Using semantics to scale up evidence-based chemical risk-assessments

Background The manual processes used for risk assessments are not scaling to the amount of data available. Although automated approaches appear promising, they must be transparent in a public policy setting. Objective Our goal is to create an automated approach that moves beyond retrieval to the extraction step of the information synthesis process, where evidence is characterized as supporting, refuting, or neutral with respect to a given outcome. Methods We combine knowledge resources and natural language processing to resolve coordinated ellipses and thus avoid surface level differences between concepts in an ontology and outcomes in an abstract. As with a systematic review, the search criterion, and inclusion and exclusion criterion are explicit. Results The system scales to 482K abstracts on 27 chemicals. Results for three endpoints that are critical for cancer risk assessments show that refuting evidence (where the outcome decreased) was higher for cell proliferation (45.9%), and general cell changes (37.7%) than for cell death (25.0%). Moreover, cell death was the only end point where supporting claims were the majority (61.3%). If the number of abstracts that measure an outcome was used as a proxy for association there would be a stronger association with cell proliferation than cell death (20/27 chemicals). However, if the amount of supporting evidence was used (where the outcome increased) the conclusion would change for 21/27 chemicals (20 from proliferation to death and 1 from death to proliferation). Conclusions We provide decision makers with a visual representation of supporting, neutral, and refuting evidence whilst maintaining the reproducibility and transparency needed for public policy. Our findings show that results from the retrieval step where the number of abstracts that measure an outcome are reported can be misleading if not accompanied with results from the extraction step where the directionality of the outcome is established.

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The P-MAPA immunomodulator partially prevents apoptosis induced by Zika virus infection in THP-1 cells

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200602140005 ◽

2020 ◽

Vol 21 ◽

Cited By ~ 1

Author(s):

Morganna C. Lima ◽

Elisa A. N. Azevedo ◽

Clarice N. L. de Morais ◽

Larissa I. O. de Sousa ◽

Bruno M. Carvalho ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Virus Infection ◽

Virus Replication ◽

Zika Virus ◽

Mammalian Cells ◽

Caspase 3 ◽

Neurological Complications ◽

Zika Virus Infection

Background: Zika virus is an emerging arbovirus of global importance. ZIKV infection is associated with a range of neurological complications such as the Congenital Zika Syndrome and Guillain Barré Syndrome. Despite the magnitude of recent outbreaks, there is no specific therapy to prevent or to alleviate disease pathology. Objective: To investigate the role of P-MAPA immunomodulator in Zika-infected THP-1 cells. Methods: THP-1 cells were subjected at Zika virus infection (Multiplicity of Infection = 0.5) followed by treatment with P-MAPA for until 96 hours post-infection. After that, the cell death was analyzed by annexin+/ PI+ and caspase 3/ 7+ staining by flow cytometry. In addition, the virus replication and cell proliferation were accessed by RT-qPCR and Ki67 staining, respectively. Results: We demonstrate that P-MAPA in vitro treatment significantly reduces Zika virus-induced cell death and caspase-3/7 activation on THP-1 infected cells, albeit it has no role in virus replication and cell proliferation. Conclusions: Our study reveals that P-MAPA seems to be a satisfactory alternative to inhibits the effects of Zika virus infection in mammalian cells.

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Single-chain Antibody Against Reg4 Suppresses Gastric Cancer Cell Growth and Enhances 5-FU-induced Cell Death in vitro

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666181122104720 ◽

2019 ◽

Vol 19 (5) ◽

pp. 610-619 ◽

Cited By ~ 3

Author(s):

Xue-Qing Zhang ◽

Lu-Ting Yu ◽

Pei Du ◽

Tian-Qi Yin ◽

Zhi-Yuan Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cell Death ◽

Cancer Cell ◽

Gastric Cancer Cell ◽

Single Chain ◽

Single Chain Antibody ◽

Ags Cells ◽

Thiazolyl Blue Tetrazolium Bromide

Background:Regenerating islet-derived gene family member 4 (Reg4), a well-investigated growth factor in the regenerative pancreas, has recently been reported to be highly associated with a majority of gastrointestinal cancers. Pathological hyper-expression or artificial over-expression of Reg4 causes acceleration of tumor growth, migration, and resistance to chemotherapeutic 5-Fluorouracil (5-FU). Until now, no method has been successfully established for eliminating the effects of Reg4 protein.Methods:This study reports the production of an engineered immunoglobin, a single-chain variable fragment (scFv-Reg4), to specifically bind Reg4 and block the bioactivity. The complementary-determining regions (CDRs) against Reg4 were assigned using MOE and ZDOCK servers. The binding affinity (KD) was determined by bio-layer interferometry (BLI). MKN45 and AGS cell proliferation was determined by Thiazolyl blue tetrazolium bromide (MTT) method and the cell apoptosis was detected by flow cytometry assay.Results:The KD of scFv-Reg4 to Reg4 was determined to be 1.91×10-8. In MKN45 and AGS cell lines, scFv- Reg4 depressed Reg4-stimulated cell proliferation and the inhibitory rates were 27.7±1.5% and 17.3±2.6%, respectively. Furthermore, scFv significantly enhanced 5-FU-induced cell death, from 23.0±1.0% to 28.4±1.2% in MKN45 and 28.2±0.7% to 36.6±0.6% in AGS cells. Treatment with scFv alone could lyse cancer cells to a certain extent, but no significance has been observed.Conclusion:The single-chain antibody (scFv-Reg4) significantly inhibited gastric cancer cell proliferation and synergistically enhanced the lethal effect of 5-FU. Thus, traditional chemo-/radio- therapeutics supplemented with scFv-Reg4 may provide advances in the strategy for gastrointestinal cancer treatment.

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Receptor Tyrosine Kinases: Role in Cancer Progression

Current Oncology ◽

10.3390/curroncol13050019 ◽

2006 ◽

Vol 13 (5) ◽

pp. 191-193

Author(s):

V. Sangwan ◽

M. Park

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Programmed Cell Death ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Normal Tissue ◽

Receptor Tyrosine Kinases ◽

Tight Control ◽

Tissue Patterning

Tight control of cell proliferation and morphogenesis in conjunction with programmed cell death (apoptosis) is required to ensure normal tissue patterning. [...]

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MicroRNAs in cell proliferation, cell death, and tumorigenesis

British Journal of Cancer ◽

10.1038/sj.bjc.6603023 ◽

2006 ◽

Vol 94 (6) ◽

pp. 776-780 ◽

Cited By ~ 691

Author(s):

H-W Hwang ◽

J T Mendell

Keyword(s):

Cell Proliferation ◽

Cell Death

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Suppression of cell proliferation and programmed cell death by dexamethasone during postnatal lung development

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00406.2000 ◽

2002 ◽

Vol 282 (3) ◽

pp. L477-L483 ◽

Cited By ~ 31

Author(s):

Cédric Luyet ◽

Peter H. Burri ◽

Johannes C. Schittny

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Programmed Cell Death ◽

Lung Development ◽

Structural Changes ◽

Tissue Transglutaminase ◽

Lung Parenchyma ◽

Lung Maturation ◽

Morphological Criteria ◽

Postnatal Lung Development

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1–0.01 μg/g, days 1–4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19–21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa ( day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

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Id2 Promotes Apoptosis by a Novel Mechanism Independent of Dimerization to Basic Helix-Loop-Helix Factors

Molecular and Cellular Biology ◽

10.1128/mcb.18.9.5435 ◽

1998 ◽

Vol 18 (9) ◽

pp. 5435-5444 ◽

Cited By ~ 78

Author(s):

Monica Florio ◽

Maria-Clemencia Hernandez ◽

Hui Yang ◽

Hui-Kuo Shu ◽

John L. Cleveland ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Target Genes ◽

