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Familial breast cancer represents a minor percentage of all human breast cancers. Mutations in two high susceptibility genes BRCA1 and BRCA2 explain around 25 % of familial breast cancers, while other high, moderate and low susceptibility genes explain up to 20 % more of breast cancer families. Thus, it is important to decipher the genetic architecture of families that show no mutations to improve genetic counselling. The comprehensive description of familial breast cancer using different techniques and platforms has shown to be very valuable for better patient diagnosis, tumour surveillance, and ultimately patient treatment. This review focuses on the complex landscape of pathological, protein, genetic and genomic features associated with BRCA1 -, BRCA2 -, and non - BRCA1/BRCA2 -related cancers described up to date. Special emphasis deserves the coexistence of distinct molecular breast cancer subtypes, the development of tumour classifiers to predict BRCA1/2 mutations, and the last insights from recent whole genome sequencing studies and miRNA profiling.

Neuroinflammation is implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Amongst potential innate immune mediators of disease, Type I interferon (IFN-I) could play an important role due to its ability to inhibit protein synthesis and affect neuronal synapses and metabolism. These effects could be cell intrinsic or non-cell autonomous mediated by glia or immune cells. We examined IFN-I in rNLS8 mice that have been engineered to express doxycycline suppressible human Transactive response DNA binding protein 43 kDa (hTDP-43) with a defective nuclear localization signal (hTDP-43ΔNLS) regulated by the neurofilament heavy chain (NEFH) promoter. Following induction of hTDP-43ΔNLS in rNLS8 mice, we observed upregulation of IFN-I stimulated genes (ISG) and, specifically, activation of the DNA sensor, cyclic GMP-AMP synthase (cGAS), as determined by mass spectrometry identification of the cyclic dinucleotide, cGAMP, in whole brain. To determine the cellular source of IFN-I, we performed single nucleus RNA sequencing of whole brain. We observed that ISG were most highly upregulated in astrocytes suggesting that astrocytes themselves were largely responsible for IFN-I production and / or response in rNLS8 mice. This observation was confirmed by immunohistochemical and immunofluorescence staining of IFN-I stimulated proteins in astrocytes in the cerebrum, especially in the hippocampus. These results point to a pivotal role of astrocytes in responding to cell damage at a relatively early phase of disease which prior studies have shown is partially reversible.

This study aimed to compare the post-activation performance enhancement (PAPE) induced by isometric and isotonic exercise on vertical jump performance. 18 healthy trained men (25.8±2.7 years; 78.4±8.2 kg; 175.7±6.1 cm; 25.4±1.8 BMI; 126.72±10.8 kg squat 1-RM) volunteered for this study. They randomly performed two different PAPE protocols: Isotonic squats (ISOTS), which consisted of 2 sets of 3 repetitions at 75% of one-maximum repetition (1-RM); and isometric squats (ISOMS), which consisted of 2 sets of 4 seconds of submaximal (75% of 1-RM) isometric contraction at 90°-knee flexion. Countermovement jump (CMJ) height was tested at baseline and 4 minutes after each conditioning set. CMJ height significantly increased after set 1 in both PAPE protocols (ISOMS: p <0.001; ES = 0.34; ISOTS: p <0.001; ES = 0.24), with respect to the baseline jump. However, after set 2 no significant changes in CMJ height were observed for any protocol (ISOMS: p = 0.162; ES = 0.11; ISOTS: p = 0.976; ES = 0.06). No significant differences (p>0.05) were found between both isometric and isotonic exercise conditions. Despite both protocols showed similar PAPE effects on CMJ height after set 1, none of the protocols demonstrated greater efficacy in increasing subsequent performance in healthy trained men.

