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https://www.readbyqxmd.com/read/29244501/origins-of-enzyme-catalysis-experimental-findings-for-c-h-activation-new-models-and-their-relevance-to-prevailing-theoretical-constructs
#1
Judith P Klinman, Adam R Offenbacher, Shenshen Hu
The physical basis for enzymatic rate accelerations is a subject of great fundamental interest and of direct relevance to areas that include the de novo design of green catalysts and the pursuit of new drug regimens. Extensive investigations of C-H activating systems have provided considerable insight into the relationship between an enzyme's overall structure and the catalytic chemistry at its active site. This Perspective highlights recent experimental data for two members of distinct, yet iconic C-H activation enzyme classes, lipoxygenases and prokaryotic alcohol dehydrogenases...
December 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29244483/biomembrane-permeabilization-statistics-of-individual-leakage-events-harmonize-the-interpretation-of-vesicle-leakage
#2
Stefan Braun, Šárka Pokorná, Radek Šachl, Martin Hof, Heiko Heerklotz, Maria Hoernke
The mode of action of membrane-active molecules such as antimicrobial, anticancer, cell penetrating, and fusion peptides and their synthetic mimics, transfection agents and drug permeation enhancers, biological signaling molecules (e.g., quorum sensing), involves either the general or local destabilization of the target membrane or the formation of defined, rather stable pores. Some effects aim at killing the cell, others need to be limited in space and time to avoid serious damage. Biological tests reveal translocation of compounds and cell death but do not provide a detailed, mechanistic, and quantitative understanding of the modes of action and their molecular basis...
December 15, 2017: ACS Nano
https://www.readbyqxmd.com/read/29244215/development-of-a-validated-liquid-chromatographic-method-for-quantification-of-sorafenib-tosylate-in-the-presence-of-stress-induced-degradation-products-and-in-biological-matrix-employing-analytical-quality-by-design-aqbd-approach
#3
Teenu Sharma, Rajneet Kaur Khurana, Atul Jain, O P Katare, Bhupinder Singh
The current research work envisages AQbD-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability indicating reversed phase high performance liquid chromatographic (RP-HPLC) method for determining stress-induced forced degradation products of sorafenib tosylate (SFN). An Ishikawa fish bone diagram was constructed to embark upon analytical target profile (ATP) and critical analytical attributes (CAAs) i.e., peak area, theoretical plates, retention time (Rt ) and peak tailing...
December 15, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29244152/regulation-of-t-cell-proliferation-with-drug-responsive-microrna-switches
#4
Remus S Wong, Yvonne Y Chen, Christina D Smolke
As molecular and cellular therapies advance in the clinic, the role of genetic regulation is becoming increasingly important for controlling therapeutic potency and safety. The emerging field of mammalian synthetic biology provides promising tools for the construction of regulatory platforms that can intervene with endogenous pathways and control cell behavior. Recent work has highlighted the development of synthetic biological systems that integrate sensing of molecular signals to regulated therapeutic function in various disease settings...
December 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29243903/update-on-current-care-guideline-psoriasis-skin-and-joints
#5
(no author information available yet)
Psoriasis is a chronic, immune-mediated, inflammatory disorder of the skin and joints. Moderate-to-server cases are associated with an independent risk of comorbidity (cardiovascular diseases and diabetes) even after adjusting for risk factors, known to be more prevalent in psoriatics compared to normal population. The systemic underlying inflammation, analogous to that observed in rheumatoid arthritis, calls for a long-term effective treatment. Screening and treatment of cardiovascular risk factors is highly recommended...
2017: Duodecim; Lääketieteellinen Aikakauskirja
https://www.readbyqxmd.com/read/29243892/new-study-designs-in-clinical-drug-development
#6
Olli Tenhunen, Miia Turpeinen, Pekka Kurki
Clinical development of a novel drug has traditionally been seen as a series of four phases, each having its own objectives in establishing the efficacy and safety of the drug. Increasingly individualized medicine and the changing mechanisms of drug action are also changing the designs of clinical drug testing. The borders of development phases become blurred and the traditional large, controlled multicenter studies may in part be replaced by individual and risk-based approaches. The indications for drugs are more precisely targeted from biological starting points, and a target-oriented development may guide the designs of clinical testing at all stages of development...
2017: Duodecim; Lääketieteellinen Aikakauskirja
https://www.readbyqxmd.com/read/29243869/biobanks-and-comprehensive-cancer-center-finland-fican-as-institutions-enabling-clinical-drug-testing
#7
Olli Carpén, Tuula Helander
Clinical trials aiming at developing targeted drug therapies require the identification of appropriate patient groups, utilizing both clinical information and the biological profile of the disease. The Finnish healthcare system provides exceptional possibilities for utilizing health data in identifying patient groups, planning of clinical sample studies and recruiting patients. Biobanks established at university hospitals together with the regional cancer centers play a central role in collecting biological specimens and attaching health data to the specimens...
