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overcoming adversity

Shringika Soni, Rakesh Kumar Ruhela, Bikash Medhi
Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder...
September 2016: Advanced Pharmaceutical Bulletin
Chu-Shiu Li, June Han Lee, Chwen-Chi Liu, Yan-Lan Chan, Christopher Wen, Mu-Lin Chiu, Min Kuang Tsai, Shan Pou Tsai, Jackson Pui Man Wai, Chwen Keng Tsao, Xifeng Wu, Chi Pang Wen
Widowhood has been increasingly encountered because of increasing longevity of women, often characterized by social stigmatization and poor physical and mental health. However, applied research to overcome its adversity has been quite limited. The goal of this study is to explore the role of physical activity in improving the health of widows.A cohort of 446,582 adults in Taiwan who successively participated in a comprehensive medical screening program starting in 1994, including 232,788 women, was followed up for mortality until 2008...
August 2016: Medicine (Baltimore)
Dorairaj Prabhakaran
Among individuals with established CVD, multiple medications (aspirin, blood pressure lowering drugs and statins) are required to manage CVD and it is well established that non adherence to prescribed treatments is substantial in the long term. Such discontinuation of CV-preventive medications and low adherence rates has been shown to affect the success of CVD prevention efforts. In low- and middle income countries only less than 20% patients receive recommended therapy for CVD prevention, but even in high-income countries treatment coverage in the community is only about 50% in those with heart disease and 35% in those with stroke...
September 2016: Journal of Hypertension
Hiroshi Yamazaki
Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species-differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used...
October 17, 2016: Chemical Research in Toxicology
Jaymit Patel, Clare Granger, Sandra Parker, Mangala Patel
OBJECTIVES: This in-vitro study investigated the effect of 'instrument lubricants' used during placement of composite restorative material, on the diametral tensile strength (DTS) and water uptake of composite specimens. METHODS: 300 posterior composite cylindrical specimens were manufactured: 60 with each instrument lubricant (ethanol, 3-step, 2-step and 1-step 'bonding agent') and 60 with no lubricant (controls). Each set of 60 specimens was evenly allocated to one of the following test groups (n=100/group): Group 1 - tested for DTS immediately after manufacture; Groups 2 and 3 - tested for DTS after immersion in phosphate-buffered saline (PBS) for 1 and 12-weeks respectively, using a Universal Instron machine...
October 13, 2016: Journal of Dentistry
Stefano Perni, Polina Prokopovich
The efficient delivery of therapeutic molecules to the cartilage of joints is major obstacle in developing useful therapeutic interventions; hence, a targeted drug delivery system for this tissue is critical. We have overcome the challenge by developing a system that employs electrostatic attraction between the negatively charged constituents of cartilage and a positively charged polymer, Poly-beta amino esters (PBAEs). We have demonstrated cartilage uptake of Dexamethasone (DEX) covalently bound to the PBAE was doubled and retention in tissues prolonged compared to the equivalent dose of the commercial drug formulation...
October 13, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Juan Francisco Morales, Sebastián Scioli Montoto, Pietro Fagilino, María Esperanza Ruiz
The blood brain barrier (BBB) is a physical and biochemical barrier that restricts the entry of certain drugs to the Central Nervous System (CNS), while allowing the passage of others. The ability to predict the permeability of a given molecule through the BBB is a key aspect in CNS drug discovery and development, since neurotherapeutic agents with molecular targets in the CNS should be able to cross the BBB, whereas peripherally acting agents should not, to minimize the risk of CNS adverse effects. In this review we examine and discuss QSAR approaches and current availability of experimental data for the construction of BBB permeability predictive models, focusing on the modeling of the biorelevant parameter unbound partitioning coefficient (Kp,uu) ...
