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Aging coincides with the progressive loss of muscle mass and strength, increased adiposity, and diminished physical function. Accordingly, interventions aimed at improving muscle, metabolic, and/or physical health are of interest to mitigate the adverse effects of aging. In this study, we tested a stem cell secretome product, which contains extracellular vesicles and growth, cytoskeletal remodeling, and immunomodulatory factors. We examined the effects of 4 weeks of 2×/week unilateral intramuscular secretome injections (quadriceps) in ambulatory aged male C57BL/6 mice (22-24 months) compared to saline-injected aged-matched controls. Secretome delivery substantially increased whole-body lean mass and decreased fat mass, corresponding to higher myofiber cross-sectional area and smaller adipocyte size, respectively. Secretome-treated mice also had greater whole-body physical function (grip strength and rotarod performance) and had higher energy expenditure and physical activity levels compared to control mice. Furthermore, secretome-treated mice had greater skeletal muscle Pax7+ cell abundance, capillary density, collagen IV turnover, reduced intramuscular lipids, and greater Akt and hormone sensitive lipase phosphorylation in adipose tissue. Finally, secretome treatment in vitro directly enhanced muscle cell growth and IL-6 production, and in adipocytes, it reduced lipid content and improved insulin sensitivity. Moreover, indirect treatment with secretome-treated myotube culture media also enhanced muscle cell growth and adipocyte size reduction. Together, these data suggest that intramuscular treatment with a stem cell secretome improves whole-body metabolism, physical function, and remodels skeletal muscle and adipose tissue in aged mice.

Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

SUMMARY Background To explore at what age youth start using tobacco and/or nicotine products, which product is used first, product initiation sequences, and whether some socio-demographic characteristics are associated with substance use initiation. Methods Data were collected from an online questionnaire disseminated through social media and professional partners, targeting youth aged 14–25 in French-speaking Switzerland in August 2022. The final sample included 1362 participants. Respondents were asked whether they had already used cigarettes, e-cigarettes, hookah, snus, or cannabis at least once in their life (yes/no) and the age of the first time was asked for each substance when the answer was positive. Additionally, participants were asked about their substance use in the past 30 days. Respondents were classified according to age at onset of each tobacco/nicotine and cannabis product, and comparisons were made based on sociodemographic variables, including gender (cisgender female/cisgender male/transgender), perceived socioeconomic status (below average/average/above average), and age. Results Overall, in addition to those who reported no consumption, four distinct initiation profiles emerged from the classification. Cigarettes remain the most commonly used first product with an average age of 15.7 years. While cigarettes and hookah are present in all profiles, the order of first consumption varies from one profile to another, with cigarettes coming first in two profiles, hookah in one and e-cigarettes in the last. Furthermore, while the most common profile contains experimental consumption of the five products considered, some profiles do not contain cannabis, e-cigarettes and/or snus, for example. When divided by age groups, both 14-17-year-olds and 18-21-year-olds reported cigarette as their first product of initiation. Across the separate age groups (14–17, 18–21, 22–25), cigarettes consistently emerge as the primary used on average. Conclusions Cigarettes remain the first product to be used, but the younger the respondents, the earlier they start using e-cigarettes, and very close to cigarettes. Regarding current consumption patterns, e-cigarettes are becoming increasingly prominent.

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain. Despite the crucial role of the BER pathway, insights into how this pathway is affected by aging in the human brain and the underlying regulatory mechanisms are very limited. By microarray analysis of four cortical brain regions from humans aged 20-99 years (n = 57), we show that the expression of core BER genes is largely downregulated during aging across brain regions. Moreover, we find that expression of many BER genes correlates positively with the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the human brain. In line with this, we identify binding sites for the BDNF-activated transcription factor, cyclic-AMP response element-binding protein (CREB), in the promoter of most BER genes and confirm the ability of BDNF to regulate several BER genes by BDNF treatment of mouse primary hippocampal neurons. Together, these findings uncover the transcriptional landscape of BER genes during aging of the brain and suggest BDNF as an important regulator of BER in the human brain.

