Cytogenetic Assessment and Risk Stratification in Myelofibrosis with Optical Genome Mapping.

Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, copy number variants, and loss of heterozygosity) in a single workflow. In this study, peripheral blood samples from a series of 21 myelofibrosis patients were analyzed via OGM. We assessed the clinical impact of the application of OGM for disease risk stratification using the DIPSS-plus, GIPSS, and MIPSS70+v2 prognostic scores compared with the standard-of-care approach. OGM, in combination with NGS, allowed for risk classification in all cases, compared to only 52% when conventional techniques were used. Cases with unsuccessful karyotypes (n = 10) using conventional techniques were fully characterized using OGM. In total, 19 additional cryptic aberrations were identified in 9 out of 21 patients (43%). No alterations were found via OGM in 4/21 patients with previously normal karyotypes. OGM upgraded the risk category for three patients with available karyotypes. This is the first study using OGM in myelofibrosis. Our data support that OGM is a valuable tool that can greatly contribute to improve disease risk stratification in myelofibrosis patients.

Absence of long-term effects of reproduction on longevity in the mouse model.

BACKGROUND: Most human demographic data, particularly those on natural fertility populations, find no relationship or even a positive association between fertility and longevity. The present study aims to ascertain whether there is a trade-off between fertility and longevity in the mouse model. METHODS: The study was focused on the first litter produced by 10- to 14-wk-old hybrid (C57BL/6JIco female X CBA/JIco male) mice. A single female/male per litter was individually housed with a male/female at the age of 25 and 52 wk, respectively, until the end of reproductive life in females or natural death in males under controlled housing conditions. Post-reproductive females and virgin mice were reared until natural death. Cox regression models with forward stepwise variable selection were fitted to examine the effect of several fertility variables on expectation of survival times. RESULTS: Virgin females displayed higher life expectancy than virgin males. The relative risk of dying for a virgin male at a particular age was 2.116 [99% confidence interval: 1.317, 3.398] times that of a virgin female. No significant differences on expectation of survival times between virgin and mated females, and between virgin and mated males were found. Furthermore, total number of pups at weaning and total number of litters produced by a dam/stud, time interval between mating and last litter, time interval between litters, and age at last litter were not significant predictors of expectation of survival times in both mated females and mated males. CONCLUSIONS: Like in most human studies, the present study evidences no relationship between total number of offspring/litters produced by a dam/stud and expectation of survival times. Moreover, the present data are in agreement with the general phenomenon of a bias in life expectancy in favor of females.

Delayed fatherhood in mice decreases reproductive fitness and longevity of offspring.

This study aims to analyze, in mice, the long-term effects of delayed fatherhood on reproductive fitness and longevity of offspring. Hybrid parental-generation (F(0)) males, at the age of 12, 70, 100, and 120 wk, were individually housed with a randomly selected 12-wk-old hybrid female. The reproductive fitness of first-generation (F(1)) females was tested from the age of 25 wk until the end of their reproductive life. In F(1) males, the testing period ranged from the age of 52 wk until death. Breeding F(1) females from the 120-wk group displayed interbirth intervals longer than females from the 12-, 70-, and 100-wk groups. Furthermore, F(2) pups begotten by F(1) studs exhibited weaning weights lower than pups from the 12- and 70-wk groups. Offspring from the 120-wk group exhibited shorter survival times associated with lower incidence of tumorigenesis and higher loss of body weight when approaching death when compared to F(1) offspring from younger age-groups. The results indicate that advanced paternal age at conception has negative long-term effects on reproductive fitness and longevity of offspring in the mouse model.

Long-term effects of delayed fatherhood in mice on postnatal development and behavioral traits of offspring.

This study aims to analyze, in mice, the long-term effects of delayed fatherhood on postnatal development, spontaneous motor activity, and learning capacity of offspring. Hybrid parental-generation (F(0)) males, at the age of 12, 70, 100, and 120 wk, were individually housed with a randomly selected 12-wk-old hybrid female. The resulting first-generation (F(1)) offspring were tested for several developmental and behavioral variables. Cumulative percentage of F(1) pups that attained immediate righting in the 120-wk group was lower than that found in the 12-, 70-, and 100-wk groups. Furthermore, the postnatal day of attaining immediate righting was higher in pups from the 120-wk group when compared to pups from the other age-groups. At the age of 20 wk, F(1) offspring from the 120-wk group displayed lower counts of motor activity than offspring from the 12-, 70-, and 100-wk groups. One week later, a higher percentage of offspring from the 100- and 120-wk groups entered the dark compartment during the retention trial of the passive-avoidance test when compared to offspring from the 12-wk group. Offspring from the 120-wk group exhibited also lower step-through latency in the retention trial than offspring from the 12-, 70-, and 100-wk groups. These results show that advanced paternal age at conception has long-term effects on preweaning development, spontaneous motor activity, and reduced passive-avoidance learning capacity of mouse offspring.