Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year.
The underlying premise of peer-to-peer (P2P) systems is the trading of digital resources among individual peers to facilitate file sharing, distributed computing, storage, collaborative applications and multimedia streaming. So-called free-riders challenge the foundations of this system by consuming resources from other peers without offering any resources in return, hindering resource exchange among peers. Therefore, immense effort has been invested in discouraging free-riding and overcoming the ill effects of such unfair use of the system. However, previous efforts have all fallen short of effectively addressing free-riding behaviour in P2P networks. This paper proposes a novel approach based on utilising a credit incentive for P2P networks, wherein a grace period is introduced during which free-riders must reimburse resources. In contrast to previous approaches, the proposed system takes into consideration the upload rate of peers and a grace period. The system has been thoroughly tested in a simulated environment, and the results show that the proposed approach effectively mitigates free-riding behaviour. Compared to previous systems, the number of downloads from free-riders decreased while downloads by contributing peers increased. The results also show that under longer grace periods, the number of downloads by fast peers (those reimbursing the system within the grace period) was greater than the number of downloads by slow peers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.