Melatonina como agente coadyuvante de quimioterapéuticos en estudios in vitro

A pesar de los grandes avances en el campo de la oncología, la falta de especificidad y/o efectividad de algunos tratamientos conlleva al paciente a soportar indeseables efectos secundarios. Esto se debe a que, aunque en menor medida, las células sanas y por extensión el resto del organismo se ven afectados por la toxicidad de los tratamientos. La melatonina presenta una potente actividad antitumoral mediada por mecanismos que incluyen efectos antiproliferativos y pro-apoptóticos, así como una potente acción antioxidante. Dicha capacidad es simultánea con una capacidad protectora sobre la célula sana frente a insultos tóxicos de naturaleza muy diversa, protegiendo así a la célula sana de daños que la puedan conducir a la apoptosis. Por lo tanto, la melatonina podría ser útil en el tratamiento de tumores en asociación con agentes quimioterapéuticos. El objetivo de la presente Tesis Doctoral ha sido estudiar los mecanismos implicados en las propiedades pro-apoptóticas de la melatonina en células tumorales humanas, como son la línea celular HeLa de cáncer cérvico-uterino así como en la línea celular HT-29 de adenocarcinoma colorrectal, valorando la participación de los receptores de membrana de la melatonina en dichos mecanismos, así como los posibles efectos de la indolamina sobre la acción de agentes quimioterápicos (5-fluorouracilo, cisplatino, citarabina, doxorrubicina y etopósido). Conforme a lo expuesto, cabe destacar que la melatonina in vitro es capaz de aumentar notablemente la sensibilidad de las células HeLa al tratamiento con cisplatino, asi como incrementar el efecto citotóxico y apoptosis inducida por el agente quimioterapéutico 5 fluorouracilo en células HT-29.Despite the great advances in the field of oncology, the lack of specificity and / or effectiveness of some treatments leads the patient to endure undesirable side effects. This is because, to a lesser extent, healthy cells and by extension the rest of the body are affected by the toxicity of treatments. Melatonin exhibits potent antitumor activity mediated by mechanisms including antiproliferative and pro-apoptotic effects as well as a potent antioxidant action. Such ability is simultaneous with a protective ability on the healthy cell against toxic insults of a very diverse nature, thus protecting the healthy cell from damage that may lead to apoptosis. Therefore, melatonin could be useful in the treatment of tumors in association with chemotherapeutic agents. The objective of this Doctoral Thesis has been to study the mechanisms involved in the pro-apoptotic properties of melatonin in human tumor cells, such as the HeLa cell line of cervico uterine cancer as well as in the HT-29 cell line of colorectal adenocarcinoma, as well as the possible effects of indolamine on the action of chemotherapeutic agents (5 fluorouracil, cisplatin, cytarabine, doxorubicin, and etoposide). According to the above, it should be noted that melatonin in vitro is able to significantly increase the sensitivity of HeLa cells to treatment with cisplatin, as well as to increase the cytotoxic effect and apoptosis induced by the chemotherapeutic agent 5 fluorouracil in HT-29 cells.Junta de Extremadura-Fondo Social Europeo de Desarrollo Regional (Fondos FEDER GR10003) grant BBB021- GR1505

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Factors Associated with SARS-CoV-2 Infection in Fully Vaccinated Nursing Home Residents and Workers

Persons living or working in nursing homes faced a higher risk of SARS-CoV-2 infections during the pandemic, resulting in heightened morbidity and mortality among older adults despite robust vaccination efforts. This prospective study evaluated the humoral and cellular immunity in fully vaccinated residents and workers from two nursing homes in Madrid, Spain, from 2020 to 2021. Measurements of IgG levels were conducted in August 2020 (pre-vaccination) and June and September 2021 (post-vaccination), alongside assessments of neutralizing antibodies and cellular responses in September 2021 among the most vulnerable individuals. Follow-up extended until February 2022 to identify risk factors for SARS-CoV-2 infection or mortality, involving 267 residents (mean age 87.6 years, 81.3% women) and 302 workers (mean age 50.7 years, 82.1% women). Residents exhibited a significantly higher likelihood of experiencing COVID-19 before June 2021 compared with nursing staff (OR [95% CI], 7.2 [3.0 to 17.2], p Omicron variant wave, residents and staff showed a similar rate of SARS-CoV-2 infection. Notably, preceding clinical or immunological factors before receiving three vaccination doses did not demonstrate associations with COVID-19 infection or overall mortality in our participant cohort

Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients