Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

<p>Abstract</p> <p>Background</p> <p>Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that <it>Atm/Brca1 </it>double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in <it>Atm </it>and <it>Brca1 </it>heterozygosity.</p> <p>Methods</p> <p>Wild type cells, <it>Atm </it>or <it>Brca1 </it>single heterozygous cells, and <it>Atm</it>/<it>Brca1 </it>double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation.</p> <p>Results</p> <p>Remarkable high transformation frequency was confirmed in <it>Atm</it>/<it>Brca1 </it>double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways.</p> <p>Conclusions</p> <p>The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.</p

Condition monitoring and fault diagnosis methods for low-speed and heavy-load slewing bearings: a literature review

Low-speed and heavy-load slewing bearings are applied broadly for major mechanical equipment. Compared with ordinary bearings, large slewing bearings have complex structures and work in variable environments. In order to increase productivity, reduce maintenance costs, and ensure the safety of people and equipment, it is of great importance to monitor and diagnose faults in real time. This paper aims at providing a state-of-the-art review on methods for condition monitoring and fault diagnosis of low-speed and heavy-load slewing bearings, including methods based on vibration analysis, acoustic emission technique, oil condition and temperature variation. Additionally, this paper discusses advantages and disadvantages of different methods. Finally, the current needs and challenges are presented to provide a reference for future research

Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis

In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins

Homologous Recombination Repair Mechanism in Clustered DNA Damage (18J430-FY2018)

Compared with low let induced simple DSBs, high LET carbon beams induced cluster DSBs include different type of DNA damage: DSBs, SSBs, cross-link, base damage, etc. In our previous data, we confirmed HR Pathway was More Relevant in response Carbon ions induced cluster DNA damage. Different types of repair pathway had important roles in cluster DNA damage in S phase cells. In this project we want to investigate how homologous recombination repair pathway works in clustered DNA damage utilizing HIMAC heavy ion accelerator terminal: 1) In cluster DNA damage, following DSBs end resection, whether other types of DNA damage are also modified or even cut. What kinds of enzyme play this role; 2) Through modified Idu-ChIP assay, we will screen what kind of repair factors play central role in this process; 3) Through multi-fluorescence DNA fiber assay, we will assess how these factors regulate DNA replication progress.This project will characterize unique detail in cluster DNA damage repair mechanism, which is separate with simple DSBs. This will support the basic theory for modifying and developing potential technique in heavy radiotherapy

Homologous Recombination Repair Mechanism in Clustered DNA Damage (18J430-FY2018)

Compared with low let induced simple DSBs, high LET carbon beams induced cluster DSBs include different type of DNA damage: DSBs, SSBs, cross-link, base damage, etc. In our previous data, we confirmed HR Pathway was More Relevant in response Carbon ions induced cluster DNA damage. Different types of repair pathway had important roles in cluster DNA damage in S phase cells. In this project we want to investigate how homologous recombination repair pathway works in clustered DNA damage utilizing HIMAC heavy ion accelerator terminal: 1) In cluster DNA damage, following DSBs end resection, whether other types of DNA damage are also modified or even cut. What kinds of enzyme play this role; 2) Through modified Idu-ChIP assay, we will screen what kind of repair factors play central role in this process; 3) Through multi-fluorescence DNA fiber assay, we will assess how these factors regulate DNA replication progress.This project will characterize unique detail in cluster DNA damage repair mechanism, which is separate with simple DSBs. This will support the basic theory for modifying and developing potential technique in heavy radiotherapy.平成30年度放射線医学総合研究所　重粒子線がん治療装置等共同利用研究報告

Combined Failure Diagnosis of Slewing Bearings Based on MCKD-CEEMD-ApEn

Large-size and heavy-load slewing bearings, which are mainly used in heavy equipment, comprise a subgroup of rolling bearings. Owing to the complexity of the structures and working conditions, it is quite challenging to effectively diagnose the combined failure and extract fault features of slewing bearings. In this study, a method was proposed to denoise and classify the combined failure of slewing bearings. First, after removing the mean, the vibration signals were denoised by maximum correlated kurtosis deconvolution. The signals were then decomposed into several intrinsic mode functions (IMFs) by complementary ensemble empirical mode decomposition (CEEMD). Appropriate IMFs were selected based on the correlation coefficient and kurtosis. The approximate entropy values of the selected IMFs were regarded as the characteristic vectors and then inputted into the support vector machine (SVM) based on multiclass classification for training. The practical combined failure signals of the 3 conditions were finally recognized and classified using SVMs. The study also compared the proposed method with 5 other methods to demonstrate the superiority and effectiveness of the proposed method

Nipple sparing mastectomy in breast cancer patients and long-term survival outcomes: An analysis of the SEER database

<div><p>Purpose</p><p>To determine the prevalence of nipple-sparing mastectomy (NSM) and its long-term survival outcomes in breast cancer patients.</p><p>Method</p><p>We used the Surveillance, Epidemiology, and End Results database and identified 2,440 breast cancer patients who received NSM during 1998–2013. We used chi-square and binary logistic regression to identify factors associated with the use of radiotherapy after NSM. We used Kaplan-Meier analysis to estimate cancer-specific survival (CSS) and overall survival (OS). We used the log-rank test and Cox regression to identify factors associated with CSS and OS.</p><p>Results</p><p>The median age of the population was 50 years. There were 725 (29.7%), 1064 (43.6%) and 651 (26.7%) patients who had Tis, T1 and T2-3 disease and 1943 (79.6%), 401 (16.4%) and 96 (3.9%) patients who had N0, N1 and N2-3 disease, respectively. The rates of RT use were 61.4%, 39.6% and 10.9% in patients with N2-3 disease, N1 or T3/N0 disease and Tis/T1-2N0 disease, respectively. Elderly age, African American race, and higher T-stage and N-stage were associated with receiving radiotherapy. For patients diagnosed between 1998–2010 (N = 763), the median follow-up was 69 months. The 5- and 10-yr CSS were 96.9% and 94.9%, respectively. The 5- and 10-yr OS were 94.1% and 88.0%, respectively. Ethnicity, T-stage and N-stage were factors independently associated with CSS, and age and T-stage were factors independently associated with OS.</p><p>Conclusions</p><p>The use of NSM has increased, and it is oncologically safe for breast cancer patients.</p></div