Obesity is linked to elevated levels of inflammatory serum markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFa). Adiponectin and resistin are adipokines related to obesity. It has been described that adipose tissue presents a high production and secretion of these diverse pro-inflammatory molecules, which may have local effects on the physiology of fat cells as well as systemic effects on other organs. Our aim was to evaluate the impact that lifestyle modifications, by following a Mediterranean Diet (MedDiet) program and physical activity (PA) training, would have on inflammatory biomarkers and adipokine profile in a Metabolically Healthy Obese (MHO) elderly population from Malaga (Andalusia, Spain). Subjects aged ≥65 years (65 to 87 years old) with obesity (BMI ≥30 kg/m2) were included in this study if they met ≤1 of the following criteria: systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥ 85 mmHg; triglycerides ≥150 mg/dL; HDL-C <40mg/dL in men and <50mg/dL women; and fasting blood glucose ≥100mg/dL. Selected subjects underwent a personalized intensive lifestyle modification. Anthropometric measurements, PA, MedDiet adherence, analytical parameters, and inflammatory biomarkers were analyzed after 12 months of intervention. 166 MHO elderly subjects, 40 (24.1%) male and 126 (75.9%) female (p < 0.0001), aged 71.7±5.2 years old (65 to 87 years old) were included in the study. After 12 months of intervention, only the waist circumference was significantly reduced in all the population (-2.5 cm, p<0.0001), although weight and BMI were maintained. MedDiet adherence increased significantly (p<0.001), but all intensity levels of PA decreased significantly (p<0.001). Concerning inflammatory biomarkers, only TNFa serum increased their levels after the intervention (p<0.001). Regarding the adipokine profile, adiponectin concentrations experienced a significant increment (p<0.001); besides, resistin concentrations decreased significantly (p<0.001). In this sense, only TNFa, adiponectin, and resistin correlated with PA. Adiponectin also correlates with insulin, triglycerides and HDL-c in baseline conditions and after 12 months of intervention; CRP, IL-6, TNFa, adiponectin, and resistin concentrations correlated with anthropometric parameters and some intensities of PA. In addition, adiponectin levels correlates with insulin, triglycerides and HDL-c. In baseline conditions, resistin levels correlated positively with TNFa (p = 0.01) and CRP (p<0.0001) levels. TNFa and IL-6 correlated positively with CRP (p = 0.03 and p<0.0001, respectively). After 12 months of intervention, only IL-6 correlated positively with CRP (p = 0.006). In addition, adipokines levels correlated positively during the process of lifestyle modification. However, during this process, only IL-6 correlated positively with itself (p<0.0001) and with CRP (p = 0.03). Healthy aging is a multifactorial biological process in which lifestyle is essential. The presence of obesity in elderly metabolically healthy population is not a problem necessarily. Elderly MHO population who eat a MedDiet and practice regularly PA are capable to modulate their production of inflammatory cytokines (CRP, IL-6, TNFa) and adipokines profile (adiponectin, resistin), preventing other metabolic disorders.

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance ( P   <  2.5 × 10 −6 ): the five known susceptibility genes ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 , together with MAP3K1 . Associations were also observed for LZTR1 , ATRIP and BARD1 with P  < 1 × 10 −4 . Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small. Meta-analysis of three large whole-exome sequencing datasets highlights protein-truncating and rare missense variants associated with breast cancer susceptibility.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1 -deficient microglia are resistant to amyloid-β 42 oligomer-induced bioenergetic changes, suggesting that amyloid-β 42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APP Swe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1 + cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology. The role of TREM1 in neurodegenerative diseases is unclear. Here the authors show that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology in a mouse model of Alzheimer disease.

The elimination of five selected emerging contaminants (1-H-benzotriazole, N , N -diethyl- m -toluamide (DEET), chlorophene, 3-methylindole, and nortriptyline HCl) dissolved in different water matrices (surface water and secondary effluents) was carried out by sequential membrane filtration and chemical oxidation processes. First, a membrane filtration (ultrafiltration (UF) or nanofiltration(NF)) pre-treatment was conducted, and both permeate and retentate were afterwards treated by chemical oxidation, using ozone or chlorine. The application of UF and especially of NF provided a large volume of permeate, whose quality can be improved by a chemical treatment to completely remove residual contaminants except 1-H-benzotriazole. Chlorination and especially ozonation have demonstrated to be effective for the reduction of emerging contaminants in the concentrated stream, thus generating an effluent that might be recycled to the activated sludge treatment in the wastewater treatment plants (WWTP). In a second group of experiments, a chemical oxidation pre-treatment (by using ozone, chlorine, O 3 /H 2 O 2 , ultraviolet (UV) radiation, or UV/H 2 O 2 ) was applied followed by a nanofiltration process. Results of removals and rejection coefficients for the emerging contaminants showed that the chemical pre-treatment exerted a positive influence on the subsequent NF process, not only in terms of ECs removal but also of dissolved organic carbon content (DOC) reduction. While global removals higher than 97 % were reached for DEET, chlorophene, 3-methylindole, and nortriptyline HCl, lower values were obtained for 1-H-benzotriazole, especially for chlorine pre-treatment and in those water matrices with high content of natural organic matter. Therefore, both sequential treatments are promising to remove the selected micropollutants while reducing the chlorine doses needed to achieve final water disinfection.

