    Peptide toxins provide valuable therapeutic leads for many diseases. As they bind to their targets with high affinity, potency is usually ensured. However, toxins also bind to off-target receptors, causing potential side effects. Thus, a major challenge in generating drugs from peptide toxins is ensuring their specificity for their intended targets. Computational methods can play an important role in solving such design problems through construction of accurate models of receptor–toxin complexes and calculation of binding free energies. Here we review the computational methods used for this purpose and their application to toxins targeting ion channels. We describe ShK and HsTX1 toxins, high-affinity blockers of the voltage-gated potassium channel Kv1.3, which could be developed as therapeutic agents for autoimmune diseases. PMID:25406005

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

    PubMed

    Browning, C

    1987-01-01

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

  2. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor- targeted therapeutics: advantages and limitations

    PubMed Central

    Williams, Dustin K.; Wang, Jingyi; Papke, Roger L.

    2011-01-01

    Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues. PMID:21575610

  3. Identification and validation of vesicant therapeutic targets using a high-throughput siRNA screening approach.

    PubMed

    Ruff, Albert L; Beach, Sarah; Lehman, John; Rothwell, Cristin; Dillman, James F

    2016-02-01

    Sulfur mustard [SM, bis-(2-chloroethyl) sulfide] is a highly reactive bifunctional alkylating agent that has been used as a vesicating agent in warfare scenarios to induce severe lung, skin, and eye injury. SM cutaneous lesions are characterized by both vesication and severe inflammation, but the molecular mechanisms that lead to these signs and symptoms are not well understood. There is a pressing need for effective therapeutics to treat this injury. An understanding of the molecular mechanisms of injury and identification of potential therapeutic targets is necessary for rational therapeutic development. We have applied a high-throughput small interfering RNA (siRNA) screening approach to the problem of SM cutaneous injury in an effort to meet these needs. Our siRNA screening efforts have initially focused on SM-induced inflammation in cutaneous injury since chronic inflammation after exposure appears to play a role in progressive clinical pathology, and intervention may improve clinical outcome. Also, targets that mitigate cellular injury should reduce the inflammatory response. Historical microarray data on this injury were mined for targets and pathways implicated in inflammation, and a siRNA library of 2,017 targets was assembled for screening. Primary screening and library deconvolution were performed using human HaCaT keratinocytes and focused on cell death and inflammatory markers as end points. Using this in vitro approach, we have identified and validated novel targets for the potential treatment of SM-induced cutaneous injury. PMID:25537185

  4. Pharmacotherapeutic intervention in impulsive preschool children: The need for a comprehensive therapeutic approach

    PubMed Central

    2011-01-01

    Impulsive and aggressive behaviour symptoms often are serious problems in children, even already at preschool age. Thus, effective treatment approaches are requested. In this comment pharmacotherapeutic treatment approaches, first of all risperidone, their limitations and alternative psychotherapeutic approaches are outlined. PMID:21489233

  5. A mentalization-based approach to the development of the therapeutic alliance in the treatment of schizophrenia.

    PubMed

    Brent, Benjamin K

    2015-02-01

    This article presents a clinical illustration of a mentalization-based approach to the development of a therapeutic alliance in the treatment of schizophrenia. A clinically focused overview of the attachment-based understanding of mentalization central to the mentalization-based treatment model is first provided. This is followed by a brief summary of the theory and evidence supporting the possible link between attachment disturbances and deficits of mental state understanding in schizophrenia. A case presentation then illustrates the application of core mentalization-based principles and interventions to enhance the therapeutic alliance by addressing disruptions of mentalization and reducing paranoia in the treatment of a patient with early course schizophrenia. PMID:25557537

  6. Planning additional drilling campaign using two-space genetic algorithm: A game theoretical approach

    NASA Astrophysics Data System (ADS)

    Kumral, Mustafa; Ozer, Umit

    2013-03-01

    Grade and tonnage are the most important technical uncertainties in mining ventures because of the use of estimations/simulations, which are mostly generated from drill data. Open pit mines are planned and designed on the basis of the blocks representing the entire orebody. Each block has different estimation/simulation variance reflecting uncertainty to some extent. The estimation/simulation realizations are submitted to mine production scheduling process. However, the use of a block model with varying estimation/simulation variances will lead to serious risk in the scheduling. In the medium of multiple simulations, the dispersion variances of blocks can be thought to regard technical uncertainties. However, the dispersion variance cannot handle uncertainty associated with varying estimation/simulation variances of blocks. This paper proposes an approach that generates the configuration of the best additional drilling campaign to generate more homogenous estimation/simulation variances of blocks. In other words, the objective is to find the best drilling configuration in such a way as to minimize grade uncertainty under budget constraint. Uncertainty measure of the optimization process in this paper is interpolation variance, which considers data locations and grades. The problem is expressed as a minmax problem, which focuses on finding the best worst-case performance i.e., minimizing interpolation variance of the block generating maximum interpolation variance. Since the optimization model requires computing the interpolation variances of blocks being simulated/estimated in each iteration, the problem cannot be solved by standard optimization tools. This motivates to use two-space genetic algorithm (GA) approach to solve the problem. The technique has two spaces: feasible drill hole configuration with minimization of interpolation variance and drill hole simulations with maximization of interpolation variance. Two-space interacts to find a minmax solution

  7. Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations.

    PubMed

    Vries, Maaike de; Bedke, Nicole; Smithers, Natalie P; Loxham, Matthew; Howarth, Peter H; Nawijn, Martijn C; Davies, Donna E

    2016-03-01

    Therapeutic options to treat virus-induced asthma exacerbations are limited and urgently needed. Therefore, we tested Pim1 kinase as potential therapeutic target in human rhinovirus (HRV) infections. We hypothesised that inhibition of Pim1 kinase reduces HRV replication by augmenting the interferon-induced anti-viral response due to increased activity of the janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway.Air-liquid interface (ALI) cultures of primary bronchial epithelial cells (PBECs) from healthy individuals and moderate-to-severe asthmatic volunteers were infected with HRV-16 with or without a specific Pim1 inhibitor; viral replication and induction of anti-viral responses were measured using RT-qPCR. Viral titres were measured by 50% tissue culture infective dose and release of interferon-γ-induced protein 10 (IP-10) and RANTES protein assessed by ELISA. Phosphorylation of STAT-1 was determined using western blotting.Viral replication was reduced in ALI cultures of healthy and asthmatic PBECs treated with the Pim1 inhibitor. Using cultures from healthy donors, enhanced STAT-1 phosphorylation upon inhibition of Pim1 kinase activity resulted in increased mRNA expression of interferon-β, interleukin-29, IP-10 and RANTES 12 h after infection and increased protein levels of IP-10 and RANTES 24 h after infection.We have identified Pim1 kinase as novel target to reduce viral replication in ALI cultures of PBECs. This may open new avenues for therapeutic interventions in virus-induced asthma exacerbations. PMID:26869670

  8. The application of gold nanoparticles as a promising therapeutic approach in breast and ovarian cancer.

    PubMed

    Kafshdooz, Leila; Kafshdooz, Taiebeh; Razban, Zohreh; Akbarzadeh, Abolfazl

    2016-08-01

    The development of specialized nanoparticles (NPs) for use in the detection and treatment of cancer is increasing. In the last few years, gold nanoparticles (AuNPs) have been greatly studied in biological and photothermal therapeutic status. AuNPs can bind to a wide range of organic molecules, and their synthesis is easy. In this review, we summarize the characteristics of AuNPs, their contributions to tumor destruction, their toxicity, and their potential in the treatment of breast and ovarian cancer. PMID:25871281

  9. Roles of NF-κB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches

    PubMed Central

    Park, Mi Hee; Hong, Jin Tae

    2016-01-01

    Nuclear factor-κB (NF-κB) is a transcription factor that plays a crucial role in various biological processes, including immune response, inflammation, cell growth and survival, and development. NF-κB is critical for human health, and aberrant NF-κB activation contributes to development of various autoimmune, inflammatory and malignant disorders including rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, multiple sclerosis and malignant tumors. Thus, inhibiting NF-κB signaling has potential therapeutic applications in cancer and inflammatory diseases. PMID:27043634

  10. Targeting brain microvascular endothelial cells: a therapeutic approach to neuroprotection against stroke

    PubMed Central

    Yu, Qi-jin; Tao, Hong; Wang, Xin; Li, Ming-chang

    2015-01-01

    Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions. PMID:26807131

  11. New advances in invasive aspergillosis immunobiology leading the way towards personalized therapeutic approaches.

    PubMed

    Obar, Joshua J; Hohl, Tobias M; Cramer, Robert A

    2016-08-01

    Invasive aspergillosis (IA) remains a devastating disease in immune compromised patients despite significant advances in our understanding of fungal virulence and host defense mechanisms. In this review, we summarize important research advances in the fight against IA with particular focus on early events in the interactions between Aspergillus fumigatus and the host that occur in the respiratory tract. Advances in understanding mechanisms of immune effector cell recruitment, antifungal effector mechanisms, and how the dynamic host-fungal interaction alters the local microenvironment to effect outcomes are highlighted. These advances illustrate exciting new therapeutic opportunities, but also emphasize the importance of understanding each unique fungus-host interaction for improving patient outcomes. PMID:27253487

  12. Phylogeny of Eunicida (Annelida) and exploring data congruence using a partition addition bootstrap alteration (PABA) approach.

    PubMed

    Struck, Torsten H; Purschke, Günter; Halanych, Kenneth M

    2006-02-01

    Even though relationships within Annelida are poorly understood, Eunicida is one of only a few major annelid lineages well supported by morphology. The seven recognized eunicid families possess sclerotized jaws that include mandibles and a maxillary apparatus. The maxillary apparatuses vary in shape and number of elements, and three main types are recognized in extant taxa: ctenognath, labidognath, and prionognath. Ctenognath jaws are usually considered to represent the plesiomorphic state of Eunicida, whereas taxa with labidognath and prionognath are thought to form a derived monophyletic assemblage. However, this hypothesis has never been tested in a statistical framework even though it holds considerable importance for understanding annelid phylogeny and possibly lophotrochozoan evolution because Eunicida has the best annelid fossil record. Therefore, we used maximum likelihood and Bayesian inference approaches to reconstruct Eunicida phylogeny using sequence data from nuclear 18S and 28S rDNA genes and mitochondrial 16S rDNA and cytochrome c oxidase subunit I genes. Additionally, we conducted three different tests to investigate suitability of combining data sets. Incongruence length difference (ILD) and Shimodaira-Hasegawa (SH) test comparisons of resultant trees under different data partitions have been widely used previously but do not give a good indication as to which nodes may be causing the conflict. Thus, we developed a partition addition bootstrap alteration (PABA) approach that evaluates congruence or conflict for any given node by determining how bootstrap scores are altered when different data partitions are added. PABA shows the contribution of each partition to the phylogeny obtained in the combined analysis. Generally, the ILD test performed worse than the other approaches in detecting incongruence. Both PABA and the SH approach indicated the 28S and COI data sets add conflicting signal, but PABA is more informative for elucidating which data

  13. Creatine supplementation as a possible new therapeutic approach for fatty liver disease: early findings.

    PubMed

    Deminice, Rafael; de Castro, Gabriela S; Brosnan, Margaret E; Brosnan, John T

    2016-08-01

    Over the last few years, consistent data have demonstrated that creatine (Cr) supplementation prevents the accumulation of fat in rat liver as well as the progression of fatty liver disease in different situations. Studies have demonstrated that Cr is effective and prevents fatty liver in high-fat and choline-deficient diets and in hepatoma cells in vitro. Because Cr synthesis is responsible for a considerable consumption of hepatic methyl groups, studies have tested the idea that Cr supplementation could modulate phospholipid formation and VLDL secretion. Studies have also demonstrated Cr is able to modulate the expression of key genes related to fatty acid oxidation in hepatocyte cell culture and in rat liver. However, to date, the mechanism by which Cr exerts protective effects against fatty liver is poorly understood. Therefore, the present review aims to summarize the studies involving the therapeutic use of Cr supplementation on fatty liver disease and to explore the mechanisms involved in one-carbon and fatty acid metabolism for the preventive effects of Cr supplementation on fat liver accumulation. Although a small number of studies have been conducted to date, we consider Cr as a new and promising therapeutic strategy to control fat accumulation in the liver as well as the progression of fatty liver disease. PMID:26832170

  14. An integrated genomic and pharmacoepigenomic approach predicts therapeutic response of zebularine in human liver cancer*

    PubMed Central

    Andersen, Jesper B.; Factor, Valentina M.; Marquardt, Jens U.; Raggi, Chiara; Lee, Yun-Han; Seo, Daekwan; Conner, Elizabeth A.; Thorgeirsson, Snorri S.

    2010-01-01

    Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine signature that classified liver cancer cell lines into two major subtypes with different drug-responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells leading to increased survival and decreased pulmonary metastasis. Integration of zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome. PMID:20962331

  15. Novel agents and new therapeutic approaches for treatment of multiple myeloma

    PubMed Central

    Ria, Roberto; Reale, Antonia; Vacca, Angelo

    2014-01-01

    This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials. PMID:25332907

  16. Pelvic floor muscle rehabilitation for patients with lifelong premature ejaculation: a novel therapeutic approach

    PubMed Central

    Palleschi, Giovanni; Fuschi, Andrea; Maggioni, Cristina; Rago, Rocco; Zucchi, Alessandro; Costantini, Elisabetta; Carbone, Antonio

    2014-01-01

    Objectives: Premature ejaculation is the most common male sexual disorder. The aim of the study was to evaluate the possible therapeutic role of pelvic floor muscle rehabilitation in patients affected by lifelong premature ejaculation. Methods: We treated 40 men with lifelong premature ejaculation, reporting, a baseline intravaginal ejaculatory latency time (IELT) ≤ 1 min, with 12-week pelvic floor muscle rehabilitation. Results: At the end of the rehabilitation, mean IELTs were calculated to evaluate the effectiveness of the therapy. At the end of the treatment, 33 (82.5%) of the 40 patients gained control of their ejaculatory reflex, with a mean IELT of 146.2 s (range: 123.6–152.4 s). A total of 13 out of 33 (39%) patients were evaluated at 6 months follow up, and they maintained a significant IELT (112.6 s) compared with their initial IELT (mean 39.8 s). Conclusions: The results obtained in our subjects treated with pelvic floor rehabilitation are promising. This therapy represents an important cost reduction compared with the standard treatment (selective serotonin reuptake inhibitors). Based on the present data, we propose pelvic floor muscle rehabilitation as a new, viable therapeutic option for the treatment of premature ejaculation. PMID:24883105

  17. Approaches targeting the FGF-FGFR system: a review of the recent patent literature and associated advanced therapeutic agents.

    PubMed

    Herbert, Corentin; Lassalle, Gilbert; Alcouffe, Chantal; Bono, Françoise

    2014-01-01

    Fibroblast growth factor receptors (FGFRs) and associated ligands (FGFs) are a family of well-validated targets for therapeutic interventions notably in cancer diseases in relation to their prominent roles in cell growth, survival, differentiation and angiogenesis. This patent review encompasses all different approaches (modulators of FGF or FGFR expression, anti-FGF antibodies, anti-FGFR antibodies, FGF traps, tyrosine-kinase (TK) inhibitors, allosteric modulators) used to block completely or partially the activities of the FGF-FGFR complexes resulting in clinical drug candidates or tool agents. Comparative analysis of biochemical, pharmacological or clinical data will be discussed for each class of molecules together with some perspectives. PMID:25489913

  18. Citric acid as the last therapeutic approach in an acute life-threatening metabolic decompensation of propionic acidaemia.

    PubMed

    Siekmeyer, Manuela; Petzold-Quinque, Stefanie; Terpe, Friederike; Beblo, Skadi; Gebhardt, Rolf; Schlensog-Schuster, Franziska; Kiess, Wieland; Siekmeyer, Werner

    2013-01-01

    The tricarboxylic acid (TCA) cycle represents the key enzymatic steps in cellular energy metabolism. Once the TCA cycle is impaired in case of inherited metabolic disorders, life-threatening episodes of metabolic decompensation and severe organ failure can arise. We present the case of a 6 ½-year-old girl with propionic acidaemia during an episode of acute life-threatening metabolic decompensation and severe lactic acidosis. Citric acid given as an oral formulation showed the potential to sustain the TCA cycle flux. This therapeutic approach may become a treatment option in a situation of acute metabolic crisis, possibly preventing severe disturbance of energy metabolism. PMID:23412866

  19. BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

    PubMed Central

    Da Costa, D; Agathanggelou, A; Perry, T; Weston, V; Petermann, E; Zlatanou, A; Oldreive, C; Wei, W; Stewart, G; Longman, J; Smith, E; Kearns, P; Knapp, S; Stankovic, T

    2013-01-01

    Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment. PMID:23872705

  20. Current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury using polymer scaffolds☆

    PubMed Central

    Madigan, Nicolas N.; McMahon, Siobhan; O’Brien, Timothy; Yaszemski, Michael J.; Windebank, Anthony J.

    2010-01-01

    This review highlights current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury. The concept of developing 3-dimensional polymer scaffolds for placement into a spinal cord transection model has recently been more extensively explored as a solution for restoring neurologic function after injury. Given the patient morbidity associated with respiratory compromise, the discrete tracts in the spinal cord conveying innervation for breathing represent an important and achievable therapeutic target. The aim is to derive new neuronal tissue from the surrounding, healthy cord that will be guided by the polymer implant through the injured area to make functional reconnections. A variety of naturally derived and synthetic biomaterial polymers have been developed for placement in the injured spinal cord. Axonal growth is supported by inherent properties of the selected polymer, the architecture of the scaffold, permissive microstructures such as pores, grooves or polymer fibres, and surface modifications to provide improved adherence and growth directionality. Structural support of axonal regeneration is combined with integrated polymeric and cellular delivery systems for therapeutic drugs and for neurotrophic molecules to regionalize growth of specific nerve populations. PMID:19737633

  1. Cardiac pathology and modern therapeutic approach in Behçet disease.

    PubMed

    Cocco, Giuseppe; Jerie, Paul

    2014-01-01

    Behçet disease (BD) is an enigmatic inflammatory disorder with multisystemic complications which is endemic in some countries but can be seen in the entire world. Valid diagnostic criteria are available. The pathology is related to a specific perivasculitis with involvement of both arteries and veins of all sizes. Minor arterial and cardiac involvement is frequent in BD but is usually asymptomatic. In exceptional cases cardiac symptoms may be the 1st manifestation of BD. The prevalence of severe cardiac complications (cardio-Behçet) should be < 10%. An impressive therapeutic improvement has been achieved by using appropriate catheterization techniques, coronary and intra-arterial stents, colchicine, drug-response modifying drugs and immunotherapy but, still cardio-Behçet has a poor prognosis. Efforts are undertaken to improve morbidity and prognosis with the use of newer drugs. An important part of the complications in BD are related to the frequent thromboembolic complications and there is high possibility that newer oral anticoagulants will be superior to the classical anticoagulants presently used. Available biologic agents have already been frequently used and seem to have improved the prognosis, but efforts are undertaken to find newer biologic agents with better therapeutic performance and less side-effects. Summarizing as much as possible the effects of the presently used biotherapy in BD, interferon-alpha is effective against many ocular, genital and perhaps vascular manifestations, but its effectiveness is limited by frequent adverse-effects (even if not dangerous for the cardiovascular system). Infliximab is a valid option in the therapy of ocular and cutaneous manifestations but it is less convincing in the therapy of vascular manifestations in vascular- and neuro-Behçet; furthermore, side-effects, including severe cardiovascular complications, are seen in a minority of patients; perhaps worse, infliximab seems to loose efficacy in the long

  2. The concurrent multiplicative-additive approach for gauge-radar/satellite multisensor precipitation estimates

    NASA Astrophysics Data System (ADS)

    Garcia-Pintado, J.; Barberá, G. G.; Erena Arrabal, M.; Castillo, V. M.

    2010-12-01

    Objective analysis schemes (OAS), also called ``succesive correction methods'' or ``observation nudging'', have been proposed for multisensor precipitation estimation combining remote sensing data (meteorological radar or satellite) with data from ground-based raingauge networks. However, opposite to the more complex geostatistical approaches, the OAS techniques for this use are not optimized. On the other hand, geostatistical techniques ideally require, at the least, modelling the covariance from the rain gauge data at every time step evaluated, which commonly cannot be soundly done. Here, we propose a new procedure (concurrent multiplicative-additive objective analysis scheme [CMA-OAS]) for operational rainfall estimation using rain gauges and meteorological radar, which does not require explicit modelling of spatial covariances. On the basis of a concurrent multiplicative-additive (CMA) decomposition of the spatially nonuniform radar bias, within-storm variability of rainfall and fractional coverage of rainfall are taken into account. Thus both spatially nonuniform radar bias, given that rainfall is detected, and bias in radar detection of rainfall are handled. The interpolation procedure of CMA-OAS is built on the OAS, whose purpose is to estimate a filtered spatial field of the variable of interest through a successive correction of residuals resulting from a Gaussian kernel smoother applied on spatial samples. The CMA-OAS, first, poses an optimization problem at each gauge-radar support point to obtain both a local multiplicative-additive radar bias decomposition and a regionalization parameter. Second, local biases and regionalization parameters are integrated into an OAS to estimate the multisensor rainfall at the ground level. The approach considers radar estimates as background a priori information (first guess), so that nudging to observations (gauges) may be relaxed smoothly to the first guess, and the relaxation shape is obtained from the sequential

  3. Novel therapeutic approaches for various cancer types using a modified sleeping beauty-based gene delivery system.

    PubMed

    Hong, In-Sun; Lee, Hwa-Yong; Kim, Hyun-Pyo

    2014-01-01

    Successful gene therapy largely depends on the selective introduction of therapeutic genes into the appropriate target cancer cells. One of the most effective and promising approaches for targeting tumor tissue during gene delivery is the use of viral vectors, which allow for high efficiency gene delivery. However, the use of viral vectors is not without risks and safety concerns, such as toxicities, a host immune response towards the viral antigens or potential viral recombination into the host's chromosome; these risks limit the clinical application of viral vectors. The Sleeping Beauty (SB) transposon-based system is an attractive, non-viral alternative to viral delivery systems. SB may be less immunogenic than the viral vector system due to its lack of viral sequences. The SB-based gene delivery system can stably integrate into the host cell genome to produce the therapeutic gene product over the lifetime of a cell. However, when compared to viral vectors, the non-viral SB-based gene delivery system still has limited therapeutic efficacy due to the lack of long-lasting gene expression potential and tumor cell specific gene transfer ability. These limitations could be overcome by modifying the SB system through the introduction of the hTERT promoter and the SV40 enhancer. In this study, a modified SB delivery system, under control of the hTERT promoter in conjunction with the SV40 enhancer, was able to successfully transfer the suicide gene (HSV-TK) into multiple types of cancer cells. The modified SB transfected cancer cells exhibited a significantly increased cancer cell specific death rate. These data suggest that our modified SB-based gene delivery system can be used as a safe and efficient tool for cancer cell specific therapeutic gene transfer and stable long-term expression. PMID:24466025

  4. Novel Therapeutic Approaches for Various Cancer Types Using a Modified Sleeping Beauty-Based Gene Delivery System

    PubMed Central

    Kim, Hyun-Pyo

    2014-01-01

    Successful gene therapy largely depends on the selective introduction of therapeutic genes into the appropriate target cancer cells. One of the most effective and promising approaches for targeting tumor tissue during gene delivery is the use of viral vectors, which allow for high efficiency gene delivery. However, the use of viral vectors is not without risks and safety concerns, such as toxicities, a host immune response towards the viral antigens or potential viral recombination into the host's chromosome; these risks limit the clinical application of viral vectors. The Sleeping Beauty (SB) transposon-based system is an attractive, non-viral alternative to viral delivery systems. SB may be less immunogenic than the viral vector system due to its lack of viral sequences. The SB-based gene delivery system can stably integrate into the host cell genome to produce the therapeutic gene product over the lifetime of a cell. However, when compared to viral vectors, the non-viral SB-based gene delivery system still has limited therapeutic efficacy due to the lack of long-lasting gene expression potential and tumor cell specific gene transfer ability. These limitations could be overcome by modifying the SB system through the introduction of the hTERT promoter and the SV40 enhancer. In this study, a modified SB delivery system, under control of the hTERT promoter in conjunction with the SV40 enhancer, was able to successfully transfer the suicide gene (HSV-TK) into multiple types of cancer cells. The modified SB transfected cancer cells exhibited a significantly increased cancer cell specific death rate. These data suggest that our modified SB-based gene delivery system can be used as a safe and efficient tool for cancer cell specific therapeutic gene transfer and stable long-term expression. PMID:24466025

  5. Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches.

    PubMed

    Beermann, Julia; Piccoli, Maria-Teresa; Viereck, Janika; Thum, Thomas

    2016-10-01

    Advances in RNA-sequencing techniques have led to the discovery of thousands of non-coding transcripts with unknown function. There are several types of non-coding linear RNAs such as microRNAs (miRNA) and long non-coding RNAs (lncRNA), as well as circular RNAs (circRNA) consisting of a closed continuous loop. This review guides the reader through important aspects of non-coding RNA biology. This includes their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system). We specifically focus on non-coding RNAs as potential therapeutic targets and diagnostic biomarkers. PMID:27535639

  6. Biologics in pediatric Crohn's disease: is it time to move to an earlier therapeutic approach?

    PubMed

    Hyams, Jeffrey S

    2014-11-01

    The treatment of Crohn's disease in children has undergone a revolution in the past decade following studies that have demonstrated the efficacy of anti-TNFα agents in producing durable clinical response/remission as well as reversal of growth delay in many patients. The positioning of biologic therapy continues to be debated. Should it be reserved for children failing conventional therapy including immunomodulators or should it be used as primary therapy shortly after diagnosis in children with more severe disease likely to suffer a more complicated disease course? Risk stratification will be crucial to any therapeutic decisions and emerging data hold promise that identification of those most likely to benefit will be available in the near future. PMID:25340425

  7. Sickle cell anemia, the first molecular disease: overview of molecular etiology, pathophysiology, and therapeutic approaches.

    PubMed

    Steinberg, Martin H

    2008-01-01

    The root cause of sickle cell disease is a single beta-globin gene mutation coding for the sickle beta-hemoglobin chain. Sickle hemoglobin tetramers polymerize when deoxygenated, damaging the sickle erythrocyte. A multifaceted pathophysiology, triggered by erythrocyte injury induced by the sickle hemoglobin polymer, and encompassing more general cellular and tissue damage caused by hypoxia, oxidant damage, inflammation, abnormal intracellular interactions, and reduced nitric oxide bioavailability, sets off the events recognized clinically as sickle cell disease. This disease is a group of related disorders where sickle hemoglobin is the principal hemoglobin species. All have varying degrees of chronic hemolytic anemia, vasculopathy, vasoocclusive disease, acute and chronic organ damage, and shortened life span. Its complex pathophysiology, of which we have a reasonable understanding, provides multiple loci for potential therapeutic intervention. PMID:19112541

  8. Recent Advances in Therapeutic Approaches for Adult T-cell Leukemia/Lymphoma

    PubMed Central

    Kato, Koji; Akashi, Koichi

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia/lymphoma virus type 1 (HTLV-1). ATLL occurs in approximately 3%–5% of HTLV-1 carriers during their lifetime and follows a heterogeneous clinical course. The Shimoyama classification has been frequently used for treatment decisions in ATLL patients, and antiviral therapy has been reportedly promising, particularly in patients with indolent type ATLL; however, the prognosis continues to be dismal for patients with aggressive-type ATLL. Recent efforts to improve treatment outcomes have been focused on the development of prognostic stratification and improved dosage, timing, and combination of therapeutic modalities, such as antiviral therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, and molecular targeted therapy. PMID:26694446

  9. Does assessing the value for money of therapeutic medical devices require a flexible approach?

    PubMed

    Iglesias, Cynthia P

    2015-02-01

    Regulation criteria for licensing pharmaceuticals and medical devices (MDs) are asymmetric. This has affected the type, quantity and quality of the evidence produced in support of MDs. This paper has three objectives: to examine the reasons behind the current licensing criteria for MDs; to identify key methodological challenges associated with pre- and post-market evaluation of MDs and to assess the extent to which existing methods for the economic evaluation of pharmaceuticals can be applied to the evaluation of MDs. The belief that MDs cannot be properly evaluated stems from a combination of historical events and complexities in implementing rigorous RCTs in this field. Existing challenges to conduct sound economic evaluation of MDs have begun to be addressed in medical research using mixed research methods. While more challenging to implement, robust evaluations of therapeutic MDs can and need to be carried out to safeguard individual's wellbeing. PMID:25583537

  10. Progress in AQP Research and New Developments in Therapeutic Approaches to Ischemic and Hemorrhagic Stroke.

    PubMed

    Previch, Lauren E; Ma, Linlin; Wright, Joshua C; Singh, Sunpreet; Geng, Xiaokun; Ding, Yuchuan

    2016-01-01

    Cerebral edema often manifests after the development of cerebrovascular disease, particularly in the case of stroke, both ischemic and hemorrhagic. Without clinical intervention, the influx of water into brain tissues leads to increased intracranial pressure, cerebral herniation, and ultimately death. Strategies to manage the development of edema constitute a major unmet therapeutic need. However, despite its major clinical significance, the mechanisms underlying cerebral water transport and edema formation remain elusive. Aquaporins (AQPs) are a class of water channel proteins which have been implicated in the regulation of water homeostasis and cerebral edema formation, and thus represent a promising target for alleviating stroke-induced cerebral edema. This review examines the significance of relevant AQPs in stroke injury and subsequently explores neuroprotective strategies aimed at modulating AQP expression, with a particular focus on AQP4, the most abundant AQP in the central nervous system. PMID:27438832

  11. The therapeutic approach to non-tuberculous mycobacterial infection of the lung.

    PubMed

    McGrath, Emmet E; Anderson, Paul B

    2010-10-01

    Non-tuberculous mycobacteria (NTM) are a group of alcohol fast, aerobic, nonmotile bacteria that are found in the environment. Recent reports indicate that their incidence and prevalence is increasing and guidelines have been developed laying down criteria for diagnosis. The treatment of these mycobacteria may be difficult, in many cases involving complex regimens containing multiple drugs. While traditional anti-tuberculosis medications are frequently used, specific therapeutic regimens depend on the organism isolated, in vitro susceptibility testing, drug tolerance and toxicity and concomitant medical disorders. In this review, we describe the diagnosis and treatment of the more important lung pathogens, describing complexities and controversies surrounding treatment with traditional, adjunctive and the newer and more experimental agents. PMID:20542128

  12. Progress in AQP Research and New Developments in Therapeutic Approaches to Ischemic and Hemorrhagic Stroke

    PubMed Central

    Previch, Lauren E.; Ma, Linlin; Wright, Joshua C.; Singh, Sunpreet; Geng, Xiaokun; Ding, Yuchuan

    2016-01-01

    Cerebral edema often manifests after the development of cerebrovascular disease, particularly in the case of stroke, both ischemic and hemorrhagic. Without clinical intervention, the influx of water into brain tissues leads to increased intracranial pressure, cerebral herniation, and ultimately death. Strategies to manage the development of edema constitute a major unmet therapeutic need. However, despite its major clinical significance, the mechanisms underlying cerebral water transport and edema formation remain elusive. Aquaporins (AQPs) are a class of water channel proteins which have been implicated in the regulation of water homeostasis and cerebral edema formation, and thus represent a promising target for alleviating stroke-induced cerebral edema. This review examines the significance of relevant AQPs in stroke injury and subsequently explores neuroprotective strategies aimed at modulating AQP expression, with a particular focus on AQP4, the most abundant AQP in the central nervous system. PMID:27438832

  13. Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis.

    PubMed

    Brenton, J Nicholas; Banwell, Brenda L

    2016-01-01

    Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination. PMID:26496907

  14. Lymphovascular and neural regulation of metastasis: Shared tumour signalling pathways and novel therapeutic approaches

    PubMed Central

    Le, C.P.; Karnezis, T.; Achen, M. G.; Stacker, S.A.; Sloan, E.K.

    2014-01-01

    The progression of cancer is supported by a wide variety of non-neoplastic cell types which make up the tumour stroma, including immune cells, endothelial cells, cancer-associated fibroblasts and nerve fibres. These host cells contribute molecular signals that enhance primary tumour growth and provide physical avenues for metastatic dissemination. This article provides an overview of the role of blood vessels, lymphatic vessels and nerve fibres in the tumour microenvironment, and highlights the interconnected molecular signalling pathways that control their development and activation in cancer. Further the review highlights the known pharmacological agents which target these pathways and discusses the potential therapeutic uses of drugs that target angiogenesis, lymphangiogenesis and stress response pathways in the different stages of cancer care. PMID:24267548

  15. Implication of Green Tea as a Possible Therapeutic Approach for Parkinson Disease.

    PubMed

    Jurado-Coronel, Juan C; Ávila-Rodriguez, Marco; Echeverria, Valentina; Hidalgo, Oscar Alejandro; Gonzalez, Janneth; Aliev, Gjumrakch; Barreto, George E

    2016-01-01

    Green tea is a beverage consumed around the world that is believed to have substantial health benefits such as reducing the risk of cancer, cardiovascular diseases, diabetes and neurodegeneration. This beverage is prepared from the leaves (steamed and dried) of the Camellia sinesis plant and contains strong antioxidant and neuroprotective phenolic compounds from which the most important is (-)-Epigallocatechin-3-gallate. Parkinson's disease (PD) is the second more common neurodegenerative disorders, after Alzheimer's disease and is characterized by degeneration of dopaminergic neurons in the pars compact of the substantia nigra of the basal ganglia. It has been shown in pre-clinical and clinical studies that green tea may be able to prevent PD, but its optimal dose or a possible mechanism explaining its health benefit in PD has not been properly established. In this review, we discuss the potential role of green tea's phenolic compounds and their therapeutic effectin modulating key signaling pathways in the PD brain. PMID:26831259

  16. Platelet derived growth factor inhibitors: A potential therapeutic approach for ocular neovascularization.

    PubMed

    Sadiq, Mohammad Ali; Hanout, Mostafa; Sarwar, Salman; Hassan, Muhammad; Do, Diana V; Nguyen, Quan Dong; Sepah, Yasir Jamal

    2015-01-01

    Retinochoroidal vascular diseases are the leading causes of blindness in the developed world. They include diabetic retinopathy (DR), retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration (AMD), and pathological myopia, among many others. Several different therapies are currently under consideration for the aforementioned disorders. In the following section, agents targeting platelet-derived growth factor (PDGF) are discussed as a potential therapeutic option for retinochoroidal vascular diseases. PDGF plays an important role in the angiogenesis cascade that is activated in retinochoroidal vascular diseases. The mechanism of action, side effects, efficacy, and the potential synergistic role of these agents in combination with other treatment options is discussed. The future of treatment of retinochoroidal vascular diseases, particularly AMD, has become more exciting due to agents such as PDGF antagonists. PMID:26586980

  17. Platelet-Derived Growth Factor Inhibitors: A Potential Therapeutic Approach for Ocular Neovascularization.

    PubMed

    Sadiq, Mohammad Ali; Hanout, Mostafa; Sarwar, Salman; Hassan, Muhammad; Agarwal, Aniruddha; Sepah, Yasir Jamal; Do, Diana V; Nguyen, Quan Dong

    2016-01-01

    Retinochoroidal vascular diseases are the leading causes of blindness in the developed world. They include diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration (AMD), and pathological myopia, among many others. Several different therapies are currently under consideration for the aforementioned disorders. In the following section, agents targeting platelet-derived growth factors (PDGF) are discussed as a potential therapeutic option for retinochoroidal vascular diseases. PDGF play an important role in the angiogenesis cascade that is activated in retinochoroidal vascular diseases. The mechanism of action, side effects, efficacy, and the potential synergistic role of these agents in combination with other treatment options is discussed. The future of treatment of retinochoroidal vascular diseases, particularly neovascular AMD, has become more exciting due to agents like PDGF antagonists. PMID:26501397

  18. New Diagnostic and Therapeutic Approaches for Preventing the Progression of Diabetic Retinopathy

    PubMed Central

    Park, Young Gun; Roh, Young-Jung

    2016-01-01

    Diabetic retinopathy (DR) is a severe sight-threatening complication of diabetes mellitus. Retinal laser photocoagulation, antivascular endothelial growth factors, steroid therapy, and pars plana vitrectomy are now used extensively to treat advanced stages of diabetic retinopathy. Currently, diagnostic devices like ultrawide field fundus fluorescein angiography and the improvement of optical coherence tomography have provided quicker and more precise diagnosis of early diabetic retinopathy. Thus, treatment protocols have been modified accordingly. Various types of lasers, including the subthreshold micropulse laser and RPE-targeting laser, and selective targeted photocoagulation may be future alternatives to conventional retinal photocoagulation, with fewer complications. The new developed intravitreal medications and implants have provided more therapeutic options, with promising results. PMID:26881240

  19. Platelet derived growth factor inhibitors: A potential therapeutic approach for ocular neovascularization

    PubMed Central

    Sadiq, Mohammad Ali; Hanout, Mostafa; Sarwar, Salman; Hassan, Muhammad; Do, Diana V.; Nguyen, Quan Dong; Sepah, Yasir Jamal

    2015-01-01

    Retinochoroidal vascular diseases are the leading causes of blindness in the developed world. They include diabetic retinopathy (DR), retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration (AMD), and pathological myopia, among many others. Several different therapies are currently under consideration for the aforementioned disorders. In the following section, agents targeting platelet-derived growth factor (PDGF) are discussed as a potential therapeutic option for retinochoroidal vascular diseases. PDGF plays an important role in the angiogenesis cascade that is activated in retinochoroidal vascular diseases. The mechanism of action, side effects, efficacy, and the potential synergistic role of these agents in combination with other treatment options is discussed. The future of treatment of retinochoroidal vascular diseases, particularly AMD, has become more exciting due to agents such as PDGF antagonists. PMID:26586980

  20. Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids.

    PubMed

    Kohnz, Rebecca A; Nomura, Daniel K

    2014-10-01

    The endocannabinoid system, most popularly known as the target of the psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), is a signaling network that modulates a diverse range of physiological processes including nociception, behavior, cognitive function, appetite, metabolism, motor control, memory formation, and inflammation. While THC and its derivatives have garnered notoriety in the eyes of the public, the endocannabinoid system consists of two endogenous signaling lipids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide), which activate cannabinoid receptors CB1 and CB2 in the nervous system and peripheral tissues. This review will focus on the recent efforts to chemically manipulate 2-AG signaling through the development of inhibitors of the 2-AG-synthesizing enzyme diacylglycerol lipase (DAGL) or the 2-AG-degrading enzyme monoacylglycerol lipase (MAGL), and assessing the therapeutic potential of DAGL and MAGL inhibitors in pain, inflammation, degenerative diseases, tissue injury, and cancer. PMID:24676249

  1. MicroRNA and multiple myeloma: from laboratory findings to translational therapeutic approaches.

    PubMed

    Rossi, Marco; Amodio, Nicola; Di Martino, Maria Teresa; Tagliaferri, Pierosandro; Tassone, Pierfrancesco; Cho, William C

    2014-01-01

    Multiple myeloma (MM) is due to the proliferation in the bone marrow of malignant plasma cells and accounts for about 10% of all hematological tumors. MM is the natural evolution of a monoclonal gammopathy of uncertain significance. Although the introduction of novel biological agents in the clinical practice has changed the natural history of the disease, MM remains incurable. MicroRNAs (miRNAs) are short non-coding RNAs that control cell functions through mRNA targeting. In the cancer setting, miRNAs have shown prognostic and predictive potentials. Several preclinical findings demonstrate their broad anticancer activities in various types of cancer, including MM. In this article, we provide an overview of the biology of miRNAs focusing on the role of miRNA deregulation in MM pathogenesis. These findings represent the basis to discuss the potential role of miRNAs as therapeutic agents against MM. PMID:24846067

  2. New technologies and therapeutic approaches for the management of pediatric diabetes.

    PubMed

    Lawlor, M T; Laffel, L M

    2001-08-01

    Evolving trends in technology and therapeutic strategies create a very exciting time for the management of diabetes. Technology, like the internet, helps us to keep up with this fast-paced, changing world of diabetes. New therapies most often begin with adult clinical trials; once safety and efficacy are demonstrated, practice recommendations follow for the pediatric population. The Diabetes Research Working Group has defined potentially important new directions and technologies for diabetes research. The group has recommended the creation of regional centers of technologic excellence, if contemporary diabetes research is to succeed. An overview of recent advances in diabetes technology follows covering five main areas: monitoring, telemedicine, insulin analogues, insulin delivery devices, and islet cell transplantation. PMID:12762958

  3. Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches.

    PubMed

    Lund-Palau, Helena; Turnbull, Andrew R; Bush, Andrew; Bardin, Emmanuelle; Cameron, Loren; Soren, Odel; Wierre-Gore, Natasha; Alton, Eric W F W; Bundy, Jacob G; Connett, Gary; Faust, Saul N; Filloux, Alain; Freemont, Paul; Jones, Andy; Khoo, Valerie; Morales, Sandra; Murphy, Ronan; Pabary, Rishi; Simbo, Ameze; Schelenz, Silke; Takats, Zoltan; Webb, Jeremy; Williams, Huw D; Davies, Jane C

    2016-06-01

    Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development. PMID:27175979

  4. From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure.

    PubMed

    Bernardo, Bianca C; Blaxall, Burns C

    2016-05-01

    Heart failure is a significant global health problem, which is becoming worse as the population ages, and remains one of the biggest burdens on our economy. Despite significant advances in cardiovascular medicine, management and surgery, mortality rates remain high, with almost half of patients with heart failure dying within five years of diagnosis. As a multifactorial clinical syndrome, heart failure still represents an epidemic threat, highlighting the need for deeper insights into disease mechanisms and the development of innovative therapeutic strategies for both treatment and prevention. In this review, we discuss conventional heart failure therapies and highlight new pharmacological agents targeting pathophysiological features of the failing heart, for example, non-coding RNAs, angiotensin receptor-neprilysin inhibitors, cardiac myosin activators, BGP-15 and molecules targeting GRK2 including M119, gallein and paroxetine. Finally, we address the disparity between phase II and phase III clinical trials that prevent the translation of emerging HF therapies into new and approved therapies. PMID:26993094

  5. Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics.

    PubMed

    Shao, Juntang; Zaro, Jennica L; Shen, Wei-Chiang

    2016-01-01

    Current subcutaneously (s.c.)-injected insulin (INS) products result in a hyperinsulin exposure to peripheral tissues (skeletal muscle and adipose) while INS hardly accesses to liver after injection. This unphysiological distribution raises risks of hypoglycemia episode and causes weight gain after long term treatment. An ideal INS replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. However, there are 2 factors that limit the ability of s.c. injected INS to restore the liver: peripheral gradient in INS deficient diabetes patients: (1) the transport of INS in capillary endothelium and peripheral tissues from the injection site; and (2) peripheral INS receptor (IR) mediated INS degradation. In this review, the tissue barriers against efficient liver targeting of s.c. injected INS are discussed and current advances in developing hepatoselective insulin therapeutics are introduced. PMID:27358753

  6. Therapeutic Approaches for Renal Colic in the Emergency Department: A Review Article

    PubMed Central

    Golzari, Samad EJ; Soleimanpour, Hassan; Rahmani, Farzad; Zamani Mehr, Nahid; Safari, Saeid; Heshmat, Yaghoub; Ebrahimi Bakhtavar, Hanieh

    2014-01-01

    Context: Renal colic is frequently described as the worst pain ever experienced, and management of this intense pain is necessary. The object of our review was to discuss different approaches of pain control for patients with acute renal colic in the emergency department. Evidence Acquisition: Studies that discussed the treatment of renal colic pain were included in this review. We collected articles from reputable internet databases. Results: Our study showed that some new treatment approaches, such as the use of lidocaine or nerve blocks, can be used to control the severe and persistent pain of renal colic. Conclusions: Some new approaches are discussed and their impact on renal colic pain control was compared with traditional therapies. The effectiveness of the new approaches in this review is similar or even better than in traditional treatments. PMID:24701420

  7. Return to Competition in a Chronic Low Back Pain Runner: Beyond a Therapeutic Exercise Approach, a Case Report

    PubMed Central

    Doria, Christian; Falciati, Luca; Castelli, Claudio Carlo; Illic, Giorgio Fanò

    2014-01-01

    Chronic low back pain (CLBP) is a disabling condition affecting both quality of life and performance in athletes. Several approaches have been proposed in the field of physiotherapy, manual therapy, physical exercise and counseling. None apparently is outdoing the other with the exception of trunk stability exercises in specific conditions. The present paper describes a clinical success in managing a CLBP runner affected by MRI documented disk herniation via dietary change. Dietary changes allowed our patient that had failed with previous standard therapeutic approaches, to regain an optimal pain-free condition. We advance the hypothesis that a visceral-autonomic concomitant or primary disturbance possibly generating mild gastrointestinal discomfort in CLBP patients should be ruled out as a possible cause of pain and disability at the somato-motor level. PMID:26913133

  8. Return to Competition in a Chronic Low Back Pain Runner: Beyond a Therapeutic Exercise Approach, a Case Report.

    PubMed

    Veneziani, Sergio; Doria, Christian; Falciati, Luca; Castelli, Claudio Carlo; Illic, Giorgio Fanò

    2014-09-23

    Chronic low back pain (CLBP) is a disabling condition affecting both quality of life and performance in athletes. Several approaches have been proposed in the field of physiotherapy, manual therapy, physical exercise and counseling. None apparently is outdoing the other with the exception of trunk stability exercises in specific conditions. The present paper describes a clinical success in managing a CLBP runner affected by MRI documented disk herniation via dietary change. Dietary changes allowed our patient that had failed with previous standard therapeutic approaches, to regain an optimal pain-free condition. We advance the hypothesis that a visceral-autonomic concomitant or primary disturbance possibly generating mild gastrointestinal discomfort in CLBP patients should be ruled out as a possible cause of pain and disability at the somato-motor level. PMID:26913133

  9. From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins.

    PubMed

    Verdes, Aida; Anand, Prachi; Gorson, Juliette; Jannetti, Stephen; Kelly, Patrick; Leffler, Abba; Simpson, Danny; Ramrattan, Girish; Holford, Mandë

    2016-01-01

    Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa. PMID:27104567

  10. From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins

    PubMed Central

    Verdes, Aida; Anand, Prachi; Gorson, Juliette; Jannetti, Stephen; Kelly, Patrick; Leffler, Abba; Simpson, Danny; Ramrattan, Girish; Holford, Mandë

    2016-01-01

    Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa. PMID:27104567

  11. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults.

    PubMed

    Leitner, Gerda C; Vogelsang, Harald

    2016-02-01

    Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn's disease (CD) and ulcerative colitis (UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria (microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroid-free long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered (oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient's disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease (CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems (Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8(+) T cells

  12. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults

    PubMed Central

    Leitner, Gerda C; Vogelsang, Harald

    2016-01-01

    Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn’s disease (CD) and ulcerative colitis (UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria (microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroid-free long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered (oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient’s disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease (CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems (Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8+ T cells

  13. Modeling particulate matter concentrations measured through mobile monitoring in a deletion/substitution/addition approach

    NASA Astrophysics Data System (ADS)

    Su, Jason G.; Hopke, Philip K.; Tian, Yilin; Baldwin, Nichole; Thurston, Sally W.; Evans, Kristin; Rich, David Q.

    2015-12-01

    Land use regression modeling (LUR) through local scale circular modeling domains has been used to predict traffic-related air pollution such as nitrogen oxides (NOX). LUR modeling for fine particulate matters (PM), which generally have smaller spatial gradients than NOX, has been typically applied for studies involving multiple study regions. To increase the spatial coverage for fine PM and key constituent concentrations, we designed a mobile monitoring network in Monroe County, New York to measure pollutant concentrations of black carbon (BC, wavelength at 880 nm), ultraviolet black carbon (UVBC, wavelength at 3700 nm) and Delta-C (the difference between the UVBC and BC concentrations) using the Clarkson University Mobile Air Pollution Monitoring Laboratory (MAPL). A Deletion/Substitution/Addition (D/S/A) algorithm was conducted, which used circular buffers as a basis for statistics. The algorithm maximizes the prediction accuracy for locations without measurements using the V-fold cross-validation technique, and it reduces overfitting compared to other approaches. We found that the D/S/A LUR modeling approach could achieve good results, with prediction powers of 60%, 63%, and 61%, respectively, for BC, UVBC, and Delta-C. The advantage of mobile monitoring is that it can monitor pollutant concentrations at hundreds of spatial points in a region, rather than the typical less than 100 points from a fixed site saturation monitoring network. This research indicates that a mobile saturation sampling network, when combined with proper modeling techniques, can uncover small area variations (e.g., 10 m) in particulate matter concentrations.

  14. HBV and HIV co-infection: Impact on liver pathobiology and therapeutic approaches

    PubMed Central

    Parvez, Mohammad Khalid

    2015-01-01

    The consequences of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infection on progression of severe liver diseases is a serious public health issue, worldwide. In the co-infection cases, about 90% of HIV-infected population is seropositive for HBV where approximately 5%-40% individuals are chronically infected. In HIV co-infected individuals, liver-related mortality is estimated over 17 times higher than those with HBV mono-infection. The spectrum of HIV-induced liver diseases includes hepatitis, steatohepatitis, endothelialitis, necrosis, granulomatosis, cirrhosis and carcinoma. Moreover, HIV co-infection significantly alters the natural history of hepatitis B, and therefore complicates the disease management. Though several studies have demonstrated impact of HIV proteins on hepatocyte biology, only a few data is available on interactions between HBV and HIV proteins. Thus, the clinical spectrum as well as the complexity of the co-infection offers challenging fronts to study the underlying molecular mechanisms, and to design effective therapeutic strategies. PMID:25625003

  15. Internet-Based Approaches to Collaborative Therapeutic Assessment: New Opportunities for Professional Psychologists

    PubMed Central

    Smith, Ronald E.; Fagan, Corey; Wilson, Nicole L.; Chen, Jessica; Corona, Marissa; Nguyen, Hong; Racz, Sarah; Shoda, Yuichi

    2011-01-01

    Collaborative (or therapeutic) assessment is an empirically supported procedure that involves the client as an active participant in the assessment process. Clients discuss data they provide with the assessor in a collaborative manner designed to provide insights and assist in setting mutually agreeable treatment goals. Internet-based procedures allow for ongoing (including daily) tracking of psychological variables and provision of immediate graphic feedback to therapists, clients, and clinical supervisors. As an example, we describe one such system: Evidence-Based Assessment System for Clinicians (EAS-C) that contains more than 30 brief and empirically validated assessment instruments that can be completed via the internet or smartphone. We also provide examples from a stress management intervention demonstrating how single-client data from a web-based daily stress and coping diary tied to the EAS-C were utilized to provide clients with individualized feedback, assess progress, identify idiographic patterns of cognitions, affect, and coping strategies, and test clinical hypotheses. Internet- and computer-based technological advances can improve service delivery and help bridge the gap that currently exists between science and practice. PMID:23894220

  16. [Heart failure due to non-infectious causes in developing countries: etiologic approach and therapeutic principles].

    PubMed

    Paule, P; Braem, L; Mioulet, D; Gil, J M; Theron, A; Héno, P; Fourcade, L

    2007-12-01

    Cardiovascular disease is a major worldwide health problem with a growing impact in developing countries. Heart failure is the clinical manifestation of many advanced cardiac disorders. It can have numerous etiologies and the incidence of non-infectious causes is increasing with socio-economic development, thus illustrating the global nature of this epidemiologic transition. Several of the numerous non-infectious causes of heart failure involve cardiac diseases specific to tropical areas including dilated cardiomyopathy, endomyocardial fibrosis, and peripartum cardiomyopathy. Other widespread disorders are becoming more common as a result of the epidemiologic transition. Cardiovascular risk factors are changing particularly with regard to the incidence of coronary artery disease, ischemic cardiomyopathy, and hypertension-related complications. The purpose of this article is to provide an overview of non-infectious causes of heart failure in terms of frequency, onset, and therapeutic requirements. Symptomatic treatment of heart failure is same as in developing countries but is often delayed due to shortcomings in the care system. PMID:18300519

  17. Microemulgel: an overwhelming approach to improve therapeutic action of drug moiety.

    PubMed

    Ashara, Kalpesh C; Paun, Jalpa S; Soniwala, M M; Chavda, J R; Mendapara, Vishal P; Mori, Nitin M

    2016-07-01

    As compared to gel and other topical preparations microemulgel has been prepared by screening of oils, emulsifier, and co-emulsifier on bases of solubility of an API in it. An API has high solubility and oil may also have more or less pharmacological property, so it may assist the therapeutic action of API. Due to presence of oil portion, it leads to more penetration of API in the skin. Oil Micelle Size was less than 500 nm which provides more area for absorption of API in the skin so more penetration and more effective than macro-emulsion. Microemulgel has an advantage of emulgel that has dual benefits of micro-emulsion and gel and several other desirable properties like good consistency, thyrotrophic, greaseless, easily spreadable as well as removable, emollient, non-staining, water soluble, longer shelf-life, bio-friendly, transparent, pleasant appearance, ability of patients for self-medication, termination of medications will be easy, etc. PMID:27330376

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

    PubMed

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

    2014-01-01

    Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils. PMID:24971152

  19. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches.

    PubMed

    Joerger, Andreas C; Fersht, Alan R

    2016-06-01

    Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. We trace the structural evolution of the p53 pathway, from germ-line surveillance in simple multicellular organisms to its pluripotential role in humans. PMID:27145840

  20. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria.

