Search Results (345)

The ultrastructural organization of different cell types involved in homeostatic growth in the cerebellum of juvenile chum salmon (Oncorhynchus keta) was investigated using transmission and scanning electron microscopy. The organization of astrocytes, oligodendrocytes, dark cells, adult-type glial and non-glial progenitors, stellate neurons, and eurydendroid cells (EDCs) in the molecular and granular layers and granular eminences was characterized. The organization of dendritic bouquets of Purkinje cells and climbing fibers was studied for the first time at the ultrastructural level, and the ultrastructural features of mossy fibers and the rosettes they form were characterized. Scanning electron microscopy (SEM) revealed the presence of single and paired adult-type neural stem/progenitor cells (aNSPCs) on the cerebellar surface and stromal clusters of aNSPCs outside the dorsal matrix zone (DMZ). Immunohistochemical (IHC) verification of proliferating cell nuclear antigen (PCNA) revealed five types of proliferating cells in the cerebellum of juvenile chum salmon: neuroepithelial cells (NECs), glial aNSPCs, and non-glial aNSPCs. A glial fibrillary acidic protein-positive (GFAP) complex consisting of radial glial fibers and aNSPCs was detected in the DMZ. At the same time, a complex of GFAP+ cerebellar afferents, consisting of differentiating mossy and climbing fibers, was found to develop in the cerebellum of juvenile chum salmon. Nestin+ non-glial aNSPCs and small nestin+ resident cells were detected in the dorsal, lateral, and basal areas, as well as in the granular layer (GrL) and granular eminences (GrEm). These cell types may contribute to the homeostatic growth of the cerebellum by acting as both active participants (PCNA+) and resident (silent) aNSPCs. Studying vimentin-positive systems in the cerebellum revealed a widespread presence of proliferating glial aNSPCs that actively contribute to homeostatic growth, as well as small resident immunopositive cells throughout the cerebellum of juvenile chum salmon. Immunolocalization of the neuronal RNA-binding protein marker (HuCD) was detected in numerous molecular layer (ML) cells at the early stages of neuronal differentiation in the dorsal and lateral regions of the cerebellum of juvenile chum salmon. HuCD + EDCs were detected for the first time in the dorsal (DZ) and basal (BZ) zones, forming broad axonal arborization. Immunolabeling of HuCD in combination with transmission electron microscopy (TEM) allowed EDCs to be characterized in the cerebellum of juvenile chum salmon for the first time. Full article