Handball is a team sport subjected to asymmetric actions that require high physical capacity demands on players. The development of large asymmetries could negatively affect sports performance. However, few studies have analyzed body composition and the force asymmetries in elite female handball players. The aim of this study was to analyze the presence of asymmetries based on limb dominance in body composition parameters and lower limb power in jumping performances in an elite women’s handball team. An entire elite women’s handball team, comprised by of 14 players, was analyzed. Dual X-ray Absorptiometry (DXA) and bioimpedance were used to analyze body composition. Force plates were used to evaluate jump performance. Results show the presence of differences between all the players in the different parameters of the CMJ jump. In addition, an asymmetry between the power of the dominant and non-dominant lower limb was observed between the players. The results show differences in muscle mass between the upper limbs, but not in the lower limbs in terms of both muscle and fat mass. However, there were no crossed asymmetries or significant differences between members based on dominance. The results suggest that the presence of asymmetries does not have to be one of the main parameters to be taken into account by coaches in elite athletes and to highlight the importance of including specific analyzes of body composition and sports performance in an individualized way.

This editorial addresses a critical oversight in recent clinical trials on neoadjuvant or perioperative immunotherapy for lung cancer, the exclusion of patients with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). The ethical implications of this exclusion are highlighted, demonstrating how it undermines principles of inclusivity and equity in clinical research. We emphasize the necessity to include these patients to enhance the generalizability of trial findings. We suggest that trial eligibility criteria be revised, and collaborations with patient advocacy groups be initiated to ensure more inclusive future trials. This approach aims to uphold ethical research practices, yielding robust, representative data, and ultimately improving patient care in oncology.

Despite significant advances in oncology, cancer care globally continues to face critical challenges, including stark disparities in access, insufficient preventive focus, fragmented primary health care (PHC) integration, unsustainable financing models, workforce shortages, and inadequate community involvement. This paper revisits the Alma Ata Declaration’s principles—health equity, universal access, preventive care, and community participation—as a conceptual framework to address these persistent issues in cancer care. We highlight opportunities to strategically integrate oncology services within strengthened PHC systems, balancing centralized specialist resources with decentralized community-based care. Evidence from diverse settings illustrates how reinforcing PHC infrastructures enhances preventive measures, early detection, and survivorship care, thus mitigating geographic and socioeconomic disparities. Sustainable financing mechanisms and targeted workforce strategies, including task-shifting and multidisciplinary training, are proposed as essential components. Effective community engagement models demonstrate improved care relevance, acceptance, and outcomes. Additionally, we emphasize the critical role of health policy alignment with universal health coverage objectives, robust pharmacoeconomic evaluations, and evidence-based national cancer control plans. Integrating Alma Ata’s principles into contemporary oncology provides a viable, scalable model to advance equitable, accessible, and sustainable cancer care globally, laying the theoretical groundwork for future research initiatives and informed policy development. Plain Language Summary Why was this study done? Despite many medical advances, cancer care remains very unequal globally. Many people worldwide still have poor access to cancer services because of high treatment costs, lack of trained medical staff, uneven healthcare resources, and weak healthcare systems. This work explores how the primary healthcare principles set by the Alma Ata Declaration—a major global health agreement from 1978 aimed at ensuring accessible health care for all—could help improve cancer care today. What did the researchers do? We reviewed challenges faced by current cancer care systems, including poor prevention, unequal access to care, high treatment costs, shortages of specialist healthcare workers, and limited community involvement. We then proposed a way to improve these issues by applying the Alma Ata principles—such as universal access, prevention-focused healthcare, and community involvement—to cancer care. We also highlighted successful real-world examples where these ideas have improved cancer services in different countries. What did the researchers find? Strengthening primary healthcare could significantly improve cancer outcomes by helping to detect cancers earlier, preventing many cases, reducing healthcare costs, and making care fairer for everyone, no matter their location or income. Involving local communities directly in healthcare planning and creating a balanced system combining specialized centers and local health services could benefit patients greatly. What do the findings mean? Applying the Alma Ata primary healthcare approach to cancer care can make it more accessible, affordable, and effective worldwide. This provides a clear roadmap for researchers, healthcare leaders, and policymakers seeking fairer and better cancer care for all people.