    PubMed

    Cenni, V; Capanni, C; Columbaro, M; Ortolani, M; D'Apice, M R; Novelli, G; Fini, M; Marmiroli, S; Scarano, E; Maraldi, N M; Squarzoni, S; Prencipe, S; Lattanzi, G

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies. PMID:22297442

  1. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

    PubMed Central

    Muñoz, Miguel; Coveñas, Rafael

    2015-01-01

    Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert an antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC. PMID:26154566

  2. Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

    PubMed Central

    Daniotti, Jose L.; Vilcaes, Aldo A.; Torres Demichelis, Vanina; Ruggiero, Fernando M.; Rodriguez-Walker, Macarena

    2013-01-01

    Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described. PMID:24392350

  3. Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates.

    PubMed

    Baroja-Mazo, Alberto; Pelegrín, Pablo

    2012-01-01

    P2X7 receptor-mediated purinergic signaling is a well-known mechanism involved in bone remodeling. The P2X7 receptor has been implicated in the pathophysiology of various bone and cartilage diseases, including rheumatoid arthritis (RA), a widespread and complex chronic inflammatory disorder. The P2X7 receptor induces the release into the synovial fluid of the proinflammatory factors (e.g., interleukin-1β, prostaglandins, and proteases) responsible for the clinical symptoms of RA. Thus, the P2X7 receptor is emerging as a novel anti-inflammatory therapeutic target, and various selective P2X7 receptor antagonists are under clinical trials. Extracellular ATP signaling acting through the P2X7 receptor is a complex and dynamic scenario, which varies over the course of inflammation. This signaling is partially modulated by the activity of ectonucleotidases, which degrade extracellular ATP to generate other active molecules such as adenosine or pyrophosphates. Recent evidence suggests differential extracellular metabolism of ATP during the resolution of inflammation to generate pyrophosphates. Extracellular pyrophosphate dampens proinflammatory signaling by promoting alternative macrophage activation. Our paper shows that bisphosphonates are metabolically stable pyrophosphate analogues that are able to mimic the anti-inflammatory function of pyrophosphates. Bisphosphonates are arising per se as promising anti-inflammatory drugs to treat RA, and this therapy could be improved when administrated in combination with P2X7 receptor antagonists. PMID:22830074

  4. Endothelin receptor antagonists in sickle cell disease: A promising new therapeutic approach.

    PubMed

    Fox, Brandon M; Kasztan, Malgorzata

    2016-08-15

    Sickle cell disease (SCD) is a genetic hematologic disorder that is characterized by a variety of potentially life threatening acute and chronic complications. Currently, hydroxyurea is the only clinically approved pharmacological therapy for the treatment of SCD, and the continued prevalence of severe disease complications underscores the desperate need for the development of new therapeutic agents. Central features of the sickle cell disease milieu, including hypoxia, oxidative stress, and thrombosis, are established enhancers of endothelin-1 (ET-1) synthesis. This conceptual connection between ET-1 and SCD was confirmed by multiple studies that demonstrated markedly elevated plasma and urinary levels of ET-1 in SCD patients. Direct evidence for the involvement of ET-1 signaling in the development of SCD pathologies has come from studies using endothelin receptor antagonists in SCD mice. This review summarizes recent studies that have implicated ET-1 signaling as a mechanistic contributor to renal, vascular, pulmonary, and nociceptive complications of sickle cell disease and discusses the potential for the use of ET receptor antagonists in the treatment of SCD. PMID:27049871

  5. Quantitative proteomics approach to screening of potential diagnostic and therapeutic targets for laryngeal carcinoma.

    PubMed

    Li, Li; Zhang, Zhenwei; Wang, Chengyu; Miao, Lei; Zhang, Jianpeng; Wang, Jiasen; Jiao, Binghua; Zhao, Shuwei

    2014-01-01

    To discover candidate biomarkers for diagnosis and detection of human laryngeal carcinoma and explore possible mechanisms of this cancer carcinogenesis, two-dimensional strong cation-exchange/reversed-phase nano-scale liquid chromatography/mass spectrometry analysis was used to identify differentially expressed proteins between the laryngeal carcinoma tissue and the adjacent normal tissue. As a result, 281 proteins with significant difference in expression were identified, and four differential proteins, Profilin-1 (PFN1), Nucleolin (NCL), Cytosolic non-specific dipeptidase (CNDP2) and Mimecan (OGN) with different subcellular localization were selectively validated. Semiquantitative RT-PCR and Western blotting were performed to detect the expression of the four proteins employing a large collection of human laryngeal carcinoma tissues, and the results validated the differentially expressed proteins identified by the proteomics. Furthermore, we knocked down PFN1 in immortalized human laryngeal squamous cell line Hep-2 cells and then the proliferation and metastasis of these transfected cells were measured. The results showed that PFN1 silencing inhibited the proliferation and affected the migration ability of Hep-2 cells, providing some new insights into the pathogenesis of PFN1 in laryngeal carcinoma. Altogether, our present data first time show that PFN1, NCL, CNDP2 and OGN are novel potential biomarkers for diagnosis and therapeutic targets for laryngeal carcinoma, and PFN1 is involved in the metastasis of laryngeal carcinoma. PMID:24587265

  6. Quantitative Proteomics Approach to Screening of Potential Diagnostic and Therapeutic Targets for Laryngeal Carcinoma

    PubMed Central

    Wang, Chengyu; Miao, Lei; Zhang, Jianpeng; Wang, Jiasen; Jiao, Binghua; Zhao, Shuwei

    2014-01-01

    To discover candidate biomarkers for diagnosis and detection of human laryngeal carcinoma and explore possible mechanisms of this cancer carcinogenesis, two-dimensional strong cation-exchange/reversed-phase nano-scale liquid chromatography/mass spectrometry analysis was used to identify differentially expressed proteins between the laryngeal carcinoma tissue and the adjacent normal tissue. As a result, 281 proteins with significant difference in expression were identified, and four differential proteins, Profilin-1 (PFN1), Nucleolin (NCL), Cytosolic non-specific dipeptidase (CNDP2) and Mimecan (OGN) with different subcellular localization were selectively validated. Semiquantitative RT-PCR and Western blotting were performed to detect the expression of the four proteins employing a large collection of human laryngeal carcinoma tissues, and the results validated the differentially expressed proteins identified by the proteomics. Furthermore, we knocked down PFN1 in immortalized human laryngeal squamous cell line Hep-2 cells and then the proliferation and metastasis of these transfected cells were measured. The results showed that PFN1 silencing inhibited the proliferation and affected the migration ability of Hep-2 cells, providing some new insights into the pathogenesis of PFN1 in laryngeal carcinoma. Altogether, our present data first time show that PFN1, NCL, CNDP2 and OGN are novel potential biomarkers for diagnosis and therapeutic targets for laryngeal carcinoma, and PFN1 is involved in the metastasis of laryngeal carcinoma. PMID:24587265

  7. Therapeutic Approaches to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Chronic Bronchitis.

    PubMed

    Solomon, George M; Raju, S Vamsee; Dransfield, Mark T; Rowe, Steven M

    2016-04-01

    Chronic obstructive pulmonary disease is a common cause of morbidity and a rising cause of mortality worldwide. Its rising impact indicates the ongoing unmet need for novel and effective therapies. Previous work has established a pathophysiological link between the chronic bronchitis phenotype of chronic obstructive pulmonary disease and cystic fibrosis as well as phenotypic similarities between these two airways diseases. An extensive body of evidence has established that cigarette smoke and its constituents contribute to acquired dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways, pointing to a mechanistic link with smoking-related and chronic bronchitis. Recent interest surrounding new drugs that target both mutant and wild-type CFTR channels has paved the way for a new treatment opportunity addressing the mucus defect in chronic bronchitis. We review the clinical and pathologic evidence for modulating CFTR to address acquired CFTR dysfunction and pragmatic issues surrounding clinical trials as well as a discussion of other ion channels that may represent alternative therapeutic targets. PMID:27115953

  8. Pelvic congestion syndrome and left renal compression syndrome - clinical features and therapeutic approaches.

    PubMed

    Jeanneret, Christina; Beier, Konstantin; von Weymarn, Alexander; Traber, Jürg

    2016-07-01

    Knowledge of the anatomy of the pelvic, gonadal and renal veins is important to understand pelvic congestion syndrome (PCS) and left renal vein compression syndrome (LRCS), which is also known as the nutcracker syndrome. LRCS is related to PCS and to the presence of vulvar, vaginal and pudendal varicose veins. The diagnosis of the two syndromes is difficult, and usually achieved with CT- or phlebography. The gold standard is the intravenous pressure measurement using conventional phlebography. The definition of PCS is described as pelvic pain, aggravated in the standing position and lasting for more than 6 months. Pain in the left flank and microhaematuria is seen in patients with LRCS. Women with multiple pregnancies are at increased risk of developing varicose vein recurrences with pelvic drainage and ovarian vein reflux after crossectomy and stripping of the great saphenous vein. The therapeutic options are: conservative treatment (medroxyprogesteron) or interventional (coiling of the ovarian vein) or operative treatment (clipping of the ovarian vein). Controlled prospective trials are needed to find the best treatment. PMID:27428495

  9. Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach.

    PubMed

    Agostinelli, E; Tempera, G; Viceconte, N; Saccoccio, S; Battaglia, V; Grancara, S; Toninello, A; Stevanato, R

    2010-02-01

    The polyamines spermine, spermidine and putrescine are ubiquitous cell components. These molecules are substrates of a class of enzymes that includes monoamine oxidases, diamine oxidases, polyamine oxidases and copper-containing amine oxidases. Amine oxidases are important because they contribute to regulate levels of mono- and polyamines. In tumors, polyamines and amine oxidases are increased as compared to normal tissues. Cytotoxicity induced by bovine serum amine oxidase (BSAO) and spermine is attributed to H(2)O(2) and aldehydes produced by the reaction. This study demonstrated that multidrug-resistant (MDR) cancer cells (colon adenocarcinoma and melanoma) are significantly more sensitive than the corresponding wild-type (WT) ones to H(2)O(2) and aldehydes, the products of BSAO-catalyzed oxidation of spermine. Transmission electron microscopy (TEM) observations showed major ultrastructural alterations of the mitochondria. These were more pronounced in MDR than in WT cells. Increasing the incubation temperature from 37 to 42 degrees Celsius enhances cytotoxicity in cells exposed to spermine metabolites. The combination BSAO/spermine prevents tumor growth, particularly well if the enzyme has been conjugated to a biocompatible hydrogel polymers. Since both wild-type and MDR cancer cells after pre-treatment with MDL 72527, a lysosomotropic compound, are sensitized to subsequent exposure to BSAO/spermine, it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumor cells. It is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting. PMID:20012114

  10. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics.

    PubMed

    North, E Jeffrey; Jackson, Mary; Lee, Richard E

    2014-01-01

    Mycolic acids are the major lipid components of the unique mycobacterial cell wall responsible for the protection of the tuberculosis bacilli from many outside threats. Mycolic acids are synthesized in the cytoplasm and transported to the outer membrane as trehalose- containing glycolipids before being esterified to the arabinogalactan portion of the cell wall and outer membrane glycolipids. The large size of these unique fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these lipids to the mycobacterial cellular survival. There are many key enzymes involved in the mycolic acid biosynthetic pathway, including fatty acid synthesis (KasA, KasB, MabA, InhA, HadABC), mycolic acid modifying enzymes (SAM-dependent methyltransferases, aNAT), fatty acid activating and condensing enzymes (FadD32, Acc, Pks13), transporters (MmpL3) and tranferases (Antigen 85A-C) all of which are excellent potential drug targets. Not surprisingly, in recent years many new compounds have been reported to inhibit specific portions of this pathway, discovered through both phenotypic screening and target enzyme screening. In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of tuberculosis drug discovery, several of which show great promise as selective tuberculosis therapeutics. PMID:24245756

  11. New Approaches to Target the Mycolic Acid Biosynthesis Pathway for the Development of Tuberculosis Therapeutics

    PubMed Central

    North, E. Jeffrey; Jackson, Mary; Lee, Richard E.

    2015-01-01

    Mycolic acids are the major lipid component of the unique mycobacterial cell wall responsible for the protection of the tuberculosis bacilli from many outside threats. Mycolic acids are synthesized in the cytoplasm and transported to the outer membrane as trehalose-containing glycolipids before being esterified to the arabinogalactan portion of the cell wall and outer membrane glycolipids. The large size of these unique fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these lipids to the mycobacterial cellular survival. There are many key enzymes involved in the mycolic acid biosynthetic pathway, including fatty acid synthesis (KasA, KasB, MabA, InhA, HadABC), mycolic acid modifying enzymes (SAM-dependent methyltransferases, aNAT), fatty acid activating and condensing enzymes (FadD32, Acc, Pks13), transporters (MmpL3) and tranferases (Antigen 85A-C) all of which are excellent potential drug targets. Not surprisingly, in recent years many new compounds have been reported to inhibit specific portions of this pathway, discovered through both phenotypic screening and target enzyme screening. In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of tuberculosis drug discovery, several of which show great promise as selective tuberculosis therapeutics. PMID:24245756

  12. Nanotechnology as a New Therapeutic Approach to Prevent the HIV-Infection of Treg Cells

    PubMed Central

    Jaramillo-Ruiz, Didiana; De La Mata, Francisco Javier; Gómez, Rafael; Correa-Rocha, Rafael; Muñoz-Fernández, Mª Ángeles

    2016-01-01

    Background HIV-1 has proved to infect regulatory T cells (Treg) modifying their phenotype and impairing their suppressive capacity. As Treg cells are a crucial component in the preservation of the immune homeostasis, we researched that the antiviral capacity of carboxilan dendrimers prevents the HIV-1 infection of Treg and their effects. The phenotype and suppressive capacity of Treg treated or non-treated with carbosilane dendrimers were studied by flow cytometry. Treated and non-treated Treg from healthy donors were infected with HIV-1NL4.3. The infection of Treg cells by HIV-1, and protective effect of two dendrimers were determined by measuring antigen p24gag in the supernatant of the culture and intracellular. Results The Treg cells were treated with cationic and anionic carbosilane dendrimers. The results showed that both dendrimers did not modify the phenotype and functionality of Treg cells compared with non- treated Treg cells. Anionic dendrimers showed high biocompatibility with normal activity of the Treg cells and in antiviral assays. These dendrimers were highly active against HIV-1 preventing the infection of Treg, and were able to protect the Treg from the Foxp3 downregulation induced by the HIV-1 infection. Conclusions This is the first work showing that the in vitro use of anionic dendrimers prevent the HIV-1 replication and the infection of expanded Treg cells in culture, which raises the possibility to use Treg cells therapeutically in HIV-1-infected subjects. PMID:26785250

  13. Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes.

    PubMed

    Barnes, Peter J

    2015-09-01

    The recognition that there are some patients with features of asthma and chronic obstructive pulmonary disease (COPD) has highlighted the need to develop more specific treatments for these clinical phenotypes. Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on TH2 cells antagonists. Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen-activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty. Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long-acting β2-agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness. PMID:26343937

  14. A therapeutic community for HIV-infected persons: an approach for prevention and control of AIDS.

    PubMed

    Warnnissorn, T

    1995-10-01

    The Therapeutic Community (TC) for HIV-infected persons is neither a hospital nor a confinement for people with HIV. Actually it is a family of friends who are in the same boat and a place of education to teach them about AIDS and relevant subjects necessary for their life in the future, and to help establish new values and life styles for them using TC tools which are adapted from the DAYTOP TC in U.S.A. The purpose was not only to build the residents, but also to encourage them to do their part in contributing to build up a better and safer society that will help to save the lives of others from AIDS. Correct knowledge in AIDS, together with the quality of honesty, responsibility and other basic attitudes that the residents acquire through the program will enable them to become a creative force in the prevention and control of AIDS. The author would say that words alone will not describe the whole TC. It requires self experience through the program in order to learn TC and understand it. PMID:8576664

  15. A natural therapeutic approach for the treatment of periodontitis by MK615.

    PubMed

    Morimoto-Yamashita, Yoko; Kawakami, Yoshiko; Tatsuyama, Syoko; Miyashita, Keiko; Emoto, Makiko; Kikuchi, Kiyoshi; Kawahara, Ko-ichi; Tokuda, Masayuki

    2015-11-01

    Periodontitis is a chronic inflammatory disease that affects the tooth-supporting tissues. Gingival fibroblasts are the most abundant cells in periodontal tissues and they participate actively in the host inflammatory response to periodontal pathogens that is known to mediate local tissue destruction in periodontitis. The Japanese apricot, known as Ume in Japanese, has been a traditional Japanese medicine for centuries and is a familiar and commonly consumed food. The health benefits of Ume are widely recognized and have been confirmed in recent studies showing that MK615, an extract of compounds from Ume, has strong anticancer and anti-inflammatory effects. However, the potential role of MK615 in oral health is unknown. We hypothesized that the anti-inflammatory activities of MK615 could be exploited to inhibit the effects of lipopolysaccharide (LPS) produced by periodontal bacterial pathogens, such as Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Here, we show that LPS-induced interleukin (IL)-6 and IL-8 production by gingival fibroblasts was dose-dependently inhibited by MK615. As a potent inhibitor of the inflammatory responses induced by periodontal pathogens, MK615 merits further testing as a therapeutic agent in inflammatory diseases such as periodontitis. PMID:26305447

  16. Sirtuin activation as a therapeutic approach against inborn errors of metabolism.

    PubMed

    Bleeker, Jeannette C; Houtkooper, Riekelt H

    2016-07-01

    Protein acylation has emerged as a large family of post translational modifications in which an acyl group can alter the function of a wide variety of proteins, especially in response to metabolic stress. The acylation state is regulated through reversible acylation/deacylation. Acylation occurs enzymatically or non-enzymatically, and responds to acyl-CoA levels. Deacylation on the other hand is controlled through the NAD(+)-dependent sirtuin proteins. In several inborn errors of metabolism (IEMs), accumulation of acyl-CoAs, due to defects in amino acid and fatty acid metabolic pathways, can lead to hyperacylation of proteins. This can have a direct effect on protein function and might play a role in pathophysiology. In this review we describe several mouse and cell models for IEM that display high levels of lysine acylation. Furthermore, we discuss how sirtuins serve as a promising therapeutic target to restore acylation state and could treat IEMs. In this context we examine several pharmacological sirtuin activators, such as resveratrol, NAD(+) precursors and PARP and CD38 inhibitors. PMID:27146436

  17. MK615: a new therapeutic approach for the treatment of oral disease.

    PubMed

    Morimoto-Yamashita, Yoko; Matsuo, Miki; Komatsuzawa, Hitoshi; Kawahara, Ko-ichi; Kikuchi, Kiyoshi; Torii, Mitsuo; Tokuda, Masayuki

    2011-08-01

    The oral cavity is inhabited by over 500 different bacterial species. Dental caries and periodontitis are major bacterial infectious diseases in the oral cavity. Prunus mume Sieb. et Zucc., which is a variety of Japanese apricot known as Ume in Japanese, has been a traditional Japanese medicine for centuries, and is a familiar and commonly consumed food. The health benefits of Ume are now being widely recognized. Recent studies showed that MK615, an extract of compounds from Ume, has strong anticancer and anti-inflammatory effects. However, the potential role of MK615 in the antimicrobial field remains unknown. Therefore, we hypothesize that MK615 has antimicrobial activities against a range of oral bacterial pathogens. Here, we show that MK615 may be a potent inhibitor of the growth of some oral bacteria and an inhibitor of biofilm formation by Streptococcus mutans, the principal etiological agent of human dental caries. Our findings suggest that MK615 has potential as a therapeutic agent for treating and preventing oral diseases such as dental caries and periodontitis. PMID:21565449

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

    PubMed Central

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

    2014-01-01

    Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils. PMID:24971152

  19. Feedlot therapeutics.

    PubMed

    Apley, M D; Fajt, V R

    1998-07-01

    This article discusses therapeutic approaches to conditions commonly encountered in feedlots. Challenges discussed include bovine respiratory complex, tracheal edema, atypical interstitial pneumonia, footrot, toe abscesses, mycoplasma arthritis, cardiovascular disease, lactic acidosis, bloat, coccidiosis, central nervous system diseases, abscesses and cellulitis, pregnancy management and abortion, and ocular disease. PMID:9704416

  20. Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS.

    PubMed

    Salinthone, Sonemany; Yadav, Vijayshree; Bourdette, Dennis N; Carr, Daniel W

    2008-06-01

    The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to Acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants such as glutathione, and chelates zinc, copper and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. By acting as an insulin mimetic agent, LA stimulates glucose uptake in many different cell types and can also modulate insulin signaling. The p38 and ERK MAP kinase pathways, AKT and NFkappaB are all regulated by LA. In addition, LA activates the prostaglandin EP2 and EP4 receptors to stimulate the production of the small molecule cyclic adenosine 5' monophosphate (cAMP). These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress associated diseases. This review discusses the known biochemical properties of LA, its antioxidant properties, its ability to modulate signal transduction pathways, and the recent progress made in the utilization of LA as a therapeutic alternative for multiple sclerosis, Alzheimer's disease and diabetic neuropathy. PMID:18537699

  1. Influences on Authoritarian and Educational/Therapeutic Approaches to School Violence Prevention

    ERIC Educational Resources Information Center

    Nickerson, Amanda B.; Spears, William H.

    2007-01-01

    This study examined the use of two philosophical approaches to school violence prevention and the factors that influence the use of specific strategies. School policies, programs, and discipline strategies assessed by the School Survey of Crime and Safety (SSOCS) were categorized as authoritarian (i.e., restrict student autonomy through punitive…

  2. School Violence: Associations with Control, Security/Enforcement, Educational/Therapeutic Approaches, and Demographic Factors

    ERIC Educational Resources Information Center

    Nickerson, Amanda B.; Martens, Matthew P.

    2008-01-01

    This study examined the extent to which three approaches to violence prevention and response were associated with the incidence of school crime and disruption after accounting for the influence of demographic variables. Secondary data analyses were conducted with four subsets of the sample of principals who completed the National Center for…

  3. Catalytic asymmetric synthesis of spirocyclic azlactones by a double Michael-addition approach.

    PubMed

    Weber, Manuel; Frey, Wolfgang; Peters, René

    2013-06-17

    Spirocyclic azlactones are shown to be useful precursors of cyclic quaternary amino acids, such as the constrained cyclohexane analogues of phenylalanine. These compounds are of interest as building blocks for the synthesis of artificial peptide analogues with controlled folds in the peptide backbone. They were prepared in the present study by a step- and atom-economic catalytic asymmetric tandem approach, requiring two steps starting from N-benzoyl glycine and divinylketones. The key of this protocol is the enantioselective formation of the azlactone spirocycles, which involves a PdII-catalyzed double 1,4-addition of an in situ generated azlactone intermediate to the dienone (a formal [5+1] cycloaddition). As the catalyst, a planar chiral ferrocene bispalladacycle was used. Mechanistic studies suggest a monometallic reaction pathway. Although the diastereoselectivity was found to be moderate, the enantioselectivity is usually high for the formation of the azlactone spirocycles, which contain up to three contiguous stereocenters. Spectroscopic studies have shown that the spirocycles often prefer a twist over a chair conformation of the cyclohexanone moiety. PMID:23613333

  4. Serum 5-LOX: a progressive protein marker for breast cancer and new approach for therapeutic target.

    PubMed

    Kumar, Rahul; Singh, Abhay Kumar; Kumar, Manoj; Shekhar, Shashank; Rai, Nitish; Kaur, Punit; Parshad, Rajinder; Dey, Sharmistha

    2016-09-01

    Lipoxygenase (LOX) pathway has emerged to have a role in carcinogenesis. There is an evidence that both 12-LOX and 5-LOX have procarcinogenic role. We have previously reported the elevated level of serum 12-LOX in breast cancer patients. This study evaluated the serum level of 5-LOX in breast cancer patients and its in vitro inhibition assessment with peptide inhibitor YWCS. The level of 5-LOX was determined by surface plasmon resonance (SPR). The peptide inhibitor of 5-LOX was designed by molecular modeling and kinetic assay was performed by spectrophotometry. The siRNA mediated 5-LOX gene silencing was performed to investigate the effect on proliferation of MDA-MB-231, breast cancer cell line. The serum 5-LOX level in breast cancer (5.69±1.97ng/µl) was almost 2-fold elevated compared to control (3.53±1.0ng/µl) (P < 0.0001). The peptide YWCS had shown competitive inhibitory effects with IC50, 2.2 µM and dissociation constant (K D), 4.92×10(-8) M. The siRNA mediated knockdown of 5-LOX, resulted in the decreased gene expression for 5-LOX and increased cell death in MDA-MB-231 cell line and thereby play a key role in reducing tumor proliferation. Thus, it can be concluded that 5-LOX is one of the potential serum protein marker for breast cancer and a promising therapeutic target for the same. PMID:27432812

  5. Methicillin resistant and susceptible Staphylococcus aureus: Appraising therapeutic approaches in the Northwest of Iran

    PubMed Central

    Hasani, Alka; Sheikhalizadeh, Vajihe; Hasani, Akbar; Naghili, Behrouz; Valizadeh, Vahide; Nikoonijad, Ali Reza

    2013-01-01

    Background and Objectives Staphylococcus aureus is a versatile organism causing mild to life threatening infections. The major threat of this organism is its multidrug resistance. The present study was carried out to investigate in - vitro activity of conventional antibiotics routinely prescribed for methicillin resistant S. aureus (MRSA) and methicillin sensitive S. aureus (MSSA) infections in the Northwest of Iran and other alternating therapeutic agents which are recommended for Gram positive organisms. Materials and Methods Clinical isolates of S. aureus were subjected to multiplex PCR for simultaneous speciation and detection of methicillin resistance. Antibacterial susceptibility pattern was determined using disk diffusion. The Minimum Inhibitory Concentrations (MICs) were determined using E-test strips. Results The results revealed presence of nuc gene in all S. aureus isolates detected phenotypically earlier whereas, mecA gene was observed in 54% of strains. On disk diffusion and MIC determination assay, all MRSA and MSSA strains were susceptible to mupirocin (except one MRSA strain), linezolid and teicoplanin. Six vancomycin intermediate S. aureus strains were detected (VISA) with MIC= 4µg/mL, 5 of them being MRSA. In disk diffusion assay, 17.3% and 3.7% of isolates showed resistance to rifampin and fusidic acid, respectively. However, MIC50 and MIC90 tests shows promising in – vitro impact. Conclusion In – vitro mupirocin was found as an effective prophylactic ointment for nasal S. aureus eradication. Our data emphasize the performance of surveillance exercises to outline the existing antibiotics prescription policies and to slow down the emergence of multidrug resistant strains. PMID:23467268

