scholarly journals MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah E. Woodfield ◽  
Yan Shi ◽  
Roma H. Patel ◽  
Zhenghu Chen ◽  
Aayushi P. Shah ◽  
...  
Keyword(s):  
Target Genes ◽  
Strongly Correlated ◽  
Liver Malignancy ◽  
Dual Inhibitor ◽  
Antiproliferative Effects ◽  
Stapled Peptide ◽  
P53 Signaling ◽  
Risk Patients ◽  
P53 Target Genes

AbstractHepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.

Abstract B35: Reactivation of p53 signaling in hepatoblastoma with a stapled peptide dual inhibitor of MDM2 and MDM4

2018 ◽  
Author(s):  
Sarah E. Woodfield ◽  
Roma H. Patel ◽  
Aryana M. Ibarra ◽  
Zhenghu Chen ◽  
Sanjeev A. Vasudevan
Keyword(s):  
Dual Inhibitor ◽  
Stapled Peptide ◽  
P53 Signaling

scholarly journals The p53-signaling pathway and colorectal cancer: Interactions between downstream p53 target genes and miRNAs

Genomics ◽  
2019 ◽  
Vol 111 (4) ◽  
pp. 762-771 ◽  
Author(s):  
Martha L. Slattery ◽  
Lila E. Mullany ◽  
Roger K. Wolff ◽  
Lori C. Sakoda ◽  
Wade S. Samowitz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Target Genes ◽  
P53 Signaling ◽  
P53 Target Genes ◽  
P53 Signaling Pathway

381: Promoter Hypermethylation Profile of Kidney Cancer with New Pro-Apoptotic P53 Target Genes and Possible Clinical Implications

2006 ◽  
Vol 175 (4S) ◽  
pp. 125-125
Author(s):  
Frank Christoph ◽  
Steffen Weikert ◽  
Carsten Kempkensteffen ◽  
Martin Schostak ◽  
Hans Krause ◽  
...  
Keyword(s):  
Kidney Cancer ◽  
Target Genes ◽  
Promoter Hypermethylation ◽  
Clinical Implications ◽  
P53 Target Genes

The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

2020 ◽  
Vol 15 (2) ◽  
pp. 154-164 ◽  
Author(s):  
Ijaz Muhammad ◽  
Noor Rahman ◽  
Gul E. Nayab ◽  
Sadaf Niaz ◽  
Mohibullah Shah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Therapy ◽  
Natural Product ◽  
Signaling Pathway ◽  
In Silico ◽  
P53 Protein ◽  
Dual Inhibitor ◽  
P53 Signaling ◽  
In Silico Studies ◽  
P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

scholarly journals Widespread gaps in the quality of care for primary biliary cholangitis in UK

2021 ◽  
pp. flgastro-2020-101713
Author(s):  
Mathuri Sivakumar ◽  
Akash Gandhi ◽  
Eathar Shakweh ◽  
Yu Meng Li ◽  
Niloufar Safinia ◽  
...  
Keyword(s):  
Quality Of Care ◽  
Medical Records ◽  
Clinical Symptoms ◽  
Primary Biliary Cholangitis ◽  
Cholestatic Liver Disease ◽  
Patient Demographics ◽  
Risk Patients ◽  
Wide Scale ◽  
The Uk

ObjectivePrimary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines.DesignData were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ2 analysis for variation in performance between trusts.Results790 patients’ medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297).ConclusionOur findings identify a broad-based deficiency in ‘real-world’ PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.

scholarly journals Case-finding for COPD clinic acceptability to patients in GPs across Hampshire: a qualitative study

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Danielle Rose ◽  
Emma Ray ◽  
Rachael H. Summers ◽  
Melinda Taylor ◽  
Helen Kruk ◽  
...  
Keyword(s):  
Negative Impact ◽  
Case Finding ◽  
Lifestyle Changes ◽  
Self Management ◽  
Mortality And Morbidity ◽  
Telephone Interviews ◽  
Shared Information ◽  
Risk Patients ◽  
Perceived Effects

