Search Results (42,357)

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy. Like cutaneous malignant melanomas, a subset of MCCs can clinically present without an identifiable primary tumour, termed Merkel cell carcinoma of unknown primary (UPMCC), with incompletely understood behaviour and prognosis. Our objectives are to evaluate the clinical presentation, management and survival outcomes in UPMCC and compare overall survival with metastatic MCC of known-primary origin. Methods: A retrospective review of 252 consecutive MCC patients (1992–2023) identified 20 cases of histologically confirmed nodal or metastatic UPMCC. Demographics, anatomical distribution, treatment and oncological outcomes were analysed. Overall survival was compared with patients presenting with metastatic MCC of known primary. Results: The cohort included 15 males and 5 females (mean age 76 years). Presentation most commonly involved inguinal (n = 7) and axillary (n = 6) nodes, followed by parotid and cervical basins (n = 4). Management was multimodal, including lymphadenectomy, radiotherapy and systemic therapy. Six patients remained disease-free at a mean follow-up of 63.3 months. The mean overall survival was 43.65 months for UPMCC versus 39.29 months for known-primary metastatic MCC. Conclusions: UPMCC most commonly presents as inguinal or axillary nodal disease. Survival outcomes suggest a trend toward improved prognosis compared to known-primary metastatic MCC. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy. In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1–dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP). While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation. We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases. Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets. Full article

Sarcomas with Murine Double Minute 2 (MDM2) amplification are considered potential candidates for MDM2-targeted therapy. However, the limited efficacy of MDM2 inhibitor monotherapy suggests that additional biological factors may influence tumor behavior and prognosis. This study investigated the relationship between MDM2 expression and the Complexity Index in SARComas (CINSARC) transcriptomic signature, a gene expression signature that reflects cell division and chromosomal instability in soft tissue sarcomas. In the public GSE21050 dataset comprising 310 soft tissue sarcomas, the MDM2-low/CINSARC-low subgroup showed the most favorable metastasis-free survival, whereas the MDM2-high/CINSARC-low subgroup had an unfavorable metastasis-free survival comparable to that of the MDM2-high/CINSARC-high group. Among the representative genes in the 12q13-15 region, fibroblast growth factor receptor substrate 2 (FRS2) showed a strong positive correlation with MDM2 expression, but no significant correlation with CINSARC, suggesting an association independent of proliferative capacity. These findings suggest that proliferation-based risk assessment alone may underestimate the metastatic risk of a subset of MDM2-high sarcomas, and FRS2 may present a biologically relevant marker of aggressive behavior independent of tumor proliferation. Full article

The purpose of this review is to highlight the complex influence of antibiotics on human fertility and the need for them not to be underestimated. In creating this review article, data and information from the following international databases were used: PubMed, Scopus and Clarivate Analytics. Only full text articles were used. Antibacterial antibiotics are a group of drugs essential in fighting infections, having multiple mechanisms of action at the level of the bacterial cell; but at the same time they also act on human cells. One of the important actions of antibiotics is on fertility. There are both experimental and clinical data showing the influence of some antibiotics on fertility. There are both positive and negative influences of these drugs on fertility. Some of the most important actions with a positive impact on fertility are: therapy of pelvic infections in women, treatment of endometritis, reduction in post-abortion infections, treatment of infections of the male genital tract—infections that reduce fertility. The most important negative implications of some antibiotics are the direct effects of reducing the production of gametes, decreasing the activity or quality of the gametes, reducing the synthesis of sexual hormones and negative influences on the evolution of pregnancy, including spontaneous abortion in some cases. Other negative influences are produced by the direct action of some antibiotics on the embryo. Some antibiotics such as azithromycin and nitrofurantoin increase the risk of miscarriage. Although only a limited number of antibiotics are known to have an influence on fertility, this influence should not be underestimated in clinical practice. Full article