  6. Targeting the Mevalonate Cascade as a New Therapeutic Approach in Heart Disease, Cancer and Pulmonary Disease

    PubMed Central

    Yeganeh, Behzad; Wiechec, Emmilia; Ande, Sudharsana R; Sharma, Pawan; Moghadam, Adel Rezaei; Post, Martin; Freed, Darren H.; Hashemi, Mohammad; Shojaei, Shahla; Zeki, Amir A.; Ghavami, Saeid

    2014-01-01

    The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer. PMID:24582968

  7. Quality Control of Widely Used Therapeutic Recombinant Proteins by a Novel Real-Time PCR Approach

    PubMed Central

    Mamnoon, Babak; Naserpour Farivar, Taghi; Kamyab, Ahmad Reza; Ilghari, Dariush; Khamesipour, Ali; Karimi Arzenani, Mohsen

    2016-01-01

    Background: Existence of bacterial host-cell DNA contamination in biopharmaceutical products is a potential risk factor for patients receiving these drugs. Hence, the quantity of contamination must be controlled under the regulatory standards. Although different methods such as hybridization assays have been employed to determine DNA impurities, these methods are labor intensive and rather expensive. In this study, a rapid real-time PCR test was served as a method of choice to quantify the E. coli host- cell DNA contamination in widely used recombinant streptokinase (rSK), and alpha interferon (IFN-α) preparations. Methods: A specific primer pair was designed to amplify a sequence inside the E. coli 16S rRNA gene. Serial dilutions of DNA extracted from E. coli host cells, along with DNA extracted from Active Pharmaceutical Ingredients of rSK, and IFN-α samples were subjected to an optimized real-time PCR assay based on SYBR Green chemistry. Results: The test enabled us to detect a small quantity of genomic DNA contamination as low as 0.0002 pg in recombinant protein-based drugs. For the first time, this study showed that DNA contamination in rSK and IFN-α preparation manufactured in Pasteur Institute of Iran is much lower than the safety limit suggested by the US FDA. Conclusion: Real-time PCR is a reliable test for rapid detection of host-cell DNA contamination, which is a major impurity of therapeutic recombinant proteins to keep manufacturers’ minds on refining drugs, and provides consumers with safer biopharmaceuticals. PMID:26047906

  8. OEM-TACE: a new therapeutic approach in unresectable intrahepatic cholangiocarcinoma.

    PubMed

    Poggi, Guido; Amatu, A; Montagna, B; Quaretti, P; Minoia, C; Sottani, C; Villani, L; Tagliaferri, B; Sottotetti, F; Rossi, O; Pozzi, E; Zappoli, F; Riccardi, A; Bernardo, G

    2009-11-01

    Intrahepatic cholangiocarcinoma (ICC) is a rare life-threatening disease, whose only treatment with potential for cure is surgical resection. However, only 27% of patients at most are suitable for surgery when first diagnosed. For patients with unresectable disease, therapeutic options are chemotherapy or chemoradiation. We evaluated the feasibility and safety of oxaliplatin-eluting microspheres transarterial chemoembolization (OEM-TACE) associated with chemotherapy (ChT) in patients affected by unresectable ICC. Between December 2005 and May 2008 we treated nine patients (six female and three male) with unresectable ICC. All patients had undergone OEM-TACE associated with chemotherapy with oxaliplatin and gemcitabine. A retrospective comparison was carried out with a historical group of 11 patients treated with ChT only, estimating the prevalence of adverse effects and the median survival of the two groups. A total of 30 TACEs were performed during the observational time (ranging from one to seven procedures per patient). OEM-TACEs were followed by few adverse effects (AEs), without G4 AEs, according to CTACAE 3.0. According to RECIST criteria, 44% (4/9) of patients achieved partial responses and 56% (5/9) stabilization of disease. Overall survival analysis in the two groups showed a significantly increased survival in patients treated with ChT and OEM-TACE, with respect to those treated with ChT (30 vs. 12.7 months; p=0.004). In conclusion, in our experience OEM-TACE associated with ChT in the treatment of advanced unresectable ICC is a safe and feasible treatment causing no major adverse events. Although RECIST criteria can underestimate the rate of responses in patients treated with locoregional therapies, we achieved very encouraging results. A randomized multicentric trial is warranted to assess the actual superiority of OEM-TACE associated with ChT compared to conventional chemotherapy. PMID:19727937

  9. New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    Saito, Satoshi; Ihara, Masafumi

    2014-01-01

    Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD. PMID:25368578

  10. The diagnostic and therapeutic challenge of nonepileptic seizures: An interdisciplinary approach

    PubMed Central

    Rayport, Shirley Ferguson; Schell, Carolyn A.

    2014-01-01

    Nonepileptic seizures were recognized in antiquity, but their diagnosis continues to be challenging in the present day. The diagnosis of seizures as nonepileptic has been based on associated physical conditions, social factors, laboratory findings, or psychological test findings. Pitfalls remain in the use of electroencephalography. We present several case studies of representative etiologies that demonstrate the value and the need for an interdisciplinary approach focusing on the individual, in the present, in all current dimensions, with careful consideration of seizure phenomena, physical explanations for symptoms, and psychodynamic profile in order to make the diagnosis and formulate successful treatment. This interdisciplinary approach provides a more comprehensive understanding of nonepileptic seizures and, more often, leads to successful outcome. PMID:25667871

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

    PubMed

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

    2012-01-01

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

  12. Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies.

    PubMed

    Senderowicz, A M

    2001-01-01

    infusional UCN-01 in combination with Ara-C or gemcitabine in patients with acute leukemia and CLL, respectively, have commenced. In conclusion, flavopiridol and UCN-01 are cdk modulators that reach biologically active concentrations effective in modulating CDK in vitro, and show encouraging results in early clinical trials in patients with refractory hematopoietic malignancies. Although important questions remain to be answered, these positive experiences will hopefully increase the therapeutic modalities in hematological malignancies. PMID:11243375

  13. Therapeutic effects of anti-spastic medication on neuromuscular abnormalities in SCI: a system identification approach.

    PubMed

    Mirbagheri, M M; Kindig, M; Niu, X; Varoqui, D

    2013-01-01

    Previous attempts to investigate the effects of antispastic medications are limited to clinical studies using that use clinical evaluations to assess. Since these measures are neither objective nor quantitative, the therapeutic effects of such medications on neuromuscular properties have not been fully evaluated. In this study, as a first attempt, we examined the effect of tizanidine, an anti-spastic medication, on modification of the neuromuscular properties of patients with chronic incomplete spinal cord injury (SCI). Each patient was administered 2 mg of tizanidine four times per day for four weeks. The spastic ankle of each patient was evaluated at baseline (prior to any medication, and then 1, 2, and 4 weeks after the start of medication. The ankle was perturbed with a small-amplitude Pseudo-Random Binary Sequence (PRBS) perturbation at various positions over the ankle range-of-motion. A parallel-cascade system identification technique, which provides an objective and quantitative measure of neuromuscular properties, was used to calculate the intrinsic and reflex stiffness. The stiffness vs. joint angle trends were then calculated for each evaluation; these curves were compared across the intervention time to determine the recovery pattern (i.e. change over time) due to the tizanidine intervention. All patients exhibited decreases in reflex stiffness (which abnormally increase after SCI) due to the medication; however, patients were observed to exhibit multiple recovery patterns. For some patients, the reflex stiffness continuously reduced over the four-week intervention period, while for other patients, the decrease during the first week (i.e. between the baseline and 1-Week evaluations) was most pronounced. Also, some patients presented a significant decrease with time, while others presented no improvement in the intrinsic stiffness. These findings suggest that tizanidine may be effective in reducing not only reflex stiffness, but also the subject

  14. Novel therapeutic strategy in the management of COPD: a systems medicine approach.

    PubMed

    Lococo, Filippo; Cesario, Alfredo; Del Bufalo, Alessandra; Ciarrocchi, Alessia; Prinzi, Giulia; Mina, Marco; Bonassi, Stefano; Russo, Patrizia

    2015-01-01

    Respiratory diseases including chronic-obstructive-pulmonary-disease (COPD) are globally increasing, with COPD predicted to become the third leading cause of global mortality by 2020. COPD is a heterogeneous disease with COPD-patients displaying different phenotypes as a result of a complex interaction between various genetic, environmental and life-style factors. In recent years, several investigations have been performed to better define such interactions, but the identification of the resulting phenotypes is still somewhat difficult, and may lead to inadequate assessment and management of COPD (usually based solely on the severity of airflow limitation parameter FEV1). In this new scenario, the management of COPD has been driven towards an integrative and holistic approach. The degree of complexity requires analyses based on large datasets (also including advanced functional genomic assays) and novel computational biology approaches (essential to extract information relevant for the clinical decision process and for the development of new drugs). Therefore, according to the emerging "systems/network medicine", COPD should be re.-evaluated considering multiple network(s) perturbations such as genetic and environmental changes. Systems Medicine (SM) platforms, in which patients are extensively characterized, offer a basis for a more targeted clinical approach, which is predictive, preventive, personalized and participatory ("P4-medicine"). It clearly emerges that in the next future, new opportunities will become available for clinical research on rare COPD patterns and for the identification of new biomarkers of comorbidity, severity, and progression. Herein, we overview the literature discussing the opportunity coming from the adoption of SMapproaches in COPD management, focusing on proteomics and metabolomics, and emphasizing the identification of disease sub-clusters, to improve the development of more effective therapies. PMID:26337103

  15. Neuroendocrine tumors of the lung: hystological classification, diagnosis, traditional and new therapeutic approaches.

    PubMed

    Cueto, A; Burigana, F; Nicolini, A; Lugnani, F

    2014-01-01

    Lung neuroendocrine tumors are neoplasms originating from bronchopulmonary neuroendocrine cells, usually Kulchitsky cells, loaded with argentaffin granules. They account for 20-25% of all primitive lung tumors, the most common being the small-cell undifferentiated carcinoma. They include different tumors, from tumors of low-grade malignancy, especially the typical carcinoids, with high survival rates after surgical therapy, to the high-grade malignancy tumors, especially small-cell undifferentiated carcinomas. The latter have very few indications for surgical treatment with a low survival rate, even after multimodal therapy. The aim of this review is to describe the present knowledge and discuss possible new developments in the management of pulmonary neuroendocrine tumors. The authors examine and discuss in particular the role that surgical techniques should have in the treatment of small-cell lung cancer in opposition to a nihilism position that has limited therapies to non-surgical approaches. The critical review of this attitude opens the door to a more aggressive approach. In the meantime the review shows that it might be possible to include the new minimally invasive percutaneous ablative techniques as cryosurgery, thermotherapy and irreversible electroporation within a modern and flexible framework. The authors also present the hypothesis that cancer stem cells (CSC) are at the basis of recurrences of small-cell lung cancer (SCLC) and therefore that the issue is of difficult solution with the conventional oncologic approach considering the chemo-resistance of CSC to drugs. For these reasons an epigenetic therapy based on differentiation factors is proposed alongside the usual surgical and chemo-radiation protocols. PMID:24304279

  16. New Therapeutic Approaches to Modulate and Correct Cystic Fibrosis Transmembrane Conductance Regulator.

    PubMed

    Ong, Thida; Ramsey, Bonnie W

    2016-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are clinically available personalized medicines approved for some individuals with cystic fibrosis (CF) to target the underlying defect of disease. This review summarizes strategies used to develop CFTR modulators as therapies that improve function and availability of CFTR protein. Lessons learned from dissemination of ivacaftor across the CF population responsive to this therapy and future approaches to predict and monitor treatment response of CFTR modulators are discussed. The goal remains to expand patient-centered and personalized therapy to all patients with CF, ultimately improving life expectancy and quality of life for this disease. PMID:27469186

  17. P2X1 receptor inhibition and soluble CD39 administration as novel approaches to widen the cardiovascular therapeutic window

    PubMed Central

    Fung, C.Y. Eleanor; Marcus, Aaron J.; Broekman, M. Johan; Mahaut-Smith, Martyn P.

    2010-01-01

    Thrombus formation at sites of disrupted atherosclerotic plaques is a leading cause of death and disability worldwide. Although the platelet is now recognized to be a central regulator of thrombus formation, development of antiplatelet reagents that selectively target thrombosis over hemostasis represents a challenge. Existing prophylactic antiplatelet therapies are centered on the use of aspirin, an irreversible cyclo-oxygenase inhibitor, and a thienopyridine such as clopidogrel (Plavix), which inactivates the ADP-stimulated P2Y12 receptor. Whilst these compounds are widely used and have beneficial effects for patients, their antithrombotic benefit is complicated by an elevated bleeding risk and substantial or partial “resistance”. Moreover, combination therapy with these two drugs increases the hemorrhagic risk even further. This review explores the possibility of inhibiting the platelet-surface ionotropic P2X1 receptor and/or elevating CD39/NTPDase1 activity as new therapeutic approaches to reduce overall platelet reactivity and recruitment of surrounding platelets at pro-thrombotic locations. Since both proteins affect platelet activation at an early stage in the events leading to thrombosis, but are less crucial in hemostasis, they provide new strategies to widen the cardiovascular therapeutic window without compromising safety. PMID:19467446

  18. [Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease].

    PubMed

    Stegmann, T J; Hoppert, T; Schneider, A; Gemeinhardt, S; Köcher, M; Ibing, R; Strupp, G

    2000-09-01

    Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction either by reducing myocardial oxygen demand, preventing further disease progression, restoring coronary blood flow pharmacologically or mechanically, or bypassing the stenotic lesions and obstructed coronary artery segments. Gene therapy, especially using angiogenic growth factors, has emerged recently as a potential new treatment for cardiovascular disease. Following extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease and peripheral vascular lesions have been performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) appear to be particularly effective in initiating neovascularization (neoangiogenesis) in hypoxic or ischemic tissues. The first clinical study on patients with coronary heart disease treated by local intramyocardial injection of FGF-1 showed a 3-fold increase of capillary density mediated by the growth factor. Also, angiogenic growth factor injection intramyocardially as sole therapy for end-stage coronary disease showed an improvement of myocardial perfusion in the target areas as well as a reduction of symptoms and an increase in working capacity. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this new approach may evolve into a fourth principle of treatment of atherosclerotic cardiovascular disease. PMID:11076317

  19. Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries12

    PubMed Central

    Levine, Mark; Padayatty, Sebastian J.; Espey, Michael Graham

    2011-01-01

    A concentration-function approach to vitamin C (ascorbate) has yielded new physiology and pharmacology discoveries. To determine the range of vitamin C concentrations possible in humans, pharmacokinetics studies were conducted. They showed that when vitamin C is ingested by mouth, plasma and tissue concentrations are tightly controlled by at least 3 mechanisms in healthy humans: absorption, tissue accumulation, and renal reabsorption. A 4th mechanism, rate of utilization, may be important in disease. With ingested amounts found in foods, vitamin C plasma concentrations do not exceed 100 μmol/L. Even with supplementation approaching maximally tolerated doses, ascorbate plasma concentrations are always <250 μmol/L and frequently <150 μmol/L. By contrast, when ascorbate is i.v. injected, tight control is bypassed until excess ascorbate is eliminated by glomerular filtration and renal excretion. With i.v. infusion, pharmacologic ascorbate concentrations of 25–30 mmol/L are safely achieved. Pharmacologic ascorbate can act as a pro-drug for hydrogen peroxide (H2O2) formation, which can lead to extracellular fluid at concentrations as high as 200 μmol/L. Pharmacologic ascorbate can elicit cytotoxicity toward cancer cells and slow the growth of tumors in experimental murine models. The effects of pharmacologic ascorbate should be further studied in diseases, such as cancer and infections, which may respond to generation of reactive oxygen species via H2O2. PMID:22332036

  20. Stimulating neuroregeneration as a therapeutic drug approach for traumatic brain injury

    PubMed Central

    Mueller, Bernhard K; Mueller, Reinhold; Schoemaker, Hans

    2009-01-01

    Traumatic brain injury, a silent epidemic of modern societies, is a largely neglected area in drug development and no drug is currently available for the treatment of patients suffering from brain trauma. Despite this grim situation, much progress has been made over the last two decades in closely related medical indications, such as spinal cord injury, giving rise to a more optimistic approach to drug development in brain trauma. Fundamental insights have been gained with animal models of central nervous system (CNS) trauma and spinal cord injury. Neuroregenerative drug candidates have been identified and two of these have progressed to clinical development for spinal cord injury patients. If successful, these drug candidates may be used to treat brain trauma patients. Significant progress has also been made in understanding the fundamental molecular mechanism underlying irreversible axonal growth arrest in the injured CNS of higher mammals. From these studies, we have learned that the axonal retraction bulb, previously regarded as a marker for failure of regenerative growth, is not static but dynamic and, therefore, amenable to pharmacotherapeutic approaches. With the development of modified magnetic resonance imaging methods, fibre tracts can be visualised in the living human brain and such imaging methods will soon be used to evaluate the neuroregenerative potential of drug candidates. These significant advances are expected to fundamentally change the often hopeless situation of brain trauma patients and will be the first step towards overcoming the silent epidemic of brain injury. PMID:19422372

  1. [Language acquisition in cleft lip-palate (CLP) children. 2. Linguistic diagnosis and therapeutic approaches].

    PubMed

    Herrmann, W; Bitter, K

    1990-01-01

    The major tests and methods used in language acquisition diagnosis in CLP children of 3 months to 6 years of age are described. Apart from methods for phonetic analysis, such as spectrography, emphasis is being placed on the assessment of listening by hearing and of semantic and meta-linguistic acquisition. Additional information is obtained on the motoric, cognitive and social development (for detecting any possible multiple handicaps in these areas). In this context the major problems covered in cleft palate parent groups are also pointed out. Finally, the speech therapy provided for preschool children with severe speech problems (as compared with the control group) is outlined. PMID:2102408

  2. Altered joint tribology in osteoarthritis: Reduced lubricin synthesis due to the inflammatory process. New horizons for therapeutic approaches.

    PubMed

    Szychlinska, M A; Leonardi, R; Al-Qahtani, M; Mobasheri, A; Musumeci, G

    2016-06-01

    Osteoarthritis (OA) is the most common form of joint disease. This review aimed to consolidate the current evidence that implicates the inflammatory process in the attenuation of synovial lubrication and joint tissue homeostasis in OA. Moreover, with these findings, we propose some evidence for novel therapeutic strategies for preventing and/or treating this complex disorder. The studies reviewed support that inflammatory mediators participate in the onset and progression of OA after joint injury. The flow of pro-inflammatory cytokines following an acute injury seems to be directly associated with altered lubricating ability in the joint tissue. The latter is associated with reduced level of lubricin, one of the major joint lubricants. Future research should focus on the development of new therapies that attenuate the inflammatory process and restore lubricin synthesis and function. This approach could support joint tribology and synovial lubrication leading to improved joint function and pain relief. PMID:27118399

  3. Short- and Long-Term Effects of Child Neuropsychological Assessment With a Collaborative and Therapeutic Approach: A Preliminary Study.

    PubMed

    Hansson, Anita; Hansson, Lina; Danielsson, Ingela; Domellöf, Erik

    2016-01-01

    This preliminary study explored if a collaborative and therapeutic approach (CTA) could reduce self-reported psychiatric symptoms (Beck Youth Inventories [BYI]) in children referred for neuropsychological assessment. Participants included 11 children (Mage = 12.4 years) receiving CTA, 11 (Mage = 12.6 years) receiving parent support, and 9 (Mage = 12.3 years) remaining on a waiting list. Contrary to both comparison groups, the CTA group reported fewer psychiatric symptoms on most BYI subscales after intervention, and this decrease was sustained for the Anger and Anxiety subscales at 6-month follow-up. Findings support a potential effectiveness of CTA in the neuropsychological assessment of children in a child psychiatric setting. PMID:25671288

  4. Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.

    PubMed

    Kucine, Nicole; Marubayashi, Sachie; Bhagwat, Neha; Papalexi, Efthymia; Koppikar, Priya; Sanchez Martin, Marta; Dong, Lauren; Tallman, Marty S; Paietta, Elisabeth; Wang, Kai; He, Jie; Lipson, Doron; Stephens, Phil; Miller, Vince; Rowe, Jacob M; Teruya-Feldstein, Julie; Mullighan, Charles G; Ferrando, Adolfo A; Krivtsov, Andrei; Armstrong, Scott; Leung, Laura; Ochiana, Stefan O; Chiosis, Gabriela; Levine, Ross L; Kleppe, Maria

    2015-11-26

    The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells. PMID:26443624

  5. The pathogenicity of splicing defects: mechanistic insights into pre-mRNA processing inform novel therapeutic approaches.

    PubMed

    Daguenet, Elisabeth; Dujardin, Gwendal; Valcárcel, Juan

    2015-12-01

    Removal of introns from pre-mRNA precursors (pre-mRNA splicing) is a necessary step for the expression of most genes in multicellular organisms, and alternative patterns of intron removal diversify and regulate the output of genomic information. Mutation or natural variation in pre-mRNA sequences, as well as in spliceosomal components and regulatory factors, has been implicated in the etiology and progression of numerous pathologies. These range from monogenic to multifactorial genetic diseases, including metabolic syndromes, muscular dystrophies, neurodegenerative and cardiovascular diseases, and cancer. Understanding the molecular mechanisms associated with splicing-related pathologies can provide key insights into the normal function and physiological context of the complex splicing machinery and establish sound basis for novel therapeutic approaches. PMID:26566663

  6. Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches

    PubMed Central

    Pereira, Olga; Sampaio-Marques, Belém; Paiva, Artur; Correia-Neves, Margarida; Castro, Isabel; Ludovico, Paula

    2015-01-01

    The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes. PMID:25537507

  7. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach

    PubMed Central

    Belda-Iniesta, Cristóbal

    2013-01-01

    K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific “synthetic lethal” interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID:25806225

  8. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach.

    PubMed

    de Castro Carpeño, Javier; Belda-Iniesta, Cristóbal

    2013-04-01

    K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific "synthetic lethal" interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID:25806225

  9. Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.

    PubMed

    Sahin, Ibrahim H; Lowery, Maeve A; Stadler, Zsofia K; Salo-Mullen, Erin; Iacobuzio-Donahue, Christine A; Kelsen, David P; O'Reilly, Eileen M

    2016-08-01

    Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach. PMID:26881472

  10. Therapeutic approaches to cystic fibrosis: memorandum from a joint WHO/ICF(M)A meeting.

    PubMed Central

    1994-01-01

    Cystic fibrosis is one of the commonest genetic diseases among Caucasians and represents an important cause of suffering and death among children and adults. In the past two decades marked prolongation of the life of patients with cystic fibrosis has been achieved as the result of improved case-finding and an extensive regimen of therapies. More recently, a variety of new approaches to therapy have been developed or proposed as the result of advances in cell physiology and molecular biology. This article summarizes the presentations and discussions made at a joint WHO/ICF(M)A (International Cystic Fibrosis (Mucoviscidosis) Association) meeting, held in Washington, DC, on 14 October 1992, and reviews the current status of possible therapies for cystic fibrosis and their implications for treatment in various countries of the world. PMID:7520369

  11. Treatment of Insomnia, Insomnia Symptoms, and Obstructive Sleep Apnea During and After Menopause: Therapeutic Approaches

    PubMed Central

    Tal, Joshua Z.; Suh, Sooyeon A.; Dowdle, Claire L.; Nowakowski, Sara

    2015-01-01

    Understanding sleep complaints among menopausal women is an emerging area of clinical and research interest. Several recent reviews have focused on mechanisms of menopausal insomnia and symptoms. In this review, we present a discussion on the most relevant and recent publications on the treatment of sleep disorders for menopausal women, with a focus on menopause-related insomnia, insomnia symptoms, and obstructive sleep apnea. We discuss both nonpharmacological and pharmacological treatments, including cognitive-behavioral therapy for insomnia (CBT-I), complementary and alternative medicine, hormone replacement therapy, sedative hypnotics, antidepressants, and continuous positive airway pressure. In addition, we briefly discuss methods and considerations of assessment of sleep disorders in menopausal women. PMID:26478725

  12. A Four-Step and Four-Criteria Approach for Evaluating Evidence of Dose Addition in Chemical Mixture Toxicity

    EPA Science Inventory

    Dose addition is the most frequently-used component-based approach for predicting dose response for a mixture of toxicologically-similar chemicals and for statistical evaluation of whether the mixture response is consistent with dose additivity and therefore predictable from the ...

  13. Prognostic features and therapeutical approaches in B-cell chronic lymphocytic leukemia: an update.

    PubMed

    Molica, S; De Rossi, G; Luciani, M; Levato, D

    1995-01-01

    In the past few decades important progress has been made in the understanding of chronic lymphocytic leukemia (CLL). Indeed, systematic studies of natural history and prognostic factors have made it possible to predict the outcome of disease. Although clinical stage (i.e. Rai and Binet stages) is the strongest predictor of survival, additional prognostic parameters, including patterns of bone marrow (BM) infiltration, lymphocyte doubling time (LDT), immunophenotype and cytogenetics, have now been identified. Furthermore, criteria of smoldering CLL (i.e. stage A, low lymphocyte count, non-diffuse BM histology, relatively high hemoglobin level, LDT > 12 months) allow identification of a subgroup of patients with indolent course and good prognosis for whom treatment should be delayed, unless progression occurs. Recent meta-analysis of clinical trials has demonstrated no survival advantage for immediate versus referred treatment in low clinical stages. The same considerations apply when comparing combination versus single-drug regimens. Purine analogues like fludarabine, 2'-chlorodeoxyadenosine and 2'-deoxycoformicin are active in CLL. Data on these drugs come from uncontrolled clinical trials; randomized studies are in progress. In addition, some issues concerning the relationship between response and survival, cross-resistance between purine analogues and eradication of the CLL clone, remain still unresolved. There are also increasing data on bone marrow transplants in CLL, although the high treatment-related mortality suggests that this procedure may have some benefit only in selected refractory young CLL patients with adverse features. This review will focus on recent progress in the prognosis and therapy of CLL. Issues that remain controversial will be a matter of discussion. PMID:7628755

  14. Prevention and treatment of allergic asthma in pregnancy: from conventional drugs to new therapeutical approaches.

    PubMed

    Cadavid, Angela P; Bannenberg, Gérard L; Arck, Petra C; Fitzgerald, Justine S; Markert, Udo R

    2011-05-01

    Different conventional anti-asthmatic and anti-allergic drugs are commonly used in pregnancy, including inhaled corticosteroids, long- and short-acting β-agonists, leukotriene modifiers, cromolyn, and theophylline. Alternatively, immunotherapy with allergens before and during pregnancy is accepted as a causal treatment of allergies, but the allergy specifity and severity in combination with a variety of application protocols and procedures cause wide heterogenity of this treatment principle. Furthermore, the pharmacokinetic characteristics and the US Food and Drug Administration (FDA) classification of conventional anti-allergic drugs and immunological implications of immunotherapy are summarized in this review, and insights on fetal programming of allergies are introduced. We propose a potential perspective of treatment with anti-inflammatory and pro-resolving mediators, such as lipoxins, resolvins and protectins; these are lipid mediators physiologically generated during the immune response from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. This proposal fits with the recently appreciated approaches to allergy prevention for the newborn child by a balanced maternal nutrition and omega-3 long-chain polyunsaturated fatty acid consumption. PMID:21342121

  15. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria

    PubMed Central

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-01-01

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies. PMID:26510963

  16. Multi-omics approach to infer cancer therapeutic targets on chromosome 20q across tumor types

    PubMed Central

    Snijders, Antoine M; Mao, Jian-Hua

    2016-01-01

    The identification of good targets is a critical step for the development of targeted therapies for cancer treatment. Here, we used a multi-omics approach to delineate potential targets on chromosome 20q, which frequently shows a complex pattern of DNA copy number amplification in many human cancers suggesting the presence of multiple driver genes. By comparing the amounts of individual mRNAs in cancer from 11 different human tissues with those in their corresponding normal tissues, we identified 18 genes that were robustly elevated across human cancers. Moreover, we found that higher expression levels of a majority of these genes were associated with poor prognosis in many human cancer types. Using DNA copy number and expression data for all 18 genes obtained from The Cancer Genome Atlas project, we discovered that amplification is a major mechanism driving overexpression of these 18 genes in the majority of human cancers. Our integrated analysis suggests that 18 genes on chromosome 20q might serve as novel potential molecular targets for targeted cancer therapy.