2017: Duodecim; Lääketieteellinen Aikakauskirja
https://www.readbyqxmd.com/read/29243830/proceedings-of-the-food-and-drug-administration-s-public-workshop-on-new-red-blood-cell-product-regulatory-science-2016
#8
Jaroslav G Vostal, Paul W Buehler, Monique P Gelderman, Abdu I Alayash, Alan Doctor, James C Zimring, Simone A Glynn, John R Hess, Harvey Klein, Jason P Acker, Philip C Spinella, Angelo D'Alessandro, Bernhard Palsson, Thomas J Raife, Michael P Busch, Timothy J McMahon, Marcos Intaglietta, Harold M Swartz, Michael A Dubick, Sylvain Cardin, Rakesh P Patel, Charles Natanson, John W Weisel, Jennifer A Muszynski, Philip J Norris, Paul M Ness
The US Food and Drug Administration (FDA) held a workshop on red blood cell (RBC) product regulatory science on October 6 and 7, 2016, at the Natcher Conference Center on the National Institutes of Health (NIH) Campus in Bethesda, Maryland. The workshop was supported by the National Heart, Lung, and Blood Institute, NIH; the Department of Defense; the Office of the Assistant Secretary for Health, Department of Health and Human Services; and the Center for Biologics Evaluation and Research, FDA. The workshop reviewed the status and scientific basis of the current regulatory framework and the available scientific tools to expand it to evaluate innovative and future RBC transfusion products...
December 15, 2017: Transfusion
https://www.readbyqxmd.com/read/29243579/recent-development-of-coumarin-derivatives-as-potential-antiplasmodial-and-antimalarial-agents
#9
Xin-Liang Hu, Chuan Gao, Zhi Xu, Ming-Liang Liu, Lian-Shun Feng, Guang-De Zhang
Malaria still remains one of the leading deadliest diseases throughout the world, leading to around 1 million deaths annually. The emergence and spread of growing resistance to the first-line antimalarials, alarming the serious problem in malaria control and demanding the need for new drugs more potent than earlier with improved absorption, distribution, metabolism, and excretion (ADME) profiles. Coumarins, which exhibited various biological properties, also displayed potential in vitro antiplasmodial and in vivo antimalarial activities...
December 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29243577/recent-developments-of-coumarin-hybrids-as-anti-fungal-agents
#10
Xin-Liang Hu, Zhi Xu, Ming-Liang Liu, Lian-Shun Feng, Guang-De Zhang
Fungi place a huge burden on global healthcare systems attributed to the fact that fungal infections are responsible for the high morbidity and mortality rates in patients who received stem cell transplantation, antineoplastic chemotherapy, organ transplants or suffered human immunodeficiency virus (HIV) infection. Unfortunately, almost none of the representative anti-fungal agents currently used in clinical therapy are ideal in terms of efficacy, anti-fungal spectrum or safety. Moreover, the rapid development of resistance to existing anti-fungal drugs has further aggravated the mortality and spread of fungi, creating an urgent need of novel anti-fungal agents...
December 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29243370/neurological-nutritional-and-alcohol-consumption-factors-underlie-cognitive-and-motor-deficits-in-chronic-alcoholism
#11
Rosemary Fama, Anne-Pascale Le Berre, Cheshire Hardcastle, Stephanie A Sassoon, Adolf Pfefferbaum, Edith V Sullivan, Natalie M Zahr
Variations in pattern and extent of cognitive and motor impairment occur in alcoholism (ALC). Causes of such heterogeneity are elusive and inconsistently accounted for by demographic or alcohol consumption differences. We examined neurological and nutritional factors as possible contributors to heterogeneity in impairment. Participants with ALC (n = 96) and a normal comparison group (n = 41) were examined on six cognitive and motor domains. Signs of historically determined subclinical Wernicke's encephalopathy were detected using the Caine et al...
December 15, 2017: Addiction Biology
https://www.readbyqxmd.com/read/29243353/first-in-human-evaluation-of-the-vascular-biocompatibility-and-biomechanical-performance-of-a-novel-ultra-high-molecular-weight-amorphous-plla-bioresorbable-scaffold-in-the-absence-of-anti-proliferative-drugs-two-year-imaging-results-in-humans
#12
Miguel Moncada, Juan A Delgado, Antonio Colombo, Pawel Gasior, Kamal Ramzipoor, Alex Estrada, Chang Lee, Danny Dokko, Juan F Granada
OBJECTIVES: In this first-in-human study, we prospectively studied the vascular compatibility and mechanical performance of a novel bare ultra-high molecular weight amorphous PLLA bioresorbable scaffold (BRS, FORTITUDE®, Amaranth Medical, Mountain View, California) up to two years after implantation using multimodality imaging techniques. BACKGROUND: The vascular biocompatibility of polymers used in BRS has not been fully characterized in the absence of anti-proliferative drugs...
December 15, 2017: Catheterization and Cardiovascular Interventions
https://www.readbyqxmd.com/read/29243176/understanding-and-reducing-complex-systems-pharmacology-models-based-on-a-novel-input-response-index
#13
Jane Knöchel, Charlotte Kloft, Wilhelm Huisinga
A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input-response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input-output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable...