Glutamate excitotoxicity is a key contributor to the pathogenesis of glaucoma, a leading cause of irreversible blindness worldwide; however, the molecular events driving progressive retinal ganglion cell (RGC) loss and axonal degeneration remain incompletely understood, and effective neuroprotective therapies are lacking. Here, we evaluated the preventive potential of K9-C-peptide, a biopolymer-conjugated human C-peptide, in a mouse model of N-methyl-D-aspartate (NMDA)-induced retinal neurodegeneration and optic nerve axonal transport impairment, and examined potential mechanisms underlying its protective effects. In NMDA-induced excitotoxic mouse retinas, intracellular Ca²⁺ elevation mediated NMDA-induced oxidative stress, including both intracellular and mitochondrial reactive oxygen species (ROS) generation and lipid peroxidation. NMDA exposure induced activation of Müller glia and microglia and upregulation of inflammatory cytokines, ultimately leading to RGC death; these effects were attenuated by prolonged intraocular delivery of ROS scavengers. K9-C-peptide significantly reduced NMDA-induced retinal degeneration, including RGC loss and retinal thinning, and preserved optic nerve axonal transport function in both whole-mount retinas and optic nerve longitudinal sections. These protective effects were associated with suppression of NMDA-induced oxidative stress, mitochondrial dysfunction, and inflammation and reactive gliosis, without altering intracellular Ca²⁺ levels. Notably, sustained intraocular delivery of human C-peptide conferred robust neuroprotection for at least 3 weeks against NMDA-induced retinal degeneration and optic nerve axonal transport impairment. These findings suggest that K9-C-peptide acts as a long-acting neuroprotective agent that mitigates oxidative stress-driven retinal damage and axonal dysfunction, highlighting its translational potential as a C-peptide-based neuroprotective strategy for retinal glutamate excitotoxicity. Full article

The ketogenic diet (KD) has demonstrated anti-proliferative effects across multiple tumor types, yet the underlying metabolic and transcriptomic mechanisms remain incompletely understood. This study employed integrated multi-omics analysis combining targeted metabolomics and RNA sequencing to elucidate KD-induced metabolic reprogramming in BRAF/NRAS wild-type, BRAF mutant, and NRAS mutant melanoma xenografts, which showed delayed tumor growth when treated with the KD. Despite pronounced metabolic and transcriptional heterogeneity across models with minimal overlap in individual KD-responsive genes, pathway-level analysis revealed convergent biological signatures. Using VIP score-based integration and supervised latent variable modeling (mixOmics DIABLO), we identified consistent KD-associated alterations in cancer-related pathways including the PI3K-Akt, MAPK, sphingolipid as well as HIF-1 signaling pathways. The KD enhanced sphingomyelin and ceramide levels and additionally induced transcriptional signatures, indicating increased ceramide synthesis and reduced ceramide breakdown. Moreover, the KD reduced transcript levels of genes encoding critical tumor regulators, including PI3K, AKT, HIF, MEK, and ERK. These findings demonstrate that despite metabolic and transcriptomic heterogeneity, the KD drives coordinated metabolic reprogramming at the pathway level, indicative of shifting lipid metabolism toward pro-apoptotic ceramides and attenuating key oncogenic signaling cascades. Our results provide insights into the KD’s anti-tumor efficacy and identify metabolic nodes amenable to therapeutic intervention in melanoma. Full article

Background and Objectives: Acute myeloid leukemia (AML) is characterized not only by its heterogeneity but also by its high relapse rate. This results in limited treatment options, especially in elderly or therapy-refractory patients. It is known that inhibiting anti-apoptotic BCL-2 family proteins can be effective; however, cellular resistance mechanisms often limit the efficacy of this treatment. We studied the effects of the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination on AML cell lines and primary AML patient cells. Materials and Methods: To analyze the effects of ABT-737 and S63845 treatment on cells, cell energy phenotype, apoptosis, and cell cycle were assessed, and gene expression by RT-qPCR and protein levels by Western blot analysis were measured. Results: Treatment with the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination reduced AML cell viability and induced apoptosis. Dual treatment also altered the expression of epigenetic regulators, as the levels of DNMT1, EZH2, SUZ12, and HDAC1 were reduced, while histone acetylation was increased. An increase in pro-apoptotic markers (PARP cleavage, caspase-9) was observed, and the expression of oncogenes (MYC, WT1) was reduced in model cell lines and primary AML patient cells. Conclusions: BCL-2 and MCL-1 inhibition, alone or in combination, induced apoptosis and altered the expression of epigenetic regulators and oncogenes in AML cell lines and primary patient cells, with no consistent advantage of combined treatment over single agents. BCL-2/MCL-1 inhibition remains a promising approach for AML, and further work should clarify which patients or disease subtypes are most likely to benefit from combined versus single-agent treatment. Full article