  17. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches

    PubMed Central

    Belizário, José E.; Napolitano, Mauro

    2015-01-01

    The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body’s microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies. PMID:26500616

  18. Minocycline with aspirin: a therapeutic approach in the treatment of diabetic neuropathy.

    PubMed

    Bhatt, L K; Veeranjaneyulu, Addepalli

    2010-12-01

    Enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to degradation of extracellular matrix in blood vessels and leads to complications of diabetes. In the present study, we have targeted MMP-2 and MMP-9 overactivation in diabetic neuropathy using a known MMP-2 and MMP-9 inhibitor, minocycline, with a non-selective COX inhibitor, aspirin. Streptozotocin-induced diabetic neuropathy was carried out in male Wistar rats and monitored by measuring the sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), tail flick latency and hot plate latency. Three weeks of treatment with a combination of minocycline and aspirin showed significant improvement in SNCV, MNCV, hot plate latency and tail flick latency when compared with diabetic control. The results of the present study suggest that MMP-2 and MMP-9 inhibition in the presence of COX inhibitor prevents the development of experimental diabetic neuropathy in rats and can be a potential approach for the treatment. PMID:20213226

  19. A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices.

    PubMed

    Arul, Vadivel; Kartha, Reena; Jayakumar, Rajadas

    2007-01-01

    Chronically elevated blood glucose levels result in reduced leukocyte function and cell malnutrition, which contribute to a high rate of wound infection and associated healing problems in diabetic patients. In the present study, the role of biotinylated GHK peptide (BioGHK) incorporated collagen biomaterial was tested for wound healing in diabetic rats. The rate of wound contraction and the levels of collagen, uronic acid, protein and DNA in the granulation tissue were determined. Further, the concentration of nitric oxide and other skin antioxidants was also monitored during the study. In diabetic rats treated with BioGHK incorporated collagen (Peptide Incorporated Collagen--PIC), the healing process was hastened with an increased rate of wound contraction. Glutathione (GSH) and ascorbic acid levels in the skin of streptozotocin-induced diabetic rats were higher in the PIC group as compared to control (Untreated) and collagen (Collagen Film--CF) treated groups. Superoxide dismutase (SOD) and catalase (CAT) activity was altered in all the groups. In vitro fibroblast cell culture studies suggest that PIC promotes fibroblast growth. Histological evaluation by haematoxylin-eosin and Masson's trichrome method revealed epithelialization, increased synthesis of collagen and activation of fibroblasts and mast cells in the PIC group. This study provides a rationale for the topical application of BioGHK incorporated collagen as a feasible and productive approach to support diabetic wound healing. PMID:17049946

  20. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

    PubMed Central

    Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; Unnasch, Thomas R.

    2016-01-01

    Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. PMID:27300294

  1. Pharmacological approaches to manage persistent symptoms of major depressive disorder: rationale and therapeutic strategies.

    PubMed

    Epstein, Irvin; Szpindel, Isaac; Katzman, Martin A

    2014-12-01

    Major depressive disorder (MDD) is a highly prevalent chronic psychiatric illness associated with significant morbidity, mortality, loss of productivity, and diminished quality of life. Typically, only a minority of patients responds to treatment and meet criteria for remission as residual symptoms may persist, the result of an inadequate course of treatment and/or the presence of persistent side effects. The foremost goal of treatment should be to restore patients to full functioning and eliminate or relieve all MDD symptoms, while being virtually free of troublesome side effects. The current available pharmacological options to manage persistent depressive symptoms include augmentation or adjunctive combination strategies, both of which target selected psychobiological systems and specific mood and somatic symptoms experienced by the patient. As well, non-pharmacological interventions including psychotherapies may be used in either first-line or adjunctive approaches. However, the evidence to date with respect to available adjunct therapies is limited by few studies and those published have utilized only a small number of subjects and lack enough data to allow for a consensus of expert opinion. This underlines the need for further longer term, large population-based studies and those that include comorbid populations, all of which are seen in real world community psychiatry. PMID:25539871

  2. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria.

    PubMed

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-01-01

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies. PMID:26510963

  3. Photothermal sensitisation as a novel therapeutic approach for tumours: studies at the cellular and animal level.

    PubMed

    Camerin, Monica; Rello, Santiago; Villanueva, Angeles; Ping, Xinzhan; Kenney, Malcolm E; Rodgers, Michael A J; Jori, Giulio

    2005-05-01

    Irradiation of B78H1 murine amelanotic melanoma cells with 850 nm light emitted from a Ti:sapphire laser, operated in a pulsed mode at high fluence rates and in the presence of Ni(II)-octabutoxy-naphthalocyanine (NiNc), promoted a photothermally sensitised process leading to fast and irreversible cell death. This resulted in the ejection of a consistent mass of cytoplasmic material from the irradiated cells that was detected by scanning electron microscopy. The extensive chemical and mechanical damage was probably caused by the photoinduced generation of an acoustic shock wave. The efficiency of the photoprocess was modulated by intracellular concentration of NiNc and maximally by the formation of aggregated naphthalocyanine clusters in specific subcellular areas. Very similar results were obtained upon irradiation of NiNc-loaded C32 human amelanotic melanoma cells and transformed murine HT-1080 and HaCaT fibroblasts. From these results, photothermal sensitisation appears to be a general phenomenon and preliminary studies with mice bearing subcutaneously transplanted amelanotic melanomas, irradiated with 850 nm light 24 h after intravenous injection of NiNc, suggest that this approach has potential for the therapy of some types of skin tumours. PMID:15911245

  4. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches.

    PubMed

    Belizário, José E; Napolitano, Mauro

    2015-01-01

    The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies. PMID:26500616

  5. CXCR₄antagonism as a therapeutic approach to prevent acute kidney injury.

    PubMed

    Zuk, A; Gershenovich, M; Ivanova, Y; MacFarland, R T; Fricker, S P; Ledbetter, S

    2014-10-01

    We examined whether antagonism of the CXCR₄receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR₄is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR₄antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR₄inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR₄antagonism with plerixafor may be a potential option to prevent AKI. PMID:25080523

  6. Combination of acamprosate and baclofen as a promising therapeutic approach for Parkinson’s disease

    PubMed Central

    Hajj, Rodolphe; Milet, Aude; Toulorge, Damien; Cholet, Nathalie; Laffaire, Julien; Foucquier, Julie; Robelet, Sandra; Mitry, Richard; Guedj, Mickael; Nabirotchkin, Serguei; Chumakov, Ilya; Cohen, Daniel

    2015-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic nigrostriatal neurons but which involves the loss of additional neurotransmitter pathways. Mono- or polytherapeutic interventions in PD patients have declining efficacy long-term and no influence on disease progression. The systematic analysis of available genetic and functional data as well as the substantial overlap between Alzheimer’s disease (AD) and PD features led us to repurpose and explore the effectiveness of a combination therapy (ABC) with two drugs – acamprosate and baclofen – that was already effective in AD animal models, for the treatment of PD. We showed in vitro that ABC strongly and synergistically protected neuronal cells from oxidative stress in the oxygen and glucose deprivation model, as well as dopaminergic neurons from cell death in the 6-hydroxydopamine (6-OHDA) rat model. Furthermore, we showed that ABC normalised altered motor symptoms in vivo in 6-OHDA-treated rats, acting by protecting dopaminergic cell bodies and their striatal terminals. Interestingly, ABC also restored a normal behaviour pattern in lesioned rats suggesting a symptomatic effect, and did not negatively interact with L-dopa. Our results demonstrate the potential value of combining repurposed drugs as a promising new strategy to treat this debilitating disease. PMID:26542636

  7. Therapeutic approaches to the treatment of recurrent respiratory papillomatosis of the aerodigestive tract (a clinical study)

    PubMed Central

    Avramov, Toma; Vetckova, Evelina; Nikolova, Maria; Valev, Dinko; Manolova, Antoaneta; Tafradgiiska, Maya; Kostadinov, Dimitar; Tchalacov, Ivan

    2014-01-01

    Recurrent respiratory papillomatosis (RRP) is a rare disease, characterized by recurrent proliferation of benign squamous cell papillomas in the larynx as well as in the other parts of the aerodigestive tract. We have compared different treatment options for RRP of the aerodigestive tract including surgical, conservative and combined approaches. A total of 43 patients with papillomatosis that received a combined therapy were followed in the period from 2009 to 2013. The treatment included electrosurgery and CO2 laser surgery alongside with either immunotherapy with Bacillus Calmette-Guerin (BCG) (Calgevax) or α-interferon. In the control group without immunotherapy (n = 16) we used conventional microlaryngeal surgery. During the follow-up, relapse occurred in two patients for the CO2 laser surgery with Calgevax immunotherapy group (n = 16). In the group treated with α-interferon preceded by CO2 laser surgery (n = 9) and electrosurgery (n = 2), relapse had occurred in three patients. Among the control group, recurrence was observed in six patients. This required re-operation. Our data showed a three times more frequent relapses among patients who were operated with conventional surgery as compared to those operated with CO2 laser surgery and Calgevax immunotherapy, and two times more often relapses in patients operated with conventional surgery as compared to those with electrosurgery and CO2 laser surgery and application of α-interferon therapy. Conventional and laser surgeries have a palliative effect, though playing an important role in ensuring the airway patency. While specific antivirus treatment for human papilloma viruses does not exist, the immune modulation with Calgevax considerably reduces the frequency of relapses, by stimulating cellular immune effector mechanisms. The combined protocol allows rarefication of relapses and improvement of patients’ quality of life, but not complete healing. PMID:26692782

  8. [Small intestinal hemorrhage due to rare etiology. Diagnostic difficulties and therapeutic approaches].

    PubMed

    Duminică, Cristina; Constantinoiu, S; Predescu, D; Mateş, I N; Iosif, Cristina

    2005-01-01

    Understanding of the pathogenesis, diagnosis, and treatment of lower GI bleeding has drastically changed during the last 50 years, but it continues to be a frequent cause of hospital admission and also a factor in hospital morbidity and mortality. Acute lower gastrointestinal hemorrhage (ALGIH) represents only 20% of the GI bleeding and the small intestine is the site of hemorrhage in about 1% of cases. Although in the last four decades, diagnostic methods for locating the precise bleeding point improved greatly, still the adequate localization of the lesion is very difficult to achieve through algorithmic approaches. We performed a clinical study and we retrospectively analyzed 5 patients (mean age = 59,8 years, 1 female) who had a surgical intervention for acute lower GI hemorrhage in the last decade, in order to emphasize diagnosis difficulties when the bleeding arises from small lesions in the small bowel that is not easily accessible for direct visualisation. Surgery was the treatment of choice in every case consisting in segmental resections of the involved small bowel, along with viscerolysis and exploratory gastro-jejunostoma. The mortality rate was 20% (1 postoperative death of cardiac etiology). There have been no specific postoperative complications in the other four patients and a good outcome was reported. The diagnosis is particularly difficult and when colonic and upper gastrointestinal evaluations fail to identify a source of bleeding, a small intestinal source should be considered. We can conclude that the most important factor in the management of ALGIH is determination of specific localization of the lesion. PMID:16372675

  9. Structure of amyloid oligomers and their mechanisms of toxicities: Targeting amyloid oligomers using novel therapeutic approaches.

    PubMed

    Salahuddin, Parveen; Fatima, Munazza Tamkeen; Abdelhameed, Ali Saber; Nusrat, Saima; Khan, Rizwan Hasan

    2016-05-23

    Protein misfolding is one of the leading causes of amyloidoses. Protein misfolding occurs from changes in environmental conditions and host of other factors, including errors in post-translational modifications, increase in the rate of degradation, error in trafficking, loss of binding partners and oxidative damage. Misfolding gives rise to the formation of partially unfolded or misfolded intermediates, which have exposed hydrophobic residues and interact with complementary intermediates to form oligomers and consequently protofibrils and fibrils. The amyloid fibrils accumulate as amyloid deposits in the brain and central nervous system in Alzheimer's disease (AD), Prion disease and Parkinson's disease (PD). Initial studies have shown that amyloid fibrils were the main culprit behind toxicity that cause neurodegenerative diseases. However, attention shifted to the cytotoxicity of amyloid fibril precursors, notably amyloid oligomers, which are the major cause of toxicity. The mechanism of toxicity triggered by amyloid oligomers remains elusive. In this review, we have focused on the current knowledge of the structures of different aggregated states, including amyloid fibril, protofibrils, annular aggregates and oligomers. Based on the studies on the mechanism of toxicities, we hypothesize two major possible mechanisms of toxicities instigated by oligomers of Aβ (amyloid beta), PrP (prion protein) (106-126), and α-Syn (alpha-synuclein) including direct formation of ion channels and neuron membrane disruption by the increase in membrane conductance or leakage in the presence of small globulomers to large prefibrillar assemblies. Finally, we have discussed various novel innovative approaches that target amyloid oligomers in Alzheimer's diseases, Prion disease and Parkinson's disease. PMID:26974374

  10. Sialendoscopy – a diagnostic and therapeutic approach subjectively rated by patients

    PubMed Central

    Wierzbicka, Małgorzata; Piskadło, Karolina; Bednarek, Mateusz; Szyfter, Witold

    2014-01-01

    Introduction Sialendoscopy is a miniinvasive procedure which shows the excretory ducts of the salivary glands. Aim To evaluate patient satisfaction with sialendoscopy in submandibular and parotid gland sialolithiasis. Material and methods The study group included 100 consecutive patients with sialolithiasis, treated by means of sialendoscopy. The analysis was designed prospectively. The patients answered closed questions of our own, in-house made questionnaire. Results The number of sialendoscopic procedures necessary for symptom resolution ranged from 1 to 3. The mean value was 1.2 and the median was 1. In 64 patients (64%) one procedure was sufficient for symptom resolution, while 10 (10%) and 8 (8%) patients required 2 and even 3 procedures, respectively. Sixty-three patients (63%) did not report any postoperative complications; 33 patients (33%) reported transient swelling of the submandibular region and 4 patients (4%) reported inflammation of the salivary gland. The level of treatment efficacy was 82%. Among 53 patients treated using sialendoscopy for the first time 92.3% rated this approach subjectively as a very good or good technique, whereas among 47 patients who had previously undergone non-endoscopic treatment, this percentage increased to 96.4%. The general level of satisfaction with the applied method did not depend on the age, gender, duration of ailments, the number of previously performed procedures or the number of sialendoscopic procedures necessary to obtain improvement and postoperative complications. Conclusions Sialendoscopy may be performed practically in any case without risking the patient's discomfort or unpleasant experience. Assessment of sialendoscopy by the patients confirmed the minimally invasive character of this technique. PMID:25561986

  11. Therapeutic Armamentarium for Stricturing Crohn's Disease: Medical Versus Endoscopic Versus Surgical Approaches.

    PubMed

    Bharadwaj, Shishira; Fleshner, Phillip; Shen, Bo

    2015-09-01

    One-third of patients with Crohn's disease (CD) present as stricturing phenotype characterized by progressive luminal narrowing and obstructive symptoms. The diagnosis and management of these patients have been intriguing and challenging. Immunomodulators and biologics have been successfully used in treating inflammatory and fistulizing CD. There are issues of efficacy and safety of biological agents in treating strictures in CD. Rapid mucosal healing from potent biological agents may predispose patients to the development of new strictures or worsening of existing strictures. On the other hand, strictures constitute one-fifth of the reasons for surgery in patients with CD. Disease recurrence is common at or proximal to the anastomotic site with the majority of these patients developing new endoscopic lesions within 1 year of surgery. The progressive nature of the disease with repetitive cycle of inflammation and stricture formation results in repeated surgery, with a risk of small bowel syndrome. There is considerable quest for bowel conserving endoscopic and surgical strategies. Endoscopic balloon dilation and stricturoplasty have emerged as valid alternatives to resection. Endoscopic balloon dilation has been shown to be feasible, safe, and effective for the short primary or anastomotic strictures. However, repeated dilations are often needed, and long-term outcomes of endoscopic balloon dilation remain to be investigated. The introduction of stricturoplasty has added another dimension to bowel saving strategy. Although postoperative recurrence rate after stricturoplasty is comparable with surgical resection, there are concerns for increased risk of malignancy in preserved bowel. Laparoscopic surgery has widely been performed with similar outcomes to open approach with fewer complications, quicker recovery, better cosmesis, and lower cost. All of these issues should be considered by physicians involved in the management of patients with stricturing CD. PMID

  12. Restoring p53 function in cancer: novel therapeutic approaches for applying the brakes to tumorigenesis.

    PubMed

    Di Cintio, Alessandra; Di Gennaro, Elena; Budillon, Alfredo

    2010-01-01

    p53 tumor suppressor gene encodes for a critical cellular protein that regulate the integrity of the cell and can induce cell cycle arrest and/or apoptosis upon cellular stresses of several origins, including chemotherapeutics. Loss of p53 function occurs in an estimated 50% of all cancers by mutations and deletions while in the presence of wild-type p53 alleles other mechanisms may affect the expression and activity of p53. Alternate mechanisms include methylation of the promoter of p53, deletion or epigenetic inactivation of the p53-positive regulator p14/ARF, elevated expression of the p53 regulators murine double minute 2 (MDM2) and MDMX, or alteration of upstream regulators of p53 such as the kinase ATM. MDM2 is a p53 E3 ubiquitin ligase that mediates the ubiquitin-dependent degradation of p53 while p14/ARF is a small MDM2-binding protein that controls the activity of MDM2 by displacing p53 and preventing its degradation. MDMX antagonize p53-dependent transcriptional control by interfering with p53 transactivation function. The understanding of the key role of p53 inactivation in cancer development generated considerable interest in developing compounds that are capable of restoring the p53 functions. Several patents have been issued on such compounds. Adenovirus-based p53 gene therapy as well as small molecules such as PRIMA that can restore the transcriptional transactivation function to mutant p53, or NUTLIN and RITA that interfere with MDM2-directed p53 degradation, have tested in a preclinical setting and some of these approaches are currently in clinical development. PMID:19663772

  13. Effective Therapeutic Approach for Head and Neck Cancer by an Engineered Minibody Targeting the EGFR Receptor

    PubMed Central

    Choi, Won-Jae; Lee, Sun Hee; Lee, Seo Yun; Kim, Soyeon; Chung, Jee Min; Jeon, Jinseon; Lee, Byoung Dae; Shin, Joo-Ho; Lee, Yun-il; Cho, Hyeseong; Lee, Jeong-Min; Kang, Ho Chul

    2014-01-01

    Cetuximab, a chimeric monoclonal antibody developed for targeting the Epidermal Growth Factor Receptor (EGFR), has been intensively used to treat cancer patients with metastatic colorectal cancer and head and neck cancer. Intact immunoglobulin G (IgG) antibody like cetuximab, however, has some limitations such as high production cost and low penetration rate from vasculature into solid tumor mass due to its large size. In attempt to overcome these limitations, we engineered cetuximab to create single chain variable fragments (scFv-CH3; Minibody) that were expressed in bacterial system. Among three engineered minibodies, we found that MI061 minibody, which is composed of the variable heavy (VH) and light (VL) region joined by an 18-residue peptide linker, displays higher solubility and better extraction properties from bacterial lysate. In addition, we validated that purified MI061 significantly interferes ligand binding to EGFR and blocks EGFR's phosphorylation. By using a protein microarray composed of 16,368 unique human proteins covering around 2,400 plasma membrane associated proteins such as receptors and channels, we also demonstrated that MI061 only recognizes the EGFR but not other proteins as compared with cetuximab. These results indicated that engineered MI061 retains both binding specificity and affinity of cetuximab for EGFR. Although it had relatively short half-life in serum, it was shown to be highly significant anti-tumor effect by inhibiting ERK pathway in A431 xenograft model. Taken together, our present study provides compelling evidence that engineered minibody is more effective and promising agent for in vivo targeting of solid tumors. PMID:25438047

  14. Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis

    PubMed Central

    Khoobchandani, Menka; Katti, Kavita; Maxwell, Adam; Fay, William P.; Katti, Kattesh V.

    2016-01-01

    In our efforts to develop new approaches to treat and prevent human vascular diseases, we report herein our results on the proliferation and migration of human smooth muscles cells (SMCs) and endothelial cells (ECs) using epigallocatechin-3-gallate conjugated gold nanoparticles (EGCg-AuNPs) as possible alternatives to drug coated stents. Detailed in vitro stability studies of EGCg-AuNPs in various biological fluids, affinity and selectivity towards SMCs and ECs have been investigated. The EGCg-AuNPs showed selective inhibitory efficacy toward the migration of SMCs. However, the endothelial cells remained unaffected under similar experimental conditions. The cellular internalization studies have indicated that EGCg-AuNPs internalize into the SMCs and ECs within short periods of time through laminin receptor mediated endocytosis mode. Favorable toxicity profiles and selective affinity toward SMCs and ECs suggest that EGCg-AuNPs may provide attractive alternatives to drug coated stents and therefore offer new therapeutic approaches in treating cardiovascular diseases. PMID:26938531

  15. A new perspective on therapeutic inhibition of advanced glycation in diabetic microvascular complications: common downstream endpoints achieved through disparate therapeutic approaches?

    PubMed

    Sourris, Karly C; Harcourt, Brooke E; Forbes, Josephine M

    2009-01-01

    A commonality among the chemically disparate compounds that inhibit the formation and accumulation of advanced glycation end products (AGEs) or their signalling pathways is their end organ protection in experimental models of diabetes complications. Although this group of therapeutics are structurally and functionally distinct with numerous mechanisms of action, the most important factor governing their therapeutic capability is clearly their ability to alleviate the tissue burden of advanced glycation, rather than the biochemical mechanism by which this is achieved. However, it remains to be determined if it is the reduction in tissue AGE levels per se or inhibition of downstream signal pathways which is ultimately required for end organ protection. For example, a number of these agents stimulate antioxidant defences, modify lipid profiles and inhibit low-grade inflammation. These novel actions emphasise the importance of further examination of the advanced glycation pathway and in particular the diverse action of these agents in ameliorating the development of diabetic complications such as nephropathy. PMID:19556753

  16. A novel approach for phosphorus recovery and no wasted sludge in enhanced biological phosphorus removal process with external COD addition.

    PubMed

    Xia, Cheng-Wang; Ma, Yun-Jie; Zhang, Fang; Lu, Yong-Ze; Zeng, Raymond J

    2014-01-01

    In enhanced biological phosphorus removal (EBPR) process, phosphorus (P) in wastewater is removed via wasted sludge without actual recovery. A novel approach to realize phosphorus recovery with special external chemical oxygen demand (COD) addition in EBPR process was proposed. During the new operating approach period, it was found that (1) no phosphorus was detected in the effluent; (2) with an external addition of 10 % of influent COD amount, 79 % phosphorus in the wastewater influent was recovered; (3) without wasted sludge, the MLVSS concentration in the system increased from 2,010 to 3,400 mg/L and kept stable after day 11 during 24-day operating period. This demonstrates that the novel approach is feasible to realize phosphorus recovery with no wasted sludge discharge in EBPR process. Furthermore, this approach decouples P removal and sludge age, which may enhance the application of membrane bioreactor for P removal. PMID:24122666

  17. Methotrexate: new therapeutic approaches.

    PubMed

    Puig, L

    2014-01-01

    Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab. PMID:23434058

  18. Curricular Approaches to Connecting Subtraction to Addition and Fostering Fluency with Basic Differences in Grade 1

    ERIC Educational Resources Information Center

    Baroody, Arthur J.

    2016-01-01

    Six widely used US Grade 1 curricula do not adequately address the following three developmental prerequisites identified by a proposed learning trajectory for the meaningful learning of the subtraction-as-addition strategy (e.g., for 13-8 think "what + 8 = 13?"): (a) reverse operations (adding 8 is undone by subtracting 8); (b) common…

  19. Evaluating Drugs and Food Additives for Public Use: A Case Studies Approach.

    ERIC Educational Resources Information Center

    Merritt, Sheridan V.

    1980-01-01

    Described is a case study used in an introductory college biology course that provides a basis for generating debate on an issue concerning the regulation of controversial food additives and prescription drugs. The case study contained within this article deals with drug screening, specifically with information related to thalidomide. (CS)

  20. Surface engineered and ligand anchored nanobioconjugate: an effective therapeutic approach for oral insulin delivery in experimental diabetic rats.

    PubMed

    Sharma, Rajeev; Gupta, Umesh; Garg, Neeraj K; Tyagi, Rajeev K; Jain, N K

    2015-03-01

    The present study was designed to enhance intestinal absorption of insulin by nanobioconjugate formulated with PEGylation and Concanavalin A based targeted synergistic approach. The attempts were aimed at maximizing bioavailability and therapeutic efficacy of insulin by incorporating it in Concanavalin A anchored PEGylated nanoconstructs. The Con A anchored PEGylated PLGA diblock copolymer was synthesized by modified surface functionalization method, and was then characterized by FTIR and 1H NMR spectrum analysis. The nanoparticles from synthesized polymers were prepared and characterized for mean size and distribution by laser diffraction spectroscopy. The physicochemically characterized (by SEM and TEM) formulations were evaluated for optimum particle size, polydispersity index, zeta potential and entrapment efficiency 196.3±4.5 nm, 0.15±0.04, -25.6±1.68 and 44.6±3.5% respectively. The insulin encapsulation efficiency and in vitro release were assessed by bicinchoninic protein assay (BCA). The in vitro results corroborated in vivo studies carried out in experimentally created diabetic albino rats. The nano-encapsulated insulin was discovered to meet the requirements by achieving better stability, improved absorption and enhanced oral bioavailability elucidated by in vivo and in vitro bioassays. PMID:25679489

  1. CNS involvement in primary Sjögren's syndrome: prevalence, clinical aspects, diagnostic assessment and therapeutic approach.

