Top 10 Biorxiv Papers Today in Pharmacology And Toxicology


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#1. Development of an imaging toolbox to assess the therapeutic potential and biodistribution of macrophages in a mouse model of multiple organ dysfunction
Jack Sharkey, Lorenzo Ressel, Nathalie Brillant, Bettina Wilm, Kevin Park, Patricia Murray
Cell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multi-spectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver and cardiac injury and the extent of functional recovery to be assessed non-invasively in a mouse model of multi-organ dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred M2 macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy improved kidney and liver function to a limited extent, but did not ameliorate histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver, but did not populate the heart. Our data suggest that the limited improvement observed in...
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Authors: 6
Total Words: 9260
Unqiue Words: 2930

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#2. Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice
Anish Engineer, Tana Saiyin, Xiangru Lu, Andrew S. Kucey, Brad L. Urquhart, Thomas A. Drysdale, Kambiz Norozi, Qingping Feng
Aims: Tetrahydrobiopterin (BH4) is a co-factor of endothelial nitric oxide synthase (eNOS), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of BH4 on eNOS uncoupling and congenital heart defects (CHDs) induced by pregestational diabetes in mice. Methods: Adult female mice were induced to pregestational diabetes by streptozotocin and bred with normal males to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHDs were identified by histological analysis. Cell proliferation, eNOS dimerization and reactive oxygen species (ROS) production were assessed in the fetal heart. Results: Pregestational diabetes results in a spectrum of CHDs in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHDs from 59% to 27% and major abnormalities, such as atrioventricular septal defect and double outlet right ventricle were absent in the sapropterin treated group....
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Sample Sizes : [37, 19, 3]
Authors: 8
Total Words: 9129
Unqiue Words: 2687

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#3. Drug Interactions Between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine
Stephen Walimbwa, Mohammed Lamorde, Catriona Waitt, Julian Kaboggoza, Laura Else, Pauline Byakika-Kibwika, Alieu Amara, Joshua Gini, Markus Winterberg, Justin Chiong, Joel Tarning, Saye H Khoo
Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need co-treatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine  interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir...
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Authors: 12
Total Words: 4958
Unqiue Words: 2191

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#4. Atropselective Oxidation of 2,2',3,3',4,6'-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes: Involvement of Arene Oxide Intermediates
Eric Uwimana, Xueshu Li, Coby Yeung, Eric V. Patterson, Hans-Joachim Lehmler
PCBs and their hydroxylated metabolites have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB developmental neurotoxicity; however, only limited information is available regarding the metabolism of these congeners in humans. We hypothesize that the oxidation of 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) is atropselective and displays inter-individual variability. To test this hypothesis, PCB 132 (50 μM) was incubated with pooled or single donor HLMs for 10, 30 or 120 min at 37 °C, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite formed by different HLM preparations was either 2,2',3,4,4',6'-hexachlorobiphenyl-3'-ol (3'-140) or 2,2',3,3',4,6'-hexachlorobiphenyl-5'-ol (5'-132). 2,2',3,3',4,6'-Hexachlorobiphenyl-4'-ol (4'-132) and 2,2',3,3',4,6'-hexachlorobiphenyl-4',5'-diol (4',5'-132) were minor...
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Sample Sizes : [3, 6, 2, 3, 3]
Authors: 5
Total Words: 12339
Unqiue Words: 3834

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#5. Predicting negative control drugs to support research in drug safety
Yun Hao, Nicholas P. Tatonetti
The lack of high-quality reference data is a major limitation in drug safety and drug discovery science. Unreliable standards prohibit the use of supervised learning methods and make evaluation of algorithms difficult. While some data is available for positive examples (e.g. which drugs are associated with a side effect), there are no systematic resources of negative controls. To solve this issue, we introduced SIDERctrl, a computational method that ranks drugs based on the likelihood of not causing a side effect. We applied SIDERctrl to predict negative controls from unreported drugs of 890 side effects in SIDER. Our predictions decreased the false negative rate by one-third according to a validation study using AEOLUS data. Three sets of predicted negative controls by different thresholds of precision were provided, and can be accessed at http://tatonettilab.org/resources/negative-drugs.html. This new reference standard will be important in chemical biology, drug development, and pharmacoepidemiology.
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jennakefeli: RT @biorxivpreprint: Predicting negative control drugs to support research in drug safety https://t.co/P2puTYyqiD #bioRxiv
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Authors: 2
Total Words: 4732
Unqiue Words: 1465

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#6. A standardised framework to identify optimal animal models for efficacy assessment in drug development
Guilherme S. Ferreira, Désirée Veening-Griffioen, Wouter Boon, Ellen Moors, Christine de Gispen-Wied, Huub Schellekens, Peter van Meer
Introduction - Poor translation of efficacy data in animal models is a potential contributor to costly and unnecessary attrition in clinical trials. Objectives – To develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy. Design and Results – We conducted an exploratory literature search to identify the key aspects to validate animal models. Eight aspects (Epidemiology, Pathophysiology, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified for which questions were drafted to evaluate the different faces of the human disease simulation. Features of the framework include standardised instructions, a weighting and scoring system to compare models as well as contextualising factors regarding model similarity and evidence uncertainty. We included a quality assessment of the internal validity of drug intervention studies included in the Pharmacological validation section for both effective and ineffective drugs in...
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biorxivpreprint: A standardised framework to identify optimal animal models for efficacy assessment in drug development https://t.co/mQdxZRNHpM #bioRxiv
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Authors: 7
Total Words: 4794
Unqiue Words: 1956