Cancer is responsible for systemic burdens, most notably cachexia and immunosuppression, that extend far beyond local tumor growth and collectively dictate poor outcomes. While often studied separately, these debilitating syndromes are deeply interconnected. On the basis of emerging evidence of growth differentiation factor 15 (GDF15)’s dual actions in immunity and metabolism, we propose that the stress-responsive hormone GDF15 is hijacked by tumors and repurposed as a central metaboceptive hub that integrates diverse oncogenic stress signals to launch a coordinated, dual pathological cascade. Systemically, it disrupts brain–body communication via glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) activation in the brainstem, driving anorexia, metabolic rewiring, and progressive wasting of skeletal muscle and adipose tissue that define cachexia. GDF15 acts as a potent immunosuppressor within the local tumor microenvironment, impairing T cell cytotoxicity and increasing the abundance of regulatory T cells. Crucially, these effects are not parallel but interlinked, forming a self-reinforcing detrimental cycle that accelerates host deterioration and therapeutic failure. This positions the GDF15-GFRAL axis as a unique dual-benefit therapeutic target with the potential to simultaneously ameliorate cachexia, improve patient function and quality of life, and revitalize anti-tumor immunity. Reframing cancer through the lens of a hijacked metabolic sensing system provides an integrated perspective that transforms this formidable challenge of concurrent host wasting and immune evasion into a druggable opportunity, charting a course for novel host-directed therapies that restore systemic homeostasis. Full article

Background and Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease of the nasal and paranasal sinus mucosa, associated with significant impairment in quality of life, frequent postoperative recurrence, and repeated need for systemic glucocorticosteroid therapy. Despite the availability of biologics targeting IL-4/IL-13, IL-5, and IgE, a subset of patients shows incomplete or insufficient clinical response. In this context, upstream targeting of epithelial alarmins, particularly thymic stromal lymphopoietin (TSLP), has emerged as a potential therapeutic strategy. To critically review current evidence on the role of TSLP in CRSwNP and to evaluate available data on the mechanism of action, clinical efficacy, and therapeutic potential of tezepelumab in severe and recurrent disease. Materials and Methods: A narrative review was conducted using PubMed, Scopus, and Web of Science. Studies published between 2016 and 2026 were included, comprising experimental research, phase II–III clinical trials, systematic reviews, and international guidelines. Results: TSLP functions as an epithelial alarmin that initiates and amplifies type 2 inflammation via dendritic cell activation, Th2 polarization, and activation of type 2 innate lymphoid cells (ILC2). Data suggests that tezepelumab, a monoclonal antibody targeting TSLP, may reduce inflammation and regulate the immune system. Evidence from asthma populations and relevant CRSwNP subgroups indicates potential improvements in nasal polyp score, congestion, olfactory function and quality of life. It is our understanding that the safety profile appears comparable to placebo, with no new safety concerns having been identified in long-term studies. Conclusions: Tezepelumab is a promising biologic that targets inflammation in CRSwNP. It may benefit severe, recurrent, treatment-resistant disease by modulating immune pathways. However, evidence is indirect and limited, and more trials are needed to define its efficacy, identify biomarkers, and clarify its role in treatment algorithms. Full article

Background: Ankle osteoarthritis (OA) differs fundamentally from knee OA: it is predominantly post-traumatic, affects younger and more active patients, and frequently arises from focal osteochondral lesions of the talus (OCLT) rather than diffuse degeneration. Cell-based and orthobiologic therapies—bone marrow aspirate concentrate (BMAC), bone marrow-derived cell transplantation (BMDC), adipose-derived mesenchymal stromal cells (ADMSCs), stromal vascular fraction (SVF), micro-fragmented adipose tissue (mFAT), and peripheral blood-derived products—have been proposed as joint-preserving options, but the evidence base has not been mapped in a way that separates degenerative post-traumatic ankle OA from focal chondral repair, or that distinguishes cells given as a standalone injection from cells given alongside a therapeutic operation. Methods: We conducted a systematic scoping review following the PRISMA-ScR framework. Human clinical studies applying cell-based therapies to post-traumatic ankle OA and/or OCLT were charted by population, cell source and preparation, mode of delivery, concomitant procedures, follow-up, and reported clinical and structural outcomes. Mode of delivery—standalone intra-articular injection versus adjunct to a concomitant surgical procedure—was pre-specified as a primary analytic axis, because it determines whether an observed effect can be attributed to the cell product at all. Given anticipated clinical and product heterogeneity and the near-absence of controlled trials of standalone injection, no meta-analysis was undertaken; the objective was to map the evidence, characterise its structure, and identify gaps. Results: Eleven clinical studies were charted. The dominant structural feature of this literature is that in nine of 11 studies the cells were co-administered with a therapeutic surgical procedure—marrow stimulation, autologous osteochondral transplantation, supramalleolar or calcaneal osteotomy, or joint debridement—so that in no charted study can the contribution of the cells be separated from that of the operation. This attribution problem, rather than any efficacy estimate, is the principal finding of the review. The remaining evidence is small, heterogeneous, and uniformly non-randomised (Level of Evidence III–V). Only two studies used standalone injection, and for degenerative post-traumatic ankle OA specifically, the standalone-injection evidence consists of a single case report. Reported clinical outcomes (AOFAS, VAS, FAOS/KOOS, Tegner) and structural surrogates (MOCART, T2-mapping, second-look arthroscopy) were generally favourable, and adverse events were mild and self-limiting; however, no study demonstrated histologically confirmed hyaline regeneration, and no adequately powered randomised trial of standalone injection for degenerative post-traumatic ankle OA was identified. Conclusions: Cell-based therapies for post-traumatic ankle OA and OCLT show promising but preliminary, hypothesis-generating signals within a fragmented evidence base in which the cellular contribution is confounded by concomitant surgery in nine of 11 charted studies; on present evidence, the field cannot claim an independent effect for the cell product. The knee OA evidence cannot be extrapolated to the ankle because of the joint’s distinct biology, aetiology, and lesion pattern. Adequately powered randomised trials of standalone intra-articular injection in well-defined degenerative post-traumatic ankle OA, using standardised product characterisation and a core outcome set with quantitative structural endpoints, are the principal advance needed. Full article

Most cancers are fatal and remain challenging to cure due to changes in tumorigenesis and therapeutic resistance. Despite significant advancements in cancer therapy, a substantial proportion of malignancies exhibit resistance to conventional therapies, driven primarily by cancer plasticity and the emergence of multidrug resistance. Recent cancer treatments include cytotoxic chemotherapy, molecular targeted therapy, and immune checkpoint inhibitors. A major hallmark of cancer cells is their ability to develop sophisticated evasion mechanisms that bypass programmed cell death when exposed to anti-cancer drugs. In addition, malignant cells evade the efficacy of anti-cancer drugs by altering cell proliferation, survival, and metastasis. To suppress oncogenic characteristics, necroptosis-based therapies have attracted substantial attention, as they can inhibit tumorigenesis and improve treatment outcomes across many cancer types. Furthermore, an increasing body of research focuses on suppressing tumorigenesis by targeting receptors that are overexpressed in cancer cells. In this review, we elucidate how tumorigenesis is inhibited by regulating the epidermal growth factor receptor (EGFR)–tumor necrosis factor receptor (TNFR) signaling pathway in necroptosis. By delineating the underlying mechanisms of these receptors, we propose that the induction of necroptosis via EGFR and TNFR represents an innovative paradigm for targeted therapy, offering a strategy to enhance clinical outcomes in treatment-resistant cancers. Full article

Periodontal diseases are highly prevalent conditions characterized by chronic inflammation, which leads to progressive destruction of tooth-supporting tissues. Conventional therapies, including scaling and root planing, grafting, and surgical procedures, are effective in controlling infection but show limited regenerative capacity. In this context, hydrogels—three-dimensional, highly hydrated polymeric biomaterials that mimic the extracellular matrix—have emerged as promising tools in periodontal regeneration. These materials can be engineered to modulate mechanical properties, porosity, and the delivery of bioactive molecules. Hydrogels can function as barrier membranes for guided tissue regeneration, scaffolds for stem cell support, and carriers for antimicrobial, anti-inflammatory, and osteogenic agents, enabling sustained and localized drug release. Recent studies have demonstrated their potential to inhibit bacterial biofilms, enhance osteogenic differentiation, and reduce inflammation in preclinical models. However, challenges remain regarding mechanical stability in the oral environment, controlled and sequential release of therapeutic agents, biocompatibility, and cost-effectiveness. Overall, hydrogels represent a promising adjunct in regenerative periodontal therapy, although further research is required to support their translation into routine clinical practice. Full article

Circulating tumor DNA (ctDNA) has emerged as a promising minimally invasive biomarker in multiple myeloma (MM), providing dynamic insight into tumor burden, clonal evolution and molecular heterogeneity. Unlike conventional bone marrow-based diagnostics, ctDNA analysis offers a systemic approach to disease assessment and may better reflect spatially heterogeneous and extramedullary disease. Recent advances in highly sensitive molecular techniques, including digital droplet polymerase chain reaction and next-generation sequencing, have improved the feasibility of ctDNA detection and longitudinal disease monitoring in MM. Increasing evidence demonstrates substantial concordance between ctDNA and bone marrow genomic profiles, while also highlighting the ability of ctDNA to identify resistant subclones, molecular relapse and genomic evolution during therapy. ctDNA has shown potential clinical utility in molecular profiling, therapeutic monitoring and minimal residual disease assessment. ctDNA may become increasingly relevant in the era of novel immunotherapies, including chimeric antigen receptor T-cell therapy and bispecific antibodies. Despite these promising applications, several biological and technical limitations still restrict routine clinical implementation, including low ctDNA concentration in patients with minimal disease burden and lack of methodological standardization. Overall, ctDNA represents a rapidly evolving tool with significant potential to improve personalized disease monitoring and therapeutic strategies in MM. Full article