Specific Binding ◽

Helix Loop Helix ◽

Cell Death Pathway ◽

Id Proteins ◽

Enhanced Expression ◽

Positive Regulators ◽

Hlh Transcription Factors

ABSTRACT Members of the helix-loop-helix (HLH) family of Id proteins have demonstrated roles in the regulation of differentiation and cell proliferation. Id proteins inhibit differentiation by HLH-mediated heterodimerization with basic HLH transcription factors. This blocks their sequence-specific binding to DNA and activation of target genes that are often expressed in a tissue-specific manner. Id proteins can also act as positive regulators of cell proliferation. The different mechanisms proposed for Id-mediated promotion of entry into S phase also involve HLH-mediated interactions affecting regulators of the G1/S transition. We have found that Id2 augments apoptosis in both interleukin-3 (IL-3)-dependent 32D.3 myeloid progenitors and U2OS osteosarcoma cells. We could not detect a similar activity for Id3. In contrast to the effects of Id2 on differentiation and cell proliferation, Id2-mediated apoptosis is independent of HLH-mediated dimerization. The ability of Id2 to promote cell death resides in its N-terminal region and is associated with the enhanced expression of a known component of the programmed cell death pathway, the proapoptotic gene BAX.

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360 BIO, the GSK3 beta blocker, is a potent inhibitor of cell proliferation and inducer of cell death of cervical carcinoma and rhabdomyosarcoma tumor cells

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(10)72067-x ◽

2010 ◽

Vol 8 (7) ◽

pp. 114

Author(s):

M. Majka ◽

W. Bobela ◽

K. Miekus

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Tumor Cells ◽

Cervical Carcinoma ◽

Beta Blocker ◽

Potent Inhibitor

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miR-103 Functions as a Tumor Suppressor by Directly Targeting Programmed Cell Death 10 in NSCLC

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x15000757094686 ◽

2018 ◽

Vol 26 (4) ◽

pp. 519-528 ◽

Cited By ~ 10

Author(s):

Dong Yang ◽

Jian-Jun Wang ◽

Jin-Song Li ◽

Qian-Yu Xu

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Death ◽

Programmed Cell Death ◽

Tumor Size ◽

Apoptotic Cell ◽

A549 Cells ◽

Invasion And Migration ◽

Metastatic Capacity ◽

And Migration

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases. Absence of miR-103 has recently been identified to be associated with metastatic capacity of primary lung tumors. However, the exact role of miR-103 in NSCLC and the molecular mechanism are unclear. In the present study, we showed that miR-103 expression was reduced in NSCLC tissues and cells. miR-103 expression was negatively correlated with tumor size and stage. The overall survival was longer in patients with higher miR-103 level than in those with lower miR-103 expression. miR-103 inhibited cell proliferation in A549 cells, decreased tumor weight and volume, and prolonged survival of tumor-implanted nude mice. miR-103 increased apoptotic cell death in A549 cells. Furthermore, miR-103 decreased the invasion and migration abilities in A549 cells, as evidenced by Transwell and wound healing results. Downregulation of miR-103 significantly reduced the level of programmed cell death 10 (PDCD10). We found a significant decrease in the relative luciferase activity of the reporter gene in A549 cells cotransfected with the miR-103 mimic and pGL3-PDCD10 WT 3′-UTR, but not pGL3-PDCD10 mut 3′-UTR. We showed that overexpression of PDCD10 significantly inhibited miR-103-induced inhibition of cell proliferation, increased apoptosis, and decreased invasion and migration in A549 cells. Moreover, we found that PDCD10 expression was increased in NSCLC tissues and cells. PDCD10 expression was positively correlated with tumor size and stage. Overexpression of PDCD10 increased cell proliferation and inhibited apoptosis in A549 cells. The data demonstrated that dysregulation of the miR-103/PDCD10 signal may be a novel therapeutic target for the treatment of NSCLC.

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