October 13, 2016: Mini Reviews in Medicinal Chemistry
Oh Young Bang, Eun Hee Kim, Jae Min Cha, Gyeong Joon Moon
Stroke is one of the leading causes of death and physical disability among adults. It has been 15 years since clinical trials of stem cell therapy in patients with stroke have been conducted using adult stem cells like mesenchymal stem cells and bone marrow mononuclear cells. Results of randomized controlled trials showed that adult stem cell therapy was safe but its efficacy was modest, underscoring the need for new stem cell therapy strategies. The primary limitations of current stem cell therapies include (a) the limited source of engraftable stem cells, (b) the presence of optimal time window for stem cell therapies, (c) inherited limitation of stem cells in terms of growth, trophic support, and differentiation potential, and (d) possible transplanted cell-mediated adverse effects, such as tumor formation...
September 2016: Journal of Stroke
Sumanta K Pal, Harry A Drabkin, James A Reeves, John D Hainsworth, Susan E Hazel, Dario A Paggiarino, Jon Wojciak, Gary Woodnutt, Rupal S Bhatt
BACKGROUND: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent...
October 11, 2016: Cancer
Fabio Martinelli, Antonino Ditto, Giorgio Bogani, Mauro Signorelli, Valentina Chiappa, Domenica Lorusso, Edward Haeusler, Francesco Raspagliesi
STUDY OBJECTIVE: To report on detection-rate (DR) of sentinel-nodes (SLNs) in endometrial-cancer (EC) patients after hysteroscopic injection of indocyanine-green (ICG) and Laparoscopic near-infrared (L-NIR) fluorescence mapping. DESIGN: Prospectively collected data. DESIGN: classification: Canadian Task Force II-2 SETTING: Gynecologic oncology referral center. PATIENTS: Consecutive patients with apparent early-stage endometrioid EC scheduled for surgical treatment: total-laparoscopic-hysterectomy, bilateral salpingo-oophorectomy, SLNs mapping...
October 7, 2016: Journal of Minimally Invasive Gynecology
Nadya Velikova, Nuria Mas, Laura Miguel-Romero, Lorena Polo Aguado, Ellen Stolte, Edoardo Zaccaria, Rui Cao, Nico Taverne, José Ramón Murguía, Ramon Martinez-Manez, Alberto Marina, Jerry Wells
Two-component systems (TCS) regulate diverse processes such as virulence, stress responses, metabolism and antibiotic resistance in bacteria but are absent in humans, making them promising targets for novel antibacterials. By incorporating recently described TCS histidine kinase autophosphorylation inhibitors (HKAIs) into ε-poly-L-lysine capped nanoparticles (NPs) we could overcome the Gram negative (Gr-) permeability barrier for the HKAIs. The observed bactericidal activity against Gr- bacteria was shown to be due to the enhanced delivery and internalization of the HKAIs and not an inhibitory or synergistic effect of the NPs...
October 5, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Gabriel N Hortobagyi, Salomon M Stemmer, Howard A Burris, Yoon-Sim Yap, Gabe S Sonke, Shani Paluch-Shimon, Mario Campone, Kimberly L Blackwell, Fabrice André, Eric P Winer, Wolfgang Janni, Sunil Verma, Pierfranco Conte, Carlos L Arteaga, David A Cameron, Katarina Petrakova, Lowell L Hart, Cristian Villanueva, Arlene Chan, Erik Jakobsen, Arnd Nusch, Olga Burdaeva, Eva-Maria Grischke, Emilio Alba, Erik Wist, Norbert Marschner, Anne M Favret, Denise Yardley, Thomas Bachelot, Ling-Ming Tseng, Sibel Blau, Fengjuan Xuan, Farida Souami, Michelle Miller, Caroline Germa, Samit Hirawat, Joyce O'Shaughnessy
Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease...
October 7, 2016: New England Journal of Medicine
Carina Muoth, Adrian Wichser, Marco Monopoli, Manuel Correia, Nicky Ehrlich, Katrin Loeschner, Audrey Gallud, Melanie Kucki, Liliane Diener, Pius Manser, Wolfram Jochum, Peter Wick, Tina Buerki-Thurnherr
There is increasing evidence that certain nanoparticles (NPs) can overcome the placental barrier, raising concerns on potential adverse effects on the growing fetus. But even in the absence of placental transfer, NPs may pose a risk to proper fetal development if they interfere with the viability and functionality of the placental tissue. The effects of NPs on the human placenta are not well studied or understood, and predictive in vitro placenta models to achieve mechanistic insights on NP-placenta interactions are essentially lacking...
