Search Results (1,202)

Colorectal cancer (CRC) is not only the third most common cancer worldwide, with 1.1 million new cases per year; it is also the second leading cause of cancer death. However, mortality has decreased since 2012 due to early detection programs and better therapeutic approaches. While many patients are diagnosed at an early stage, there is up to 50% relapse after optimal initial treatment. Therefore, it is crucial to explore the mechanism underlying the development of recurrences and metastasis. It is known that tumors release dormant cells that escape chemotherapy and nest in a target organ without proliferating. Under certain circumstances that are not yet entirely clear, they can be activated and metastasize. Therefore, the objective of this work is to explore the detailed mechanisms of dormancy, including early detection of recurrence and therapeutic approaches for the treatment of CRC. The specific objectives are to determine biomarkers that may be useful in identifying dormant cells to detect minimal residual disease (MRD) after surgery and predicting disease progression, as well as evaluating biomarkers that are susceptible to therapeutic intervention. Full article

Status epilepticus occurs when a seizure lasts more than five minutes or when multiple seizures occur with incomplete return to baseline. SE induces a myriad of pathological changes involving synaptic and extra-synaptic factors. The transition from a self-limiting seizure to a self-sustaining one is established by maladaptive receptor trafficking, whereby GABA_A receptors are progressively endocytosed while glutamatergic receptors (NMDA and AMPA) are transported to the synaptic membrane, causing excitotoxicity and alteration in glutamate-dependent downstream signaling. The subsequent influx of Ca²⁺ exposes neurons to increased levels of [Ca²⁺]i, which overwhelms mitochondrial buffering, resulting in irreversible mitochondrial membrane depolarization and mitochondrial injury. Oxidative stress resulting from mitochondrial leakage and increased production of reactive oxygen species activates the inflammasome and induces a damage-associated molecular pattern. Neuroinflammation perpetuates oxidative stress and exacerbates mitochondrial injury, thereby jeopardizing mitochondrial energy supply in a state of accelerated ATP consumption. Additionally, Ca²⁺ overload can directly damage neurons by activating enzymes involved in the breakdown of proteins, phospholipids, and nucleic acids. The cumulative effect of these effector pathways is neuronal injury and neuronal death. Surviving neurons undergo long-term alterations that serve as a substrate for epileptogenesis. This review highlights the multifaceted mechanisms underlying SE self-sustainability, pharmacoresistance, and subsequent epileptogenesis. Full article

Hemorrhage is the leading cause of preventable death in trauma care, requiring rapid and accurate detection to guide effective interventions. Hemorrhagic shock can be masked by underlying compensatory mechanisms, which may lead to delayed decision-making that can compromise casualty care. In this proof-of-concept study, we aimed to develop and evaluate machine learning models to predict Percent Estimated Blood Loss from a photoplethysmography waveform, offering non-invasive, field deployable solutions. Different model types were tuned and optimized using data captured during a hemorrhage and resuscitation swine study. Through this optimization process, we evaluated different time-lengths of prediction windows, machine learning model architectures, and data normalization approaches. Models were successful at predicting Percent Estimated Blood Loss in blind swine subjects with coefficient of determination values exceeding 0.8. This provides evidence that Percent Estimated Blood Loss can be accurately derived from non-invasive signals, improving its utility for trauma care and casualty triage in the pre-hospital and emergency medicine environment. Full article

Background/Objectives: Suicide is among the biggest causes of death in the world. In recent years, suicide rates have increased remarkably in developing countries such as Türkiye. Therefore, there is a need to understand the psychological mechanisms underlying suicidal ideation and behaviors. Within this context, this study aimed to examine the complex relationships between psychological strain and suicide rumination. Methods: The study was conducted on 470 university students because young adults constitute the largest suicide risk group in Türkiye. Results: The findings showed that psychological strain was a significant predictor of suicide rumination. Additionally, depression was found to play a mediating role between psychological strain and suicide rumination. Furthermore, both resilient coping and perceived social support were shown to play a moderating role in the relationships among psychological strain, depression, and suicide rumination. The results confirmed the Strain Theory of Suicide in a sample from Türkiye. Conclusions: These findings are expected to contribute to psychologists, psychiatrists and public health specialists’ development of suicide prevention and intervention programs for university students. These suicide prevention and intervention efforts may focus on enhancing resilient coping and perceived social support in combating psychological strain and depression. Full article