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#7. Isoform-specific NADPH oxidase inhibition for pharmacological target validation
Thao-Vi Dao, Sebastian Altenhöfer, Mahmoud H. Elbatreek, Ana I. Casas, Peter Lijnen, Merlijn J. Meens, Ulla Knaus, Harald H.H.W. Schmidt
Unphysiological reactive oxygen species (ROS) formation is considered an important pathomechanism for several diseasephenotypes with high unmet medical need. After the clinical failure of antioxidants, inhibition of disease-relevant enzymatic sources of ROS appears to be the most promising alternative approach. With respect to most promising drug target, NADPH oxidases (NOXs) stand out, however, validation has been restricted mainly to genetically modified mice. Validation in other species including human is lacking and it is unclear whether the different NOX isoforms are sufficiently distinct for selective pharmacological inhibition. Here we show for the five most advanced NOX inhibitors that pharmacological isoform selectivity can be achieved. NOX1 was most potently (IC50) targeted by ML171 (0.1 μM); NOX2, by VAS2870 (0.7 μM); NOX4, by M13 (0.01 μM) and NOX5, by ML090 (0.01 μM). Of note, previously unrecognised non-specific antioxidant and assay artefacts may limit interpretations in some systems, which included, surprisingly,...
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Authors: 8
Total Words: 6259
Unqiue Words: 2208

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#8. Predicting Response to Platin Chemotherapy Agents with Biochemically-inspired Machine Learning
Eliseos J Mucaki, Jonathan Z.L Zhao, Dan Lizotte, Peter K Rogan
Selection of effective genes that accurately predict chemotherapy response could improve cancer outcomes. We compare optimized gene signatures for cisplatin, carboplatin, and oxaliplatin response in the same cell lines, and respectively validate each with cancer patient data. Supervised support vector machine learning was used to derive gene sets whose expression was related to cell line GI50 values by backwards feature selection with cross-validation. Specific genes and functional pathways distinguishing sensitive from resistant cell lines are identified by contrasting signatures obtained at extreme vs. median GI50 thresholds. Ensembles of gene signatures at different thresholds are combined to reduce dependence on specific GI50 values for predicting drug response. The most accurate models for each platin are: cisplatin: BARD1, BCL2, BCL2L1, CDKN2C, FAAP24, FEN1, MAP3K1, MAPK13, MAPK3, NFKB1, NFKB2, SLC22A5, SLC31A2, TLR4, TWIST1 ; carboplatin: AKT1, EIF3K, ERCC1, GNGT1, GSR, MTHFR, NEDD4L, NLRP1, NRAS, RAF1, SGK1, TIGD1, TP53,...
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PeterKRogan: Accepted for publication in Signal Transduction and Targeted Therapy: Predicting Response to Platin Chemotherapy Agents with Biochemically-inspired Machine Learning https://t.co/3ZIyLjlP6R
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Authors: 4
Total Words: 11550
Unqiue Words: 3637

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#9. Knockdown of butyrylcholinesterase but not inhibition by chlorpyrifos alters early differentiation mechanisms in human neural stem cells
Angela K. Teithof, Jason R. Richardson, Ronald P. Hart
Butyrylcholinesterase (BChE) is the evolutionary counterpart to acetylcholinesterase (AChE). Both are expressed early in nervous system development prior to cholinergic synapse formation. The organophosphate pesticide chlorpyrifos (CPF) primarily exerts toxicity through inhibition of AChE, which results in excess cholinergic stimulation at the synapse. We hypothesized that inhibition of AChE and BChE by CPF may impair early neurogenesis in neural stem cells (NSCs). To model neurodevelopment in vitro, we used human NSCs derived from induced pluripotent stem cells (iPSCs) with a focus on initial differentiation mechanisms. Over six days of NSC differentiation, BChE activity and mRNA expression significantly increased, while AChE activity and expression remained unchanged. CPF treatment (10 microM) caused 82% and 92% inhibition of AChE and BChE, respectively. CPF exposure had no effect on cell viability or the expression of differentiation markers HES5, DCX or MAP2. However, shRNA-knockdown of BChE expression resulted in decreased or...
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biorxivpreprint: Knockdown of butyrylcholinesterase but not inhibition by chlorpyrifos alters early differentiation mechanisms in human neural stem cells https://t.co/3cExGiqhiq #bioRxiv
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Authors: 3
Total Words: 7654
Unqiue Words: 2544

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#10. The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.
Petra Spirhanzlova, Sebastien Le Mevel, Karn Wejaphikul, Bilal Mughal, Jean-David Gothie, Anthony Sebillot, Lucille Butruille, Michelle Leemans, Theo Visser, Sylvie Remaud, Jean-Baptiste Fini, Barbara Demeneix
Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4'-OH-pyriproxyfen (4'-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4'OH-PPF (> 3 mg/L ) to act as a TRα antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4'OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4'OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly,...
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biorxivpreprint: The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors. https://t.co/f0Vf2raTLE #bioRxiv
outbreaksci: Read it? Rate it. If you read "The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroproge..." (https://t.co/rQ8uYluXf0), provide an @outbreaksci rapid review here [prototype]: https://t.co/acDeHAyHI3
outbreaksci: New #Zika preprint: The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors. https://t.co/rQ8uYluXf0
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Authors: 12
Total Words: 8836
Unqiue Words: 3441

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