Skin cancer is the most common cancer worldwide. The incidence of skin cancer has been increasing worldwide. Nearly 75% of all skin cancers are basal cell carcinomas (BCC), cutaneous squamous cell carcinoma (cSCC) represents approximately 20%, and those remaining are melanomas (4%) or other rare tumors (1%). Given the high cure rates and the ability to histologically confirm tumor clearance, surgical therapy is the gold standard for the treatment of skin cancer. Conventional surgery is the most employed technique for the removal of non-melanoma skin cancer (NMSCs). Mohs Micrographic Surgery (MMS) is the most precise surgical method for the treatment of non-melanoma skin cancer, allowing for 100% margin evaluation, being the gold-standard method for surgical treatment of non-melanoma skin cancer. Whenever it is possible to obtain wide margins (4 to 6 mm), cure rates vary from 70% to 99%. Imiquimod, a synthetic imidazoquinolinone amine, is a topical immune response modifier approved by the U.S. Food and Drug Administration (FDA) for the treatment of external anogenital warts, actinic keratosis (AK), and superficial basal cell carcinoma (sBCC). The efficacy of imiquimod is primarily attributed to its ability to modulate both innate and adaptive immune responses, as well as its direct effects on cancer cells. Imiquimod exerts its immunomodulatory effects by activating Toll-like receptors 7 and 8 (TLR7/8) on various immune cells, including dendritic cells, macrophages, and natural killer (NK) cells. Upon binding to these receptors, imiquimod triggers the MyD88-dependent signaling pathway, leading to the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factors (IRFs). This cascade leads to the production of pro-inflammatory cytokines, including interferon-alpha (IFN-α), tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), and interleukin-6 (IL-6). These cytokines enhance local inflammation, recruit additional immune cells to the tumor site, and stimulate antigen presentation, thereby promoting an anti-tumor immune response. Radiation therapy (RTh) may be employed as a primary treatment to BCC. It may also be employed as an adjuvant treatment to surgery for SCC and aggressive subtypes of BCC. RTh triggers both direct and indirect DNA damage on cancer cells and generates reactive oxygen species (ROS) within cells. ROS trigger oxidative damage to DNA, proteins, and lipids, exacerbating the cellular stress and contributing to tumor cell death. Recently, immunotherapy emerged as a revolutionary treatment for all stages of SCC. Cemiplimab is a human programmed cell death 1 (PD-1)-blocking antibody that triggers a response to over 50% of patients with locally advanced and metastatic SCC. A randomized clinical trial (RCT) published in 2022 revealed that cemiplimab was highly effective in the neoadjuvant treatment of large SCCs. The drug promoted a significant tumor size decrease, enabling organ-sparing operations and a much better cosmetic effect. A few months ago, a RCT of cemiplimab on adjuvant therapy for locally aggressive SCC was published. Interestingly, cemiplimab was administered to patients with local or regional cutaneous squamous cell carcinoma after surgical resection and postoperative radiotherapy, at high risk for recurrence owing to nodal features, revealed that cemiplimab led to much lower risks both of locoregional recurrence and distant recurrence. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), comprising approximately 20% of newly diagnosed BC cases. The poor prognosis, high recurrence rates, and inefficacy of hormone-based therapies make TNBC one of the greatest challenges in contemporary oncology. The unique immunological features of TNBC, including relatively high tumor mutational burden, abundance of tumor-infiltrating lymphocytes, and elevated PD-L1 expression, offer a wide range of opportunities for immunotherapeutic approaches, of which the most progressive and promising are neoantigen-driven ones. This review examines the current landscape of neoantigen-based therapeutic approaches in TNBC treatment, spanning from discovery methodologies to clinical applications. We provide a critical analysis of the tumor microenvironment (TME) in TNBC, highlighting the balance between its immunoactivating (CD8+ T-cells, dendritic cells) and immunosuppressive (regulatory T-cells, M2 macrophages) components as the key determinant of therapeutic success, as well as reviewing the emerging approaches to TME reprogramming and recruiting in favor of better outcomes. We also present state-of the-art methods in neoantigen identification and prioritization, covering the landscape of technological platforms and prediction algorithms, addressing the existing accuracy limitations along with emerging computational solutions, and comprehensively discussing the TNBC neoantigen spectrum. Our analysis shows the strong domination of patient-specific (“private”) neoantigens over shared variants in the TNBC, with TP53 as the only gene with recurrent variants. Finally, we extensively cover neoantigen-recruiting therapeutic modalities including adoptive cell therapies, personalized vaccine platforms (peptide-based, mRNA/DNA vaccines, dendritic cell vaccines), and oncolytic viruses-based approaches. Our study of current clinical trials demonstrates the substantial gap between early proof-of-concept experiments and further applicability of neoantigen-driven therapies. The major challenges hampering the success of such methods include neoantigen prediction inaccuracy rates, high manufacturing costs, and time consumption. Promising ways to overcome these difficulties include the development of combinational strategies, TME modeling and modifying, and improvement of the therapy delivery properties, along with the optimization of production workflows and cost-effectiveness of vaccine development. Full article

Histiocytic sarcoma (HS) is an ultra-rare hematopoietic neoplasm that frequently occurs in extranodal sites of adults. Clinically, HS demonstrates aggressive behavior and can arise de novo or in association with other hematological neoplasms. The median overall survival from the time of diagnosis is approximately six months. Histologically, HS is composed of sheets of large, round to oval cells with abundant eosinophilic cytoplasm and can be confused with a variety of benign and malignant conditions. Immunohistochemistry plays a crucial role in the diagnosis of HS, showing expression of CD163, CD68, lysozyme, and PU.1 and negative staining with follicular dendritic cell markers and myeloid cell markers. Recent studies have demonstrated a high rate of PD-L1 expression, suggesting a potential therapeutic target. Several genomic alterations have been identified in HS, including mutations involving the RAS/MAPK and PI3K/AKT/mTOR signaling pathways, CDKN2A mutations/deletions, and TP53 mutations. There is no standard protocol for the management of HS. Surgical resection with or without radiotherapy is the most common first-line treatment for unifocal/localized disease. The systemic treatment options for multifocal/disseminated disease are very limited. This review provides an overview of the current knowledge on the clinicoradiological features, histopathology, pathogenesis, and management of HS. Full article