Objectives: To investigate the efficacy and underlying mechanisms of IBCar’s biological activity in breast cancer models, both in cell culture and in mice, and to compare its effects on cancer versus normal cells. Methods: The cytotoxicity of IBCar was evaluated using the MTS assay to assess metabolic activity and the clonogenic assay to determine reproductive integrity. The impact of IBCar on microtubule integrity, mitochondrial function, and multiple signaling pathways was analyzed using Western blotting, microarray analysis, and live cell imaging. The therapeutic effectiveness of orally administered IBCar was assessed in a transgenic mouse model of Luminal B breast cancer and in mice implanted with subcutaneous triple-negative breast cancer xenografts. Results: IBCar demonstrated potent cytotoxicity across a diverse panel of breast cancer cell lines, including those with mutant or wild-type TP53, and cell lines with short and long doubling times. Comparative analysis revealed distinct responses between normal and cancer cells, including differences in IBCar’s effects on the mitochondrial membrane potential, endoplasmic reticulum stress and activation of cell death pathways. In breast cancer cells, IBCar was cytotoxic at nanomolar concentrations, caused irreversible microtubule depolymerization leading to sustained mitochondrial dysfunction, endoplasmic reticulum stress, and induced apoptosis. In normal cells, protective mechanisms included reversible microtubule depolymerization and activation of pro-survival signaling via the caspase-8 and riptosome pathways. The therapeutic potential of IBCar was confirmed in mouse models of Luminal B and triple negative BC, where it exhibited strong antitumor activity without detectable toxicity. Conclusions: These findings collectively support IBCar as a promising, effective, and safe therapeutic candidate for breast cancer treatment. Full article

Background/Objectives: The incidence and prevalence of ischemic stroke, a leading cause of death and disability worldwide, are significantly higher in older adults than in younger individuals. Senescence induces a variety of biological changes that influence the pathogenesis of diseases such as ischemic stroke, thereby necessitating age-specific medical treatments. However, the molecular mechanisms underlying age-related differences in ischemic stroke progression remain poorly understood. Methods: We compared the histological and molecular features of ischemic stroke in a photothrombotic mouse model, focusing on 9-week-old (young) and 90-week-old (old) mice. Results: We found that microglial accumulation at the infarct region of the cerebral cortex was significantly lower in old mice than in young ones. This reduction in the microglial response was accompanied by a decrease in the morphological robustness of the astrocytes forming the glial scar. Furthermore, the mRNA expression of proinflammatory cytokines CXCL10, CCL2, and TNF-α, which were upregulated in the infarct region, was considerably higher in the old mice than in the young ones. Cytokine expression was well correlated with the mRNA levels of Toll-like receptor 4 (TLR4), a key regulator of neuroinflammation in old mice, but less correlated with them in young mice. Interestingly, Tlr4 mRNA expression in young mice was negatively correlated with the mRNA expression of the epigenetic regulator HDAC7, whereas this correlation was positive in old mice. Conclusions: These findings suggest that age-dependent changes in epigenetic regulation, such as the interaction between HDAC7 and TLR4, may contribute to the distinct pathological progression of ischemic stroke in older individuals. Full article

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Its sustained proliferative signaling poses a major challenge for effective therapeutic intervention. Since CRC originates from aberrantly proliferating crypt cells, limiting proliferation or inducing senescence may offer a promising treatment approach. Lycium barbarum glycopeptide (LbGP), a traditional Chinese medicine component, is known for its immunomodulatory and other beneficial effects. This study aims to examine the anti-tumor effects of LbGP in CRC as well as its underlying mechanisms of action. We used CT26 CRC cells to investigate the effects of LbGP on tumor proliferation both in vitro and in an allograft mouse model. LbGP treatment significantly inhibited CT26 cell proliferation in vitro and suppressed tumor growth in CT26-implanted mice. Furthermore, LbGP treatment significantly upregulated p53/p21 levels both in vitro and in vivo, leading to CT26 cell cycle arrest in the S phase and the induction of tumor cell senescence. These findings demonstrate that LbGP effectively induces CRC cell cycle arrest and senescence via the p53/p21 pathway and may serve as a promising candidate for CRC adjuvant therapy. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to loss of muscle control, and, ultimately, respiratory failure and death. Despite some advances in recent years, the underlying genetic and molecular mechanisms of ALS remain largely elusive. In this respect, a better understanding of these mechanisms is needed to identify new and biologically relevant therapeutic targets that could be developed into treatments that are truly disease-modifying, in that they address the underlying causes rather than the symptoms of ALS. In this study, we used two approaches to model multi-omics data in order to map and elucidate the genetic and molecular mechanisms involved in ALS, i.e., the molecular landscape building approach and the Patrimony platform. These two methods are complementary because they rely upon different omics data sets, analytic methods, and scoring systems to identify and rank therapeutic target candidates. The orthogonal combination of the two modeling approaches led to significant convergences, as well as some complementarity, both for validating existing therapeutic targets and identifying novel targets. As for validating existing targets, we found that, out of 217 different targets that have been or are being investigated for drug development, 10 have high scores in both the landscape and Patrimony models, suggesting that they are highly relevant for ALS. Moreover, through both models, we identified or corroborated novel putative drug targets for ALS. A notable example of such a target is MATR3, a protein that has strong genetic, molecular, and functional links with ALS pathology. In conclusion, by using two distinct and highly complementary disease modeling approaches, this study enhances our understanding of ALS pathogenesis and provides a framework for prioritizing new therapeutic targets. Moreover, our findings underscore the potential of leveraging multi-omics analyses to improve target discovery and accelerate the development of effective treatments for ALS, and potentially other related complex human diseases. Full article

Background: Osteogenesis imperfecta (OI) is a rare genetic connective tissue disorder characterized by bone fragility, most often caused by pathogenic variants in type I collagen genes. In this context, we aimed to describe the clinical and epidemiological characteristics of patients with OI who were hospitalized for coronavirus disease (COVID)-19 in Brazil between 2020 and 2024. Methods: We conducted a retrospective descriptive analysis using data from the Brazilian Unified Health System (SUS, which stands for the Portuguese Sistema Único de Saúde) through the Open-Data-SUS platform. Patients with a confirmed diagnosis of OI and hospitalization due to COVID-19 were included. Descriptive statistical analysis was performed to evaluate demographic, clinical, and outcome-related variables. We included all hospitalized COVID-19 cases with a confirmed diagnosis of OI between 2020 and 2024. Results: Thirteen hospitalized patients with OI and COVID-19 were identified. Most were adults (9; 69.2%), male (7; 53.8%), self-identified as White (9; 69.2%), and all were residents of urban areas (13; 100.0%). The most frequent symptoms were fever (10; 76.9%), cough (9; 69.2%), oxygen desaturation (9; 69.2%), dyspnea (8; 61.5%), and respiratory distress (7; 53.8%). Two patients had heart disease, one had chronic lung disease, and one was obese. As for vaccination status, five patients (38.5%) had been vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Four patients (30.8%) required admission to an intensive care unit (ICU), and six (46.2%) required noninvasive ventilatory support. Among those admitted to the ICU, only two required invasive mechanical ventilation. The clinical outcome was death in two cases (15.4%). Both patients were male, White, and had not been vaccinated against SARS-CoV-2. One was 47 years old, was not admitted to the ICU, but required noninvasive ventilation. Despite the underlying condition most patients had favorable outcomes, consistent with an international report. Conclusions: This is the first report to describe the clinical and epidemiological profile of patients with OI hospitalized for COVID-19 in Brazil, providing initial insights into how a rare bone disorder intersects with an acute respiratory infection. The generally favorable outcomes observed—despite the underlying skeletal fragility—suggest that individuals with OI are not necessarily at disproportionate risk of severe COVID-19, particularly when appropriately monitored. The occurrence of deaths only among unvaccinated patients underscores the critical role of SARS-CoV-2 vaccination in this population. Although pharmacological treatment data were unavailable, the potential protective effects of bisphosphonates and vitamin D merit further exploration. These findings support the need for early preventive strategies, systematic vaccination efforts, and dedicated clinical protocols for rare disease populations during infectious disease outbreaks. Full article

Background: Staphylococcus spp. represent the most prevalent Gram-positive organisms in children with malignancies or undergoing haematopoietic cell transplantation (HCT), contributing to significant morbidity and mortality. This study aimed to assess the epidemiology, risk factors, treatment strategies, and outcomes of staphylococcal infections (SIs) in paediatric haemato-oncology (PHO) and HCT patients in Poland over a 12-year period. Methods: A retrospective, multicentre study was conducted across 17 paediatric oncology centres in Poland. The clinical and microbiological data of patients under the age of 18, diagnosed with malignancies or post-HCT, were analysed for confirmed SI between 2012 and 2023. The variables assessed included demographics, underlying conditions, infection type and source, antimicrobial susceptibility, treatment, and 30-day infection-free survival. Results: Among 1725 patients with SI, 1433 were PHO and 292 were HCT patients. The cumulative incidence of SI was 12.7% in PHO and 14.3% in HCT patients (p = 0.008). The 30-day survival rate was significantly higher in PHO compared to HCT patients (98.4% vs. 93.2%, p < 0.001). Most deaths were caused by S. epidermidis, S. haemolyticus, and S. hominis, predominantly involving methicillin-resistant coagulase-negative Staphylococci (MRCNS). Multivariate Cox regression identified undergoing HCT (HR = 3.0, 95% CI: 1.6–5.6, p < 0.001) and treatment of infection > 10 days (HR = 2.0, 95% CI: 1.1–3.6, p = 0.019) as independent risk factors for mortality. Conclusions: Staphylococcal infections pose a significant challenge in paediatric oncology and transplant populations. Optimising prevention, diagnostics, and antimicrobial therapy is crucial for improving outcomes in these high-risk groups. Full article

Metastases are the leading cause of cancer-related deaths. The spread of neoplasms involves multiple mechanisms, with metastatic tumors exhibiting molecular behaviors distinct from their primary counterparts. The key hallmarks of metastatic lesions include chromosomal instability, copy number alterations (CNAs), and a reduced degree of subclonality. Furthermore, metabolic adaptations such as enhanced glycogen synthesis and storage, as well as increased fatty acid oxidation (FAO), play a critical role in sustaining energy supply in metastases and contributing to chemoresistance. FAO promotes the infiltration of macrophages into the tumor, where they polarize to the M2 phenotype, which is associated with immune suppression and tissue remodeling. Additionally, the tumor microbiome and the action of cytotoxic drugs trigger neutrophil extravasation through inflammatory pathways. Chemoresistant neutrophils in the tumor microenvironment can suppress effector lymphocyte activation and facilitate the formation of neutrophil extracellular traps (NETs), which are linked to drug resistance. This article examines the genomic features of metastatic tumors, along with the metabolic and immunological dynamics within the metastatic tumor microenvironment, and their contribution to drug resistance. It also discusses the molecular mechanisms underlying resistance to chemotherapeutic agents commonly used in the treatment of metastatic cancer. Full article

Background: Exophiala spp. are dematiaceous fungi with opportunistic pathogenic potential and a widespread environmental presence. Clinical cases of Exophiala spp. fungemia are uncommon. Although rarely encountered in the general population, these organisms are increasingly reported in immunocompromised individuals or those with complex underlying health conditions. Objectives: This review seeks to examine all documented human cases of Exophiala spp. fungemia, with particular focus on aspects such as epidemiology, microbiological features, resistance patterns, therapeutic approaches and associated mortality rates. Methods: A narrative review was conducted using data sourced from the PubMed/MedLine and Scopus databases. Results: A total of 19 articles described infections in 32 patients involving Exophiala spp. fungemia. The mean patient age was 49.2 years, and 65.6% were male. Central venous catheters emerged as the leading predisposing factor (96.9%). Fever represented the most frequent clinical presentation (50%), followed by organ dysfunction (21.9%). The yeast generally demonstrated susceptibility to voriconazole and itraconazole. Voriconazole was also the most frequently administered antifungal (62.5%), followed by amphotericin (31.3%) and micafungin (28.1%). Overall mortality reached 34.4%, with 25% of deaths specifically caused by the infection. Conclusions: Given the potential of Exophiala spp. to cause severe fungemia, healthcare professionals, particularly clinicians and microbiologists, should consider this pathogen in the differential diagnosis when black yeast is detected in blood cultures, especially in patients with immunodeficiency or significant comorbidities, to ensure timely and accurate identification. Full article

