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Screening for Colorectal Adenoma and Adenocarcinoma
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
In a recent study from Indianapolis, a multi-target faecal DNA test was compared with a FIT test set at a cut-off of 20 µgHb/g faeces in almost 10,000 asymptomatic people at average risk of colorectal cancer.26 The DNA test comprised quantitative molecular assays for Kras mutations, aberrant NDRG4 and BMP3 methylation and β-actin (a reference gene for human DNA quantity). The sensitivity of the DNA test for cancer was 92.3% compared with 73.8% for FIT, but the specificities were 86.6% and 96.4% respectively amongst participants with non-advanced adenomas or negative finding on colonoscopy. This means that although more cancers would be detected by the DNA test, 13.4% of the whole population with no significant disease (1,228/9,167 in this case) would require a colonoscopy with the DNA test compared with only 3.6% (330) with the FIT test. The main weakness of this study is that it did not take into account the flexibility of the quantitative FIT test, and had the FIT been used at a lower cut-off haemoglobin concentration, it would have achieved better sensitivity albeit at the cost of lower specificity.
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of companies have worked on epigenetics-based risk tests for CRC. For example, Exact Sciences Corporation developed the CologuardTM assay which is based on DNA fragments found in stool samples. This FDA-approved test detects methylated DNA markers (e.g., aberrantly methylated BMP3 and NDRG4 gene promoter regions, mutant KRAS and β-actin) in colorectal cells. It also provides a quantitative immunochemical assay for human hemoglobin in stool samples. It is based on the principle that a tumor or precancerous tissue in the colon will shed cancer cells along with some blood into the gut lumen. Another company, Orion Genomics Inc, developed the Orion Colorectal Cancer Risk TestTM based on the loss of imprinting of the IGF2 gene. This test, not commercialized in its original form, was aimed at identifying individuals at increased risk of developing CRC. Gene imprinting refers to the process by which one copy of the gene (i.e., an allele) is normally expressed, but the other allele is silenced through epigenetic markers of parental origin. When there is a loss of imprinting, both alleles are expressed. IGF2 is a growth-promoting gene and is normally imprinted (i.e., methylated) in humans. The company found that a loss of imprinting of the IGF2 gene in peripheral blood leukocytes could indicate an increased risk of developing CRC. Another approach is to compare the ccfDNA extracted from a patient’s blood samples with a database based on blood samples from individuals with that particular type of cancer. The ccfDNA is amplified and sequenced prior to the comparison. Chronix Biomedical Inc. has been working on this approach and has suggested that supplemental blood tests might be used to detect risk factors associated with prostate and breast cancer.
Methylation profile of colon cancer genes in colorectal precursor lesions and tumor tissue: perspectives for screening
Published in Scandinavian Journal of Gastroenterology, 2021
Thais Sobanski, Lidia Maria Rebolho Batista Arantes, Wellington dos Santos, Marcus Matsushita, Marco Antonio de Oliveira, Maraisa Costa, Ana Carolina de Carvalho, Gustavo Noriz Berardinelli, Kari Syrjänen, Rui Manuel Reis, Denise Peixoto Guimarães
Two other promising diagnostic markers investigated in the present study were NDRG4 and BMP3. DNA methylation frequency, as well as the SE for CRC endpoint, of NDRG4 (73.6%) and BMP3 (55.3%) genes were lower than that of ALX4 or SEPT9, only 6.1% of DNA methylation being found in the normal tissue adjacent to the tumor, and no methylation at all for either gene in the normal tissue. Our findings support the recommendation that methylation of NDRG4 and BMP3 genes be used as cancer-specific biomarkers. BMP3 methylation frequencies found in our study were similar to those observed by Houshmand et al. (56.6% in CRC and 6.6% in the normal tissue adjacent to the tumor) [29]. In contrast, Park et al. found a frequency of 76.5% in CRC cases but also a substantial percentage of NDGR4 methylation (37.5%) in the tissues adjacent to the tumor [30]. In adenomas, the frequency reported for NDRG4 and BMP3 DNA methylation was 76 and 68%, respectively, similar to the results obtained previously (73 and 55%, respectively) [31].
Myrtenol improves brain damage and promotes angiogenesis in rats with cerebral infarction by activating the ERK1/2 signalling pathway
Published in Pharmaceutical Biology, 2021
Shengming Huang, Zhanguo Tan, Jirui Cai, Zhiping Wang, Yuejun Tian
Apoptosis is a vital pathophysiological mechanism associated with I/R, and reperfusion could accelerate the apoptotic death process induced by ischaemia (Villa et al. 2003). Compelling findings indicate the inhibition of apoptosis as a key protective mechanism against cerebral I/R injury (Baldrati et al. 2020; Yu et al. 2020). Wen et al. (2019) demonstrated that N-Myc downstream-regulated gene 4 (NDRG4) protected cerebral IR injury by inhibiting cell apoptosis and regulated cerebral cell apoptosis by increasing BDNF expression. In this study, the results also revealed that the apoptosis of hippocampal neurons was significantly increased after cerebral I/R injury, and myrtenol could suppress the apoptosis in brain tissues. Bcl-2 family related proteins, including anti-apoptotic proteins (such as Bcl-2, Bcl-xL) and pro-apoptotic proteins (such as Bax, Bcl-xS), has been proven to play an important role in the execution of apoptosis (Sergio et al. 2018). It has been confirmed that Bcl-2 can inhibit oxide-induced apoptosis, while Bax promotes the release of cytochrome C and activates caspase-3, which is considered to be the ultimate executor of apoptosis (Abu Zeid et al. 2018). In addition, the increase in Bcl-2 expression and the decrease in Bax expression in the hippocampus after ischaemia can protect against cerebral ischaemic injury by reducing neuronal cell apoptosis (Yi et al. 2020). We also found that myrtenol prevented the down-regulation of Bcl-2 and the upregulation of Bax, as well as the activity of caspase-3 induced by MCAO. Therefore, the inhibitory effect of myrtenol on neuronal apoptosis in MCAO rats may involve its regulation of apoptosis-related proteins.