scholarly journals Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

2020 ◽  
Author(s):  
Nicoleta Anghel ◽  
Pablo A. Winzer ◽  
Dennis Imhof ◽  
Joachim Müller ◽  
Javier Langa ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Embryo Development ◽  
Mammalian Cells ◽  
Zebrafish Embryo ◽  
Kinase Inhibitors ◽  
Corn Oil ◽  
Neospora Caninum ◽  
Clear Correlation ◽  
Related Factors ◽  
The Impact

AbstractBumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice, were assessed in pregnant mice. Drugs were emulsified in corn oil and applied by gavage for 5 days. Five BKIs did not affect pregnancy, 5 BKIs exhibited 15-35% of neonatal mortality, and 5 compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilized eggs to 0.2-50μM of BKIs and microscopical monitoring of embryo development in a blinded manner during 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows to calculate an impact score (Si) that indicates at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for 9 compounds no clear correlation between Si and pregnancy outcome was visible. However, those 3 BKIs affecting zebrafish embryos only at high concentrations (40μM or higher) did not impair mouse pregnancy at all, and those 3 compounds that inhibited zebrafish embryo development already at 0.2μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has a limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude, that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects.

scholarly journals Zinc transporter ZIP10 forms a heteromer with ZIP6 which regulates embryonic development and cell migration

2016 ◽  
Vol 473 (16) ◽  
pp. 2531-2544 ◽  
Author(s):  
Kathryn M. Taylor ◽  
Issa A. Muraina ◽  
Dylan Brethour ◽  
Gerold Schmitt-Ulms ◽  
Thirayost Nimmanon ◽  
...  
Keyword(s):  
Cell Migration ◽  
Embryonic Development ◽  
Embryo Development ◽  
Mammalian Cells ◽  
Zebrafish Embryo ◽  
Zinc Transporter

Zinc is involved in cell migration during embryo development and in cancer. We show that a zinc transporter consisting of two proteins, ZIP6 and ZIP10, stimulates both cell migration and division in mammalian cells and in the zebrafish embryo.

Prospective, observational registry of branded imatinib (IM) and nilotinib (NIL) exposure in pregnant women: Voluntary post-authorization safety study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS6638-TPS6638
Author(s):  
Matthews Juma ◽  
Solveig Ericson ◽  
Dawn Fun Eng ◽  
Sandip Acharya ◽  
Darshan Wariabharaj ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Birth Defects ◽  
Kinase Inhibitors ◽  
Disease Status ◽  
Treatment Interruption ◽  
Primary Objective ◽  
Childbearing Age ◽  
Adverse Pregnancy ◽  
Maternal Disease ◽  
The Impact

TPS6638 Background: Family planning decisions for cancer patients of childbearing age are impacted by their diagnosis. IM and NIL are category D drugs (demonstrated risk to the fetus based on mechanism of action and findings in animals; however, the benefits of therapy may outweigh the potential risk to the fetus); women should be advised not to become pregnant when taking these drugs. Limited data exist concerning safety of these drugs during pregnancy and consequences of interrupting treatment. The registry does not recommend patients receiving IM or NIL become pregnant, but serves only to document exposures that occur, and collect information on pregnancy outcome, maternal course of disease, and infant follow-up. Methods: The registry intends to enroll 150 women (≥18 years) treated with branded IM and NIL within 6 mo before or during pregnancy (generic IM and NIL reports are excluded). Schedule of visits and treatment is according to local standard of care. Women are divided into 2 exposure cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs) within 14 d of conception or at any time during pregnancy; 2) interrupted TKI: received TKIs within 6 mo before conception but interrupted TKIs in preparation for/due to pregnancy. To identify signals of teratogenicity, the registry uses a general population baseline rate of birth defects, and the prevalence of defects in cohorts 1 and 2 may be compared. Cases are quantitatively analyzed for the emergence of unique defects or patterns of defects. Primary objective: monitor TKI-exposed pregnancies to estimate the prevalence of birth defects (calculated by dividing number of birth defects by total number of exposed live births from cohort 1). Secondary objectives are to: 1) determine the impact of treatment interruption on maternal disease status; 2) assess and estimate the prevalence of serious adverse pregnancy outcomes; and 3) assess and estimate the prevalence of developmental delays and functional deficits among infants during the first year of life. Maternal disease status is analyzed, comparing disease status at registration, pregnancy outcome, and 1 y after birth, stratified by length of TKI interruption.

scholarly journals Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

2020 ◽  
Vol 56 (3) ◽  
pp. 106099
Author(s):  
Nicoleta Anghel ◽  
Pablo A. Winzer ◽  
Dennis Imhof ◽  
Joachim Müller ◽  
Xavier Langa ◽  
...  
Keyword(s):  
Embryo Development ◽  
Zebrafish Embryo ◽  
Kinase Inhibitors ◽  
Comparative Assessment

Does kraft hardwood and softwood pulp viscosity correlate to paper properties?

TAPPI Journal ◽  
2016 ◽  
Vol 15 (10) ◽  
pp. 643-651 ◽  
Author(s):  
ROBERT J. OGLESBY ◽  
HUMPHREY J. MOYNIHAN ◽  
RICARDO B. SANTOS ◽  
ASHOK GHOSH ◽  
PETER W. HART
Keyword(s):  
Physical Properties ◽  
Strength Loss ◽  
Strength Properties ◽  
Clear Correlation ◽  
Paper Properties ◽  
Physical Strength ◽  
Pulp Viscosity ◽  
Softwood Pulp ◽  
The Impact ◽  
Related Paper

The impact of commercially prepared, fully bleached pulp viscosity variation on handsheet physical properties was evaluated at different levels of pulp refining. Hardwood pulps from the same brownstock species mix, cooking parameters, and kappa numbers were processed through two different commercial bleach plants: one with a D0(EP)D1D2 sequence and the second with an OD0(EOP)D1 sequence. Additionally, a commercial softwood (predominately Scotts pine) brownstock pulp bleached by an OD0(EP)D1D2 sequence was employed in this study. Pulps with viscosities ranging from 14 to 21 mPa∙s were refined in a Valley beater to two freeness levels, and the associated handsheet physical properties were measured in this study. Over the pulp viscosity range of 14 to 21 mPa∙s, no clear correlation was found to exist between pulp viscosity and related paper physical properties. Finally, a series of laboratory prepared bleached pulps were purposely prepared under non-ideal conditions to reduce their final viscosities to lower values. Handsheets made from these pulps were tested in their unbeaten condition for physical strength properties. Significant and rapid strength loss occurred when the measured pulp viscosity dropped below 12 mPa∙s; overall strength properties showed no correlation to viscosity above the critical 12 mPa∙s value.

A Study On Impact Of Work Life Related Factors On Employee Engagement In Health Care Sector Workers In Dindigul District.

2019 ◽  
Vol 118 (7) ◽  
pp. 20-26
Author(s):  
S. JAYARAMAN ◽  
R. Sindhya ◽  
P. Vijiyalakshmi
Keyword(s):  
Health Care ◽  
Path Analysis ◽  
Employee Engagement ◽  
Health Care Workers ◽  
Health Care Sector ◽  
Work Life ◽  
Primary Data ◽  
Related Factors ◽  
Care Workers ◽  
The Impact

this research aims to find out the intensity of Employee Engagement of the health care sector workers and the relationship between the Work life factors and Employee Engagement of Health care sector workers in Dindigul District. Primary data were used in this research, were collected from 298 Health care workers from Dindigul District. Questionnaire was the major tool used to gather the primary data from the selected sample respondents. For this purpose, a well structured questionnaire was constructed with the help of professionals and the practiced employees of various health care units in Dindigul District. The health care employees were chosen by simple random sampling method. The investigative measures of regression Path analysis, and simple percentage analysis were utilized to find the impact of work life related factors with the Employee Engagement. The maximum Health care workers were generally satisfied with their jobs. The analytical procedure of path analysis multiple regressions was utilized to determine the predicting strength among Work life factors and the employee engagement. This study provides an another view about the importance of Work life factors and Employee engagement for organizational effectiveness and performance .

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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