Dysgeusia is a clinically consequential, but still under-standardized, toxicity of cancer treatment. In the immunotherapy era, taste disturbances are increasingly relevant for patients receiving immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapies and T-cell-redirecting bispecific antibodies, with G protein-coupled receptor family C group 5 member D (GPRC5D)-directed treatment in multiple myeloma representing a particularly instructive high-burden model. We performed a structured critical narrative review with evidence mapping. PubMed/MEDLINE was searched from database inception to June 2026, complemented by citation tracking in Google Scholar, ClinicalTrials.gov searches and guideline documents relevant to oncology nutrition, oral supportive care and cancer-related taste dysfunction. Search concepts covered cancer-related dysgeusia, immunotherapy-associated oral toxicity, GPRC5D/talquetamab-associated dysgeusia, oncology nutrition, oral–gut microbiome biology, natural taste modulators and miraculin-based interventions. Dysgeusia can reduce appetite, food enjoyment, dietary diversity and protein energy intake, thereby contributing to weight loss, malnutrition risk, distress, social withdrawal and, in severe cases, treatment modification or discontinuation. Available evidence is heterogeneous: general cancer-treatment-associated dysgeusia is supported by broader observational and interventional literature; immunotherapy-associated dysgeusia is less systematically characterized; and GPRC5D/talquetamab-associated dysgeusia represents the most clinically visible and target-specific immunotherapy-associated phenotype. Emerging pilot data suggest that dried miracle berry or miraculin-containing products may improve selected taste perception and nutritional parameters in cancer-related dysgeusia, but direct evidence in immunotherapy-associated dysgeusia is not yet established. We, therefore, propose a claim-disciplined precision supportive-care framework integrating systematic taste phenotyping, early nutritional risk assessment, oral health evaluation, microbiome-aware but hypothesis-generating endpoints, individualized flavor and texture adaptation, cautious use of natural taste modulators in selected patients and iterative monitoring of patient-centered outcomes. Future trials should test whether dysgeusia-focused nutritional and taste-modulating supportive care interventions can improve intake, quality of life and treatment persistence without compromising immunotherapy safety or efficacy. Full article

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy arising from a single-nucleotide transversion (GAG → GTG) at codon six of the HBB gene on chromosome 11, substituting glutamic acid with valine in the β-globin chain and producing hemoglobin S (HbS). Under hypoxic conditions, HbS polymerizes and distorts erythrocytes into the characteristic sickle shape, initiating a cascade of vaso-occlusion, chronic hemolytic anemia, and progressive multi-organ damage that defines the clinical burden of this disease. Although SCD has ancient origins in sub-Saharan Africa, the Indian subcontinent, the Middle East, and the Mediterranean, regions where it conferred heterozygous resistance to malaria, the ease of human migration has long since made it a global health concern, affecting an estimated 300,000–400,000 newborns annually. Advances in molecular and genomic research have deepened our understanding of SCD pathophysiology, revealing the central contributions of hemoglobin polymerization, oxidative stress, endothelial inflammation, and nitric oxide depletion to disease progression. Current management rests on supportive pharmacological interventions, including hydroxyurea, chronic transfusion therapy, L-glutamine, and multimodal pain management, complemented by lifestyle modifications. Curative approaches have advanced substantially: hematopoietic stem cell transplantation (HSCT) remains the established standard of cure, while the regulatory approvals in late 2023 of the CRISPR/Cas9-based exagamglogene autotemcel (Casgevy) and the lentiviral vector-based lovotibeglogene autotemcel (Lyfgenia) represent the most transformative development in the history of SCD therapeutics. This review traces the disease from its ancient origins and molecular characterization through to its clinical manifestations, inheritance patterns, screening strategies, and the full spectrum of current and emerging therapies. Persistent challenges, prohibitive treatment costs, healthcare inequities, the ethical dimensions of genome editing, and the urgent need for long-term safety data, are examined critically, with a view to informing the research and policy agenda that must accompany these remarkable scientific advances. Full article