AbstractDespite high mortality and morbidity, COPD remains under-diagnosed. Case-finding strategies are possible, but patients’ perspectives are unexplored. Using qualitative methods, we explored the patient perspective of a case-finding intervention among at-risk patients in primary care. Semi-structured telephone interviews were transcribed and thematic analysis utilised. Seven patients without (mean age 64.5 years (58–74), n = 4) and 8 with obstructed spirometry (mean age 63.5 (53–75), n = 4) were interviewed. Themes identified were motives, challenges and concerns regarding attending the clinic. These included wanting to be well; to help with research; concern over negative impact to life from COPD diagnosis; perceived utility of the clinic; quality of information given; staff manner, approachability and knowledge; and perceived effects of the clinic on lifestyle, self-management and symptoms. The intervention was generally deemed useful and reassuring, although shared information was too detailed or irrelevant for some. Several reported positive lifestyle changes, improved symptoms and improved self-management.

scholarly journals Residual Corticosteroid Production in Autoimmune Addison Disease

2020 ◽  
Vol 105 (7) ◽  
pp. 2430-2441
Author(s):  
Åse Bjorvatn Sævik ◽  
Anna-Karin Åkerman ◽  
Paal Methlie ◽  
Marcus Quinkler ◽  
Anders Palmstrøm Jørgensen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Disease Duration ◽  
Plasma Renin ◽  
Serum Cortisol ◽  
Strongly Correlated ◽  
Cross Sectional ◽  
Addison Disease ◽  
Serum Aldosterone ◽  
Liquid Chromatography Tandem Mass

Abstract Context Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after &gt; 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P &lt; 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P &lt; 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P &lt; 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P &lt; 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P &lt; 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P &lt; 0.001) and plasma adrenocorticotropic hormone (ACTH; r = –0.487; P &lt; 0.001). Conclusion In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.

244An automated beat exclusion algorithm to improve beat-to-beat P-wave morphology analysis

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
D Tachmatzidis ◽  
D Filos ◽  
I Chouvarda ◽  
A Tsarouchas ◽  
D Mouselimis ◽  
...  
Keyword(s):  
P Wave ◽  
Strongly Correlated ◽  
Wave Analysis ◽  
Morphology Analysis ◽  
Wave Morphology ◽  
History Of ◽  
Ectopic Beats ◽  
Rater Variability ◽  
Operator Workload

Abstract Background A manually beat-to-beat P-wave analysis has previously revealed the existence of multiple P-wave morphologies in patients with paroxysmal Atrial Fibrillation (AF) while on sinus rhythm, distinguishing them from healthy, AF free patients. Purpose The aim of this study was to investigate the effectiveness of an Automated Beat Exclusion algorithm (ABE) that excludes noisy or ectopic beats, replacing manual beat evaluation during beat-to-beat P-wave analysis, by assessing its effect on inter-rater variability and reproducibility. Methods Beat-to-beat P-wave morphology analysis was performed on 34 ten-minute ECG recordings of patients with a history of AF. Each recording was analyzed independently by two clinical experts for a total of four analysis runs; once with ABE and once again with the manual exclusion of ineligible beats. The inter-rater variability and reproducibility of the analysis with and without ABE were assessed by comparing the agreement of analysis runs with respect to secondary morphology detection, primary morphology ECG template and the percentage of both, as these aspects have been previously used to discriminate PAF patients from controls. Results Comparing ABE to manual exclusion in detecting secondary P-wave morphologies displayed substantial (Cohen"s k = 0.69) to almost perfect (k = 0.82) agreement. Area difference among auto and manually calculated main morphology templates was in every case &lt;5% (p &lt; 0.01) and the correlation coefficient was &gt;0.99 (p &lt; 0.01). Finally, the percentages of beats classified to the primary or secondary morphology per recording by each analysis were strongly correlated, for both main and secondary P-wave morphologies, ranging from ρ=0.756 to ρ=0.940 (picture) Conclusion The use of the ABE algorithm does not diminish inter-rater variability and reproducibility of the analysis. The primary and secondary P-wave morphologies produced by all analyses were similar, both in terms of their template and their frequency. Based on the results of this study, the ABE algorithm incorporated in the beat-to-beat P-wave morphology analysis drastically reduces operator workload without influencing the quality of the analysis. Abstract Figure.

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