October 6, 2016: Nanoscale
Marcella Brescia, Manuela Zaccolo
Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling are known to be involved in several pathologies. As a consequence, PDEs have long been recognized as potential drug targets, and they have been the focus of intense research for the development of therapeutic agents. A number of PDE inhibitors are currently available for the treatment of disease, including obstructive pulmonary disease, erectile dysfunction, and heart failure...
October 2, 2016: International Journal of Molecular Sciences
Elisa Garbayo, Eduardo Ansorena, Hugo Lana, María Del Mar Carmona-Abellan, Irene Marcilla, José Luis Lanciego, María Rosario Luquin, María José Blanco-Prieto
Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time...
December 2016: Biomaterials
Ana Vanessa Nascimento, Amit Singh, Hassan Bousbaa, Domingos Ferreira, Bruno Sarmento, Mansoor M Amiji
: Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs...
September 30, 2016: Acta Biomaterialia
Torsten Zuberbier, Mark B Abelson, Cezmi A Akdis, Claus Bachert, Uwe Berger, Carsten Bindslev-Jensen, Georg Boelke, Jean Bousquet, Giorgio Walter Canonica, Thomas B Casale, Marek Jutel, Marek L Kowalski, Enzo Madonini, Nikolaos G Papadopoulos, Oliver Pfaar, Torsten Sehlinger, Karl-Christian Bergmann
BACKGROUND: Field clinical trials of pollen allergy are impacted by the impossibility to predict and to determine individual allergen exposure, due to many factors (e.g., pollen season, atmospheric variations, pollutants, lifestyles). Environmental exposure chambers (EEC), delivering a fixed amount of allergens in a controlled environmental setting, can overcome these limitations. EECs are currently already used in phase 2, 3, and even 4 trials. Unfortunately, few chambers exist in the world, and this makes it difficult to perform large, multicenter clinical trials...
September 30, 2016: Journal of Allergy and Clinical Immunology
Ertan Kucuksayan, Tomris Ozben
Cancer is a multifactorial disease including interactions of complex genetic and environmental factors. Clinical efficacy of anticancer chemotherapies is hampered by various factors including multidrug resistance (MDR). There is a strong need to discover more potent novel cancer drugs to kill cancer cells selectively. The recent new strategy for cancer treatment involves the design and synthesis of hybrid compounds as multitargeted anticancer agents. In this review, we focus on studies using hybrid compounds which were designed and synthesized from two or more different bioactive moieties conjugating them into a single hybrid drug...
September 27, 2016: Current Topics in Medicinal Chemistry
Bart W Faber, Stephan Hellwig, Sophie Houard, Nicolas Havelange, Jürgen Drossard, Hubert Mertens, Alexander Croon, Robin Kastilan, Richard Byrne, Nicole van der Werff, Marjolein van der Eijk, Alan W Thomas, Clemens H M Kocken, Edmond J Remarque
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading asexual blood stage vaccine candidate for malaria. In preparation for clinical trials, three Diversity Covering (DiCo) PfAMA1 ectodomain proteins, designed to overcome the intrinsic polymorphism that is present in PfAMA1, were produced under Good Manufacturing Practice (GMP) in Pichia pastoris. Using identical methodology, the 3 strains were cultivated in 70-L scale fed-batch fermentations and PfAMA1-DiCos were purified by two chromatography steps, an ultrafiltration/diafiltration procedure and size exclusion chromatography, resulting in highly pure (>95%) PfAMA1-DiCo1, PfAMA1 DiCo2 and PfAMA1 DiCo3, with final yields of 1...
2016: PloS One
Karol Jaroch, Maciej Karolak, Przemysław Górski, Alina Jaroch, Adrian Krajewski, Aleksandra Ilnicka, Anna Sloderbach, Tomasz Stefański, Stanisław Sobiak
For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways...
August 24, 2016: Pharmacological Reports: PR
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