December 14, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29243172/therapeutic-delivery-of-simvastatin-loaded-in-pla-peg-polymersomes-resulted-in-amplification-of-anti-inflammatory-effects-in-activated-microglia
#14
Dharani Manickavasagam, Kimberly Novak, Moses O Oyewumi
Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood-brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly(D,L) lactic acid) diblock co-polymers...
December 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29243035/systemic-lupus-erythematosus-and-ocular-involvement-an-overview
#15
REVIEW
Rosanna Dammacco
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of undefined etiology and with remarkably heterogeneous clinical features. Virtually any organ system can be affected, including the eye. SLE-related eye involvement can be diagnosed in approximately one-third of the patients and is usually indicative of disease activity. An early diagnosis and the adoption of suitable therapeutic measures are necessary to prevent sight-threatening consequences, especially in patients with juvenile SLE. Periocular lesions, such as eyelid involvement and orbital inflammation, are relatively rare and, in case of orbital masses, may require a biopsy control...
December 14, 2017: Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/29243027/lactobacillus-rhamnosus-reduces-parasite-load-on-toxocara-canis-experimental-infection-in-mice-but-has-no-effect-on-the-parasite-in-vitro
#16
Débora Liliane Walcher, Luis Augusto Xavier Cruz, Paula de Lima Telmo, Lourdes Helena Rodrigues Martins, Luciana Farias da Costa de Avila, Maria Elisabeth Aires Berne, Carlos James Scaini
Human toxocariasis is a neglected global parasitic zoonosis. The efficacy of drug treatment for this disease has been hindered by the biological complexity of the main etiological agent, the nematode Toxocara canis. Experimental studies have shown the potential of probiotics to promote a reduction in the parasite load of T. canis larvae. This study aimed to evaluate the effect of probiotic Lactobacillus rhamnosus ATCC 7469 on the parasite load of BALB/c mice with acute toxocariasis and evaluate the direct effect of this probiotic on T...
December 14, 2017: Parasitology Research
https://www.readbyqxmd.com/read/29242609/automating-drug-discovery
#17
REVIEW
Gisbert Schneider
Small-molecule drug discovery can be viewed as a challenging multidimensional problem in which various characteristics of compounds - including efficacy, pharmacokinetics and safety - need to be optimized in parallel to provide drug candidates. Recent advances in areas such as microfluidics-assisted chemical synthesis and biological testing, as well as artificial intelligence systems that improve a design hypothesis through feedback analysis, are now providing a basis for the introduction of greater automation into aspects of this process...
December 15, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29242597/rheological-droplet-interface-bilayers-rheo-dibs-probing-the-unstirred-water-layer-effect-on-membrane-permeability-via-spinning-disk-induced-shear-stress
#18
Nathan E Barlow, Guido Bolognesi, Stuart Haylock, Anthony J Flemming, Nicholas J Brooks, Laura M C Barter, Oscar Ces
A new rheological droplet interface bilayer (rheo-DIB) device is presented as a tool to apply shear stress on biological lipid membranes. Despite their exciting potential for affecting high-throughput membrane translocation studies, permeability assays conducted using DIBs have neglected the effect of the unstirred water layer (UWL). However as demonstrated in this study, neglecting this phenomenon can cause significant underestimates in membrane permeability measurements which in turn limits their ability to predict key processes such as drug translocation rates across lipid membranes...
December 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29242381/therapeutic-targeting-of-non-coding-rnas-in-cancer
#19
REVIEW
Ondrej Slaby, Richard Laga, Ondrej Sedlacek
The majority of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) affect normal expression of the genes, including oncogenes and tumour suppressive genes, which make them a new class of targets for drug development in cancer. Although microRNAs (miRNAs) are the most studied regulatory ncRNAs to date, and miRNA-targeted therapeutics have already reached clinical development, including the mimics of the tumour suppressive miRNAs miR-34 and miR-16, which reached phase I clinical trials for the treatment of liver cancer and mesothelioma, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognised...
December 14, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29242316/colorectal-cancer-consensus-molecular-subtypes-translated-to-preclinical-models-uncover-potentially-targetable-cancer-cell-dependencies
#20
Anita Sveen, Jarle Bruun, Peter W Eide, Ina A Eilertsen, Lorena Ramirez, Astrid Murumägi, Mariliina A Arjama, Stine A Danielsen, Kushtrim Kryeziu, Elena Elez, Josep Tabernero, Justin Guinney, Hector G Palmer, Arild Nesbakken, Olli Kallioniemi, Rodrigo Dienstmann, Ragnhild A Lothe
PURPOSE: Response to standard oncological treatment is limited in colorectal cancer (CRC). The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing, however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. EXPERIMENTAL DESIGN: We analyzed CMS in primary CRCs, cell lines and patient-derived xenografts (PDXs). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n=459 drugs) to analyze subtype-specific drug sensitivities...
December 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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