Long-term associations between objective sleep quality and quantity and verbal memory performance in normal cognition and mild cognitive impairment.

Introduction: Although the link between sleep and memory function is well established, associations between sleep macrostructure and memory function in normal cognition and Mild Cognitive Impairment remain unclear. We aimed to investigate the longitudinal associations of baseline objectively assessed sleep quality and duration, as well as time in bed, with verbal memory capacity over a 7-9 year period. Participants are a well-characterized subsample of 148 persons (mean age at baseline: 72.8 ± 6.7 years) from the Cretan Aging Cohort. Based on comprehensive neuropsychiatric and neuropsychological evaluation at baseline, participants were diagnosed with Mild Cognitive Impairment (MCI; n = 79) or found to be cognitively unimpaired (CNI; n = 69). Sleep quality/quantity was estimated from a 3-day consecutive actigraphy recording, whereas verbal memory capacity was examined using the Rey Auditory Verbal Learning Test (RAVLT) and the Greek Passage Memory Test at baseline and follow-up. Panel models were applied to the data using AMOS including several sociodemographic and clinical covariates. Results: Sleep efficiency at baseline directly predicted subsequent memory performance in the total group (immediate passage recall: ß = 0.266, p = 0.001; immediate word list recall: ß = 0.172, p = 0.01; delayed passage retrieval: ß = 0.214, p = 0.002) with the effects in Passage Memory reaching significance in both clinical groups. Wake after sleep onset time directly predicted follow-up immediate passage recall in the total sample (ß = -0.211, p = 0.001) and in the MCI group (ß = -0.235, p = 0.02). In the total sample, longer 24-h sleep duration was associated with reduced memory performance indirectly through increased sleep duration at follow-up (immediate passage recall: ß = -0.045, p = 0.01; passage retention index: ß = -0.051, p = 0.01; RAVLT-delayed recall: ß = -0.048, p = 0.009; RAVLT-retention index:ß = -0.066, p = 0.004). Similar indirect effects were found for baseline 24-h time in bed. Indirect effects of sleep duration/time in bed were found predominantly in the MCI group. Discussion: Findings corroborate and expand previous work suggesting that poor sleep quality and long sleep duration predict worse memory function in elderly. Timely interventions to improve sleep could help prevent or delay age-related memory decline among non-demented elderly.

The impact of COVID-19 pandemic on elderly with neurocognitive disorders.