Lung cancer is one of the most common and deadly forms of cancer worldwide, despite sustained efforts to encourage smoking cessation and raise awareness of the risk factors. In Romania, lung cancer is a significant health challenge, being the leading cause of death caused by cancer, especially amongst men. The incidence of lung cancer in connective tissue disease (CTD) varies in different studies from 4.5% in rheumatoid arthritis (RA), to 4.4% in polymyositis or dermatomyositis, and up to 11.1% in systemic sclerosis. However, older studies have shown an increased risk of cancer in patients with rheumatoid arthritis (RA), ranging from 10% to 30% compared to the general population, particularly in those undergoing methotrexate therapy. Rheumatoid arthritis affects approximately 40 per 100,000 people annually worldwide, with a three- to four-fold higher incidence in women. Non-small cell lung cancer (NSCLC), the most common lung cancer subtype, has been linked to RA, yet the association remains poorly defined, with limited insight into the underlying molecular mechanisms. We present the case of a 61-year-old male with a 49-pack-year smoking history and a known diagnosis of rheumatoid arthritis, currently managed with methotrexate therapy. He was admitted for evaluation due to a progressive decline in general condition, characterized by worsening dyspnea and chest pain, symptoms that had been longstanding but had markedly exacerbated over the past two weeks. Based on a chest CT performed prior to the patient’s admission to our clinic, subsequent diagnostic investigations established the diagnosis of pulmonary adenocarcinoma. The diagnostic process proved to be particularly challenging due to the presence of multiple comorbidities, which significantly impacted both the diagnostic approach and the overall clinical trajectory. Full article

Sudden cardiac death (SCD) is a major public health concern, being a leading cause of death worldwide. SCD is particularly alarming for individuals with apparently good health, as it often occurs without preceding warning signs. Unfortunately, traditional autopsy methods frequently fail to identify the precise cause of death in these cases, highlighting the need for advanced techniques to elucidate underlying mechanisms. Recent advances in molecular biology over the past few years, particularly in proteomics, transcriptomics, and metabolomics techniques, have led to an expanded understanding of gene expression, protein activity, and metabolic changes, offering valuable insights into fatal cardiac events. Combining multi-omics methods with bioinformatics and machine learning algorithms significantly enhances our ability to uncover the processes behind lethal cardiac dysfunctions by identifying new useful biomarkers (like cardiac myosin-binding protein C, acylcarnitines, or microRNAs) to reveal molecular pathways linked to SCD. This narrative review summarizes the role of multi-omics approaches in forensic diagnosis by exploring current applications in unexplained cases and the benefits of integrating merged techniques in otherwise negative autopsies. We also discuss the potential for developing personalized and preventive forensic medicine, the technical limitations of currently available methods, and the ethical considerations arising from these advancements. Full article

Cardiovascular diseases (CVDs) and Alzheimer’s disease (AD) are among the top 10 causes of death worldwide. Accumulating evidence suggests connections between CVD risk factors―including hypertension (HTN), hyperlipidemia (HLP), diabetes mellitus (DM), obesity, and physical inactivity―and AD. The Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) dietary pattern has recently garnered considerable attention as a key preventive strategy for both CVDs and AD. While previous studies have examined the connections between CVD risk factors and AD, they have not thoroughly explored their underlying mechanisms. Therefore, the current literature review aims to synthesize the literature and highlight underlying mechanisms from preclinical to clinical studies to elucidate the relationship between CVD risk factors, AD, and the role of the MIND dietary pattern in these conditions. The MIND dietary pattern emphasizes foods rich in antioxidants and brain-healthy nutrients such as vitamin E, folate, polyphenols, flavonoids, carotenoids, fiber, monounsaturated fatty acids, and omega-3 fatty acids. These components have been associated with reduced amyloid-β accumulation in preclinical studies and may contribute to the prevention of AD, either directly or indirectly by affecting CVD risk factors. Despite the extensive evidence from preclinical and observational studies, few clinical trials have investigated the effects of the MIND dietary pattern on cognitive health. Therefore, long-term clinical trials are required to better understand and establish the potential role of the MIND dietary pattern in preventing and managing AD. Full article