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Current intensive treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has substantial side effects, highlighting a need for novel biomarkers to improve risk stratification. Canonical biomarkers, such as genetics and immunophenotype, are largely not used in pediatric T-ALL stratification. This study aimed to validate the prognostic relevance of DNA methylation CpG island methylator phenotype (CIMP) risk stratification in 2 pediatric T-ALL patient cohorts: the Nordic Society of Paediatric Haematology (NOPHO) ALL2008 T-ALL study cohort (n = 192) and the Dutch Childhood Oncology Group (DCOG) ALL-10/ALL-11 validation cohorts (n = 156). Both cohorts revealed that combining CIMP classification at diagnosis with measurable residual disease (MRD) at treatment day 29 (D29) or 33 (D33) significantly improved outcome prediction. The poor prognosis subgroup, characterized by CIMP low/D29 or D33 MRD ≥ 0.1%, had a cumulative incidence of relapse (pCIR5yr) of 29% and 23% and overall survival (pOS5yr) of 59.7% and 65.4%, in NOPHO and DCOG, respectively. Conversely, a good prognosis subgroup was also identified representing CIMP high/D29 or D33 MRD < 0.1% with pCIR5yr of 0% and 3.4% and pOS5yr of 98.2% and 94.8%, in NOPHO and DCOG, respectively. For NOPHO, MRD was also evaluated on D15, and the relapse prediction accuracy of CIMP/D29 MRD (0.79) and CIMP/D15 MRD (0.75) classification was comparable, indicating potential for earlier stratification. The evaluation of the biology behind the CIMP subgroups revealed associations with transcriptome profiles, genomic aberrations, and mitotic history, suggesting distinct routes for leukemia development. In conclusion, integrating MRD assessment with the novel CIMP biomarker has the potential to improve risk stratification in pediatric T-ALL and guide future therapeutic decisions.

Bats are a diverse and ecologically important group of mammals that exhibit remarkable diversity in their feeding habits. These diverse feeding habits are thought to be reflected in the composition and function of their gut microbiota, which plays important roles in nutrient acquisition, immune function, and overall health. Despite the rich biodiversity of bat species in South America, there is a lack of microbiome studies focusing on bats from this region. Such studies could offer major insights into conservation efforts and the preservation of biodiversity in South America. In this work, we aimed to compare the gut microbiota of four bat species with different feeding habits from Southern Brazil, including nectarivorous, frugivorous, insectivorous, and hematophagous bats. Our findings demonstrate that feeding habits can have a significant impact on the diversity and composition of bat gut microbiotas, with each species exhibiting unique metabolic potentials related to their dietary niches. In addition, the identification of potentially pathogenic bacteria suggests that the carriage of microbial pathogens by bats may vary, depending on feeding habits and host-specific factors. These findings provide novel insights into the relationship between bat feeding habits and gut microbiota composition, highlighting the need to promote diverse habitats and food sources to support these ecologically important species.

The hippocampus is affected early in Alzheimer’s disease (AD) and altered hippocampal functioning influences normal cognitive aging. Here, we used task-based functional MRI to assess if the APOE ɛ4 allele or a polygenic risk score (PRS) for AD was linked to longitudinal changes in memory-related hippocampal activation in normal aging (baseline age 50–95, n = 292; n = 182 at 4 years follow-up, subsequently non-demented for at least 2 years). Mixed-models were used to predict level and change in hippocampal activation by APOE ɛ4 status and PRS based on gene variants previously linked to AD at p ≤ 1, p < 0.05, or p < 5e−8 (excluding APOE). APOE ɛ4 and PRS_p<5e−8 significantly predicted AD risk in a larger sample from the same study population (n = 1542), while PRS_p≤1 predicted memory decline. APOE ɛ4 was linked to decreased hippocampal activation over time, with the most prominent effect in the posterior hippocampi, while PRS was unrelated to hippocampal activation at all p-thresholds. These results suggests a link for APOE ɛ4, but not for AD genetics in general, on functional changes of the hippocampi in normal aging.

