Training the next generation of pluripotent stem cell researchers

Human pluripotent stem cells (PSCs) have the unique properties of being able to proliferate indefinitely in their undifferentiated state and of being able to differentiate into any somatic cell type. These cells are thus posited to be extremely useful for furthering our understanding of both normal and abnormal human development, providing a human cell preparation that can be used to screen for new reagents or therapeutic agents, and generating large numbers of differentiated cells that can be used for transplantation purposes. PSCs in culture have a specific morphology and they express characteristic surface antigens and nuclear transcription factors; thus, PSC culture is very specific and requires a core skill set for successful propagation of these unique cells. Specialized PSC training courses have been extremely valuable in seeding the scientific community with researchers that possess this skill set

Numerical model development to predict the behaviour of infant/neonate crash dummy restrained inside of an incubator under deceleration

In this paper, advanced finite element (FE) methods are developed to investigate the effect of deceleration on the crash dummy test complied with British Standard Engineering (BS EN 1789). These techniques, which are related to material modelling, joints and contacts, offer an advanced numerical model representing an infant incubator with all complex boundary conditions and design contents. It is shown that the response of an infant incubator is a function of the ratchet straps, the tension on the belts, the belt type and the distance of the belts from the edges of the incubator, which can significantly affect the experienced acceleration, by the infant. The validation process is performed against experimental studies and various case parameters such as crash dummy mass and negative acceleration impulse are discussed in detail. The developed numerical model is capable to predict the behaviour of the crash dummy and the incubator in terms of acceleration, trajectory and kinematics by less than 8% error

Global Methylation in Exposure Biology and Translational Medical Science

Background: Many groups are actively investigating how the epigenetic state relates to environmental exposures and development of disease, including cancer. There are myriad choices for capturing and measuring the epigenetic state of a tissue, ranging from assessing the total methyl-CpG content to array-based platforms that simultaneously probe hundreds of thousands of CpG loci. There is an emerging literature that uses CpG methylation at repetitive sequences, including LINE-1 (long interspersed nuclear element-1) elements, to capture the epigenomic state

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration

MLH1-methylated endometrial cancer under 60 years of age as the “sentinel” cancer in female carriers of high-risk constitutional MLH1 epimutation

Objective. Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to de-termine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1- methylated tumors.Methods. We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; Columbus-area (n = 68, all ages) and Ohio Colo-rectal Cancer Prevention Initiative (OCCPI) (n = 24, <60 years).Results. Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (similar to 50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic second-hits affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (similar to 17%) patients <50 years and one of 45 patients (similar to 2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three pa-tients with underlying constitutional MLH1 methylation.Conclusions. A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or syn-chronous/metachronous tumors (any age) displaying MLH1 methylation.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/)