Search Results (2,895)

Obesity and metabolic dysfunction are established risk factors for luminal breast cancer, yet current preclinical models inadequately recapitulate the complex metabolic and immune interactions driving tumorigenesis. To develop and characterize an immunocompetent rat model of luminal breast cancer induced by chronic exposure to a cafeteria diet mimicking Western obesogenic nutrition. Female rats were fed a cafeteria diet or standard chow from weaning. Metabolic parameters, plasma biomarkers (including leptin, insulin, IGF-1, adiponectin, and estrone), mammary gland histology, tumor incidence, and gene expression profiles were longitudinally evaluated. Gene expression was assessed by PCR arrays and qPCR. A subgroup underwent dietary reversal to assess the reversibility of molecular alterations. Cafeteria diet induced significant obesity (mean weight 426.76 g vs. 263.09 g controls, p < 0.001) and increased leptin levels without altering insulin, IGF-1, or inflammatory markers. Histological analysis showed increased ductal ectasia and benign lesions, with earlier fibroadenoma and luminal carcinoma development in diet-fed rats. Tumors exhibited luminal phenotype, low Ki67, and elevated PAI-1 expression. Gene expression alterations were time point specific and revealed early downregulation of ID1 and COX2, followed by upregulation of MMP2, THBS1, TWIST1, and PAI-1. Short-term dietary reversal normalized several gene expression changes. Overall tumor incidence was modest (~12%), reflecting early tumor-promoting microenvironmental changes rather than aggressive carcinogenesis. This immunocompetent cafeteria diet rat model recapitulates key metabolic, histological, and molecular features of obesity-associated luminal breast cancer and offers a valuable platform for studying early tumorigenic mechanisms and prevention strategies without carcinogen-induced confounders. Full article

Background/Objectives: Pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by iron overload and hypomagnesemia, both contributing to immune dysfunction and post-transplant morbidity. The combined impact of these metabolic disturbances on pediatric allo-HSCT outcomes remains unexplored. This study aims to determine whether hypomagnesemia can serve as a prognostic biomarker for delayed immune reconstitution and explores its interplay with iron overload in predicting post-transplant complications and survival outcomes. Methods: A retrospective analysis was conducted on 163 pediatric allo-HSCT recipients. Serum magnesium levels were measured at defined intervals post-transplant, and outcomes were correlated with CD4+ T cell recovery, time to engraftment, incidence of graft-versus-host disease (GVHD), and survival within 12 months. Iron status, including siderosis severity, was evaluated using imaging and laboratory parameters obtained from clinical records. Results: Patients who died within 12 months post-transplant exhibited significantly lower magnesium levels. Hypomagnesemia was associated with delayed CD4+ T cell recovery, prolonged engraftment, and an increased risk of acute GVHD. A strong inverse correlation was observed between magnesium levels and the severity of siderosis. Iron overload appeared to exacerbate magnesium deficiency. Additionally, the coexistence of hypomagnesemia and siderosis significantly increased the risk of immune dysfunction and early mortality. No significant association was found with chronic GVHD. Conclusions: Hypomagnesemia is a significant, early predictor of poor outcomes in pediatric allo-HSCT, particularly in the context of iron overload, underscoring the need for early intervention, including iron chelation and MRI, to improve outcomes. Full article

Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling. Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions. While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases. This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS. Full article