This study focuses on the detailed investigation of the eutectic Aluminium Silicon (Al-12.6 wt% Si) alloy, which was solidified without and with a 10 mT induction rotating magnetic field (RMF). The experiments were conducted as part of the MICAST Hungary project, as the mirror experiments were solidified in the Solidification and Quenching Furnace (SQF) at the International Space Station (ISS). The mirror samples were solidified using solidification parameters similar to the ISS experiments. This study examined the meso-structure of the samples and the eutectic microstructure in both stirred (RMF-applied) and non-stirred (RMF-free) samples. Special attention was given to the influence of magnetic stirring on key microstructural features, such as the eutectic lamellae distance, the length of the lamellae, and the spatial orientation of the lamellae were investigated. Measuring and analysing these parameters gives us an overall picture of the microstructure of the eutectics. The 10 mT low-intensity RMF used in the experiment has a demonstrable effect on the formation of the eutectic structure; short aluminium dendrites concentrate at both edges of the stirred sample, and their proportion decreases as the sample approaches its end. In contrast, in the non-stirred sample, long, elongated Al dendrites solidify parallel to the direction of heat removal, and their proportion and size continuously increase as the sample progresses. Furthermore, a possible relationship was found between the decrease in the eutectic lamella length and the lamellae’s average distance. Full article

The emergence of the SARS-CoV-2 JN.1 lineage in late 2023 marked a major shift in viral evolution. By January 2024, it had displaced XBB variants to become the dominant strain worldwide. JN.1 and its descendants are antigenically distinct from earlier Omicron subvariants, with approximately 30 additional spike mutations compared to XBB-derived viruses. The combination of these features alongside growing evidence of considerable immune evasion prompted the FDA to recommend that vaccine formulations be updated to target JN.1 rather than XBB.1.5. The continued dominance of JN.1-derived variants necessitates the characterization of viral infection in established animal models to inform vaccine efficacy and elucidate host–pathogen interactions driving disease outcomes. In this study, transgenic mice expressing human ACE2 were infected with SARS-CoV-2 subvariants JN.1, KP.2, and EG.5.1 to compare the pathogenicity of JN.1-lineage and XBB-lineage SARS-CoV-2 viruses. Infection with JN.1 and KP.2 resulted in attenuated disease, with animals exhibiting minimal clinical symptoms and no significant weight loss. In contrast, EG.5.1-infected mice exhibited rapid progression to severe clinical disease, substantial weight loss, and 100% mortality within 7 days of infection. All variants replicated effectively within the upper and lower respiratory tracts and caused significant lung pathology. Notably, EG.5.1 resulted in neuroinvasive infection with a significantly high viral burden in the brain. Additionally, EG.5.1 infection resulted in a significant increase in CD8⁺ T cell and CD11b⁺ CD11c⁺ dendritic cell populations in infected lungs. Full article

Laser welding, a vital process in modern industry, offers significant technical and economic benefits, including improved part quality, precision, productivity, and cost reduction. This study significantly enhances our understanding of heat-treatable weldability (AA2024, AA2017, AA6061) and non-heat-treatable AA5083 aluminum alloys. It establishes a “weldability window” based on power density and interaction time, identifying three key domains: insufficient penetration, full penetration with regular weld, and irregular weld or cutoff. The study’s findings reveal that heat-treatable alloys soften in the fusion zone due to the dissolution of reinforcing precipitates during welding. In contrast, non-heat-treatable alloys exhibit hardening due to a fine dendritic microstructure. The fusion zone features fine dendrites, and in the heat-affected zone (HAZ), coarse particles and liquation at the fusion line are observed, particularly in AA6061 and 2024 alloys. The study also shows that the joint efficiency, a measure of the weld’s load-bearing capacity, is approximately 90% for the AA5083 alloy and 80% for the heat-treatable alloys. These findings significantly contribute to our understanding of welding processes. They can be used to optimize laser welding processes, thereby ensuring the production of high-quality and reliable joints in industrial applications. Full article

Over the past few decades, lithium-ion batteries (LIBs) have gained significant attention due to their inherent potential for environmental sustainability and unparalleled energy storage efficiency. Meanwhile, polymer electrolytes have gained popularity in several fields due to their ability to adapt to various battery geometries, enhanced safety features, greater thermal stability, and effectiveness in reducing dendrite growth on the anode. However, their relatively low ionic conductivity compared to liquid electrolytes has limited their application in high-performance devices. This limitation has led to recent studies revolving around the development of poly(ionic liquids) (PILs), particularly imidazolium-mediated polymer backbones as novel electrolyte materials, which can increase the conductivity with fine-tuning structural benefits, while maintaining the advantages of both solid and gel electrolytes. In this study, a curated dataset of 120 data points representing eight different polymers was used to predict ionic conductivity in imidazolium-based PILs as well as the emerging ionene substructures. For this purpose, four ML models: CatBoost, Random Forest, XGBoost, and LightGBM were employed by incorporating chemical structure and temperature as the models’ inputs. The best-performing model was further employed to estimate the conductivity of novel ionenes, offering insights into the potential of advanced polymer architectures for next-generation LIB electrolytes. This approach provides a cost-effective and intelligent pathway to accelerate the design of high-performance electrolyte materials. Full article