Assessing the levels of oxidative stress markers and antioxidant enzymes in the brain is crucial in evaluating its antioxidant capacity and understanding the influence of various dietary patterns on brain well-being. This study aimed to investigate the antioxidant status and oxidative damage in the brain of bat species with different feeding habits to gain insights into their protective mechanisms against oxidative stress and their interspecific variation. The levels of oxidative damage markers and the activities of antioxidants were measured in the brain of four bat species with different feeding habits, namely insectivorous, frugivorous, nectarivorous, and hematophagous. Insectivorous bats showed higher levels of SOD and fumarase compared to the other groups, while hematophagous bats showed lower levels of these enzymes. On the other hand, the activities of glutathione peroxidase and glutathione S-transferase were higher in hematophagous bats and lower in insectivorous bats. The carbonyl groups and malondialdehyde levels were lower in frugivores, while they were similar in the other feeding guilds. Nitrite and nitrate levels were higher in the hematophagous group and relatively lower in all other groups. The GSSG/GSH ratio was higher in the hematophagous group and lower in frugivores. Overall, our results indicate that the levels of oxidative stress markers and the activities of antioxidant enzymes in the brain vary significantly among bat species with different feeding habitats. The findings suggest that the antioxidant status of the brain is influenced by diet and feeding habits.

The aim of this study was to compare the oxidative metabolism of four neotropical bat species with different feeding habits and investigate the relationship between their feeding habits and oxidative status. In terms of oxidative damage, our findings revealed major differences among the four bat species. In particular, hematophagous bats had lower levels of oxidative damage in the heart but higher levels in the liver. Nectarivorous bats had lower levels of carbonyl groups in the kidneys compared to insectivorous and hematophagous bats. The activity of various antioxidant and non-antioxidant enzymes in the heart, liver, and kidney also showed significant differences among the bat species. H2O2 consumption was lower in the heart of hematophagous bats, while insectivorous bats exhibited the highest enzymatic activity in the kidney. SOD activity was lower in the heart of hematophagous bats and lower in nectarivorous bats in the liver. Fumarase activity was higher in the heart of frugivorous/insectivorous and lower in nectarivorous/hematophagous bats. GPx activity was higher in the heart of nectarivorous/insectivorous and higher in the kidney of insectivorous bats. GST activity was higher in the heart of nectarivorous and lower in hematophagous bats. The correlation analysis between oxidative markers and enzymatic/non-enzymatic antioxidants in the heart, liver, and kidney exhibited distinct patterns of correlations due to variations in antioxidant defense mechanisms and oxidative stress responses in different organs. The observed differences in oxidative damage, antioxidant enzyme activities, and correlations between oxidative markers and antioxidants highlight the adaptability and complexity of the antioxidant defense systems in these bats. Each organ appears to have specific demands and adaptations to cope with oxidative stress based on its physiological functions and exposure to dietary components. Our results have major significance for the conservation and management of bats, which are threatened species despite being crucial components of ecosystems. Our study's implications go beyond bat biology and offer valuable insights into comparative oxidative physiology.

Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, hasshown promise for Alzheimer’s disease (AD) prediction.Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA)measures and identifying novel early blood-based DNAm AD-prediction biomarkers.

Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models(LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16years before clinical onset, and post-onset follow-up. NovelDNAmbiomarkers were generated with epigenome-wide LMMs,and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10–16 years), and post-AD-onset time-points.

Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkersshowed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions(p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE 4-carriership(OR = 1.38 per 1 SD DNAmscore increase versus OR= 13.58 for 4-allele carriage; AUCs = 77.2% versus 87.0%). Literaturereview showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with ouridentified CpGs.

Conclusion: The limited predictive value of EAA for AD extends prior findings by considering a longer follow-up time, andwith appropriate control for age, sex, APOE, and blood-cell proportions. Results also highlight challenges with replicatingdiscriminatory or predictive CpGs across studies.

Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer’s disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.

Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.

Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1–24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404–7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947–2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.

Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.