Since the COVID-19 pandemic outburst, numerous studies have reported on the holistic approach of the disease, which has negative consequences on physical and mental health as well as short- and long-term effects on cognition, independently of age. The context of the pandemic brought significant demands on public health systems, leading to restrictive measures against coronavirus expansion (quarantines, physical distancing policies, etc.). Such measures are reported to increase perceived loneliness and helplessness and may exacerbate feelings of emotional distress.1 Elderly diagnosed with neurocognitive disorders, i.e., mild cognitive impairment (MCI) or dementia, may present multifaceted cognitive deficits accompanied by neuropsychiatric symptoms, medical comorbidities, and high mortality rates. Furthermore, elderly with MCI/dementia are more vulnerable to SARS-COV-2 infection and disease complications due to decreased compliance with protective measures and multimorbidity. Simultaneously, limited access to health care services, distancing from their loved ones, abrupt changes in their daily routines or cancellation of daycare programs may make them more susceptible to pandemic secondary effects. According to the World Health Organization about 55 million people live with dementia globally. Dementia diagnosis was reported as an independent risk factor for increased mortality rate among the elderly infected with SARS-COV-2.2 Cross-sectional studies conducted all over Europe reported increased cognitive deterioration rate in patients with MCI and dementia during lockdown compared to the pre-lockdown period, as well as among dementia patients infected with COVID-19 compared to those not infected.3 Exacerbation of pre-existing sleep/appetite dysregulation and aberrant motor behavior, worsened symptoms of apathy, depression, and agitation, a rise in delirium episodes and disease-related falls and onset of behavioral symptoms during quarantine occurred.4 Also, patients living alone expressed excessive worrying and an overall decline in well-being. However, results from a large cohort study conducted in England failed to distinguish COVID-19 effects on dementia patients' psychological state between 2018 and 2020, possibly due to the small number of dementia patients recruited and disease severity.5 Among the Greek elderly, dementia prevalence rates range between 5-10.8% and 32.4% for MCI incidence.6,7 Only a few studies have investigated the impact of COVID-19 quarantine on mental and psychological health of the Greek elderly diagnosed with cognitive disorders. A longitudinal study was conducted between 2018 and 2020 including a rather large number of elderly people with MCI or Alzheimer's disease (AD). The authors compared the objectively assessed deterioration difference pre- and during the quarantine in terms of cognition, behavior and function level. They concluded that no significant quarantine-related changes were detected in cognition between the three time points, although the possibility that behavioral and psychological deterioration indirectly affected cognitive and functional decline among AD patients cannot be excluded.8 In a cross-sectional study conducted during the first quarantine period (i.e., February to May 2020), critical aspects of everyday life (mood, physical health, communication) as well as compliance with confinement policies were examined based on subjective information provided by caregivers of elderly with MCI or dementia. Based on their findings, the authors report that MCI and dementia patients exhibited a significant overall decline, whereas those with dementia were more likely to deteriorate in terms of neuropsychiatric symptoms (apathy, mood changes, psychomotor anxiety), excessive worrying, and limited compliance with measures against COVID-19 expansion.9 In an effort to minimize possible deleterious effects of the pandemic-related quarantine on the elderly with neurocognitive disorders, telemedicine was implemented instead. Neuropsychological online testing, systematic monitoring of clinical outcome (compliance with pharmacotherapy) and motivational interventions such as physical activity programs were accommodated using user-friendly applications and telephone consultations.10 Nevertheless, limited access to and familiarization with technology, severity of cognitive deficits, and demographic factors (i.e., low educational and socioeconomic status), may have limited positive outcomes in the current population. In conclusion, the combined effect of neurocognitive disorders and the pandemic exceeds the healthcare system's demands, posing in some cases insurmountable challenges. To minimize the negative effect of future similar conditions, focus should be given on the following directions: Patient-oriented, holistic protocols for systematic monitoring of clinical course, future cognitive decline, and timely psychiatric/neuropsychological interventions when necessary. Specialized training for caregivers' and nursing staff focusing on the inclusion of self-hygiene measures in patients' daily routine. Patients' familiarization with online tools both for cognitive enhancement programs and for diagnostic/ monitoring purposes.

In conversation with Lori Passmore.

Lori Passmore is a Group Leader at the MRC Laboratory of Molecular Biology (MRC-LMB). She studied Biochemistry at the University of British Columbia in Vancouver (Canada), before moving to the UK in 1999 for a PhD at the Institute of Cancer Research. After completing her PhD, Lori moved to Cambridge, where she became a Post-Doctoral Fellow at the MRC-LMB. In 2009, Lori started her own group at the MRC-LMB and was subsequently awarded an ERC Starting Grant (2011), an ERC Consolidator Grant (2017) and a Wellcome Discovery Award (2023). She was also elected into the EMBO Young Investigator Programme (2015) and EMBO Membership (2018). Lori's research focusses on the determination of the structures of protein complexes that regulate gene expression, using primarily cryo-electron microscopy and in vitro assays. Her work has contributed significantly to our understanding of the underlying molecular mechanisms of cellular processes, giving insights into human physiology and disease. In this interview, Lori provides an overview of her research and discusses current challenges in the field, recalls the key events and collaborations that have helped shape her successful research career and offers advice to early career scientists.

Cretan Aging Cohort-Phase III: Methodology and Descriptive Characteristics of a Long-Term Longitudinal Study on Predictors of Cognitive Decline in Non-Demented Elderly from Crete, Greece.

