Search Results (31,316)

A remarkably well-preserved skeleton of a male Mammuthus meridionalis, approximately 60 years old, from the Early Pleistocene that is housed at the Castle of L’Aquila (Italy) exhibits a fractured left tusk with severe bone erosion of the alveolus and premaxillary bone, as well as marked spinal deformities. The cranial region underwent ultrasonographic, radiological, and histological examinations, while morphological and biomechanical analyses were conducted on the vertebral column. Microscopic analysis revealed intra vitam lesions, including woven bone fibers indicative of early bone remodeling and lamellar bone with expanded and remodeled Haversian systems. These findings are consistent with osteomyelitis and bone sequestration, likely resulting from chronic pulpitis following the tusk fracture, possibly due to an accident or interspecific combat. The vertebral column shows cervical scoliosis, compensatory curves, fusion between the first cervical vertebrae, and asymmetric articular facets, suggesting postural adaptations. Evidence of altered molar wear and masticatory function also support long-term survival post-trauma. Additionally, lesions compatible with spondyloarthropathy, an inflammatory spinal condition not previously documented in Mammuthus meridionalis, were identified. These findings provide new insights into the pathology and adaptive responses of extinct proboscideans, demonstrating the critical role of (paleo)histological methods in reconstructing trauma, disease, and aspects of life history in fossil vertebrates. Full article

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood–brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets—including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites—that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody–drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases. Full article

Mycoplasmal pneumonia of sheep (MPS), caused by Mesomycoplasma (Mycoplasma) ovipneumoniae, profoundly impacts ovine productivity and survival. Although gut–lung microbiota interactions are increasingly recognized in respiratory diseases, whether similar crosstalk occurs between the lung and rumen microbiota in MPS-affected sheep remains unknown. To investigate alterations in the lung and rumen microbiota of sheep with MPS, the crosstalk between these microbial communities, and their impacts on growth phenotypes. From a cohort of 414 naturally infected six-month-old male Hu sheep, we selected 10 individuals with severe pulmonary pathology and 10 healthy controls for detailed phenotypic and microbiome analyses. Assessment of 359 phenotypic traits revealed that MPS significantly impairs feed efficiency and growth rate (p < 0.05). Through 16S rRNA gene sequencing, we found that MPS significantly altered the pulmonary microbiota community structure (p < 0.01), with a noticeable impact on the rumen microbiota composition (p = 0.059). Succinivibrionaceae_UCG-001 was significantly depleted in both the rumen and lungs of diseased sheep (p < 0.05) and strongly associated with reduced average daily feed intake (p < 0.05). In addition, pulmonary Pasteurella and ruminal Succinivibrionaceae_UCG-002 were significantly enriched in MPS-affected sheep, showed a strong positive correlation (p < 0.05), and were both negatively associated with feed efficiency (p < 0.05). Notably, Pasteurella multocida subsp. gallicida may act as a keystone species influencing feed efficiency. These findings point to a previously unrecognized rumen-lung microbial axis that may modulate host productivity in sheep affected by MPS. This work provides new insights into the pathogenesis of MPS and offers potential targets for therapeutic intervention and management. Full article

Ischemic heart disease (IHD) represents a leading cause of global morbidity and mortality. Despite significant advances in treatment achieved over recent decades, as well as various therapeutic strategies available to manage IHD progression currently, the global incidence of this disorder remains high. This review examines essential cell biology aspects of adenosine receptors (ARs), along with the effects of known synthetic small-molecule AR ligands, to provide an up-to-date view on the therapeutic potential towards IHD treatment. In particular, we report here advancements made on a selection of AR synthetic ligands that have demonstrated efficacy in pre-clinical or clinical studies, thereby holding promise as new therapeutic candidates in the field of IHD. Although this work adds further evidence that clinically valid small-molecule therapeutic agents targeting ARs exist, their use represents an emerging area, with most drug prototypes still in the pre-clinical developmental stage and many lacking large-scale clinical trials. The future lies in identifying improved AR synthetic ligands with enhanced efficacy and selectivity, as well as reduced adverse side effects, along with establishing a platform of specific and diversified pre-clinical tests, to inform in turn the resulting clinical investigations. Full article

Background/Objectives: Heart failure with preserved ejection fraction (HFpEF) has increased in prevalence as the population ages and associated comorbidities increase. Remote ischemic preconditioning (RIPC) has been shown to provide protection against ischemic injury to the heart and other organs. Therefore, the aim of this project will be to analyse the effectiveness of RIPC in terms of arterial stiffness, endothelial function, diastolic function, and exercise capacity in patients with HFpEF. Methods: The PIRIC-FEp study will be a parallel, randomised controlled trial with two groups conducted at the Faculty of Nursing in Cuenca, University of Castilla-La Mancha. Individuals who are diagnosed with HFpEF and are older than 40 years, with a left ventricular ejection fraction ≥50% and a sedentary lifestyle, will be included. The exclusion criteria will include, among others, patients with noncardiac causes of heart failure symptoms, significant pulmonary disease, diabetes, peripheral vascular disease, or myocardial infarction within the previous three months. A sample size of 48 patients was estimated, with 24 for each group. Participants will be randomly allocated (1:1) to either the RIPC intervention group or the control group to evaluate the effects on arterial stiffness, endothelial function, diastolic function, and exercise capacity. Assessments will be conducted at baseline and after a three-month follow-up period. Results: The findings will be published in a peer-reviewed journal article. Conclusions: This study is important for daily clinical practice because it provides a new approach for the treatment of HFpEF patients via RIPC. Full article

Corneal diseases are among the leading causes of blindness worldwide and the standard treatment is the transplantation of corneal donor tissue. Treatment for cornea-related visual impairment and blindness is, however, often constrained by the global shortage of suitable donor grafts. To alleviate the shortage of corneal donor tissue, new treatment options have been explored in the last decade. The discovery of induced pluripotent stem cells (iPSCs), which has revolutionized regenerative medicine, offers immense potential for corneal repair and regeneration. Using iPSCs can provide a renewable source for generating various corneal cell types, including corneal epithelial cells, stromal keratocytes, and corneal endothelial cells. To document the recent progress towards the clinical application of iPSC-derived corneal cells, this review summarizes the latest advancements in iPSC-derived corneal cell therapies, ranging from differentiation protocols and preclinical studies to the first clinical trials, and discusses the challenges for successful translation to the clinic. Full article

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article

Hodgkin’s Lymphoma (HL) affects approximately 8500 individuals annually in the United States. The 5-year relative survival rate has improved to 88.5%, driven by transformative advances in immunotherapy and precision oncology. The integration of Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) has redefined treatment paradigms. The phase III SWOG S1826 trial established nivolumab plus doxorubicin, vinblastine, and dacarbazine (N + AVD) as an emerging new standard for advanced-stage HL, achieving a 2-year progression-free survival (PFS) of 92% compared to 83% for BV plus AVD (HR 0.48, 95% CI: 0.33–0.70), with superior safety, particularly in patients over 60. In relapsed/refractory HL, pembrolizumab outperforms BV, with a median PFS of 13.2 versus 8.3 months (HR 0.65, 95% CI: 0.48–0.88), as demonstrated in the KEYNOTE-204 trial. Emerging strategies, including novel ICI combinations, minimal residual disease (MRD) monitoring via circulating tumor DNA (ctDNA), and artificial intelligence (AI)-driven diagnostics, promise to further personalize therapy. This review synthesizes HL’s epidemiology, pathogenesis, diagnostic innovations, and therapeutic advances, highlighting the role of precision medicine in addressing unmet needs and disparities in HL care. Full article

Organoids allow to model healthy and diseased human tissues. and have applications in developmental biology, drug discovery, and cell therapy. Traditionally cultured in immersion/suspension, organoids face issues like lack of standardization, fusion, hypoxia-induced necrosis, continuous agitation, and high media volume requirements. To address these issues, we developed an air–liquid interface (ALi) technology for culturing organoids, termed AirLiwell. It uses non-adhesive microwells for generating and maintaining individualized organoids on an air–liquid interface. This method ensures high standardization, prevents organoid fusion, eliminates the need for agitation, simplifies media changes, reduces media volume, and is compatible with Good Manufacturing Practices. We compared the ALi method to standard immersion culture for midbrain organoids, detailing the process from human pluripotent stem cell (hPSC) culture to organoid maturation and analysis. Air–liquid interface organoids (3D-ALi) showed optimized size and shape standardization. RNA sequencing and immunostaining confirmed neural/dopaminergic specification. Single-cell RNA sequencing revealed that immersion organoids (3D-i) contained 16% fibroblast-like, 23% myeloid-like, and 61% neural cells (49% neurons), whereas 3D-ALi organoids comprised 99% neural cells (86% neurons). Functionally, 3D-ALi organoids showed a striking electrophysiological synchronization, unlike the heterogeneous activity of 3D-i organoids. This standardized organoid platform improves reproducibility and scalability, demonstrated here with midbrain organoids. The use of midbrain organoids is particularly relevant for neuroscience and neurodegenerative diseases, such as Parkinson’s disease, due to their high incidence, opening new perspectives in disease modeling and cell therapy. In addition to hPSC-derived organoids, the method’s versatility extends to cancer organoids and 3D cultures from primary human cells. Full article

Determining the transmission routes of pathogens in indoor environments is challenging, with most studies limited to specific case analyses and pilot experiments. When pathogens are instantaneously released by a patient in an indoor environment, the peak infection risk may not occur immediately but may instead appear at a specific moment during the pathogen’s spread. We developed a concise model to describe the temporal crest of infection risk. The model incorporates the transmission and degradation characteristics of aerosols and surface particles to predict infection risks via air and surface routes. Only four real-world outbreaks met the criteria for validating this phenomenon. Based on the available data, norovirus is likely to transmit primarily via surface touch (i.e., the fomite route). In contrast, crests of infection risk were not observed in outbreaks of respiratory diseases (e.g., SARS-CoV-2), suggesting a minimal probability of surface transmission in such cases. The new model can serve as a preliminary indicator for identifying different indoor pathogen transmission routes (e.g., food, air, or fomite). Further analyses of pathogens’ transmission routes require additional evidence. Full article

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article

Background: Pancreatic adenocarcinoma (PDAC) with liver oligometastases (LOM) presents a therapeutic challenge, with optimal management strategies remaining uncertain. This study evaluates the long-term outcomes, patterns of disease progression, and potential factors influencing prognosis in this patient subset. Methods: Patients diagnosed with PDAC and LOM were retrospectively analyzed. Disease progression patterns, causes of death, and predictors of long-term outcomes were assessed. Results: Among 1442 patients diagnosed with metastatic PDAC between November 2009 and July 2024, 129 (9%) presented with LOM, defined as ≤3 liver lesions each measuring <2 cm. Patients with LOM had significantly improved overall survival (OS) compared to those with high-burden disease (p = 0.026). The cause of death (local regional disease vs. systemic disease) could be determined in 74 patients (57%), among whom age at diagnosis, history of smoking, and white blood cell (WBC) count differed significantly between groups. However, no significant difference in OS was observed between the two groups (p = 0.64). Sixteen patients (22%) died from local complications of the primary tumor, including 6 patients (7%) who showed no evidence of new or progressive metastases. In competing risk and multivariable analysis, a history of smoking remained the only factor significantly associated with death due to local complications. Conclusions: Approximately one in five patients with PDAC-LOM died from local tumor-related complications—some without metastatic progression—highlighting a potential role for surgical intervention. Further multicenter studies are warranted to refine diagnostic criteria and better identify patients who may benefit from surgery. Full article

T-cell-engaging antibodies are a promising new type of treatment for patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma, which has changed the prognosis and evolution of these patients in clinical trials. Bispecific antibodies (BsAbs) bind to two different targets (B and T lymphocytes) at the same time and in this way mimic the action of CAR (chimeric antigen receptor) T-cells. They are the T-cell-engaging antibodies most used in practice and are a solution for patients who do not respond to second- or later-line therapies, including chemoimmunotherapy, followed by salvage chemotherapy and hematopoietic stem cell transplantation. They are a therapeutic option for patients who are ineligible for CAR T-cell therapy and are also active in those with prior exposure to CAR T-cell treatment. A remarkable advantage of BsAbs is their rapid availability, even if the disease progresses rapidly, unlike CAR T-cell treatment, and they avoid the practical and financial challenges raised by autologous CAR T-cell therapies. CAR-T has been proven to have better efficacy compared to BsAbs, but cytokine release syndrome and neurotoxicity have appeared significantly more frequently in patients treated with CAR T-cells. The possibility of combining BsAbs with chemotherapy and their administration for relapses or as a frontline therapy is being studied to increase their efficacy. BsAbs are a life-saving therapy for many patients with diffuse large B-cell malignant non-Hodgkin’s lymphoma (NHL) who have a poor prognosis with classical therapies, but are not without adverse effects and require careful monitoring. Full article

Pimelea is one of the highly toxic plants in Australia, particularly affecting cattle. It contains simplexin, a potent toxin that can cause Pimelea poisoning (St. George Disease) in livestock. A survey was conducted to assess the current impact of Pimelea on livestock production, pasture systems, and financial losses among agricultural producers. In addition, information was also sought about the environmental conditions that facilitate its growth and the effectiveness of existing management strategies. The survey responses were obtained from producers affected by Pimelea across nine different Local Government Areas, through three States, viz., Queensland, New South Wales, and South Australia. Pimelea was reported to significantly affect animal production, with 97% of producers surveyed acknowledging its detrimental effects. Among livestock, cattle were the most severely affected (94%), when compared to sheep (13%), goats (3%), and horses (3%). The presence of Pimelea was mostly observed in spring (65%) and winter (48%), although 29% of respondents indicated that it could be present all year-round under favorable rainfall conditions. Germination was associated with light to moderate rainfall (52%), while only 24% linked it to heavy rainfall. Pimelea simplex F. Muell. was the most frequently encountered species (71%), followed by Pimelea trichostachya Lindl. (26%). Infestations were reported to occur annually by 47% of producers, with 41% noting occurrences every 2 to 5 years. Financially, producers estimated average annual losses of AUD 67,000, with 50% reporting an average of 26 cattle deaths per year, reaching up to 105 deaths in severe years. Some producers were spending up to AUD 2100 per annum to manage Pimelea. While chemical and physical controls were commonly employed, integrating competitive pastures and alternative livestock, such as sheep and goats, was considered as a potential management strategy. This study reiterates the need for further research on sustainable pasture management practices to reduce Pimelea-related risks to livestock and agricultural production systems. Full article