Whether the spongiotic reaction caused by the interaction of keratinocytes, T-lymphocytes, inflammatory dendritic epidermal cells (IDECs), and Langerhans cells (LCs) observed in atopic dermatitis (AD) represents a common feature of spongiosis in various skin diseases remains unclear. We analyzed the characteristics of spongiosis in AD compared with those in other eczematous dermatitis and inflammatory skin diseases by using immunohistochemical methods. Infiltration of IDECs (CD11c+ cells and/or CD206+ cells) and T-lymphocytes, accompanied by degenerated keratinocytes and aggregated LCs (CD207+ cells), was frequently observed as a common feature of spongiosis in multiple conditions. However, IDECs expressing IgE were identified exclusively in IgE-mediated AD. Aggregation of IDECs was predominantly observed in the spongiosis of adaptive immune-mediated eczematous disorders, such as AD and allergic contact dermatitis. These IDEC aggregations constituted the major components of the epidermal dendritic cell clusters seen in AD and other eczematous or eczematoid dermatoses, and may serve as a useful distinguishing marker from Pautrier collections seen in cutaneous T-cell lymphoma. These findings suggest that IDECs, in cooperation with other immune cells, may play a pivotal role in spongiosis formation in AD and various skin diseases, although the underlying immunopathological mechanisms differ among these conditions. Full article

This study systematically investigates the homogenization-induced Laves phase dissolution kinetics and recrystallization mechanisms in laser powder bed fusion (L-PBF) processed IN718 superalloy. The as-built material exhibits a characteristic fine dendritic microstructure with interdendritic Laves phase segregation and high dislocation density, featuring directional sub-grain boundaries aligned with the build direction. Laves phase dissolution demonstrates dual-stage kinetics: initial rapid dissolution (0–15 min) governed by bulk atomic diffusion, followed by interface reaction-controlled deceleration (15–60 min) after 1 h at 1150 °C. Complete dissolution of the Laves phase is achieved after 3.7 h at 1150 °C. Recrystallization initiates preferentially at serrated grain boundaries through boundary bulging mechanisms, driven by localized orientation gradients and stored energy differentials. Grain growth kinetics obey a fourth-power time dependence, confirming Ostwald ripening-controlled boundary migration via grain boundary diffusion. Such a study is expected to be helpful in understanding the microstructural development of L-PBF-built IN718 under heat treatments. Full article

Gleason score (GS) is one of the best predictors of prostate cancer (PCa) aggressiveness; however, its biological features need to be elucidated. This study aimed to explore the biological characteristics of localized/locally advanced PCa stratified using in silico GS analysis. Biological features were analyzed using gene set variation analysis and the xCell algorithm with mRNA expression in two independent public databases: The Cancer Genome Atlas (TCGA) (n = 493; radical prostatectomy cohort) and GSE116918 (n = 248; radiation therapy cohort). GS levels were positively correlated with the activity levels of cell proliferation-related gene sets, including E2F targets, the G2M checkpoint, the mitotic spindle, and MYC targets v1 and v2 in both cohorts. Furthermore, GS levels were positively associated with the activity levels of immune-related gene sets and infiltrating fractions of immune cells, including CD4+ memory T cells, dendritic cells, M1 macrophages, and Th2 cells, in both cohorts. Notably, GS levels were positively associated with the score levels of homologous recombination defects, intratumor heterogeneity, fraction genome alteration, neoantigens, and mutation rates in the TCGA cohort. In conclusion, PCa with high GS levels was associated with cancer cell proliferation, immune cell infiltration, and high mutation rates, which may reflect worse clinical outcomes. Full article

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental condition characterized by early-onset, intractable epilepsy, motor and cognitive impairment, and autistic-like features. Although constitutive Cdkl5 knockout (KO) models have established the importance of CDKL5 during early brain development, CDKL5’s role in the mature brain remains poorly defined. Here, we employed an inducible, conditional KO model in which Cdkl5 is selectively deleted from forebrain glutamatergic neurons in adult mice to investigate the postdevelopmental functions of CDKL5. Using a total of 48 adult male mice, including Cdkl5^flox/Y(Cre⁺) (n = 30) and Cdkl5^flox/Y(Cre⁻) littermate controls (n = 18), we found that tamoxifen-induced Cdkl5 deletion led to prominent behavioral impairments, including deficits in motor coordination, reduced sociability, and impaired hippocampus-dependent spatial memory, while behavioral features such as hyperactivity and stereotypic jumping, typically present in germline KOs, were absent. Sensory functions, including olfaction and pain perception, were also preserved. At the cellular level, the loss of Cdkl5 resulted in a marked reduction in excitatory synapse density in the cortex and hippocampus, accompanied by increased numbers of immature dendritic spines and decreased mature spines. Neuronal loss in the hippocampal CA1 region and selective microglial activation in the cortex were also observed. These alterations closely resemble those seen in constitutive KO models, underscoring the ongoing requirement for CDKL5 expression in excitatory neurons for maintaining synaptic integrity and neuronal homeostasis in the adult brain. This study underscores the importance of temporally controlled models for investigating the mechanisms underlying CDD pathophysiology in the adult brain. Full article