Identifying modifiable factors that may predict long-term cognitive decline in the elderly with adequate daily functionality is critical. Such factors may include poor sleep quality and quantity, sleep-related breathing disorders, inflammatory cytokines and stress hormones, as well as mental health problems. This work reports the methodology and descriptive characteristics of a long-term, multidisciplinary study on modifiable risk factors for cognitive status progression, focusing on the 7-year follow-up. Participants were recruited from a large community-dwelling cohort residing in Crete, Greece (CAC; Cretan Aging Cohort). Baseline assessments were conducted in 2013-2014 (Phase I and II, circa 6-month time interval) and follow-up in 2020-2022 (Phase III). In total, 151 individuals completed the Phase III evaluation. Of those, 71 were cognitively non-impaired (CNI group) in Phase II and 80 had been diagnosed with mild cognitive impairment (MCI). In addition to sociodemographic, lifestyle, medical, neuropsychological, and neuropsychiatric data, objective sleep was assessed based on actigraphy (Phase II and III) and home polysomnography (Phase III), while inflammation markers and stress hormones were measured in both phases. Despite the homogeneity of the sample in most sociodemographic indices, MCI persons were significantly older (mean age = 75.03 years, SD = 6.34) and genetically predisposed for cognitive deterioration (APOE ε4 allele carriership). Also, at follow-up, we detected a significant increase in self-reported anxiety symptoms along with a substantial rise in psychotropic medication use and incidence of major medical morbidities. The longitudinal design of the CAC study may provide significant data on possible modifiable factors in the course of cognitive progression in the community-dwelling elderly.

In conversation with Peter Macheroux.

Peter Macheroux is Professor of Biochemistry and Head of the Institute of Biochemistry at Graz University of Technology in Austria. Peter's research spans a diverse selection of topics, and his work has contributed significantly towards advancing our understanding of bacterial enzymology, plant physiology and the molecular pathways that underlie human pathophysiology. Among Peter's many scientific achievements, he has led the team that recognised DPP3 as a biomarker for cardiovascular diseases, with the subsequent therapeutic implications of the development of DPP3 inhibitors. In this interview-based article, Peter provides an overview of his research focus and goals, recalls some of his great scientific breakthroughs and describes what the key current challenges in his research field are.

Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner.

BACKGROUND: Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor. METHODS: In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method. RESULTS: We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells. CONCLUSIONS: In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.

Professor Dame Janet Thornton to receive 'The FEBS Journal Open Science Award'.

Professor Dame Janet Thornton has been named as the inaugural recipient of 'The FEBS Journal Open Science Award' for her major role in the development of ELIXIR, the pan-European infrastructure for biological data, as well as the creation of freely available computational tools and knowledge resources.

Cancer epigenetics: promises and pitfalls for cancer therapy.

Over the past few decades, epigenetic regulators have emerged as major players in cellular processes that drive cancer initiation and progression, and subsequently modulate the responsiveness of cancers to therapeutic agents. This Special Issue of The FEBS Journal, Cancer Epigenetics, features an exciting collection of review articles that focus on the functions of a broad spectrum of epigenetic modulators in cancer. The diverse topics explored herein range from the roles of transposable elements and chromatin architecture in cancer and the most recent research advances on cancer-associated histone variants (oncohistones), to the effects of altered epigenetics on transcription and advanced cancer cell phenotypes. Moreover, the prospective key function of cancer metabolism in linking epigenetics and transcriptional regulation, and the potential of epigenetics for targeted cancer therapeutics is discussed. We hope that this collection of articles will give readers an enlightening overview of the most recent advances in the fast-moving field of cancer epigenetics.

In Conversation with Tony Letai.

Anthony Letai is Professor in Medicine at Harvard Medical School and Dana Farber Cancer Institute, and President of The Society for Functional Precision Medicine. Among Tony's scientific achievements, work from his lab contributed toward the FDA approval of Venetoclax combination treatment for adult acute myeloid leukemia (AML) patients. Moreover, his studies on cancer cell death have led to the development of BH3 profiling, an assay that allows for the definition of how close a cell is to the threshold required to commit to apoptosis, which can be used to improve clinical outcomes for cancer patients. In this interview, Tony relays the story behind some of his scientific breakthroughs, discusses the importance of function when designing targeted cancer therapies, gives an overview of BH3 profiling and its application to cancer therapy, and recalls the key events and collaborations that drove his successful research career.

