scholarly journals A Preliminary Study on the Impact of UCK2 Knockdown in DLD-1 Colorectal Cells Treated with DHODH Inhibitor

2021 ◽  
Vol 50 (7) ◽  
pp. 1935-1946
Author(s):  
Mohamad Fairus Abdul Kadir ◽  
Puteri Shafinaz Abdul-Rahman ◽  
Kavitha Nellore ◽  
Shatrah Othman
Keyword(s):  
Dihydroorotate Dehydrogenase ◽  
Wild Type ◽  
Salvage Pathway ◽  
Reversal Effect ◽  
Proliferative Effect ◽  
Dna And Rna ◽  
Brequinar Sodium ◽  
Cell Proliferation Inhibition ◽  
Preliminary Study ◽  
The Impact

Brequinar sodium (BQR) is a well-studied inhibitor of the dihydroorotate dehydrogenase (DHODH) enzyme. Both the DHODH and uridine-cytidine kinase 2 (UCK2) enzymes have been reported to be over-expressed in cancer cells to maintain the cells high demand for DNA and RNA for their proliferation. In this study, we aim to further sensitize cells to the effects of BQR by knocking down the UCK2 activity. In DLD-1 UCK2 knockdown cells, no change in the sensitivity of cells to BQR was observed. Uridine is known to reverse the anti-proliferative effect of DHODH inhibitors via the salvage pathway. We observed abrogation of approximately 30% of the uridine reversal effect in UCK2 knockdown cells compared to the wild type cells. Our finding indicates that the loss of UCK2 activity in the salvage pathway did not enhance the BQR-mediated cell proliferation inhibition but it abrogates the uridine reversal in the cells.

Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice

2015 ◽  
Vol 223 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Christina Leibrock ◽  
Michael Hierlmeier ◽  
Undine E. Lang ◽  
Florian Lang
Keyword(s):  
Forced Swimming Test ◽  
Open Field Test ◽  
Wild Type ◽  
Average Speed ◽  
Closed Area ◽  
Light Area ◽  
Swimming Test ◽  
The Impact ◽  
Center Area ◽  
Dark Transition

Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.

Preliminary Study of the Impact of Critical Success Factors on Project Success in Pakistan

2014 ◽  
Vol 1 (4) ◽  
pp. 9-13 ◽  
Author(s):  
Aqeel Ahmed ◽  
Muhammad Sehail Younis
Keyword(s):  
Critical Success Factors ◽  
Success Factors ◽  
Project Success ◽  
Workforce Planning ◽  
Survey Instrument ◽  
Past Performance ◽  
Cronbach Alpha ◽  
Critical Success ◽  
Preliminary Study ◽  
The Impact

This preliminary study attempts to link among the critical success factors on overall project success in public sector organizations in Pakistan.  In this study it’s reflected that major critical success factors (soundness of Business & workforce, planning & control, quality performance and past performance) can enhance the success of the project in Pakistan.  The purpose of this preliminary study was to verify the reliability of the survey instrument which has been used in European countries. It was found that the planning & control was the highest Cronbach Alpha value, while the ranged for each constructs in the present study from 0.68 to 0.88.  Therefore, based on the Cronbach alpha value score, the proposed survey instrument has fulfilled the basic requirement of a valid instrument.

scholarly journals Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 772
Author(s):  
Javier Conde ◽  
Marlene Schwarzfischer ◽  
Egle Katkeviciute ◽  
Janine Häfliger ◽  
Anna Niechcial ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Titanium Dioxide ◽  
Genetic Risk ◽  
Intestinal Inflammation ◽  
Sodium Sulphate ◽  
Food Additive ◽  
Wild Type ◽  
Dextran Sodium Sulphate ◽  
Risk Gene ◽  
The Impact

Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk

Abnormal Spinal Cord Myelination due to Oligodendrocyte Dysfunction in a Model of Huntington’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Costanza Ferrari Bardile ◽  
Harwin Sidik ◽  
Reynard Quek ◽  
Nur Amirah Binte Mohammad Yusof ◽  
Marta Garcia-Miralles ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Oligodendrocyte Progenitor Cells ◽  
Wild Type ◽  
Specific Expression ◽  
Relative Contribution ◽  
Related Proteins ◽  
The Impact ◽  
Cervical Area

Background: The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington’s disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective: We aim to characterize spinal cord WM abnormalities in a mouse model of HD and evaluate whether selective removal of mutant huntingtin (mHTT) from oligodendroglia rescues these deficits. Methods: Histological assessments were used to determine the area of GM and WM in the spinal cord of 12-month-old BACHD mice, while electron microscopy was used to analyze myelin fibers in the cervical area of the spinal cord. To investigate the impact of inactivation of mHTT in oligodendroglia on these measures, we used the previously described BACHDxNG2Cre mouse line where mHTT is specifically reduced in oligodendrocyte progenitor cells. Results: We show that spinal GM and WM areas are significantly atrophied in HD mice compared to wild-type controls. We further demonstrate that specific reduction of mHTT in oligodendroglial cells rescues the atrophy of spinal cord WM, but not GM, observed in HD mice. Inactivation of mHTT in oligodendroglia had no effect on the density of oligodendroglial cells but enhanced the expression of myelin-related proteins in the spinal cord. Conclusion: Our findings demonstrate that the myelination abnormalities observed in brain WM structures in HD extend to the spinal cord and suggest that specific expression of mHTT in oligodendrocytes contributes to such abnormalities.

A First Step towards a Tribological Approach to Investigate Cutting Tool Wear

2014 ◽  
Vol 611-612 ◽  
pp. 452-459 ◽  
Author(s):  
Giovenco Axel ◽  
Frédéric Valiorgue ◽  
Cédric Courbon ◽  
Joël Rech ◽  
Ugo Masciantonio
Keyword(s):  
Tool Wear ◽  
Cutting Tool ◽  
304L Stainless Steel ◽  
Fe Modelling ◽  
Wear Model ◽  
Cutting Tool Wear ◽  
The Will ◽  
Preliminary Study ◽  
The Impact ◽  
Macroscopic Parameters

The present work is motivated by the will to improve Finite Element (FE) Modelling of cutting tool wear. As a first step, the characterisation of wear mechanisms and identification of a wear model appear to be fundamental. The key idea of this work consists in using a dedicated tribometer, able to simulate relevant tribological conditions encountered in cutting (pressure, velocity). The tribometer can be used to estimate the evolution of wear versus time for various tribological conditions (pressure, velocity, temperature). Based on this design of experiments, it becomes possible to identify analytically a wear model. As a preliminary study this paper will be focused on the impact of sliding speed at the contact interface between 304L stainless steel and tungsten carbide (WC) coated with titanium nitride (TiN) pin. This experiment enables to observe a modification of wear phenomena between sliding speeds of 60 m/min and 180 m/min. Finally, the impact on macroscopic parameters has been observed.

scholarly journals Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

2008 ◽  
Vol 26 (33) ◽  
pp. 5352-5359 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robert G. Maki ◽  
Christopher L. Corless ◽  
Cristina R. Antonescu ◽  
Amy Harlow ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Clinical Activity ◽  
Wild Type ◽  
Mutational Status ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11 ◽  
The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

Impact of the cystic fibrosis mutation F508del-CFTR on renal cyst formation and growth

2012 ◽  
Vol 303 (8) ◽  
pp. F1176-F1186 ◽  
Author(s):  
Hongyu Li ◽  
Wanding Yang ◽  
Filipa Mendes ◽  
Margarida D. Amaral ◽  
David N. Sheppard
Keyword(s):  
Cystic Fibrosis ◽  
Cell Proliferation ◽  
Mdck Cells ◽  
Ussing Chamber ◽  
Cyst Formation ◽  
Transepithelial Resistance ◽  
Collagen Gels ◽  
Wild Type ◽  
Fluid Accumulation ◽  
The Impact

In autosomal dominant polycystic kidney disease (ADPKD), cystic fibrosis transmembrane conductance regulator (CFTR), the protein product of the gene defective in cystic fibrosis (CF), plays a crucial role in fluid accumulation, which promotes cyst swelling. Several studies have identified individuals afflicted by both ADPKD and CF. Two studies suggested that CF mutations might attenuate the severity of ADPKD, whereas a third found no evidence of a protective effect. In this study, we investigated the impact of the commonest CF mutation F508del-CFTR on the formation and growth of renal cysts. As a model system, we used Madin-Darby canine kidney (MDCK) epithelial cells engineered to express wild-type and F508del human CFTR. We grew MDCK cysts in collagen gels in the presence of the cAMP agonist forskolin and measured transepithelial resistance and Cl− secretion with the Ussing chamber technique and assayed cell proliferation using nonpolarized MDCK cells. When compared with untransfected MDCK cells, cells expressing wild-type CFTR generated substantial numbers of large cysts, which grew markedly over time. By contrast, MDCK cells expressing F508del-CFTR formed very few tiny cysts that failed to enlarge. Interestingly, treatment of F508del-CFTR cysts with the CFTR corrector VRT-325 and the CFTR corrector-potentiator VRT-532 increased the number, but not size, of F508del-CFTR cysts, possibly because VRT-325 inhibited strongly cell proliferation. Based on its effects on transepithelial resistance, Cl− secretion, and cell proliferation, we conclude that the F508del-CFTR mutation disrupts cyst formation and growth by perturbing strongly fluid accumulation within the cyst lumen without compromising epithelial integrity.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

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