Penile intraepithelial neoplasia (PeIN) is a rare but clinically significant condition that can progress to invasive squamous carcinoma. Early diagnosis is crucial but often challenging due to its heterogeneous clinical and dermoscopic presentation, which can mimic other benign or malignant lesions. In this study, we report two cases of pigmented penile lesions evaluated using non-invasive imaging techniques: reflectance confocal microscopy (RCM) and line-field confocal optical coherence tomography (LC-OCT). Both methods revealed characteristic features such as hyperkeratosis, parakeratosis, acanthosis, nuclear pleomorphism of keratinocytes, and the presence of bright intraepithelial dendritic cells, correlating closely with histopathological findings of high-grade basaloid PeIN. Our findings highlight the valuable role of RCM and LC-OCT in improving the differential diagnosis of genital lesions, potentially reducing the need for invasive diagnostic procedures and ensuring early, appropriate management. Full article

Alzheimer’s disease (AD) early screening requires non-invasive, high-sensitivity detection of low-abundance biomarkers in complex biofluids like saliva. In this study, we present a miniaturized, silicon-based electrochemical sensor for sequential detection of two AD salivary biomarkers, lactoferrin (Lf) and amyloid β-protein 1-42 (Aβ_1-42), on a single reusable electrode. The sensor features a three-electrode system fabricated by sputter-coating a quartz substrate with gold (Au) sensing electrodes, which are further modified with gold nanoparticles (AuNPs) to form 3D dendritic structures that enhance surface area and electron transfer. To improve specificity, immunomagnetic beads (MBs) are employed to selectively capture and isolate target biomarkers from saliva samples. These MB–biomarker complexes are introduced into a polydimethylsiloxane chamber aligned with Au sensing electrodes, where a detachable magnet localizes the complexes onto the electrode surface to amplify redox signals. The AuNPs/MBs sensor achieves detection limits of 2 μg/mL for Lf and 0.1 pg/mL for Aβ_1-42, outperforming commercial ELISA kits (37.5 pg/mL for Aβ_1-42) and covering physiological salivary concentrations. After the MBs capture the biomarkers, the sensor can output the result within one minute. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) measurements confirm enhanced electron transfer kinetics on AuNP-decorated surfaces, while linear correlations (R² > 0.95) validate quantitative accuracy across biomarker ranges. The compact and integrated design eliminates reliance on bulky instrumentation and enables user-friendly operation, establishing a promising platform for portable, cost-effective AD screening and monitoring. Full article

Cancer continues to pose a significant challenge to global health, resulting in millions of deaths annually despite advancements in treatments like surgery, chemotherapy, and radiotherapy. A key factor complicating successful outcomes is the presence of cancer stem cells (CSCs), which possess distinctive features that facilitate tumor initiation and progression as well as resistance to therapies. These cells are adept at evading conventional treatments and can hinder the effectiveness of immunotherapy, often manipulating the tumor microenvironment to suppress immune responses. This review delves into the complex interplay between CSCs and immune cells, emphasizing their contributions to tumor heterogeneity and therapeutic resistance. By investigating the CSC niche in which these cells thrive and their complex interactions with the immune system, we aim to reveal new therapeutic avenues that could enhance patient outcomes and minimize the risk of recurrence. CSCs are characterized by remarkable self-renewal and plasticity, allowing them to transition between stem-like and differentiated states in response to various stimuli. Their existence within the CSC niche confers immune protection and maintains stem-like properties while promoting immune evasion. Activating key signaling pathways and specific surface markers is crucial in developing CSC traits, pointing to potential strategies for effective tumor eradication. Conventional therapies often fail to eliminate CSCs, which can lead to tumor recurrence. Therefore, innovative immunotherapeutic strategies such as dendritic cell vaccines (DC vaccines), chimeric antigen receptor (CAR) engineered T cells, and immune checkpoint inhibitors (ICIs) are under examination. This review sheds light on CSC’s roles across different malignancies, highlighting the necessity for innovative targeted approaches in cancer treatment. Full article