Background/Objective: Early-onset neonatal sepsis (EOS), defined as infection occurring within the first 72 h after birth, remains a major contributor to neonatal morbidity and mortality worldwide. Although advances in perinatal care have improved overall outcomes, the diagnosis of EOS continues to be challenging. Clinical presentations are often nonspecific, laboratory confirmation is often delayed, and immune responses vary considerably among neonates. Expanding our understanding of the molecular mechanisms underlying EOS is essential in enhancing early detection, refining risk stratification, and guiding therapeutic strategies. This systematic review aims to synthesize the available information on the molecular pathways involved in EOS, focusing on pathogen-induced inflammation, systemic immune responses, sterile inflammatory processes, interactions between infectious and non-infectious pathways, as well as emerging molecular diagnostic approaches. Methods: A comprehensive review of original research articles and reviews published between January 2015 and January 2025 was conducted; studies were included based on their focus on human neonates and their analysis of molecular or immunological mechanisms relevant to EOS pathogenesis, immune dysregulation, or novel diagnostic strategies. Results: Pathogen-driven inflammation typically involves the activation of Toll-like receptors (TLRs), the recruitment of neutrophils, and the release of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, particularly in response to vertical transmission of organisms like Escherichia coli and Streptococcus agalactiae. Systemic inflammatory responses are marked by cytokine dysregulation, contributing to multi-organ dysfunction. Sterile inflammation, often initiated by hypoxia–reperfusion injury or intrauterine stress, amplifies susceptibility to sepsis. Interactions between immune, metabolic, and endothelial pathways further exacerbate tissue injury. Recent advances, including transcriptomic profiling, microRNA-based biomarkers, and immune checkpoint studies, offer promising strategies for earlier diagnosis and individualized therapeutic options. Conclusions: EOS arises from a complex interplay of infectious and sterile inflammatory mechanisms. A deeper molecular understanding holds promise for advancing correct diagnostics and targeted therapies, aiming to improve neonatal outcomes. Full article

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may be triggered by infections such as dengue virus. Due to overlapping features with severe dengue and sepsis, diagnosis of HLH in dengue-infected patients remains challenging. Methods: We conducted a narrative review and individual patient data meta-analysis of published cases of dengue-associated HLH. Eligible studies were identified through a search of PubMed and Scopus databases up to 5 March 2025. Clinical, laboratory, microbiological, treatment, and outcome data were extracted and analyzed. Results: A total of 133 patients from 71 studies were included. The median patient age was 18 years, and 56.8% were male. Common clinical features included fever (96.9%), cytopenias, organomegaly, and liver dysfunction. ALT elevation, jaundice, and hypofibrinogenemia were associated with mortality. DENV-1 was the most common serotype (57.4%) and was negatively associated with death. Overall, 19.3% of patients died. Multivariate analysis did not identify independent mortality predictors. Conclusions: Dengue-associated HLH predominantly affects young individuals and carries significant mortality. Key indicators of poor prognosis include hepatic dysfunction and the presence of shock or organ failure. Early recognition and prompt immunomodulatory treatment, particularly corticosteroids, may improve outcomes. Full article

Breast cancer (BC) is a neoplasm characterized by high heterogeneity and is influenced by intrinsic molecular subtypes and clinical stage, aspects that remain underexplored in the Colombian population. This study aimed to characterize metabolic alterations associated with subtypes and disease progression in a group of newly diagnosed, treatment-naive Colombian women using an untargeted metabolomics approach. To improve metabolite coverage, samples were analyzed using LC-QTOF-MS and GC-QTOF-MS, along with amino acid profiling. The Luminal B subtype exhibited elevated levels of long-chain acylcarnitines and higher free fatty acid concentrations than the other subtypes. It also presented elevated levels of carbohydrates and essential glycolytic intermediates, suggesting that this subtype may adopt a hybrid metabolic phenotype characterized by increased glycolytic flux as well as enhanced fatty acid catabolism. Tumor, Node, and Metastasis (TNM) staging analysis revealed progressive metabolic reprogramming of BC. In advanced stages, a sustained increase in phosphatidylcholines and a decrease in lysophosphatidylcholines were observed, reflecting lipid alterations associated with key roles in tumor progression. In early stages (I-II), plasma metabolites with high discriminatory power were identified, such as glutamic acid, ribose, and glycerol, which are associated with dysfunctions in energy and carbohydrate metabolism. These results highlight metabolomics as a promising tool for the early diagnosis, clinical follow-up, and molecular characterization of BC. Full article

Cirrhosis remains a significant global health burden, responsible for nearly 4% of annual deaths worldwide. Despite progress in antiviral therapies and public health measures, its prevalence has plateaued, particularly in regions affected by viral hepatitis, alcohol misuse, and metabolic syndrome. This review presents a comprehensive synthesis of the multifactorial drivers of cirrhosis, including hepatocyte injury, liver stellate cell activation, and immune-mediated inflammation. The emphasis is on the central role of metabolic dysfunction, characterized by mitochondrial impairment, altered lipid and glucose metabolism, hormonal imbalance, and systemic inflammation, in exacerbating disease progression. While current therapies may slow the progression of early-stage disease, they are very often ineffective in reversing established fibrosis. Emerging molecular strategies offer promising alternatives by targeting key pathogenic pathways. These include AMPK activators (e.g., metformin, AICAR), FGF21 analogs, and mitochondria-targeted agents (e.g., MitoQ, urolithin A, NAD+ precursors) to restore bioenergetic balance and reduce oxidative stress. Other approaches, such as mesenchymal stem cell therapy, inflammasome inhibition, and hormonal modulation, aim to suppress fibrogenesis and restore liver homeostasis. The integration of systems biology and multi-omics profiling supports patient stratification and precision medicine. This review highlights a shift toward mechanism-based interventions that have the potential to alter cirrhosis outcomes and improve patient survival. Full article

Although intracranial hypertension (ICH) has traditionally been framed as simply a numerical escalation of intracranial pressure (ICP) and usually dealt with in its clinical form and not in terms of its complex underlying pathophysiology, an emerging body of evidence indicates that ICH is not simply an elevated ICP process but a complex process of molecular dysregulation, glymphatic dysfunction, and neurovascular insufficiency. Our aim in this paper is to provide a complete synthesis of all the new thinking that is occurring in this space, primarily on the intersection of glymphatic dysfunction and cerebral vein physiology. The aspiration is to review how glymphatic dysfunction, largely secondary to aquaporin-4 (AQP4) dysfunction, can lead to delayed cerebrospinal fluid (CSF) clearance and thus the accumulation of extravascular fluid resulting in elevated ICP. A range of other factors such as oxidative stress, endothelin-1, and neuroinflammation seem to significantly impair cerebral autoregulation, making ICH challenging to manage. Combining recent studies, we intend to provide a revised conceptualization of ICH that recognizes the nuance and complexity of ICH that is understated by previous models. We wish to also address novel diagnostics aimed at better capturing the dynamic nature of ICH. Recent advances in non-invasive imaging (i.e., 4D flow MRI and dynamic contrast-enhanced MRI; DCE-MRI) allow for better visualization of dynamic changes to the glymphatic and cerebral blood flow (CBF) system. Finally, wearable ICP monitors and AI-assisted diagnostics will create opportunities for these continuous and real-time assessments, especially in limited resource settings. Our goal is to provide examples of opportunities that exist that might augment early recognition and improve personalized care while ensuring we realize practical challenges and limitations. We also consider what may be therapeutically possible now and in the future. Therapeutic opportunities discussed include CRISPR-based gene editing aimed at restoring AQP4 function, nano-robotics aimed at drug targeting, and bioelectronic devices purposed for ICP modulation. Certainly, these proposals are innovative in nature but will require ethically responsible confirmation of long-term safety and availability, particularly to low- and middle-income countries (LMICs), where the burdens of secondary ICH remain preeminent. Throughout the review, we will be restrained to a balanced pursuit of innovative ideas and ethical considerations to attain global health equity. It is not our intent to provide unequivocal answers, but instead to encourage informed discussions at the intersections of research, clinical practice, and the public health field. We hope this review may stimulate further discussion about ICH and highlight research opportunities to conduct translational research in modern neuroscience with real, approachable, and patient-centered care. Full article

Sepsis represents a major cause of mortality, especially among patients with liver cirrhosis, who are at increased risk due to immune dysfunction, gut-derived bacterial translocation, and altered hepatic metabolism. Traditional biomarkers such as C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) often have reduced diagnostic reliability in this subgroup, due to impaired liver and renal function. Presepsin, a soluble fragment of CD14 released during phagocytic activation, has emerged as a promising biomarker for early sepsis detection. This systematic review explores the diagnostic and prognostic utility of presepsin in cirrhotic and non-cirrhotic patients with suspected infection. Data from multiple clinical studies indicate that presepsin levels correlate with infection severity and clinical scores such as SOFA and APACHE II. In cirrhotic patients, presepsin demonstrates superior sensitivity and specificity compared to conventional biomarkers, maintaining diagnostic value despite hepatic dysfunction. Its utility extends to differentiating bacterial infections from fungal infections and monitoring treatment response. While preliminary evidence is compelling, further prospective, multicenter studies are required to validate its integration into standard care algorithms. Presepsin may become a valuable addition to clinical decision-making tools, particularly in hepatology-focused sepsis management. Full article

Background and Objectives: Type 2 diabetes mellitus (T2DM) is associated with subclinical cardiovascular changes, such as increased arterial stiffness and myocardial dysfunction. Vitamin D deficiency has been recognized as a potential contributing factor to vascular disease; however, its impact on early cardiac changes associated with T2DM remains poorly understood. Our aim was to evaluate the association between serum levels of 25-hydroxyvitamin D3 [25(OH)D3], arterial stiffness, and left ventricular global longitudinal strain (LV GLS) in patients with T2DM who do not have a clinically evident cardiovascular disease. Material and methods: This cross-sectional study evaluated the carotid intima–media thickness (IMT), aortic pulse wave velocity (PWVao), LV GLS, and serum 25(OH)D3 levels in patients diagnosed with T2DM (n = 65) compared to healthy control subjects (n = 55). Independent predictors of arterial stiffness were identified by a multivariate logistic regression analysis. Results: Patients with T2DM showed a significant increase in IMT and PWVao, a reduction in LV GLS, and low levels of 25(OH)D3 compared to subjects in the control group (all p < 0.05). Both vitamin D deficiency and T2DM were found to be independently associated with an increased arterial stiffness, with odds ratios of 2.4 and 4.8, respectively. A significant inverse relationship was identified between 25(OH)D3 levels and markers of arterial stiffness, as well as LV GLS, suggesting a possible association between the vitamin D status and the early onset of cardiovascular dysfunction. Conclusions: Patients with T2DM show early signs of heart and blood vessel problems, even with an ejection fraction that remains within normal limits. There is a significant correlation between vitamin D deficiency and increased arterial stiffness, along with impaired LV GLS, indicating its possible involvement in cardiovascular complications associated with diabetes. These findings support the utility of integrating vascular, myocardial, and vitamin D assessments in early cardiovascular risk stratification for T2DM patients. Full article

Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13–18; mean BMI = 36 ± 6.4 kg/m²). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC–mass spectrometry, peak oxygen uptake (VO_{2 peak}) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = −0.39, p = 0.047), total cholesterol (rho = −0.55, p = 0.002), and LDL-C (rho = −0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = −0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO₂ peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk. Full article

Neuronal ceroid lipofuscinoses (NCLs) are paediatric neurodegenerative disorders that primarily affect the central nervous system (CNS). The high prevalence of gastrointestinal (GI) symptoms has prompted researchers and clinicians to move beyond an exclusively “brain-centric” perspective. At the molecular level, mutations in CLN genes lead to lysosomal dysfunction and impaired autophagy, resulting in intracellular accumulation of storage material that disrupts both central and enteric neuronal homeostasis. To systematically examine current clinical and preclinical knowledge on gut involvement in NCLs, with a focus on recent findings related to the enteric nervous system and gut microbiota. We conducted a systematic review following the PRISMA guidelines using PubMed as the sole database. Both clinical (human) and preclinical (animal) studies were included. A total of 18 studies met the inclusion criteria, focusing on gastrointestinal dysfunction, nervous system involvement, and gut microbiota. We found that the nature of GI symptoms was multifactorial in NCLs, involving not only the CNS but also the autonomic and enteric nervous systems, which were affected early by lysosomal deposits and enteric neuron degeneration. Of note, preclinical studies showed that gene therapy could improve not only CNS manifestations but also GI ones, which may have beneficial implications for patient care. While the role of the ENS seems to be clearer, that of gut microbiota needs to be further clarified. Current evidence from preclinical models highlighted alterations in the composition of the microbiota and suggested a possible influence on the progression and modulation of neurological symptoms. However, these results need to be confirmed by further studies demonstrating the causality of this relationship. GI involvement is a key feature of NCLs, with early impact on the enteric nervous system and possible links to gut microbiota. Although preclinical findings—particularly on gene therapy—are encouraging due to their dual impact on both CNS and GI manifestations, the causal role of the gut microbiota remains to be fully elucidated. In this context, the development of sensitive and specific outcome measures to assess GI symptoms in clinical trials is crucial for evaluating the efficacy of future therapeutic interventions. Full article

Iron deficiency (ID) is the most prevalent micronutrient deficiency globally, affecting approximately one in four individuals, with a particularly high burden among children, women of reproductive age, and populations in low- and middle-income countries. It contributes significantly to the global burden of disease, with consequences ranging from impaired cognitive and motor development in children to increased risks during pregnancy, including low birth weight, preterm delivery, and maternal mortality, as well as reduced physical performance and quality of life in adults. ID often precedes iron deficiency anemia (IDA), though clinical and functional impairments—such as cognitive deficits, immune dysfunction, and fatigue—can occur even in the absence of anemia. Despite its widespread nature, challenges remain in precisely defining, diagnosing, and treating ID effectively. Advances in diagnostic tools allow for earlier detection, while novel therapeutic strategies, including updated oral dosing regimens and modern intravenous iron formulations, offer improved efficacy and tolerability. These approaches are particularly valuable in minimizing gastrointestinal side effects and enhancing patient adherence. This review is based on a comprehensive literature search conducted primarily through PubMed and Scopus, emphasizing studies published within the past 10–15 years. It is thematically structured to explore the epidemiology, health consequences, diagnostic complexities, and therapeutic developments related to ID. It highlights the multifactorial nature of ID and underscores the urgent need for early identification, targeted interventions, and updated clinical guidelines to reduce the long-term health and societal impacts of this preventable and treatable condition. Full article

There are currently no approved therapeutic treatments targeting metabolic dysfunction-associated steatotic liver disease (MASLD). Albumin, a liver-produced plasma protein with anti-inflammatory and antioxidant properties, is reduced in advanced liver disease. Considering the role of chronic obesity-induced inflammation in MASLD pathogenesis, we investigated whether albumin administration could prevent disease progression to metabolic dysfunction-associated steatohepatitis (MASH). MASLD was induced in mice using a high-fat and high-cholesterol (PC) treatment for 8 weeks, followed by treatment with bovine serum albumin (BSA; 0.8 mg/kg) every three days for another 8 weeks. This regimen prevented time-dependent weight gain, regardless of diet, with 57% and 27% reductions in mice fed a standard chow (Std Chow) or PC diet, respectively. Further, supplementation reduced nuclear factor kappa B (NF-κB) activation by 2.8-fold (p = 0.0328) in PC-fed mice, consistent with albumin’s known anti-inflammatory properties. Unexpectedly, albumin also reduced hepatic neutral lipid accumulation and circulating non-esterified fatty acids. While PC-fed mice did not exhibit full progression to MASH, albumin treatment significantly increased hepatic matrix metalloproteinase-2 expression, suggesting the inhibition of early fibrotic signalling. While further studies are needed to elucidate the underlying mechanisms, these findings offer new insight into the potential of albumin, either alone or in combination with other therapies, to reduce hepatic steatosis in MASLD. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article