    PubMed

    Govoni, M; Padovan, M; Rizzo, N; Trotta, F

    2001-01-01

    Among the systemic manifestations of primary Sjögren's syndrome, neurological involvement is still an intriguing and debated issue. Although peripheral nervous system abnormalities are a well documented occurrence with a reported prevalence ranging from 10 to 20%, opinions differ as to the prevalence of CNS disease, with suggestions from 'nonexistent' to 'very common'. The lack of agreement probably reflects the different populations selected, different inclusion criteria and lack of rigorous epidemiological studies. In our experience, CNS involvement was detected in 7 of 87 (8%) unselected consecutive patients observed over a period of 5 years. The spectrum of CNS involvement is wide, including focal, diffuse, neuropsychiatric and spinal cord symptoms, frequently characterised by insidious onset, remitting course and, sometimes, progressive evolution. The diagnostic approach enabling early recognition of this complication relies on careful clinical assessment using history and physical examination combined with neuropsychological testing and instrumental, laboratory and imaging investigations such as magnetic resonance imaging, single photon emission computed tomography, electrophysiological testing and CSF analysis. The clinical picture often shows spontaneous remission, but when overt neurological symptoms occur or become progressive, therapeutic interventions with high dose corticosteroids and cytotoxic agents, such as intravenous cyclophosphamide pulse therapy, may be indicated. PMID:11524032

  2. Roles of Triolein and Lipolytic Protein in the Pathogenesis and Survival of Mycobacterium tuberculosis: a Novel Therapeutic Approach.

    PubMed

    Monu; Meena, Laxman S

    2016-04-01

    Discovery of novel secreted enzymes and proteins in Mycobacterium tuberculosis (M. tuberculosis) are imperative to understanding the pathogenic system for pathogenesis requires attention. Till date, the groups of these secreted enzymes are not meaningfully characterized in terms of M. tuberculosis. In this way, cutinase, a small lipolytic protein, exists in both bacteria and fungi as well which have a potential catalytic activity. During our search, we have found a few genes of M. tuberculosis demonstrating a same significant lipase action as fungi Fusarium solani cutinase contain. Genome sequencing of M. tuberculosis uncover a lot of proteins, wherein (Rv1758, Rv1984c, Rv2301, Rv3451, Rv3452, Rv3724A, Rv3724B, and Rv3802c) genes have been noted which are exhibiting a cutinase-like activity and closely homologous to that of F. solani cutinase and having the ability to hydrolyze model substrates including p-nitrophenyl butyrate (p-PNB), cutin, triacylglycerols (TAGs), and triolein (TO), yet their biological significance in pathogenesis stays subtle and uncharacterized. In a basic perspective, the measure of cutinase expressed by M. tuberculosis and part of these small lipolytic enzymes in the pathologic discipline require thorough characterization. So, through focusing on cutinase-encoding genes in M. tuberculosis and their active catalytic motif could help to build up a novel therapeutic approach. PMID:26679705

  3. An Approach to the Classification of Potential Reserve Additions of Giant Oil Fields of the World

    USGS Publications Warehouse

    Klett, T.R.; Tennyson, M.E.

    2008-01-01

    This report contains slides and notes for slides for a presentation given to the Committee on Sustainable Energy and the Ad Hoc Group of Experts on Harmonization of Fossil Energy and Mineral Resources Terminology on 17 October 2007 in Geneva, Switzerland. The presentation describes the U.S. Geological Survey study to characterize and quantify petroleum-reserve additions, and the application of this study to help classify the quantities.

  4. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches

    SciTech Connect

    Salo, Tuula; Vered, Marilena; Bello, Ibrahim O.; Nyberg, Pia; Bitu, Carolina Cavalcante; Zlotogorski Hurvitz, Ayelet; Dayan, Dan

    2014-07-15

    The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes and the concomitant need for development of new therapeutic approaches will be discussed. - Highlights: • Tumor depth and budding, hypoxia and TME cells associate with worse prognosis. • Pro-tumoral CAFs and CAI cells aid proliferation, invasion and spread hypoxia. • Some ECM-bound factors exert pro-angiogenic or pro-tumor activities. • Tumor spread is greatly dependent on ECM proteolysis, mediated by TME cells. • Direct targeting of TME components for treatment is still experimental.

  5. Rainfall estimation by rain gauge-radar combination: A concurrent multiplicative-additive approach

    NASA Astrophysics Data System (ADS)

    GarcíA-Pintado, Javier; Barberá, Gonzalo G.; Erena, Manuel; Castillo, Victor M.

    2009-01-01

    A procedure (concurrent multiplicative-additive objective analysis scheme [CMA-OAS]) is proposed for operational rainfall estimation using rain gauges and radar data. On the basis of a concurrent multiplicative-additive (CMA) decomposition of the spatially nonuniform radar bias, within-storm variability of rainfall and fractional coverage of rainfall are taken into account. Thus both spatially nonuniform radar bias, given that rainfall is detected, and bias in radar detection of rainfall are handled. The interpolation procedure of CMA-OAS is built on Barnes' objective analysis scheme (OAS), whose purpose is to estimate a filtered spatial field of the variable of interest through a successive correction of residuals resulting from a Gaussian kernel smoother applied on spatial samples. The CMA-OAS, first, poses an optimization problem at each gauge-radar support point to obtain both a local multiplicative-additive radar bias decomposition and a regionalization parameter. Second, local biases and regionalization parameters are integrated into an OAS to estimate the multisensor rainfall at the ground level. The procedure is suited to relatively sparse rain gauge networks. To show the procedure, six storms are analyzed at hourly steps over 10,663 km2. Results generally indicated an improved quality with respect to other methods evaluated: a standard mean-field bias adjustment, a spatially variable adjustment with multiplicative factors, and ordinary cokriging.

  6. "Of Mind, Body, and Spirit": Therapeutic Foster Care - An Innovative Approach to Healing from an NTU Perspective.

    ERIC Educational Resources Information Center

    Gregory, Shawan D. P.; Phillips, Frederick B.

    1997-01-01

    Examines Progressive Life Center's (PLC) Therapeutic Foster Care program and its incorporation of NTU psychotherapy into its program model. Describes how PLC strives to improve the delivery of mental health services through culturally competent therapeutic techniques for African Americans, including seriously emotionally disturbed children. (MOK)

  7. Overview of Alzheimer's Disease and Some Therapeutic Approaches Targeting Aβ by Using Several Synthetic and Herbal Compounds

    PubMed Central

    Singh, Sandeep Kumar; Srivastav, Saurabh; Yadav, Amarish Kumar; Srikrishna, Saripella; Perry, George

    2016-01-01

    Alzheimer's disease (AD) is a complex age-related neurodegenerative disease. In this review, we carefully detail amyloid-β metabolism and its role in AD. We also consider the various genetic animal models used to evaluate therapeutics. Finally, we consider the role of synthetic and plant-based compounds in therapeutics. PMID:27034741

  8. The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

    PubMed Central

    Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D.; Gripp, Karen W.; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum A.; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A.; Roberts, Amy; Silva, Alcino J.; Sittampalam, Sitta G.; Zhang, Chao; Schoyer, Lisa

    2015-01-01

    “The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach” was held at the Renaissance Orlando at SeaWorld Hotel (August 2–4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. PMID:25900621

  9. Correction of an active space telescope mirror using a gradient approach and an additional deformable mirror

    NASA Astrophysics Data System (ADS)

    Allen, Matthew R.; Kim, Jae Jun; Agrawal, Brij N.

    2015-09-01

    High development cost is a challenge for space telescopes and imaging satellites. One of the primary reasons for this high cost is the development of the primary mirror, which must meet diffraction limit surface figure requirements. Recent efforts to develop lower cost, lightweight, replicable primary mirrors include development of silicon carbide actuated hybrid mirrors and carbon fiber mirrors. The silicon carbide actuated hybrid mirrors at the Naval Postgraduate School do not meet the surface quality required for an optical telescope due to high spatial frequency residual surface errors. A technique under investigation at the Naval Postgraduate School is to correct the residual surface figure error using a deformable mirror in the optical path. We present a closed loop feedback gradient controller to actively control a SMT active segment and an additional deformable mirror to reduce residual wavefront error. The simulations and experimental results show that the gradient controller reduces the residual wavefront error more than an integral controller.

  10. Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core.

    PubMed

    Bernardi, Luca; Fochi, Mariafrancesca; Carbone, Riccardo; Martinelli, Ada; Fox, Martin E; Cobley, Christopher J; Kandagatla, Bhaskar; Oruganti, Srinivas; Dahanukar, Vilas H; Carlone, Armando

    2015-12-21

    In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals. PMID:26602867

  11. Empirical Approach to Understanding the Fatigue Behavior of Metals Made Using Additive Manufacturing

    NASA Astrophysics Data System (ADS)

    Witkin, David B.; Albright, Thomas V.; Patel, Dhruv N.

    2016-04-01

    High-cycle fatigue measurements were performed on alloys prepared by powder-bed fusion additive manufacturing techniques. Selective laser melted (SLM) nickel-based superalloy 625 and electron beam melted (EBM) Ti-6Al-4V specimens were prepared as round fatigue specimens and tested with as-built surfaces at stress ratios of -1, 0.1 and 0.5. Data collected at R = -1 were used to construct Goodman diagrams that correspond closely to measured experimental data collected at R > 0. A second way to interpret the HCF data is based on the influence of surface roughness on fatigue, and approximate the surface feature size as a notch. On this basis, the data were interpreted using the fatigue notch factor k f and average stress models relating k f and stress concentration factor K t. The depth and root radius of surface features associated with fatigue crack initiation were used to estimate a K t of 2.8 for SLM 625. For Ti-6Al-4V, a direct estimate of K t from HCF data was not possible, but approximate values of k f based on HCF data and K t from crack initiation site geometry are found to explain other published EBM Ti-6Al-4V.

  12. Biomechanical investigation into the structural design of porous additive manufactured cages using numerical and experimental approaches.

    PubMed

    Tsai, Pei-I; Hsu, Ching-Chi; Chen, San-Yuan; Wu, Tsung-Han; Huang, Chih-Chieh

    2016-09-01

    Traditional solid cages have been widely used in posterior lumbar interbody fusion (PLIF) surgery. However, solid cages significantly affect the loading mechanism of the human spine due to their extremely high structural stiffness. Previous studies proposed and investigated porous additive manufactured (AM) cages; however, their biomechanical performances were analyzed using oversimplified bone-implant numerical models. Thus, the aim of this study was to investigate the outer shape and inner porous structure of the AM cages. The outer shape of the AM cages was discovered using a simulation-based genetic algorithm; their inner porous structure was subsequently analyzed parametrically using T10-S1 multilevel spine models. Finally, six types of the AM cages, which were manufactured using selective laser melting, were tested to validate the numerical outcomes. The subsidence resistance of the optimum design was superior to the conventional cage designs. A porous AM cage with a pillar diameter of 0.4mm, a pillar angle of 40°, and a porosity of between 69% and 80% revealed better biomechanical performances. Both the numerical and experimental outcomes can help surgeons to understand the biomechanics of PLIF surgery combined with the use of AM cages. PMID:27392226

  13. Acidic ionic liquids as sustainable approach of cellulose and lignocellulosic biomass conversion without additional catalysts.

    PubMed

    Lopes, André M da Costa; Bogel-Łukasik, Rafał

    2015-03-01

    The use of ionic liquids (ILs) for biomass processing has attracted considerable attention recently as it provides distinct features for pre-treated biomass and fractionated materials in comparison to conventional processes. Process intensification through integration of dissolution, fractionation, hydrolysis and/or conversion in one pot should be accomplished to maximise economic and technological feasibility. The possibility of using alternative ILs capable not only of dissolving and deconstructing selectively biomass but also of catalysing reactions simultaneously are a potential solution of this problem. In this Review a critical overview of the state of the art and perspectives of the hydrolysis and conversion of cellulose and lignocellulosic biomass using acidic ILs using no additional catalyst are provided. The efficiency of the process is mainly considered with regard to the hydrolysis and conversion yields obtained and the selectivity of each reaction. The process conditions can be easily tuned to obtain sugars and/or platform chemicals, such as furans and organic acids. On the other hand, product recovery from the IL and its purity are the main challenges for the acceptance of this technology as a feasible alternative to conventional processes. PMID:25703380

  14. Empirical Approach to Understanding the Fatigue Behavior of Metals Made Using Additive Manufacturing

    NASA Astrophysics Data System (ADS)

    Witkin, David B.; Albright, Thomas V.; Patel, Dhruv N.

    2016-08-01

    High-cycle fatigue measurements were performed on alloys prepared by powder-bed fusion additive manufacturing techniques. Selective laser melted (SLM) nickel-based superalloy 625 and electron beam melted (EBM) Ti-6Al-4V specimens were prepared as round fatigue specimens and tested with as-built surfaces at stress ratios of -1, 0.1 and 0.5. Data collected at R = -1 were used to construct Goodman diagrams that correspond closely to measured experimental data collected at R > 0. A second way to interpret the HCF data is based on the influence of surface roughness on fatigue, and approximate the surface feature size as a notch. On this basis, the data were interpreted using the fatigue notch factor k f and average stress models relating k f and stress concentration factor K t. The depth and root radius of surface features associated with fatigue crack initiation were used to estimate a K t of 2.8 for SLM 625. For Ti-6Al-4V, a direct estimate of K t from HCF data was not possible, but approximate values of k f based on HCF data and K t from crack initiation site geometry are found to explain other published EBM Ti-6Al-4V.

  15. A sustainable and resilient approach through biochar addition in wood polymer composites.

    PubMed

    Das, Oisik; Sarmah, Ajit K; Bhattacharyya, Debes

    2015-04-15

    Biocomposites have been used for sustainability for a few years now and considerable advancements have been made to perfect the physical and mechanical properties. However, there still remain some considerable disadvantages (such as inferior mechanical strength, thickness swell, and rotting) which restrict their proper utilization in wider markets. Attempts have been made to remedy these drawbacks but still further investigation is required to address all the issues and alleviate as many shortcomings as possible. Additionally, concerns related to landfill gas emission prompted the necessity for effective utilization of organic wastes. Lignocellulosic wastes can be valorized by thermo-chemical conversion to form a carbonaceous and renewable material called biochar. Keeping these two problems in mind, a relatively novel idea is recommended for the manufacture of biocomposites where biochar made from pyrolysis of waste could be added with wood and plastic. It is expected to mitigate the general disadvantages of conventional wood plastic composites (WPCs) and at the same time manage landfill wastes giving rise to a potential new breed of improved next generation biocomposites. Furthermore, a 'resilient' perspective is conferred where the long term viability of the state-of-the-art product could be ensured. PMID:25634737

  16. A novel approach in organic waste utilization through biochar addition in wood/polypropylene composites.

    PubMed

    Das, Oisik; Sarmah, Ajit K; Bhattacharyya, Debes

    2015-04-01

    In an attempt to concurrently address the issues related to landfill gas emission and utilization of organic wastes, a relatively novel idea is introduced to develop biocomposites where biochar made from pyrolysis of waste wood (Pinus radiata) is added with the same wood, plastic/polymer (polypropylene) and maleated anhydride polypropylene (MAPP). Experiments were conducted by manufacturing wood and polypropylene composites (WPCs) mixed with 6 wt%, 12 wt%, 18 wt%, 24 wt%, and 30 wt% biochar. Though 6 wt% addition had similar properties to that of the control (composite without biochar), increasing biochar content to 24 wt% improved the composite's tensile/flexural strengths and moduli. The biochar, having high surface area due to fine particles and being highly carbonised, acted as reinforcing filler in the biocomposite. Composites having 12 wt% and 18 wt% of biochar were found to be the most ductile and thermally stable, respectively. This study demonstrates that, WPCs added with biochar has good potential to mitigate wastes while simultaneously producing biocomposites having properties that might be suited for various end applications. PMID:25677179

  17. A novel approach in organic waste utilization through biochar addition in wood/polypropylene composites

    SciTech Connect

    Das, Oisik; Sarmah, Ajit K.; Bhattacharyya, Debes

    2015-04-15

    Highlights: • Biochar made from waste wood was added with wood polypropylene composites. • 24% biochar gave the best mechanical properties. • 6% biochar had no effect on physico-mechanical properties of composites. • Coupling agent remained unreacted in composites having higher amount of biochar. - Abstract: In an attempt to concurrently address the issues related to landfill gas emission and utilization of organic wastes, a relatively novel idea is introduced to develop biocomposites where biochar made from pyrolysis of waste wood (Pinus radiata) is added with the same wood, plastic/polymer (polypropylene) and maleated anhydride polypropylene (MAPP). Experiments were conducted by manufacturing wood and polypropylene composites (WPCs) mixed with 6 wt%, 12 wt%, 18 wt%, 24 wt%, and 30 wt% biochar. Though 6 wt% addition had similar properties to that of the control (composite without biochar), increasing biochar content to 24 wt% improved the composite’s tensile/flexural strengths and moduli. The biochar, having high surface area due to fine particles and being highly carbonised, acted as reinforcing filler in the biocomposite. Composites having 12 wt% and 18 wt% of biochar were found to be the most ductile and thermally stable, respectively. This study demonstrates that, WPCs added with biochar has good potential to mitigate wastes while simultaneously producing biocomposites having properties that might be suited for various end applications.

  18. Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics.

    PubMed

    Woodcock, Joanna M; Coolen, Carl; Goodwin, Katy L; Baek, Dong Jae; Bittman, Robert; Samuel, Michael S; Pitson, Stuart M; Lopez, Angel F

    2015-06-10

    14-3-3 proteins play a pivotal role in controlling cell proliferation and survival, two commonly dysregulated hallmarks of cancers. 14-3-3 protein expression is enhanced in many human cancers and correlates with more aggressive tumors and poor prognosis, suggesting a role for 14-3-3 proteins in tumorigenesis and/or progression. We showed previously that the dimeric state of 14-3-3 proteins is regulated by the lipid sphingosine, a physiological inducer of apoptosis. As the functions of 14-3-3 proteins are dependent on their dimeric state, this sphingosine-mediated 14-3-3 regulation provides a possible means to target dimeric 14-3-3 for therapeutic effect. However, sphingosine mimics are needed that are not susceptible to sphingolipid metabolism. We show here the identification and optimization of sphingosine mimetics that render dimeric 14-3-3 susceptible to phosphorylation at a site buried in the dimer interface and induce mitochondrial-mediated apoptosis. Two such compounds, RB-011 and RB-012, disrupt 14-3-3 dimers at low micromolar concentrations and induce rapid down-regulation of Raf-MAPK and PI3K-Akt signaling in Jurkat cells. Importantly, both RB-011 and RB-012 induce apoptosis of human A549 lung cancer cells and RB-012, through disruption of MAPK signaling, reduces xenograft growth in mice. Thus, these compounds provide proof-of-principle for this novel 14-3-3-targeting approach for anti-cancer drug discovery. PMID:25971334

  19. Increase in Cellular Cyclic AMP Concentrations Reverses the Profibrogenic Phenotype of Cardiac Myofibroblasts: A Novel Therapeutic Approach for Cardiac Fibrosis

    PubMed Central

    Lu, David; Aroonsakool, Nakon; Yokoyama, Utako; Patel, Hemal H.

    2013-01-01

    Tissue fibrosis is characterized by excessive production, deposition, and contraction of the extracellular matrix (ECM). The second messenger cAMP has antifibrotic effects in fibroblasts from several tissues, including cardiac fibroblasts (CFs). Increased cellular cAMP levels can prevent the transformation of CFs into profibrogenic myofibroblasts, a critical step that precedes increased ECM deposition and tissue fibrosis. Here we tested two hypotheses: 1) myofibroblasts have a decreased ability to accumulate cAMP in response to G protein–coupled receptor (GPCR) agonists, and 2) increasing cAMP will not only prevent, but also reverse, the myofibroblast phenotype. We found that myofibroblasts produce less cAMP in response to GPCR agonists or forskolin and have decreased expression of several adenylyl cyclase (AC) isoforms and increased expression of multiple cyclic nucleotide phosphodiesterases (PDEs). Furthermore, we found that forskolin-promoted increases in cAMP or N6-phenyladenosine-cAMP, a protein kinase A–selective analog, reverse the myofibroblast phenotype, as assessed by the expression of collagen Iα1, α–smooth muscle actin, plasminogen activator inhibitor–1, and cellular contractile abilities, all hallmarks of a fibrogenic state. These results indicate that: 1) altered expression of AC and PDE isoforms yield a decrease in cAMP concentrations of cardiac myofibroblasts (relative to CFs) that likely contributes to their profibrotic state, and 2) approaches to increase cAMP concentrations not only prevent fibroblast-to-myofibroblast transformation but also can reverse the profibrotic myofibroblastic phenotype. We conclude that therapeutic strategies designed to enhance cellular cAMP concentrations in CFs may provide a means to reverse excessive scar formation following injury and to treat cardiac fibrosis. PMID:24085841

  20. Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach

    PubMed Central

    Shanmugham, Buvaneswari; Pan, Archana

    2013-01-01

    Mycobacterium abscessus, a non-tuberculous rapidly growing mycobacterium, is recognized as an emerging human pathogen causing a variety of infections ranging from skin and soft tissue infections to severe pulmonary infections. Lack of an optimal treatment regimen and emergence of multi-drug resistance in clinical isolates necessitate the development of better/new drugs against this pathogen. The present study aims at identification and qualitative characterization of promising drug targets in M. abscessus using a novel hierarchical in silico approach, encompassing three phases of analyses. In phase I, five sets of proteins were mined through chokepoint, plasmid, pathway, virulence factors, and resistance genes and protein network analysis. These were filtered in phase II, in order to find out promising drug target candidates through subtractive channel of analysis. The analysis resulted in 40 therapeutic candidates which are likely to be essential for the survival of the pathogen and non-homologous to host, human anti-targets, and gut flora. Many of the identified targets were found to be involved in different metabolisms (viz., amino acid, energy, carbohydrate, fatty acid, and nucleotide), xenobiotics degradation, and bacterial pathogenicity. Finally, in phase III, the candidate targets were qualitatively characterized through cellular localization, broad spectrum, interactome, functionality, and druggability analysis. The study explained their subcellular location identifying drug/vaccine targets, possibility of being broad spectrum target candidate, functional association with metabolically interacting proteins, cellular function (if hypothetical), and finally, druggable property. Outcome of the present study could facilitate the identification of novel antibacterial agents for better treatment of M. abscesses infections. PMID:23527108

  1. Cell-lineage regulated myogenesis for dystrophin replacement: a novel therapeutic approach for treatment of muscular dystrophy.

    PubMed

    Kimura, En; Han, Jay J; Li, Sheng; Fall, Brent; Ra, Jennifer; Haraguchi, Miki; Tapscott, Stephen J; Chamberlain, Jeffrey S

    2008-08-15

    Duchenne muscular dystrophy (DMD) is characterized in skeletal muscle by cycles of myofiber necrosis and regeneration leading to loss of muscle fibers and replacement with fibrotic connective and adipose tissue. The ongoing activation and recruitment of muscle satellite cells for myofiber regeneration results in loss of regenerative capacity in part due to proliferative senescence. We explored a method whereby new myoblasts could be generated in dystrophic muscles by transplantation of primary fibroblasts engineered to express a micro-dystrophin/enhanced green fluorescent protein (muDys/eGFP) fusion gene together with a tamoxifen-inducible form of the myogenic regulator MyoD [MyoD-ER(T)]. Fibroblasts isolated from mdx(4cv) mice, a mouse model for DMD, were efficiently transduced with lentiviral vectors expressing muDys/eGFP and MyoD-ER(T) and underwent myogenic conversion when exposed to tamoxifen. These cells could also be induced to differentiate into muDys/eGFP-expressing myocytes and myotubes. Transplantation of transduced mdx(4cv) fibroblasts into mdx(4cv) muscles enabled tamoxifen-dependent regeneration of myofibers that express muDys. This lineage control method therefore allows replenishment of myogenic stem cells using autologous fibroblasts carrying an exogenous dystrophin gene. This strategy carries several potential advantages over conventional myoblast transplantation methods including: (i) the relative simplicity of culturing fibroblasts compared with myoblasts, (ii) a readily available cell source and ease of expansion and (iii) the ability to induce MyoD gene expression in vivo via administration of a medication. Our study provides a proof of concept for a novel gene/stem cell therapy technique and opens another potential therapeutic approach for degenerative muscle disorders. PMID:18511457

  2. Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches

    PubMed Central

    Hussein, D; Starr, A; Heikal, L; McNeill, E; Channon, K M; Brown, P R; Sutton, B J; McDonnell, J M; Nandi, M

    2015-01-01

    Background and Purpose 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH4 restores vascular function in patients. Unfortunately, oral BH4 has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH4 synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L-phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo. Experimental Approach Detailed characterization of GCH1–GFRP protein–protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH4 biosynthesis in vivo were investigated following L-phe treatment (100 mg·kg−1, p.o.). Key Results GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH4, an effect absent in GCH1(fl/fl)-Tie2Cre mice. Conclusions and Implications Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH4 in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1–GFRP complex have the potential to elevate endothelial BH4 biosynthesis for numerous cardiovascular disorders. PMID:26014146

  3. A genetic approach to the development of new therapeutic phages to fight pseudomonas aeruginosa in wound infections.

    PubMed

    Krylov, Victor; Shaburova, Olga; Krylov, Sergey; Pleteneva, Elena

    2013-01-01

    Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent ("lytic") and temperate ("lysogenic") bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine. PMID:23344559

  4. A Genetic Approach to the Development of New Therapeutic Phages to Fight Pseudomonas Aeruginosa in Wound Infections

    PubMed Central

    Krylov, Victor; Shaburova, Olga; Krylov, Sergey; Pleteneva, Elena

    2012-01-01

    Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent (“lytic”) and temperate (“lysogenic”) bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine. PMID:23344559

  5. Nanolipodendrosome-loaded glatiramer acetate and myogenic differentiation 1 as augmentation therapeutic strategy approaches in muscular dystrophy

    PubMed Central

    Afzal, Ehsan; Zakeri, Saba; Keyhanvar, Peyman; Bagheri, Meisam; Mahjoubi, Parvin; Asadian, Mahtab; Omoomi, Nogol; Dehqanian, Mohammad; Ghalandarlaki, Negar; Darvishmohammadi, Tahmineh; Farjadian, Fatemeh; Golvajoee, Mohammad Sadegh; Afzal, Shadi; Ghaffari, Maryam; Cohan, Reza Ahangari; Gravand, Amin; Ardestani, Mehdi Shafiee

    2013-01-01

    Backgrond Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion – like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 [MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. Methods In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. Results The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation. PMID:23966782

  6. Heterogeneity in the therapeutic approach to relapsed elderly patients with acute myeloid leukaemia: a survey from the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Acute Leukaemia Working Party.

    PubMed

    Ferrara, Felicetto; Fazi, Paola; Venditti, Adriano; Pagano, Livio; Amadori, Sergio; Mandelli, Franco

    2008-06-01

    The percentage of long-term survivors in acute myeloid leukaemia (AML) in the elderly does not exceed 10-15% of patients enrolled into clinical trials because of lower complete remission (CR) rates and higher incidence of relapse. However, few data are available as the treatment of elderly patients with relapsed disease is concerned. The aim of this study was of collecting data on criteria adopted for the treatment of these patients. A questionnaire was e-mailed to 32 haematologic institutions involved in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group. Questions to be addressed regarded: (1) per cent of relapsed elderly patients treated with aggressive salvage chemotherapy; (2) the selection criteria adopted for inclusion into intensive reinduction; (3) the specific treatment adopted; (4) the treatment given to patients not eligible for intensive salvage. Per cent of patients enrolled into aggressive salvage regimens varied from 10 to 80% (median 50%). The most frequent factor influencing the therapeutic choice was performance status (97%). Additional factors were age >70 years (44%) and duration of first CR (53%). Fludarabine including regimens were most frequently used as aggressive salvage therapy (59%), while gemtuzumab ozogamicin was adopted in various combinations at 11 out of 32 institutions (34%). For patients not eligible to aggressive therapy, the most frequent approach included hydroxyurea (59%). Low dose ARA-C (LDARA-C) was adopted at five centres: as single agent (n = 1), with 6-thioguanine (n = 1), with vitamin D3 and all-trans retinoic acid (ATRA) (n = 2), or with ATRA alone (n = 1). The FLT3 inhibitor CEP-701 was used at one centre. We conclude that the treatment of AML in elderly relapsed patients is extremely heterogeneous. A marked selection is operated as to inclusion into aggressive salvage regimens and only a small minority of patients are offered experimental approaches. PMID:18271064

  7. Superposition-additive approach: thermodynamic parameters of clusterization of monosubstituted alkanes at the air/water interface.

    PubMed

    Vysotsky, Yu B; Belyaeva, E A; Fomina, E S; Fainerman, V B; Aksenenko, E V; Vollhardt, D; Miller, R

    2011-12-21

    The applicability of the superposition-additive approach for the calculation of the thermodynamic parameters of formation and atomization of conjugate systems, their dipole electric polarisabilities, molecular diamagnetic susceptibilities, π-electron circular currents, as well as for the estimation of the thermodynamic parameters of substituted alkanes, was demonstrated earlier. Now the applicability of the superposition-additive approach for the description of clusterization of fatty alcohols, thioalcohols, amines, carboxylic acids at the air/water interface is studied. Two superposition-additive schemes are used that ensure the maximum superimposition of the graphs of the considered molecular structures including the intermolecular CH-HC interactions within the clusters. The thermodynamic parameters of clusterization are calculated for dimers, trimers and tetramers. The calculations are based on the values of enthalpy, entropy and Gibbs' energy of clusterization calculated earlier using the semiempirical quantum chemical PM3 method. It is shown that the proposed approach is capable of the reproduction with sufficiently enough accuracy of the values calculated previously. PMID:22042000

  8. Additional disturbances as a beneficial tool for restoration of post-mining sites: a multi-taxa approach.

    PubMed

    Řehounková, Klára; Čížek, Lukáš; Řehounek, Jiří; Šebelíková, Lenka; Tropek, Robert; Lencová, Kamila; Bogusch, Petr; Marhoul, Pavel; Máca, Jan

    2016-07-01

    Open interior sands represent a highly threatened habitat in Europe. In recent times, their associated organisms have often found secondary refuges outside their natural habitats, mainly in sand pits. We investigated the effects of different restoration approaches, i.e. spontaneous succession without additional disturbances, spontaneous succession with additional disturbances caused by recreational activities, and forestry reclamation, on the diversity and conservation values of spiders, beetles, flies, bees and wasps, orthopterans and vascular plants in a large sand pit in the Czech Republic, Central Europe. Out of 406 species recorded in total, 112 were classified as open sand specialists and 71 as threatened. The sites restored through spontaneous succession with additional disturbances hosted the largest proportion of open sand specialists and threatened species. The forestry reclamations, in contrast, hosted few such species. The sites with spontaneous succession without disturbances represent a transition between these two approaches. While restoration through spontaneous succession favours biodiversity in contrast to forestry reclamation, additional disturbances are necessary to maintain early successional habitats essential for threatened species and open sand specialists. Therefore, recreational activities seem to be an economically efficient restoration tool that will also benefit biodiversity in sand pits. PMID:27053054

  9. Innovative therapeutic strategies for recessive dystrophic epidermolysis bullosa.

    PubMed

    Larcher, F; Del Río, M

    2015-06-01

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

  10. Therapeutic perspectives in hypertension: novel means for renin–angiotensin–aldosterone system modulation and emerging device-based approaches

    PubMed Central

    Unger, Thomas; Paulis, Ludovit; Sica, Domenic A.

    2011-01-01

    The conventional antihypertensive therapies including renin–angiotensin–aldosterone system antagonists (converting enzyme inhibitors, receptor blockers, renin inhibitors, and mineralocorticoid receptor blockers), diuretics, β-blockers, and calcium channel blockers are variably successful in achieving the challenging target blood pressure values in hypertensive patients. Difficult to treat hypertension is still a commonly observed problem world-wide. A number of drugs are considered to be used as novel therapies for hypertension. Renalase supplementation, vasopeptidase inhibitors, endothelin antagonists, and especially aldosterone antagonists (aldosterone synthase inhibitors and novel selective mineralocorticoid receptor blockers) are considered an option in resistant hypertension. In addition, the aldosterone antagonists as well as (pro)renin receptor blockers or AT2 receptor agonists might attenuate end-organ damage. This array of medications has now been complemented by a number of new approaches of non-pharmacological strategies including vaccination, genomic interference, controlled breathing, baroreflex activation, and probably most successfully renal denervation techniques. However, the progress on innovative therapies seems to be slow and the problem of resistant hypertension and proper blood pressure control appears to be still persisting. Therefore the regimens of currently available drugs are being fine-tuned, resulting in the establishment of several novel fixed-dose combinations including triple combinations with the aim to facilitate proper blood pressure control. It remains an exciting question which approach will confer the best blood pressure control and risk reduction in this tricky disease. PMID:21951628

  11. Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: a novel synergistic therapeutic approach.

    PubMed

    Kiebala, Michelle; Skalska, Jolanta; Casulo, Carla; Brookes, Paul S; Peterson, Derick R; Hilchey, Shannon P; Dai, Yun; Grant, Steven; Maggirwar, Sanjay B; Bernstein, Steven H

    2015-02-01

    B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined nontoxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin system, with nontoxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. Auranofin interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle-cell lymphoma cells. Additionally, there was less toxicity toward normal B cells. Low AUR concentrations inhibited thioredoxin reductase (TrxR) activity, an effect significantly increased by BSO cotreatment. Overexpression of TrxR partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited nuclear factor κB (NF-κB) signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells overexpressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induces malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies. PMID:25448488

  12. [The role of biological sciences in understanding the genesis and a new therapeutic approach to Alzheimer's disease].

    PubMed

    Tęgowska, Eugenia; Wosińska, Adrianna

    2011-01-01

    The paper contrasts the historical view on causal factors in Alzheimer's disease (AD) with the modern concept of the symptoms' origin. Biological sciences dealing with cell structure and physiology enabled comprehension of the role of mitochondrial defects in the processes of formation of neurofibrillary tangles and β-amyloid, which in turn gives hope for developing a new, more effective therapeutic strategy for AD. It has been established that although mitochondria constantly generate free radicals, from which they are protected by their own defensive systems, in some situations these systems become deregulated, which leads to free radical-based mitochondrial defects. This causes an energetic deficit in neurons and a further increase in the free radical pool. As a result, due to compensation processes, formation of tangles and/or acceleration of β-amyloid production takes place. The nature of these processes is initially a protective one, due to their anti-oxidative action, but as the amount of the formations increases, their beneficial effect wanes. They become a storage place for substances enhancing free radical processes, which makes them toxic themselves. It is such an approach to the primary causal factor for AD which lies at the roots of the new view on AD therapy, suggesting the use of methylene blue-based drugs, laser or intranasally applied insulin. A necessary condition, however, for these methods' effectiveness is definitely an earlier diagnosis of the disease. Although there are numerous diagnostic methods for AD, their low specificity and high price, often accompanied by a considerable level of patient discomfort, make them unsuitable for early, prodromal screening. In this matter a promising method may be provided using an olfactory test, which is an inexpensive and non-invasive method and thus suitable for screening, although as a test of low specificity, it should be combined with other methods. Introducing new methods of AD treatment does not

  13. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion.

    PubMed

    Miyara, Makoto; Wing, Kajsa; Sakaguchi, Shimon

    2009-04-01

    Forkhead box protein 3-positive regulatory T (Treg) cells are indispensable for the maintenance of self-tolerance and immune homeostasis. They can also be exploited for the treatment of immunologic diseases, including autoimmune diseases and allergy, by way of activating and expanding antigen-specific Treg cells in vivo. Cell therapy with in vitro activated and expanded Treg cells can be another therapeutic modality. The feasibility of such Treg cell-based therapeutic strategies is discussed based on recent advances in our understanding of the molecular and cellular basis of Treg cell development and function. PMID:19348913

  14. The Additive Inflammatory In Vivo and In Vitro Effects of IL-7 and TSLP in Arthritis Underscore the Therapeutic Rationale for Dual Blockade

    PubMed Central

    Hillen, Maarten R.; Hartgring, Sarita A. Y.; Willis, Cynthia R.; Radstake, Timothy R. D. J.; Hack, Cornelis E.; Lafeber, Floris P. J. G.; van Roon, Joel A. G

    2015-01-01

    Introduction The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied. Methods Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed. Results Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors. Conclusion TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA. PMID:26110994

  15. Radiation Therapy in the Management of Head-and-Neck Cancer of Unknown Primary Origin: How Does the Addition of Concurrent Chemotherapy Affect the Therapeutic Ratio?

    SciTech Connect

    Chen, Allen M.; Farwell, D. Gregory; Lau, Derick H.; Li Baoqing; Luu, Quang; Donald, Paul J.

    2011-10-01

    Purpose: To determine how the addition of cisplatin-based concurrent chemotherapy to radiation therapy influences outcomes among a cohort of patients treated for head-and-neck cancer of unknown primary origin. Methods and Materials: The medical records of 60 consecutive patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Thirty-two patients (53%) were treated by concurrent chemoradiation, and 28 patients (47%) were treated by radiation therapy alone. Forty-five patients (75%) received radiation therapy after surgical resection, and 15 patients (25%) received primary radiation therapy. Thirty-five patients (58%) were treated by intensity-modulated radiotherapy. Results: The 2-year estimates of overall survival, local-regional control, and progression-free survival were 89%, 89%, and 79%, respectively, among patients treated by chemoradiation, compared to 90%, 92%, and 83%, respectively, among patients treated by radiation therapy alone (p > 0.05, for all). Exploratory analysis failed to identify any subset of patients who benefited from the addition of concurrent chemotherapy to radiation therapy. The use of concurrent chemotherapy was associated with a significantly increased incidence of Grade 3+ acute and late toxicity (p < 0.001, for both). Conclusions: Concurrent chemoradiation is associated with significant toxicity without a clear advantage to overall survival, local-regional control, and progression-free survival in the treatment of head-and-neck cancer of unknown primary origin. Although selection bias cannot be ignored, prospective data are needed to further address this question.

  16. Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia

    NASA Astrophysics Data System (ADS)

    Chai, Dongyul; Juhasz, Tibor; Brown, Donald J.; Jester, James V.

    2013-03-01

    In this study we test the hypothesis that nonlinear optical (NLO) multiphoton photoactivation of riboflavin using a focused femtosecond (FS) laser light can be used to induce cross-linking (CXL) and mechanically stiffen collagen as a potential clinical therapy for the treatment of keratoconus and corneal ectasia. Riboflavin-soaked, compressed collagen hydrogels are cross-linked using a FS laser tuned to 760 nm and set to either 100 mW (NLO CXL I) or 150 mW (NLO CXL II) of laser power. FS pulses are focused into the hydrogel using a 0.75 NA objective lens, and the hydrogel is three-dimensionally scanned. Measurement of hydrogel stiffness by indentation testing show that the calculated elastic modulus (E) values are significantly increased over twofold following NLO CXL I and II compared with baseline values (P<0.05). Additionally, no significant differences are detected between NLO CXL and single photon, UVA CXL (P>0.05). This data suggests that NLO CXL has a comparable effect to conventional UVA CXL in mechanically stiffening collagen and may provide a safe and effective approach to localize CXL at different regions and depths within the cornea.

  17. Modeling the Impact of School-Based Universal Depression Screening on Additional Service Capacity Needs: A System Dynamics Approach.

    PubMed

    Lyon, Aaron R; Maras, Melissa A; Pate, Christina M; Igusa, Takeru; Vander Stoep, Ann

    2016-03-01

    Although it is widely known that the occurrence of depression increases over the course of adolescence, symptoms of mood disorders frequently go undetected. While schools are viable settings for conducting universal screening to systematically identify students in need of services for common health conditions, particularly those that adversely affect school performance, few school districts routinely screen their students for depression. Among the most commonly referenced barriers are concerns that the number of students identified may exceed schools' service delivery capacities, but few studies have evaluated this concern systematically. System dynamics (SD) modeling may prove a useful approach for answering questions of this sort. The goal of the current paper is therefore to demonstrate how SD modeling can be applied to inform implementation decisions in communities. In our demonstration, we used SD modeling to estimate the additional service demand generated by universal depression screening in a typical high school. We then simulated the effects of implementing "compensatory approaches" designed to address anticipated increases in service need through (1) the allocation of additional staff time and (2) improvements in the effectiveness of mental health interventions. Results support the ability of screening to facilitate more rapid entry into services and suggest that improving the effectiveness of mental health services for students with depression via the implementation of an evidence-based treatment protocol may have a limited impact on overall recovery rates and service availability. In our example, the SD approach proved useful in informing systems' decision-making about the adoption of a new school mental health service. PMID:25601192

  18. Alzheimer's disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products.

    PubMed

    Awasthi, Manika; Singh, Swati; Pandey, Veda P; Dwivedi, Upendra N

    2016-02-15

    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by amyloid beta (Aβ) deposition in brain with subsequent formation of neuritic plaques leading to dementia. A number of therapeutic strategies targeted against Aβ depositions have been rigorously explored which provided successful results corresponding to the existing symptomatic treatments. However, at the same time, several failures corresponding to the disease altering therapies and drugs have also been observed due to potential drawbacks in understanding of the pathogenesis of the disease, development of drug candidates and subsequent designing of clinical trials. Preclinical research, along with experimental and clinical studies, is continuously providing novel information which may reveal multi-target directed ligands and combination therapies for targeting Aβ. Thus, in view of the estimated increase in the number of AD patients globally, the present review attempts to summarize the available evidence dealing with various therapeutic approaches targeting Aβ, focusing specifically on pharmaceutical compounds under various stages of clinical trials. Furthermore, in view of a number of computational advances having significant impact in the field of computer aided drug design, we have also presented results of analysis of natural compounds as potential therapeutic molecules in preventing Aβ plaque formation using in silico approaches. PMID:26810552

  19. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity.

    PubMed

    Maruta, Hiroshi

    2014-05-01

    Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals. PMID:23943274

  20. Atomic electron affinities and the role of symmetry between electron addition and subtraction in a corrected Koopmans approach.

    PubMed

    Teale, A M; De Proft, F; Geerlings, P; Tozer, D J

    2014-07-28

    The essential aspects of zero-temperature grand-canonical ensemble density-functional theory are reviewed in the context of spin-density-functional theory and are used to highlight the assumption of symmetry between electron addition and subtraction that underlies the corrected Koopmans approach of Tozer and De Proft (TDP) for computing electron affinities. The issue of symmetry is then investigated in a systematic study of atomic electron affinities, comparing TDP affinities with those from a conventional Koopmans evaluation and electronic energy differences. Although it cannot compete with affinities determined from energy differences, the TDP expression yields results that are a significant improvement over those from the conventional Koopmans expression. Key insight into the results from both expressions is provided by an analysis of plots of the electronic energy as a function of the number of electrons, which highlight the extent of symmetry between addition and subtraction. The accuracy of the TDP affinities is closely related to the nature of the orbitals involved in the electron addition and subtraction, being particularly poor in cases where there is a change in principal quantum number, but relatively accurate within a single manifold of orbitals. The analysis is then extended to a consideration of the ground state Mulliken electronegativity and chemical hardness. The findings further emphasize the key role of symmetry in determining the quality of the results. PMID:24406854

  1. A novel approach for the simultaneous quantification of a therapeutic monoclonal antibody in serum produced from two distinct host cell lines

    PubMed Central

    Geist, Brian J.; Davis, Darryl; McIntosh, Thomas; Yang, Tong-Yuan; Goldberg, Kenneth; Han, Chao; Pendley, Charles; Davis, Hugh M.

    2013-01-01

    Therapeutic monoclonal antibodies (mAbs) possess a high degree of heterogeneity associated with the cell expression system employed in manufacturing, most notably glycosylation. Traditional immunoassay formats used to quantify therapeutic mAbs are unable to discriminate between different glycosylation patterns that may exist on the same protein amino acid sequence. Mass spectrometry provides a technique to distinguish specific glycosylation patterns of the therapeutic antibody within the same sample, thereby allowing for simultaneous quantification of the same mAb with different glycosylation patterns. Here we demonstrate a two-step approach to successfully differentiate and quantify serum mixtures of a recombinant therapeutic mAb produced in two different host cell lines (CHO vs. Sp2/0) with distinct glycosylation profiles. Glycosylation analysis of the therapeutic mAb, CNTO 328 (siltuximab), was accomplished through sample pretreatment consisting of immunoaffinity purification (IAP) and enrichment, followed by liquid chromatography (LC) and mass spectrometry (MS). LC-MS analysis was used to determine the percentage of CNTO 328 in the sample derived from either cell line based on the N-linked G1F oligosaccharide on the mAb. The relative amount of G1F derived from each cell line was compared with ratios of CNTO 328 reference standards prepared in buffer. Glycoform ratios were converted to concentrations using an immunoassay measuring total CNTO 328 that does not distinguish between the different glycoforms. Validation of the IAP/LC-MS method included intra-run and inter-run variability, method sensitivity and freeze-thaw stability. The method was accurate (%bias range = -7.30–13.68%) and reproducible (%CV range = 1.49–10.81%) with a LOQ of 2.5 μg/mL. PMID:23182963

  2. [Additional administration of dutasteride in patients with benign prostatic hyperplasia who did not respond sufficiently to α1-adrenoceptor antagonist : investigation of clinical factors affecting the therapeutic effect of dutasteride].

    PubMed

    Masuda, Mitsunobu; Murai, Tetsuo; Osada, Yutaka; Kawai, Masaki; Kasuga, Jun; Yokomizo, Yumiko; Kuroda, Shinnosuke; Nakamura, Mami; Noguchi, Go

    2014-02-01

    We performed additional administration of dutasteride in patients who did not respond sufficiently to α1-adrenoceptor antagonist treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) (LUTS/BPH). Among 76 registered patients, efficacy was analyzed in 58 patients. International Prostate Symptom Score (IPSS), subscores for voiding and storage symptoms and quality of life (QOL) on the IPSS, and Overactive Bladder Symptom Score (OABSS) were all significantly improved from the third month of administration compared to the time of initiating additional administration of dutasteride. Additional administration of dutasteride also significantly reduced prostate volume, and residual urine with the exception of the sixth month after administration. Age at initiation of administration and voiding symptom subscore on the IPSS were clinical factors affecting the therapeutic effects of dutasteride. The rate of improvement with treatment decreased with increasing age at initiation of dutasteride administration, and increased as voiding symptom subscore on the IPSS increased. Therefore, additional administration of dutasteride appears useful for cases of LUTS/BPH in which a sufficient response is not achieved with α1-adrenoceptor antagonist treatment. Because patients who have severe voiding symptoms or begin dutasteride at an early age may be expected to respond particularly well to dutasteride in terms of clinical efficacy, they were considered to be suitable targets for additional administration. PMID:24755815

  3. A mathematical approach to optimal selection of dose values in the additive dose method of ERP dosimetry

    SciTech Connect

    Hayes, R.B.; Haskell, E.H.; Kenner, G.H.

    1996-01-01

    Additive dose methods commonly used in electron paramagnetic resonance (EPR) dosimetry are time consuming and labor intensive. We have developed a mathematical approach for determining optimal spacing of applied doses and the number of spectra which should be taken at each dose level. Expected uncertainitites in the data points are assumed to be normally distributed with a fixed standard deviation and linearity of dose response is also assumed. The optimum spacing and number of points necessary for the minimal error can be estimated, as can the likely error in the resulting estimate. When low doses are being estimated for tooth enamel samples the optimal spacing is shown to be a concentration of points near the zero dose value with fewer spectra taken at a single high dose value within the range of known linearity. Optimization of the analytical process results in increased accuracy and sample throughput.

  4. The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

    NASA Astrophysics Data System (ADS)

    Bürli, Roland W.; Thomas, Elizabeth; Beaumont, Vahri

    Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

  5. Parameter Estimation for a Physically-Based Model Using Multi-Objective Approach Constrained With Additional Internal States

    NASA Astrophysics Data System (ADS)

    Zhang, G.; Fenicia, F.; Savenije, H. H.

    2007-12-01

    Parameter estimation (i.e. model calibration) is a critical procedure for not only determining a successful model application, but also assessing model uncertainties, thus helping improve model development. Physically-based distributed hydrological models are increasingly used as required in water management because of the complexity of the processes to be represented. Given the fact that the distributed catchment characteristics, represented by parameters, could not be directly measured in most cases, model calibration is therefore inevitable. Calibration and uncertainty assessment for such complex models are more challenging than for those simpler ones due to the large number of parameters associated with integrated multiple processes description and large computing resources demands. There is ample literature on the approaches to model parameter estimation and applications of such approaches. Multi-objective Pareto-optimality approaches, such as MOSCEM-UA, are amongst the state-the-art approaches in modeling practices. The multi-objective optimization approaches, however, have not yet widely applied to physically-based distributed models, due to the aforementioned challenging issues. This work presents an application of MOSCEM-UA algorithm to a newly developed physically-based model REWASH. REWASH is a model based on the Representative Elementary Watershed (REW) concept that describes hydrological processes at the watershed scale, using the basic physical conservation laws. The elementary watersheds, i.e. the sub-watersheds are the hydrological response units of a catchment when using REWASH model. In this study, REWASH model was applied to simulate rainfall-runoff relation for the Hesperange catchment in Luxembourg. Due to its physically-based and semi-distributed nature, the applied hydrological model reproduces not only stream flows at the catchment outlet and the sub-watersheds' outlets, but subsurface flows and groundwater table variations as well

  6. An analytical approach to the problem of inverse optimization with additive objective functions: an application to human prehension

    PubMed Central

    Pesin, Yakov B.; Niu, Xun; Latash, Mark L.

    2010-01-01

    We consider the problem of what is being optimized in human actions with respect to various aspects of human movements and different motor tasks. From the mathematical point of view this problem consists of finding an unknown objective function given the values at which it reaches its minimum. This problem is called the inverse optimization problem. Until now the main approach to this problems has been the cut-and-try method, which consists of introducing an objective function and checking how it reflects the experimental data. Using this approach, different objective functions have been proposed for the same motor action. In the current paper we focus on inverse optimization problems with additive objective functions and linear constraints. Such problems are typical in human movement science. The problem of muscle (or finger) force sharing is an example. For such problems we obtain sufficient conditions for uniqueness and propose a method for determining the objective functions. To illustrate our method we analyze the problem of force sharing among the fingers in a grasping task. We estimate the objective function from the experimental data and show that it can predict the force-sharing pattern for a vast range of external forces and torques applied to the grasped object. The resulting objective function is quadratic with essentially non-zero linear terms. PMID:19902213

  7. Awareness Levels about Breast Cancer Risk Factors, Early Warning Signs, and Screening and Therapeutic Approaches among Iranian Adult Women: A large Population Based Study Using Latent Class Analysis

    PubMed Central

    Tazhibi, Mahdi

    2014-01-01

    Background and Objective. Breast cancer (BC) continues to be a major cause of morbidity and mortality among women throughout the world and in Iran. Lack of awareness and early detection program in developing country is a main reason for escalating the mortality. The present research was conducted to assess the Iranian women's level of knowledge about breast cancer risk factors, early warning signs, and therapeutic and screening approaches, and their correlated determinants. Methods. In a cross-sectional study, 2250 women before participating at a community based screening and public educational program in an institute of cancer research in Isfahan, Iran, in 2012 were investigated using a self-administered questionnaire about risk factors, early warning signs, and therapeutic and screening approaches of BC. Latent class regression as a comprehensive statistical method was used for evaluating the level of knowledge and its correlated determinants. Results. Only 33.2%, 31.9%, 26.7%, and 35.8% of study participants had high awareness levels about screening approaches, risk factors, early warning signs and therapeutic modalities of breast cancer, respectively, and majority had poor to moderate knowledge levels. Most effective predictors of high level of awareness were higher educational qualifications, attending in screening and public educational programs, personal problem, and family history of BC, respectively. Conclusion. Results of current study indicated that the levels of awareness among study population about key elements of BC are low. These findings reenforce the continuing need for more BC education through conducting public and professional programs that are intended to raise awareness among younger, single women and those with low educational attainments and without family history. PMID:25295257

  8. A papain-induced disc degeneration model for the assessment of thermo-reversible hydrogel-cells therapeutic approach.

    PubMed

    Malonzo, C; Chan, S C W; Kabiri, A; Eglin, D; Grad, S; Bonél, H M; Benneker, L M; Gantenbein-Ritter, B

    2015-12-01

    Nucleus pulposus (NP) regeneration by the application of injectable cell-embedded hydrogels is an appealing approach for tissue engineering. We investigated a thermo-reversible hydrogel (TR-HG), based on a modified polysaccharide with a thermo-reversible polyamide [poly(N-isopropylacrylamide), pNIPAM], which is made to behave as a liquid at room temperature and hardens at > 32 °C. In order to test the hydrogel, a papain-induced bovine caudal disc degeneration model (PDDM), creating a cavity in the NP, was employed. Human mesenchymal stem cells (hMSCs) or autologous bovine NP cells (bNPCs) were seeded in TR-HG; hMSCs were additionally preconditioned with rhGDF-5 for 7 days. Then, TR-HG was reversed to a fluid and the cell suspension injected into the PDDM and kept under static loading for 7 days. Experimental design was: (D1) fresh disc control + PBS injection; (D2) PDDM + PBS injection; (D3) PDDM + TR-HG (material control); (D4) PDDM + TR-HG + bNPCs; (D5) PDDM + TR-HG + hMSCs. Magnetic resonance imaging performed before and after loading, on days 9 and 16, allowed imaging of the hydrogel-filled PDDM and assessment of disc height and volume changes. In gel-injected discs the NP region showed a major drop in volume and disc height during culture under static load. The RT-PCR results of injected hMSCs showed significant upregulation of ACAN, COL2A1, VCAN and SOX9 during culture in the disc cavity, whereas the gene expression profile of NP cells remained unchanged. The cell viability of injected cells (NPCs or hMSCs) was maintained at over 86% in 3D culture and dropped to ~72% after organ culture. Our results underline the need for load-bearing hydrogels that are also cyto-compatible. PMID:23303720

  9. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue.

    PubMed

    Schwartz, Joseph; Winters, Jeffrey L; Padmanabhan, Anand; Balogun, Rasheed A; Delaney, Meghan; Linenberger, Michael L; Szczepiorkowski, Zbigniew M; Williams, Mark E; Wu, Yanyun; Shaz, Beth H

    2013-07-01

    The American Society for Apheresis (ASFA) JCA Special Issue Writing Committee is charged with reviewing, updating and categorizating indications for therapeutic apheresis. Beginning with the 2007 ASFA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approach in the grading and categorization of indications. This Sixth Edition of the ASFA Special Issue has further improved the process of using evidence-based medicine in the recommendations by consistently applying the category and GRADE system definitions, but eliminating the "level of evidence" criteria (from the University HealthCare Consortium) utilized in prior editions given redundancy between GRADE and University HealthCare Consortium systems. The general layout and concept of a fact sheet that was utilized in the Fourth and Fifth Editions, has been largely maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. This article consists of 78 fact sheets (increased from 2010) for therapeutic indications in ASFA categories I through IV, with many diseases categorized having multiple clinical presentations/situations which are individually graded and categorized. PMID:23868759

  10. Advances and challenges in analytical characterization of biotechnology products: mass spectrometry-based approaches to study properties and behavior of protein therapeutics

    PubMed Central

    Kaltashov, Igor A.; Bobst, Cedric E.; Abzalimov, Rinat R.; Wang, Guanbo; Baykal, Burcu; Wang, Shunhai

    2011-01-01

    Biopharmaceuticals are a unique class of medicines due to their extreme structural complexity. The structure of these therapeutic proteins is critically important for their efficacy and safety, and the ability to characterize it at various levels (from sequence to conformation) is critical not only at the quality control stage, but also throughout the discovery and design stages. Biological mass spectrometry (MS) offers a variety of approaches to study structure and behavior of complex protein drugs and has already become a default tool for characterizing the covalent structure of protein therapeutics, including sequence and post-translational modifications. Recently, MS-based methods have also begun enjoying a dramatic growth in popularity as a means to provide information on higher order structure and dynamics of biotechnology products. In particular, hydrogen/deuterium exchange MS and charge state distribution analysis of protein ions in electrospray ionization (ESI)MS offer a convenient way to assess the integrity of protein conformation. Native ESI MS also allows the interactions of protein drugs with their therapeutic targets and other physiological partners to be monitored using simple model systems. MS-based methods are also applied to study pharmacokinetics of biopharmaceutical products, where they begin to rival traditional immunoassays. MS already provides valuable support to all stages of development of biopharmaceuticals, from discovery to post-approval monitoring, and its impact on the field of biopharmaceutical analysis will undoubtedly continue to grow. PMID:21619926

  11. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue.

    PubMed

    Schwartz, Joseph; Padmanabhan, Anand; Aqui, Nicole; Balogun, Rasheed A; Connelly-Smith, Laura; Delaney, Meghan; Dunbar, Nancy M; Witt, Volker; Wu, Yanyun; Shaz, Beth H

    2016-06-01

    The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc. PMID:27322218

  12. A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy

    PubMed Central

    Maruani, Antoine; Smith, Mark E.B.; Miranda, Enrique; Chester, Kerry A.; Chudasama, Vijay; Caddick, Stephen

    2015-01-01

    Although recent methods for the engineering of antibody–drug conjugates (ADCs) have gone some way to addressing the challenging issues of ADC construction, significant hurdles still remain. There is clear demand for the construction of novel ADC platforms that offer greater stability, homogeneity and flexibility. Here we describe a significant step towards a platform for next-generation antibody-based therapeutics by providing constructs that combine site-specific modification, exceptional versatility and high stability, with retention of antibody binding and structure post-modification. The relevance of the work in a biological context is also demonstrated in a cytotoxicity assay and a cell internalization study with HER2-positive and -negative breast cancer cell lines. PMID:25824906

  13. Gut Microbiota as a Target in the Pathogenesis of Metabolic Disorders: A New Approach to Novel Therapeutic Agents.

    PubMed

    Ejtahed, H-S; Soroush, A-R; Angoorani, P; Larijani, B; Hasani-Ranjbar, S

    2016-06-01

    As the prevalence of metabolic disorders increases dramatically, the importance of identifying environmental factors affecting metabolism control becomes greater accordingly. Gut microbiota, a complex ecosystem inhabiting the human gastrointestinal tract, is one of these potential factors. Recently, the evidence has shown the associations between alteration in gut microbiota composition and obesity, diabetes, and osteoporosis. However, the causality of gut microbiota on metabolic health has yet to be explored in intervention studies and the underlying mechanisms need to be investigated more in depth. Gut microbiota plays critical roles in the control of immunity, food intake, lipid accumulation, production of short chain fatty acids, insulin signaling, and regulation of bone mass. The gut microbiota represents a novel potential therapeutic strategy for the treatment of metabolic disorders. In this review, we provide insights into the role of the gut microbiota in metabolic disorders and its modulating interventions such as prebiotics, probiotics, and fecal microbiota transplantation. PMID:27203411

  14. Novel diagnostic and therapeutic approaches for autoimmune diabetes – a prime time to treat insulitis as a disease

    PubMed Central

    Grönholm, Juha; Lenardo, Michael J

    2015-01-01

    Type 1 diabetes is a progressive autoimmune disease with no curative treatment, making prevention critical. At the time of diagnosis, a majority of the insulin secreting β-cells has already been destroyed. Insulitis, lymphocytic infiltration to the pancreatic islets, is believed to begin months to years before the clinical symptoms of insulin deficiency appear. Insulitis should be treated as its own disease, for it is a known precursor to autoimmune diabetes. Because it is difficult to detect insulitic cellular infiltrates noninvasively, considerable interest has been focused on the levels of islet autoantibodies in blood as measurable diagnostic markers for islet autoimmunity. The traditional islet autoantibody detection assays have many limitations. New electrochemiluminescence-based autoantibody detection assays have the potential to overcome these challenges and they offer promising, cost-effective screening tools in identifying high-risk individuals for trials of preventive interventions. Here, we outline diagnostic and therapeutic strategies to overcome pancreatic β-cell destroying insulitis. PMID:25486604

  15. Cystic Fibrosis Therapeutics

    PubMed Central

    Ramsey, Bonnie W.

    2013-01-01

    A great deal of excitement and hope has followed the successful trials and US Food and Drug Administration approval of the drug ivacaftor (Kalydeco), the first therapy available that targets the underlying defect that causes cystic fibrosis (CF). Although this drug has currently demonstrated a clinical benefit for a small minority of the CF population, the developmental pathway established by ivacaftor paves the way for other CF transmembrane conductance regulator (CFTR) modulators that may benefit many more patients. In addition to investigating CFTR modulators, researchers are actively developing numerous other innovative CF therapies. In this review, we use the catalog of treatments currently under evaluation with the support of the Cystic Fibrosis Foundation, known as the Cystic Fibrosis Foundation Therapeutics Pipeline, as a platform to discuss the variety of candidate treatments for CF lung disease that promise to improve CF care. Many of these approaches target the individual components of the relentless cycle of airway obstruction, inflammation, and infection characteristic of lung disease in CF, whereas others are aimed directly at the gene defect, or the resulting dysfunctional protein, that instigates this cycle. We discuss how new findings from the laboratory have informed not only the development of novel therapeutics, but also the rationales for their use and the outcomes used to measure their effects. By reviewing the breadth of candidate treatments currently in development, as well as the recent progress in CF therapies reflected by the evolution of the therapeutics pipeline over the past few years, we hope to build upon the optimism and anticipation generated by the recent success of Kalydeco. PMID:23276843

  16. A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation

    PubMed Central

    Kleikers, Pamela WM.; Hooijmans, Carlijn; Göb, Eva; Langhauser, Friederike; Rewell, Sarah SJ.; Radermacher, Kim; Ritskes-Hoitinga, Merel; Howells, David W.; Kleinschnitz, Christoph; HHW Schmidt, Harald

    2015-01-01

    Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2-/y studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias. PMID:26310318

  17. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question

    PubMed Central

    Alfarouk, Khalid O.; Verduzco, Daniel; Rauch, Cyril; Muddathir, Abdel Khalig; Adil, H. H Bashir; Elhassan, Gamal O.; Ibrahim, Muntaser E.; David Polo Orozco, Julian; Cardone, Rosa Angela; Reshkin, Stephan J.; Harguindey, Salvador

    2014-01-01

    Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intracellular alkaline pH (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then proposea new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced. PMID:25621294

  18. VEGF-releasing biodegradable nanospheres administered by craniotomy: a novel therapeutic approach in the APP/Ps1 mouse model of Alzheimer's disease.

    PubMed

    Herrán, Enara; Pérez-González, Rocio; Igartua, Manoli; Pedraz, José Luis; Carro, Eva; Hernández, Rosa María

    2013-08-28

    This study attempts to develop a novel nanotechnology-based strategy to deliver vascular endothelial growth factor (VEGF) to the brain, as a possible therapeutic approach for AD. For this purpose, VEGF was encapsulated in biodegradable poly(lactic-co-glycolic acid) (PLGA) nanospheres (VEGF-NS). The nanosphere particle size was about 200 nm, with a narrow size distribution, and the zeta potential around -30 mV. The encapsulation efficiency of VEGF was 44.06±5.61%, showing a biphasic release profile in vitro. The biological activity and neuroprotective effect of encapsulated VEGF were investigated in neuronal cell cultures, confirming the neuronal proliferative effect and the protection against Aβ₄₂ induced neurotoxicity. In vivo studies were carried out in amyloid precursor protein/presenilin-1 (APP/Ps1) mice administering VEGF-NS through minimally invasive craniotomy. The results obtained showed that VEGF-NS were able to improve behavioral deficits, decrease Aβ deposits and promote angiogenesis, as well as reduce neuronal loss and cerebrovascular abnormalities. Furthermore, their ability to protect neuronal cultures against neuroinflammation induced by LPS provides new insight for future therapeutic approaches in other neurodegenerative disorders. PMID:23684689

  19. The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches.

    PubMed

    Grivas, Petros D; Melas, Marilena; Papavassiliou, Athanasios G

    2015-12-01

    Bladder cancer is a major cause of morbidity, mortality and health-related costs. Urothelial carcinoma is by far the most common histologic type of bladder cancer and may also arise from the upper urinary tract, e.g. renal pelvis and ureter, as well as from the proximal urethra. There have been no major advances in the development of new systemic therapies for urothelial carcinoma for over two decades, which may be related to prior lack of profound comprehension of biological pathogenetic mechanisms. However, in the last few years there has been a major shift in the development of new promising therapies that stem from improved molecular profiling of this malignancy. Developments in molecular biology, genomics, bioinformatics and immunology provide a solid foundation for therapeutic advances. A plethora of novel treatment targets and biomarkers are being evaluated, but there has been no molecular biomarker with established clinical utility so far. Genomic characterization of each patient's tumor has not been implemented due to the high cost, lack of validated standardized techniques that could be available in different laboratories, as well as absence of validated biomarkers and available therapeutic agents with clinically proven benefit. However, genomic characterization before treatment has now started to be implemented in novel clinical trial designs in order to contribute to proper patient selection based on biomarker-based enrichment strategies. Several "umbrella" or "basket" type, molecular biomarkers-based trials, in which patient eligibility and/or stratification is based on the presence of specific genetic alterations regardless of tissue of origin and/or histology, are being launched. Mathematical models and bioinformatics platforms that perform high level computational integrated pathway analysis may reveal clinical relevant signaling pathways amenable for targeting in individual patient tumors. Moreover, the high mutational burden of urothelial

  20. Microbial synthetic biology for human therapeutics.

    PubMed

    Jain, Aastha; Bhatia, Pooja; Chugh, Archana

    2012-06-01

    The emerging field of synthetic biology holds tremendous potential for developing novel drugs to treat various human conditions. The current study discusses the scope of synthetic biology for human therapeutics via microbial approach. In this context, synthetic biology aims at designing, engineering and building new microbial synthetic cells that do not pre-exist in nature as well as re-engineer existing microbes for synthesis of therapeutic products. It is expected that the construction of novel microbial genetic circuitry for human therapeutics will greatly benefit from the data generated by 'omics' approaches and multidisciplinary nature of synthetic biology. Development of novel antimicrobial drugs and vaccines by engineering microbial systems are a promising area of research in the field of synthetic biology for human theragnostics. Expression of plant based medicinal compounds in the microbial system using synthetic biology tools is another avenue dealt in the present study. Additionally, the study suggest that the traditional medicinal knowledge can do value addition for developing novel drugs in the microbial systems using synthetic biology tools. The presented work envisions the success of synthetic biology for human therapeutics via microbial approach in a holistic manner. Keeping this in view, various legal and socio-ethical concerns emerging from the use of synthetic biology via microbial approach such as patenting, biosafety and biosecurity issues have been touched upon in the later sections. PMID:23730360

  1. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches

    PubMed Central

    Morales, Inelia; Guzmán-Martínez, Leonardo; Cerda-Troncoso, Cristóbal; Farías, Gonzalo A.; Maccioni, Ricardo B.

    2014-01-01

    Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this disease are still diffuse, one of the reasons for the delay in finding an effective treatment. In the search for new targets to search for novel therapeutic avenues, clinical studies in patients who used anti-inflammatory drugs indicating a lower incidence of AD have been of value to support the neuroinflammatory hypothesis of the neurodegenerative processes and the role of innate immunity in this disease. Neuroinflammation appears to occur as a consequence of a series of damage signals, including trauma, infection, oxidative agents, redox iron, oligomers of τ and β-amyloid, etc. In this context, our theory of Neuroimmunomodulation focus on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents. Here, we discuss about the role of microglial and astrocytic cells, the principal agents in neuroinflammation process, in the development of neurodegenerative diseases such as AD. In this context, we also evaluated the potential relevance of natural anti-inflammatory components, which include curcumin and the novel Andean Compound, as agents for AD prevention and as a coadjuvant for AD treatments. PMID:24795567

  2. Lessons from genetics: is it time to revise the therapeutic approach to children with steroid-resistant nephrotic syndrome?

    PubMed

    Becherucci, Francesca; Mazzinghi, Benedetta; Provenzano, Aldesia; Murer, Luisa; Giglio, Sabrina; Romagnani, Paola

    2016-08-01

    Primitive nephrotic syndrome is one of the most common glomerular diseases in childhood and represents the clinical manifestation of various pathologic changes in the kidney. In children, nephrotic syndrome is classified based on the initial response to empiric corticosteroid treatment, which is considered as the best predictor of patients' final outcome. The advent of next-generation sequencing technology showed that genetic alterations in structural genes of the podocyte can be recognized in a significant proportion of not only familial or syndromic patients with steroid-resistant nephrotic syndrome (SRNS), but also of sporadic cases, raising the question of whether it is time to update current protocols of patient care. In this review, we discuss the implications derived from several studies describing a high prevalence in children with SRNS of pathogenic mutations in a group of genes and their unresponsiveness to immunosuppressive therapy. We propose a diagnostic and therapeutic algorithm to reduce the exposure to immunosuppressants in individuals with unresponsive forms of the disease, sparing patients the untoward side effects of prolonged ineffective treatments, and at the same time guaranteeing the optimal immunosuppressive or other new therapy in potentially responsive patients. PMID:27209298

  3. Endogenous anti-inflammatory neuropeptides and pro-resolving lipid mediators: a new therapeutic approach for immune disorders

    PubMed Central

    Anderson, Per; Delgado, Mario

    2008-01-01

    Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of inflammatory and autoimmune diseases. Although much is known about the molecular basis of initiating signals and pro-inflammatory chemical mediators in inflammation, it has only recently become apparent that endogenous stop signals are critical at early checkpoints within the temporal events of inflammation. Some neuropeptides and lipid mediators that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance and/or inflammation resolution. Here we examine the latest research findings, which indicate that neuropeptides participate in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. On the other hand, we also focus on lipid mediators biosynthesized from ω-3 and ω-6 polyunsaturated fatty-acids in inflammatory exudates that promote the resolution phase of acute inflammation by regulating leucocyte influx to and efflux from local inflamed sites. Both anti-inflammatory neuropeptides and pro-resolving lipid mediators have shown therapeutic potential for a variety of inflammatory and autoimmune disorders and could be used as biotemplates for the development of novel pharmacologic agents. PMID:18554314

  4. Analytical approaches for the detection of emerging therapeutics and non-approved drugs in human doping controls.

    PubMed

    Thevis, Mario; Schänzer, Wilhelm

    2014-12-01

    The number and diversity of potentially performance-enhancing substances is continuously growing, fueled by new pharmaceutical developments but also by the inventiveness and, at the same time, unscrupulousness of black-market (designer) drug producers and providers. In terms of sports drug testing, this situation necessitates reactive as well as proactive research and expansion of the analytical armamentarium to ensure timely, adequate, and comprehensive doping controls. This review summarizes literature published over the past 5 years on new drug entities, discontinued therapeutics, and 'tailored' compounds classified as doping agents according to the regulations of the World Anti-Doping Agency, with particular attention to analytical strategies enabling their detection in human blood or urine. Among these compounds, low- and high-molecular mass substances of peptidic (e.g. modified insulin-like growth factor-1, TB-500, hematide/peginesatide, growth hormone releasing peptides, AOD-9604, etc.) and non-peptidic (selective androgen receptor modulators, hypoxia-inducible factor stabilizers, siRNA, S-107 and ARM036/aladorian, etc.) as well as inorganic (cobalt) nature are considered and discussed in terms of specific requirements originating from physicochemical properties, concentration levels, metabolism, and their amenability for chromatographic-mass spectrometric or alternative detection methods. PMID:24906629

  5. Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications.

    PubMed

    Wang, Jun; Bi, Weina; Cheng, Alice; Freire, Daniel; Vempati, Prashant; Zhao, Wei; Gong, Bing; Janle, Elsa M; Chen, Tzu-Ying; Ferruzzi, Mario G; Schmeidler, James; Ho, Lap; Pasinetti, Giulio M

    2014-01-01

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and currently has no cure. Its onset and progression are influenced by multiple factors. There is growing consensus that successful treatment will rely on simultaneously targeting multiple pathological features of AD. Polyphenol compounds have many proven health benefits. In this study, we tested the hypothesis that combining three polyphenolic preparations (grape seed extract, resveratrol, and Concord grape juice extract), with different polyphenolic compositions and partially redundant bioactivities, may simultaneously and synergistically mitigate amyloid-β (Aβ) mediated neuropathology and cognitive impairments in a mouse model of AD. We found that administration of the polyphenols in combination did not alter the profile of bioactive polyphenol metabolites in the brain. We also found that combination treatment resulted in better protection against cognitive impairments compared to individual treatments, in J20 AD mice. Electrophysiological examination showed that acute treatment with select brain penetrating polyphenol metabolites, derived from these polyphenols, improved oligomeric Aβ (oAβ)-induced long term potentiation (LTP) deficits in hippocampal slices. Moreover, we found greatly reduced total amyloid content in the brain following combination treatment. Our studies provided experimental evidence that application of polyphenols targeting multiple disease-mechanisms may yield a greater likelihood of therapeutic efficacy. PMID:24672477

  6. "Bunched Black Swans" in Complex Geosystems: Cross-Disciplinary Approaches to the Additive and Multiplicative Modelling of Correlated Extreme Bursts

    NASA Astrophysics Data System (ADS)

    Watkins, N. W.; Rypdal, M.; Lovsletten, O.

    2012-12-01

    -stationarity explicitly built in. In record breaking statistics, a record is defined in the sense used in everyday language, to be the largest value yet recorded in a time series, for example, the 2004 Sumatran Boxing Day earthquake was at the time the largest to be digitally recorded. The third group of approaches (e.g. avalanches) are explicitly spatiotemporal and so also include spatial structure. This presentation will discuss two examples of our recent work on the burst problem. We will show numerical results extending the preliminary results presented in [Watkins et al, PRE, 2009] using a standard additive model, linear fractional stable motion (LFSM). LFSM explicitly includes both heavy tails and long range dependence, allowing us to study how these 2 effects compete in determining the burst duration and size exponent probability distributions. We will contrast these simulations with new analytical studies of bursts in a multiplicative process, the multifractal random walk (MRW). We will present an analytical derivation for the scaling of the burst durations and make a preliminary comparison with data from the AE index from solar-terrestrial physics. We believe our result is more generally applicable than the MRW model, and that it applies to a broad class of multifractal processes.

  7. Characterization of a Saccharomyces cerevisiae fermentation process for production of a therapeutic recombinant protein using a multivariate Bayesian approach.

    PubMed

    Fu, Zhibiao; Baker, Daniel; Cheng, Aili; Leighton, Julie; Appelbaum, Edward; Aon, Juan

    2016-05-01

    The principle of quality by design (QbD) has been widely applied to biopharmaceutical manufacturing processes. Process characterization is an essential step to implement the QbD concept to establish the design space and to define the proven acceptable ranges (PAR) for critical process parameters (CPPs). In this study, we present characterization of a Saccharomyces cerevisiae fermentation process using risk assessment analysis, statistical design of experiments (DoE), and the multivariate Bayesian predictive approach. The critical quality attributes (CQAs) and CPPs were identified with a risk assessment. The statistical model for each attribute was established using the results from the DoE study with consideration given to interactions between CPPs. Both the conventional overlapping contour plot and the multivariate Bayesian predictive approaches were used to establish the region of process operating conditions where all attributes met their specifications simultaneously. The quantitative Bayesian predictive approach was chosen to define the PARs for the CPPs, which apply to the manufacturing control strategy. Experience from the 10,000 L manufacturing scale process validation, including 64 continued process verification batches, indicates that the CPPs remain under a state of control and within the established PARs. The end product quality attributes were within their drug substance specifications. The probability generated with the Bayesian approach was also used as a tool to assess CPP deviations. This approach can be extended to develop other production process characterization and quantify a reliable operating region. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:799-812, 2016. PMID:27095416

  8. Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring.

    PubMed

    Grandjean, Etienne Marc; Aubry, Jean-Michel

    2009-01-01

    After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn

  9. Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer.

    PubMed

    Fan, Li-Ching; Teng, Hao-Wei; Shiau, Chung-Wai; Tai, Wei-Tien; Hung, Man-Hsin; Yang, Shung-Haur; Jiang, Jeng-Kai; Chen, Kuen-Feng

    2015-09-01

    STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3(Tyr705) level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43-induced apoptosis and decreased p-STAT3(Tyr705) level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3(Tyr705) level. These data suggest that SC-43-induced apoptosis mediated through the loss of p-STAT3(Tyr705) was dependent on SHP-1 function. Importantly, SC-43-enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3(Tyr705) signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3(Tyr705)expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3(Tyr705) expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3(Tyr705) expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC. PMID:26476076

  10. Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer12

    PubMed Central

    Fan, Li-Ching; Teng, Hao-Wei; Shiau, Chung-Wai; Tai, Wei-Tien; Hung, Man-Hsin; Yang, Shung-Haur; Jiang, Jeng-Kai; Chen, Kuen-Feng

    2015-01-01

    STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3Tyr705 level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43–induced apoptosis and decreased p-STAT3Tyr705 level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3Tyr705 level. These data suggest that SC-43–induced apoptosis mediated through the loss of p-STAT3Tyr705 was dependent on SHP-1 function. Importantly, SC-43–enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3Tyr705 signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3Tyr705expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3Tyr705 expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3Tyr705 expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC. PMID:26476076

  11. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders.

    PubMed

    Viollet, B; Mounier, R; Leclerc, J; Yazigi, A; Foretz, M; Andreelli, F

    2007-12-01

    effects provide the rationale for the development of new therapeutic strategies in metabolic disorders. PMID:17997341

  12. Regulation of protein conformation by Pin1 offers novel disease mechanisms and therapeutic approaches in Alzheimer's disease.

    PubMed

    Driver, Jane A; Zhou, Xiao Zhen; Lu, Kun Ping

    2014-02-01

    Pin1 is a unique enzyme that changes the shape of target proteins by acting on specific amino acids that have been phosphorylated: serine or threonine residues that precede proline. Pin1 catalyzes the flip between two distinct orientations, called cis and trans, around the proline bond. This change in shape has profound effects on protein function and is a major signaling mechanism in the cell. Abnormal regulation of Pin1 has been associated with premature aging and multiple pathological processes, notably cancer and Alzheimer's disease (AD), two major age-related diseases. In AD, Pin1 affects two proteins thought to be key to disease pathology: the amyloid precursor protein (APP) and the microtubule-binding protein tau, by switching them from a dysfunctional shape (cis) back to a functional one (trans), which can be distinguished by cis and trans-specific antibodies. In the brains of people with AD, Pin1 is absent or inactivated and cis tau is accumulated at early stages of AD. In the absence of Pin1, APP is processed into toxic beta-amyloid and tau becomes misshapen to form tangles. As a result, Pin1-deficient mice develop age-dependent tau and Aβ pathologies and neuronal degeneration and loss. Thus, regulation of protein conformation by Pin1 has a critical neuroprotective role and offers a novel diagnostic and therapeutic target for AD. Notably, antibodies or vaccines specifically against the dysfunctional misshapen tau (while leaving the functional one untouched) may offer early diagnosis and treatment of AD and related disorders. PMID:24534472

  13. Surgical mistake causing an high recto-vaginal fistula. A case report with combined surgical and endoscopic approach: therapeutic considerations

    PubMed Central

    2013-01-01

    Background Rectovaginal fistulas (RVFs) have multiple causes, size and location on which the surgical treatment depends. Description The Authors consider different approaches to RVFs and describe a clinical case of recurrent high RVF. Conclusions Most RVFs can be successfully repaired, although many interventions may be necessary. A colostomy with delayed repair may improve RVFs outcome. Moreover, several authors indicate Mucosal Advancement Flap and Babcock-Bacon technique as the treatments of choice respectively for low and high RVFs (complex and recurrent) and emphasize the placement of endoscopic prothesis in cases of difficult healing of the anastomosis. PMID:24266908

  14. Biomimetic Particles as Therapeutics

    PubMed Central

    Green, Jordan J.

    2015-01-01

    In recent years, there have been major advances in the development of novel nanoparticle and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health. PMID:26277289

  15. The Role of Plasma Kallikrein-Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches.

    PubMed

    Abdulaal, Marwan; Haddad, Nour Maya N; Sun, Jennifer K; Silva, Paolo S

    2016-01-01

    Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is cu