The Mossbauer effect using Fe-57-ferrabisdicarbollide ([o-(57)FESAN](-)): a glance into the potential of a low-dose approach for glioblastoma radiotherapy

Although a variety of cancers are initially susceptible to chemotherapy, they eventually develop multi-drug resistance. To overcome this situation, more effective and selective treatments are necessary using anti-tumour agents that act in two or more ways and offer greater therapeutic benefits over single-mechanism entities. In this study, we report on treating cancer with Na[3,3′-57Fe(1,2-C2B9H11)2], which offers the possibility of dual action (radiation-drug combinations) to improve the clinical benefits and reduce healthy tissue toxicity. An approach to evaluating the potential of [o-57FESAN]− to treat glioblastoma using the Mössbauer effect is presented. As the therapeutic outcomes rely on the amount and distribution of [o-57FESAN]− inside the cells, several studies, using magnetization, Mössbauer spectroscopy and nuclear microscopy techniques, were performed to ascertain the uptake of [o-57FESAN]− in U87 glioblastoma cells. [o-57FESAN]− was found to be within the cells; 29% of its uptake was in the nuclear fraction, which is a particularly desirable target, because the nucleus is the cell's control centre where DNA and the transcription machinery reside. Irradiation studies with 2D and 3D cellular models of U87 cells showed that the growth inhibition effect observed was more pronounced when [o-57FESAN]− was used in combination with the Mössbauer effect in low total dose regimens, suggesting that this procedure either alone or as adjuvant may be useful for glioblastoma treatment.This work was supported by the Spanish Ministerio de Economía y Competitividad (PID2019-106832RB-100) and the Generalitat de Catalunya (2017SGR1720) and by the Fundação para a Ciência e Tecnologia (FCT/MEC) for projects UID/MULTI/04349/2020, PTDC/BTM-TEC/29256/2017, UIDB/04565/2020, UIDP/04565/2020 (iBB/IST), LA/P/0140/2020 (Associate Laboratory Institute for Health and Bioeconomy – i4HB), PTDC/QUI-QIN/32240/2017, LISBOA-01-0145-FEDER-022096 (National Infrastructure Roadmap, LTHMFL-NECL) and GCT grant to A. C. Cerdeira (BL156/2019_IST-ID). A. B. Buades was enrolled in the PhD program of the UAB. C. I. G. Pinto is enrolled in the PhD scholarship 689 DFA/BD/07119/2020. The authors thank Dr Moulay Sougrati, Charles Gerhardt Institute, ICGM UMR 5253, Montpellier, France for a kind gift of 57FeCl2. The LMRI (Metrology Laboratory of Ionizing Radiation) team is acknowledged for their support in the X-ray irradiation setup.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

Diet of two syntopic species of Crenuchidae (Ostariophysi: Characiformes) in an Amazonian rocky stream

Abstract This study assessed the diet of two poorly known syntopic fish species of the family Crenuchidae, Characidium aff. declivirostre and Leptocharacidium omospilus, in a Presidente Figueiredo´ rocky stream, Amazonas, Brazil. The stomach contents were analyzed and their Frequency of Occurrence (FO %) and Relative Volume (Vol %) were combined in a Feeding Index (IAi). We examined 20 individuals of C. aff. declivirostre and 23 of L. omospilus. The Morisita-Horn Index was used to estimate the overlap between the diets of these species. Immature insects were the most valuable items consumed by both fish species. The diet of C. aff. declivirostre was mainly composed of larvae and pupae of Chironomidae, while L. omospilus predominantly consumed larvae of Hydroptilidae, Hydropyschidae and Pyralidae. Thus, both species were classified as autochthonous insectivorous. Characidium aff. declivirostre was considered a more specialized species, probably reflecting lower feeding plasticity or the use of more restricted microhabitats compared to L. omospilus. When the food items were analyzed at the family taxonomic level, the diet overlap between these species was considered moderate (Morisita-Horn Index = 0.4). However, a more thorough analysis, at the genus level, indicates a very low diet overlap. Therefore, we conclude that the feeding segregation between C. aff. declivirostre and L. omospilus may favor their co-existence, despite their high phylogenetic closeness

Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia

Background There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-C linical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials