Search results for "GENETICS"

Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma

2017

Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. I…

Intron variants of the p53 gene are associated with increased risk for ovarian cancer but not in carriers of BRCA1 or BRCA2 germline mutations

1999

Two biallelic polymorphisms in introns 3 and 6 of the p53 gene were analysed for a possible risk-modifying effect for ovarian cancer. Germline DNA was genotyped from 310 German Caucasian ovarian cancer patients and 364 healthy controls. We also typed 124 affected and 276 unaffected female carriers with known deleterious BRCA1 or BRCA2 germline mutation from high-risk breast-ovarian cancer families. Genotyping was based on PCR and high-resolution gel electrophoresis. German ovarian cancer patients who carried the rare allele of the MspI restriction fragment length polymorphism (RELP) in intron 6 were found to have an overall 1.93-fold increased risk (95% confidence internal (CI) 1.27–2.91) w…

High-SETD8 inactivates p53 in neuroblastoma

2017

Endoderm development requires centrioles to restrain p53-mediated apoptosis in the absence of ERK activity

2021

Centrioles comprise the heart of centrosomes, microtubule-organizing centers. To study the function of centrioles in lung and gut development, we genetically disrupted centrioles throughout the mouse endoderm. Surprisingly, removing centrioles from the endoderm did not disrupt intestinal growth or development but blocked lung branching. In the lung, acentriolar SOX2-expressing airway epithelial cells apoptosed. Loss of centrioles activated p53, and removing p53 restored survival of SOX2-expressing cells, lung branching, and mouse viability. To investigate how endodermal p53 activation specifically killed acentriolar SOX2-expressing cells, we assessed ERK, a prosurvival cue. ERK was active t…

Digital control circuitry for the p53 dynamics in cancer cell and apoptosis

2010

Abstract Experimental work and theoretical models deduce a “digital” response of the p53 transcription factor when genomic integrity is damaged. The mutual influence of p53 and its antagonist, the Mdm2 oncogene, is closed in a feedback. This paper proposes an aerospace-based architecture for translating the p53/Mdm2/DNA damage network into a digital circuitry in which the optimal control theory is applied for obtaining the requested dynamic evolutions of some considered cell species for repairing a DNA damage. The purpose of this paper is to demonstrate the usefulness of such digital circuitry design to detect and predict the cell species dynamics for shedding light on their inner and mutua…

Mutations in p53 Gene Exons in a Sample from the South of Spain in Oral Cancer

2021

[Background+ Cancer is a genetic disease caused by mutations in DNA and epigenetic alterations that control gene expression. The majority of epidermoid carcinomas develop within the fields of epithelial genetic alterations. The mechanisms underlying tumorigenesis of epidermoid carcinoma are as yet unknown; therefore, precise identification of the risk factors is needed.

Reliability of Frail and Barthel Tests for Detecting Frailty in Palliative Oncological Patients in a Home Hospitalization Unit: A Comparative Study.

2022

Cancer is a condition that can increase the risk of frailty. In addition, palliative oncological patients in home hospitalization can find their activities of daily living affected. The main objective was to measure the degree of frailty in the oncological population in home hospitalization comparing Barthel and Frail-VIG Indexes. This is a descriptive cross-sectional study. A sample of oncological patients in home hospitalization (n = 50) that included 27 men and 23 women were recruited, and disability due to frailty was measured using the VIG frailty index and the Barthel scale for Activities of Daily Living (ADLs). Spearman’s correlation coefficients were categorized as weak (rs &l…

The Palliative Care in the Metastatic Spinal Tumors. A Systematic Review on the Radiotherapy and Surgical Perspective

2022

Spine represents the most common site for metastatic disease involvement. Due to the close relationship between the spinal cord and critical structures, therapeutic management of spinal metastases remains challenging. Spinal localization can lead to neurological sequelae, which can significantly affect the quality of life in patients with a limited life expectancy. The authors conducted a systematic literature review according to PRISMA guidelines in order to determine the impact of the most updated palliative care on spinal metastases. The initial literature search retrieved 2526 articles, manually screened based on detailed exclusion criteria. Finally, 65 studies met the inclusion criteri…

Gender differences in the battle against COVID‐19: Impact of genetics, comorbidities, inflammation and lifestyle on differences in outcomes

2020

Abstract It has been over six months now since the entire globe was struck by the new Coronavirus Disease 2019 (COVID‐19; aka severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]), which has affected 215 nations. The medical and scientific communities continue to search for and study potential treatments for COVID‐19 as well as an effective vaccine. As of 21 June 2020, 11.4 million cases have been confirmed worldwide, with approximately 530,000 deaths. A large number of scientific papers have been produced, hundreds of thousands of patients have been hospitalized and studied, several treatments and vaccines are being tested in randomized clinical trials, social distancing regulation…

Evolutionary Dynamics of Pathoadaptation Revealed by Three Independent Acquisitions of the VirB/D4 Type IV Secretion System in Bartonella

2017

The α-proteobacterial genus Bartonella comprises a group of ubiquitous mammalian pathogens that are studied as a model for the evolution of bacterial pathogenesis. Vast abundance of two particular phylogenetic lineages of Bartonella had been linked to enhanced host adaptability enabled by lineage-specific acquisition of a VirB/D4 type IV secretion system (T4SS) and parallel evolution of complex effector repertoires. However, the limited availability of genome sequences from one of those lineages as well as other, remote branches of Bartonella has so far hampered comprehensive understanding of how the VirB/D4 T4SS and its effectors called Beps have shaped Bartonella evolution. Here, we repor…