ABSTRACT Background Disease recurrence after surgical resection for pancreatic ductal adenocarcinoma can affect more than 50% of patients in the first 12 months after resection. The goal of this current systematic review and meta‐analysis is to assess the ability of preoperative inflammatory scores to predict early recurrence after resection and to identify the best candidates for surgical resection. Methods Medline and Web of Science databases were searched for studies reporting inflammatory scores and oncological outcomes in patients with PDAC after curative‐intent resection. The systematic review revealed that the most common scores were modified Glasgow Prognostic Score (mGPS), Prognostic Nutritional Index (PNI), platelet‐to‐lymphocyte ratio (PLR), neutrophil‐to‐lymphocyte ratio (NLR), and Systemic Immune‐Inflammation Index (SII). After, a meta‐analysis was performed to determine the prognostic value of these scores in early recurrence (12 months) after resection. A subgroup analysis was also carried out in patients who had upfront surgery and in those who underwent neoadjuvant chemotherapy. The ROBINS‐I tool was used to assess the risk of bias. Results The literature search retrieved 1864 articles, 16 of which were eligible for analysis. The included studies comprised 4460 patients. Nine studies reported outcomes for mGPS, four studies for PNI, seven studies for PLR, eight studies for NLR, and two studies for SII. In the meta‐analysis, mGPS, NLR, and PLR showed significantly higher rates of early recurrence in the high‐score groups compared to the low‐score groups. Analyzing the sensitivity and specificity of these scores showed no significant difference in their diagnostic accuracy (mGPS area under the curve [AUC] = 0.534; NLR AUC = 0.628, and PLR AUC = 0.607). High and low PNI and SII scores demonstrated similar rates of early recurrence. Conclusion mGPS, PNI, PLR, NLR, and SII scores did not show a suitable diagnostic accuracy to predict PDAC recurrence in the first 12 months after resection. Therefore, these inflammatory scores should not be used to select the best candidates or to preclude a possible surgical indication.

Abstract Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

Several studies have demonstrated, both in vitro and in animal models, the anti-tumor efficacy of high-dose ascorbate treatment against a variety of tumor entities, including glioblastoma, the most common and aggressive primary malignant brain tumor. The aim of this study was to investigate the effects of high-dose ascorbate as well as dehydroascorbic acid on human glioblastoma cell lines and to evaluate different treatment conditions for the combined administration of ascorbate with magnesium (Mg2+) and iron (Fe3+). Intracellular levels of reactive oxygen species and the induction of cell death following ascorbate treatment were also investigated. We demonstrated high cytotoxicity and antiproliferative efficacy of high-dose ascorbate in human glioblastoma cells, whereas much weaker effects were observed for dehydroascorbic acid. Ascorbate-induced cell death was independent of apoptosis. Both the reduction in cell viability and the ascorbate-induced generation of intracellular reactive oxygen species could be significantly increased by incubating the cells with Fe3+ before ascorbate treatment. This work demonstrates, for the first time, an increase in ascorbate-induced intracellular ROS formation and cytotoxicity in human glioblastoma cells by pre-treatment of the tumor cells with ferric iron, as well as caspase-3 independence of cell death induced by high-dose ascorbate. Instead, the cell death mechanism caused by high-dose ascorbate in glioblastoma cells shows evidence of ferroptosis. The results of the present work provide insights into the efficacy and mode of action of pharmacological ascorbate for the therapy of glioblastoma, as well as indications for possible approaches to increase the effectiveness of ascorbate treatment.

Using secondary data has many advantages, but there are also many limitations, including the lack of relevant information. This article draws on a previous study that used secondary data to investigate substance use in young, elite athletes. Three types of missing data appeared: missing data, lack of information about the data collection process, and unavailable data. Other concerns were also highlighted, such as coverage and sampling errors. The impacts of secondary data on scientific research results can be divided into unavoidable changes and researchers' choices. The research question should guide the option to use secondary data, and it is essential to assess the level of constraint that will result from it early on. Additionally, along with the quality of information available, consistency in questionnaires is vital for broadening the scope and ensuring research progress.