TRF1 averts chromatin remodelling, recombination and replication dependent-break induced replication at mouse telomeres.

Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

Assessment of Radiobiological α/ß Ratio in Lung Cancer and Fibroblast Cell Lines Using Viability Assays.

BACKGROUND/AIM: Altered fractionation is an area of intense clinical research in radiation oncology. Estimation of the α/ß ratio of individual carcinomas after establishment of primary cell cultures from tumor biopsies may prove of importance in the individualization of radiotherapy schemes. MATERIALS AND METHODS: Here we proposed a simple method to estimate the α/ß ratio in cultured cell lines (two lung carcinomas: A549 and H1299; one lung fibroblast cell line: MRC5), using viability assays. RESULTS: For the A549 cell line, the α/ß ratio ranged from 14-25 Gy, for H1299 from 11-43 Gy and for the MRC5 fibroblast cell line this was far lower, ranging from 0.69 to 6 Gy. The α/ß ratio decreased when extracted from comparisons of lower dose per fraction schemes. CONCLUSION: The α/ß ratio of a cell line can be easily defined after simple viability/dose fractionation experiments.

The Ideological Frame of the Genetic Basis of Cancer: The Important Role of miRNAs.

The elucidation of the genetic basis of cancer is the result of the research conducted since the beginning of the previous century, which peaked during the decades of 1960s and 1970s. It has been achieved through two different but convergent routes: the first includes the study of oncogenic viruses in rodents and birds and the second includes the use of chemical carcinogens in cells or in animal model systems (mice). Within this framework, the identification of genes that present mutations, alterations in expression levels, and epigenetic modifications has been facilitated through the development of animal carcinogenesis models. One of these models is the well-characterized mouse multistage skin cancer system discussed in this review. In addition, recent evidence shows the great significance that cancer stem cells seem to have in the emergence and progression of carcinogenesis. Finally, herein we discuss the critical role that miRNAs have emerged to play in cancer progression. miRNAs emerged as molecules with an impact on most cancer-related cellular processes, involving cell proliferation, cell death (apoptosis), angiogenesis, migration/motility, and rearrangement of the cytoskeleton. Their discovery has given rise to studies with a focus on miRNAs as key players in crucial oncogenesis-related processes and thus as potential targets in cancer therapeutics.

Let-7, mir-98 and mir-183 as biomarkers for cancer and schizophrenia [corrected].

Recent evidence supports a role of microRNAs in cancer and psychiatric disorders such as schizophrenia and bipolar disorder, through their regulatory role on the expression of multiple genes. The rather rare co-morbidity of cancer and schizophrenia is an old hypothesis which needs further research on microRNAs as molecules that might exert their oncosuppressive or oncogenic activity in the context of their role in psychiatric disorders. The expression pattern of a variety of different microRNAs was investigated in patients (N = 6) suffering from schizophrenia termed control, patients with a solid tumor (N = 10) and patients with both schizophrenia and tumor (N = 8). miRNA profiling was performed on whole blood samples using the miRCURY LNA microRNA Array technology (6th & 7th generation). A subset of 3 microRNAs showed a statistically significant differential expression between the control and the study groups. Specifically, significant down-regulation of the let-7p-5p, miR-98-5p and of miR-183-5p in the study groups (tumor alone and tumorand schizophrenia) was observed (p<0.05). The results of the present study showed that let-7, miR-98 and miR-183 may play an important oncosuppressive role through their regulatory impact in gene expression irrespective of the presence of schizophrenia, although a larger sample size is required to validate these results. Nevertheless, further studies are warranted in order to highlight a possible role of these and other micro-RNAs in the molecular pathways of schizophrenia.