scholarly journals Supporting evidence-based analysis for modified risk tobacco products through a toxicology data-sharing infrastructure

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 12 ◽  
Author(s):  
Stéphanie Boué ◽  
Thomas Exner ◽  
Samik Ghosh ◽  
Vincenzo Belcastro ◽  
Joh Dokler ◽  
...  
Keyword(s):  
Data Sharing ◽  
Data Science ◽  
Disease Risk ◽  
Open Data ◽  
Supporting Evidence ◽  
Tobacco Products ◽  
Us Fda ◽  
Using Data

The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products.  Establishing a product’s potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cigarette smoking.  Best practices encourage verification of the data from such studies through sharing and open standards. Building on the experience gained from the OpenTox project, a proof-of-concept database and website (INTERVALS) has been developed to share results from both in vivo inhalation studies and in vitro studies conducted by Philip Morris International R&D to assess candidate MRTPs. As datasets are often generated by diverse methods and standards, they need to be traceable, curated, and the methods used well described so that knowledge can be gained using data science principles and tools. The data-management framework described here accounts for the latest standards of data sharing and research reproducibility. Curated data and methods descriptions have been prepared in ISA-Tab format and stored in a database accessible via a search portal on the INTERVALS website. The portal allows users to browse the data by study or mechanism (e.g., inflammation, oxidative stress) and obtain information relevant to study design, methods, and the most important results. Given the successful development of the initial infrastructure, the goal is to grow this initiative and establish a public repository for 21st-century preclinical systems toxicology MRTP assessment data and results that supports open data principles.

scholarly journals Supporting evidence-based analysis for modified risk tobacco products through a toxicology data-sharing infrastructure

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 12 ◽  
Author(s):  
Stéphanie Boué ◽  
Thomas Exner ◽  
Samik Ghosh ◽  
Vincenzo Belcastro ◽  
Joh Dokler ◽  
...  
Keyword(s):  
Data Sharing ◽  
Data Science ◽  
Disease Risk ◽  
Open Data ◽  
Supporting Evidence ◽  
Tobacco Products ◽  
Us Fda ◽  
Using Data

The US FDA defines modified risk tobacco products (MRTPs) as products that aim to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products.  Establishing a product’s potential as an MRTP requires scientific substantiation including toxicity studies and measures of disease risk relative to those of cigarette smoking.  Best practices encourage verification of the data from such studies through sharing and open standards. Building on the experience gained from the OpenTox project, a proof-of-concept database and website (INTERVALS) has been developed to share results from both in vivo inhalation studies and in vitro studies conducted by Philip Morris International R&D to assess candidate MRTPs. As datasets are often generated by diverse methods and standards, they need to be traceable, curated, and the methods used well described so that knowledge can be gained using data science principles and tools. The data-management framework described here accounts for the latest standards of data sharing and research reproducibility. Curated data and methods descriptions have been prepared in ISA-Tab format and stored in a database accessible via a search portal on the INTERVALS website. The portal allows users to browse the data by study or mechanism (e.g., inflammation, oxidative stress) and obtain information relevant to study design, methods, and the most important results. Given the successful development of the initial infrastructure, the goal is to grow this initiative and establish a public repository for 21st-century preclinical systems toxicology MRTP assessment data and results that supports open data principles.

Studies of two temperature-sensitive mutants of Mengo virus

1979 ◽  
Vol 57 (6) ◽  
pp. 902-913 ◽  
Author(s):  
Patrick W. K. Lee ◽  
John S. Colter
Keyword(s):  
Rna Synthesis ◽  
Viral Rna ◽  
Temperature Sensitive ◽  
Supporting Evidence ◽  
Structural Polypeptide ◽  
Infected Cells ◽  
Mengo Virus ◽  
In Vitro Stability

Studies of the synthesis of viral ribonucleates and polypeptides in cells infected with two RNA−ts mutants of Mengo virus (ts 135 and ts 520) have shown that when ts 135 infected cells are shifted from the permissive (33 °C) to the nonpermissive (39 °C) temperature: (i) the synthesis of all three species of viral RNA (single stranded, replicative form, and replicative intermediate) is inhibited to about the same extent, and (ii) the posttranslational cleavage of structural polypeptide precursors A and B is partially blocked. Investigations of the in vivo and in vitro stability of the viral RNA replicase suggest that the RNA− phentotype reflects a temperature-sensitive defect in the enzyme. The second defect does not appear to result from the inhibition of viral RNA synthesis at 39 °C, since normal cleavage of polypeptides A and B occurs in wt Mengo-infected cells in which viral RNA synthesis is blocked by cordycepin, and at the nonpermissive temperature in ts 520 infected cells. Considered in toto, the evidence suggests that ts 135 is a double mutant.Subviral (53 S) particles have been shown to accumulate in ts 520 (but not ts 135) infected cells when cultures are shifted from 33 to 39 °C. This observation provides supporting evidence for the proposal that this recently discovered particle is an intermediate in the assembly pathway of Mengo virions.

Electrophysiological characterization and computational models of HVC neurons in the zebra finch

2013 ◽  
Vol 110 (5) ◽  
pp. 1227-1245 ◽  
Author(s):  
Arij Daou ◽  
Matthew T. Ross ◽  
Frank Johnson ◽  
Richard L. Hyson ◽  
Richard Bertram
Keyword(s):  
Computational Models ◽  
Premotor Cortex ◽  
Brain Slices ◽  
Ionic Currents ◽  
Proper Name ◽  
Using Data ◽  
Electrophysiological Characterization

The nucleus HVC (proper name) within the avian analog of mammal premotor cortex produces stereotyped instructions through the motor pathway leading to precise, learned vocalization by songbirds. Electrophysiological characterization of component HVC neurons is an important requirement in building a model to understand HVC function. The HVC contains three neural populations: neurons that project to the RA (robust nucleus of arcopallium), neurons that project to Area X (of the avian basal ganglia), and interneurons. These three populations are interconnected with specific patterns of excitatory and inhibitory connectivity, and they fire with characteristic patterns both in vivo and in vitro. We performed whole cell current-clamp recordings on HVC neurons within brain slices to examine their intrinsic firing properties and determine which ionic currents are responsible for their characteristic firing patterns. We also developed conductance-based models for the different neurons and calibrated the models using data from our brain slice work. These models were then used to generate predictions about the makeup of the ionic currents that are responsible for the different responses to stimuli. These predictions were then tested and verified in the slice using pharmacological manipulations. The model and the slice work highlight roles of a hyperpolarization-activated inward current ( Ih), a low-threshold T-type Ca2+ current ( ICa-T), an A-type K+ current ( IA), a Ca2+-activated K+ current ( ISK), and a Na+-dependent K+ current ( IKNa) in driving the characteristic neural patterns observed in the three HVC neuronal populations. The result is an improved characterization of the HVC neurons responsible for song production in the songbird.

scholarly journals Raphanus sativus ameliorates atherogeneic lipid profiles in hypercholesterolemic rats and hypercholesterolemia-associated peroxidative liver damage

2011 ◽  
Vol 7 (3) ◽  
pp. 1385-1394 ◽  
Author(s):  
Mozammel Haque ◽  
Jahirul Islam ◽  
Asiqur Rahaman ◽  
Fowzia Akter Selina ◽  
Mohammad Azizur Rahman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Raphanus Sativus ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Water Extract ◽  
Density Lipoprotein ◽  
Lipid Peroxide ◽  
Hot Water

Objective: Raphanus sativus is a hugely used edible root vegetable. We investigated whether the feeding of the Raphanus sativus hot water extract (RSE) ameliorates atherogenic lipid profile and oxidative stress in hypercholesterolemia. Methods: After feeding of the RSE to hypercholesterolemic rats for 6 weeks, the levels of plasma and hepatic total cholesterol (TC), triglyceride (TG), and plasma high density lipoprotein-cholesterol (HDL-C) and fecal TC levels were studied. The effects of RSE on the hepatic enzymes, namely alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), the levels of lipid peroxide (LPO) and liver histology were also evaluated. Results: Hypercholesterolemia increased the levels of TC and TG in the plasma and livers. The levels of ALT, AST and ALP in plasma and LPO in the liver also increased. The dietary RSE, however, significantly ameliorated the above atherogenic lipids and liver enzymes. The RSE significantly reduced the levels of LPO in the liver, suggesting an in vivo protection against of oxidative stress. The RSE also inhibited the in vitro Fenton’s reagent-induced oxidative stress, thus corroborating the in vivo anti-LPO actions of RSE. The levels of hepatic LPO were positively correlated with plasma AST (r=0.76; P <0.05) and ALT (r=0.43; P<0.05) levels. Histologically, the livers of the RSE-fed hypercholesterolemic rats exhibited lesser fatty droplets and reduced inflammatory cells. Conclusion: Finally, R. sativus extract lowers the cardiovascular disease risk factors under hypercholesterolemic situation by increasing the plasma/hepatic clearance of cholesterol and improving the hypercholesterolemia-induced oxidative damage of hepatic tissues.

scholarly journals Preservatives in glaucoma medication

2018 ◽  
Vol 102 (11) ◽  
pp. 1497-1503 ◽  
Author(s):  
David W Steven ◽  
Pouya Alaghband ◽  
Kin Sheng Lim
Keyword(s):  
Supporting Evidence ◽  
Laboratory Studies ◽  
Regulatory Requirements ◽  
Glaucoma Medication ◽  
Clinically Significant ◽  
Extensive Body ◽  
Randomised Controlled ◽  
Preservative Free

Preservatives continue to be in widespread use in ophthalmic medications due to the convenience they provide, regulatory requirements and the higher cost of alternatives. Benzalkonium chloride (BAK) remains the most commonly used preservative but there is a trend towards the use of preservative-free (PF) drops for glaucoma, although at a higher price. An extensive body of literature explores BAK toxicity on ocular structures in animal and laboratory studies (in vitro and in vivo). Non-randomised controlled studies have provided some supporting evidence of its toxicity in patients, especially in those with pre-existing ocular surface disease (OSD) or on multiple medications. However, there have been very few randomised controlled trials that compare the same medication with and without BAK preservative. Several of these trials have never been published in any peer reviewed journals. Notwithstanding, those that have been published, have not demonstrated any clear benefits of the BAK-free formulations. Short duration and exclusion of those with OSD are limitations of these studies. There is a lack of evidence of clinically significant harm from a small number of BAK preserved drops in patients without OSD. This means that generally more expensive PF glaucoma medications should only be recommended for those on poly pharmacy or those with OSD but are not necessarily required for all patients.

A reinvestigation of the function of the mammalian urinary bladder

1977 ◽  
Vol 232 (3) ◽  
pp. F187-F195 ◽  
Author(s):  
S. A. Lewis
Keyword(s):  
Urinary Bladder ◽  
Membrane Surface ◽  
Apical Cell ◽  
Membrane Damage ◽  
In Vitro Experiments ◽  
Apical Cell Membrane ◽  
Cell Membrane Damage ◽  
Using Data

The function of adult mammalian urinary bladder is evaluated in light of recent in vitro experiments. The discrepancy between in vivo and in vitro experimental results is examined and a possible solution proposed. Techniques for eliminating edge damage and measuring apical membrane surface area are described. A new chamber design for microelectrode studies is illustrated. The possibility of apical cell membrane damage caused by microelectrodes is critically examined and tested using the polyene antibiotic Nystatin. Using data from transepithelial and microelectrode experiments, a model for net Na+ transport across the bladder is proposed and then critically analyzed. The possible clinical implications of the in vitro experiments are briefly discussed.

scholarly journals In Vitro Models, Standards, and Experimental Methods for Tobacco Products

2019 ◽  
Vol 30 (1) ◽  
pp. 16-21 ◽  
Author(s):  
T. Aghaloo ◽  
J.J. Kim ◽  
T. Gordon ◽  
H.P. Behrsing
Keyword(s):  
Cigarette Smoking ◽  
Electronic Cigarettes ◽  
Testing Machine ◽  
The United States ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Tobacco Products ◽  
Direct Exposure

Traditional tobacco products have well-known systemic and local oral effects, including inflammation, vasoconstriction, delayed wound healing, and increased severity of periodontal disease. Specifically in the oral cavity and the lung, cigarette smoking produces cancer, increased infectivity, acute and chronic inflammation, changes in gene expression in epithelial lining cells, and microbiome changes. In recent years, cigarette smoking has greatly decreased in the United States, but the use of new tobacco products has gained tremendous popularity. Without significant knowledge of the oral sequelae of products such as electronic cigarettes, researchers must evaluate current in vitro and in vivo methods to study these agents, as well as develop new tools to adequately study their effects. Some in vitro testing has been performed for electronic cigarettes, including toxicologic models and assays, but these mostly study the effect on the respiratory tract. Recently, direct exposure of the aerosol to in vitro 3-dimensional tissue constructs has been performed, demonstrating changes in cell viability and inflammatory cytokines. For in vivo studies, a universal e-cigarette testing machine or standard vaping regime is needed. A standard research electronic cigarette has recently been developed by the National Institute of Drug Abuse, and other devices delivering aerosols with different nicotine concentrations are becoming available. One of the biggest challenges in this research is keeping up with the new products and the rapidly changing technologies in the industry.

scholarly journals Dickkopf-1: A Promising Target for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hang Yin Chu ◽  
Zihao Chen ◽  
Luyao Wang ◽  
Zong-Kang Zhang ◽  
Xinhuan Tan ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Functional Studies ◽  
Promising Target ◽  
Using Data ◽  
Dickkopf 1

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.

scholarly journals Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs

2020 ◽  
Vol 21 (5) ◽  
pp. 1791 ◽  
Author(s):  
Darcy C. Engelhart ◽  
Jeffry C. Granados ◽  
Da Shi ◽  
Milton H. Saier Jr. ◽  
Michael E. Baker ◽  
...  
Keyword(s):  
Cyclic Nucleotides ◽  
Signaling Molecules ◽  
In Vitro Assays ◽  
Specific Substrate ◽  
In Vivo Models ◽  
Using Data ◽  
Carnitine Derivatives ◽  
Metabolite Network

The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as “drug” transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.

scholarly journals Experimental and Clinical Applications of Red and Near-Infrared Photobiomodulation on Endothelial Dysfunction: A Review

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 274 ◽  
Author(s):  
Esteban Colombo ◽  
Antonio Signore ◽  
Stefano Aicardi ◽  
Angelina Zekiy ◽  
Anatoliy Utyuzh ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Near Infrared ◽  
Disease Risk ◽  
In Vivo Studies ◽  
Infrared Light ◽  
Animal Cells ◽  
Atp Production ◽  
Main Regulator

Background: Under physiological conditions, endothelial cells are the main regulator of arterial tone homeostasis and vascular growth, sensing and transducing signals between tissue and blood. Disease risk factors can lead to their unbalanced homeostasis, known as endothelial dysfunction. Red and near-infrared light can interact with animal cells and modulate their metabolism upon interaction with mitochondria’s cytochromes, which leads to increased oxygen consumption, ATP production and ROS, as well as to regulate NO release and intracellular Ca2+ concentration. This medical subject is known as photobiomodulation (PBM). We present a review of the literature on the in vitro and in vivo effects of PBM on endothelial dysfunction. Methods: A search strategy was developed consistent with the PRISMA statement. The PubMed, Scopus, Cochrane, and Scholar electronic databases were consulted to search for in vitro and in vivo studies. Results: Fifty out of >12,000 articles were selected. Conclusions: The PBM can modulate endothelial dysfunction, improving inflammation, angiogenesis, and vasodilatation. Among the studies, 808 nm and 18 J (0.2 W, 2.05 cm2) intracoronary irradiation can prevent restenosis as well as 645 nm and 20 J (0.25 W, 2 cm2) can stimulate angiogenesis. PBM can also support hypertension cure. However, more extensive randomised controlled trials are necessary.

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