This article summarizes the methodology for the identification of practitioners’ challenges, in the context of the H2020 funded project FIRE-IN (Fire and Rescue Innovation Network) activities. The project consisted of five thematic areas or “Thematic Working Groups”, as they are called, i.e., Search and Rescue Emergency Response, Structure Fires, Landscape Fires Crisis Mitigation, Natural Hazard Mitigation and Chemical Biological Radiological Nuclear and Explosives, and three iterations, each one including the identification of capability challenges, the screening for solutions, that can potentially address these challenges, and the request for ideas regarding future innovations that will complement already existing ones and will assist in covering capability gaps. This article focuses on the natural hazard mitigation working group and tsunamis in the Mediterranean region as a case study for the 3rd and last iteration of the project. The scenario of a tsunami occurrence in the Mediterranean is the basis for the FIRE-IN 3rd cycle workshop, as an indicative example of a high impact – low probability event, which aims to identify practitioners’ Future Common Capability Challenges in Europe. The current status of the tsunami hazard in Europe, national and international tsunami risk mitigation measures and procedures and operational experience from recent events are also discussed. Focus is provided on the natural hazard mitigation and tsunami related practitioners’ challenges, while results from the FIRE-IN request for ideas process and the interaction between practitioners, researchers and industry are also discussed. The aim is to present practitioners’ current and future capability challenges , one of the main outcomes of the FIRE-IN project, and to provide further guidelines to stakeholders of disaster management towards a safer Europe, mainly, through preparedness and adaptation for stronger and resilient societies.

IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

Abstract Intraoperative radiation therapy (IORT) is a radiation technique applying a single fraction with a high dose during surgery. We report the first abdomino-pelvic application of an image-guided intraoperative electron radiation therapy with intraoperative real time dose calculation based on the individual intraoperative patient anatomy. A patient suffering from locoregionally recurrent rectal cancer after treatment with neoadjuvant re-chemoradiation was chosen for this approach. After surgical removal of the recurrence, an adequate IORT applicator was placed as usual. A novel mobile imaging device (ImagingRing, MedPhoton) was positioned around the patient covering the region to be treated with the IORT-applicator in place. It allowed the acquisition of three-dimensional intraoperative cone-beam computed tomography images suitable for dose calculation using an automated scaling (heuristic object and head scatter as well as hardening corrections) of Hounsfield units. After image acquisition confirmed the correct applicator position, the images were transferred to our treatment planning system for intraoperative dose calculation. Treatment could be accomplished using the calculated dose distribution. We herein describe the details of the procedure including necessary adjustments in the typically used IORT equipment and work flow. We further discuss the pros and cons of this new approach generally overcoming a decade long limitation of IORT procedures as well as future perspectives regarding IORT treatments.

Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimer's disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood. In this study, we investigated the role of age-associated stressors on H3K9me3 regulation and examined if changes in H3K9me3 were age dependent. We used cultured hippocampal neurons at 6, 12, and 21 days in vitro (DIV) to examine the effect of different stressors on H3K9me3 across neuron ages. We found that the oxidative stressor hydrogen peroxide (H2O2) does not induce H3K9me3 in 12 DIV neurons. Inhibiting BDNF signaling via TrkB-Fc elevated H3K9me3 in 12 and 21 DIV neurons compared to 6 DIV neurons. Antioxidant treatment prevented H3K9me3 elevation in 12 DIV neurons treated with TrkB-Fc and H2O2. H2O2 elevated the epigenetic regulator SIRT1 in 6 DIV neurons but did not increase H3K9me3 levels. Our findings demonstrate that inhibiting BDNF signaling elevates hippocampal H3K9me3 in a manner dependent on in vitro age and oxidative stress.

Surgery plays a central role in the treatment of benign and malignant pancreatic diseases. Artificial intelligence (AI) is an important upcoming technology to support surgeons in pre-, intra-, and postoperative diagnosis, decision-making and training toward an optimized patient care. Current AI applications show a promising role in the evaluation of preoperative images for prediction of malignancy and resectability, intraoperative decision support, surgical training as well as a postoperative risk stratification to personalize the management of complications. This scoping review summarizes the most up to date developments of AI in pancreatic surgery with the highest available level of evidence.

Background: There is a gap in the literature regarding data on sexting among youth under the age of 16 whereas the problems related to this practice could affect them more because of their ongoing development. This study aims to determine the prevalence rate and characteristics of sending one's own sexually related image among middle-school teens. Methods: Data were obtained from a web-based in-school survey conducted between October 2019 and February 2020. The sample comprised 3006 (mean age 13.7; 50.2% males) 10th-grade pupils in the canton of Vaud (Switzerland). Participants were asked "Have you ever sent a sexually related/sexy image of yourself?". Analysis of variance/chi-square tests and multinomial regression analyses were used to compare the groups. Results: Overall, 93.0% reported never, 3.7% once and 3.3% several times. No gender differences were found. Sending was associated with older age, low academic performance, cyberbullying victimization and reception of unsolicited sexually related images. Conclusions: Education and health professionals should be aware that it is necessary to discuss the theme, perhaps with a more global approach including pressure, consent, exchange of nonsexual images, and so on from an early age. The context and reasons for sending remain to be explored, particularly to determine if the pressure is greater at this age.

Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3's catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.

NUT (nuclear-protein-in-testis) carcinoma (NC) is a highly aggressive tumor disease. Given that current treatment regimens offer a median survival of six months only, it is likely that this type of tumor requires an extended multimodal treatment approach to improve prognosis. In an earlier case report, we could show that an oncolytic herpes simplex virus (T-VEC) is functional in NC patients. To identify further combination partners for T-VEC, we have investigated the anti-tumoral effects of T-VEC and five different small molecule inhibitors (SMIs) alone and in combination in human NC cell lines. Dual combinations were found to result in higher rates of tumor cell reductions when compared to the respective monotherapy as demonstrated by viability assays and real-time tumor cell growth monitoring. Interestingly, we found that the combination of T-VEC with SMIs resulted in both stronger and earlier reductions in the expression of c-Myc, a main driver of NC cell proliferation, when compared to T-VEC monotherapy. These results indicate the great potential of combinatorial therapies using oncolytic viruses and SMIs to control the highly aggressive behavior of NC cancers and probably will pave the way for innovative multimodal clinical studies in the near future.

The beneficial effects of exercise on cognition are well established; however specific exercise parameters regarding the frequency and duration of physical activity that provide optimal cognitive health have not been well defined. Here, we explore the effects of the duration of exercise and sedentary periods on long-term object location memory (OLM) in mice. We use a weak object location training paradigm that is subthreshold for long-term memory formation in sedentary controls, and demonstrate that exercise enables long-term memories to form. We show that 14- and 21-d of running wheel access enables mice to discriminate between familiar and novel object locations after a 24 h delay, while 2- or 7-d running wheel access provides insufficient exercise for such memory enhancement using the subthreshold learning paradigm. After 14- and 21-d of wheel running, exercise-induced cognitive enhancement then decays back to baseline performance following 3-d of sedentary activity. However, exercise-induced cognitive enhancement can be reactivated by an additional period of just 2 d exercise, previously shown to be insufficient to induce cognitive enhancement on its own. The reactivating period of exercise is capable of enhancing memory after three- or seven-sedentary days, but not 14-d. These data suggest a type of "molecular memory" for the exercise stimulus, in that once exercise duration reaches a certain threshold, it establishes a temporal window during which subsequent low-level exercise can capitalize on the neurobiological adaptations induced by the initial period of exercise, enabling it to maintain the benefits on cognitive function. These findings provide new information that may help to guide future clinical studies in exercise.