Search Results (236,386)

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

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself a transcriptional factor, BRCA1, through its multiple protein interaction domains, exerts transcriptional coregulation. In addition, BRCA1 expression alters cellular metabolism including inhibition of de novo fatty acid synthesis, changes in cellular bioenergetics, and activation of antioxidant defenses. Some of these actions may contribute to its global oncosuppressive effects. However, the breadth of metabolic pathways reprogrammed by BRCA1 is not fully elucidated. Methods: Breast cancer cells expressing BRCA1 were investigated by multiplatform metabolomics, metabolism-related transcriptomics, and joint metabolomics/transcriptomics data processing techniques, namely two-way orthogonal partial least squares and pathway analysis. Results: Joint analyses revealed the most important metabolites, genes, and pathways of metabolic reprogramming in BRCA1-expressing breast cancer cells. The breadth of metabolic reprogramming included fatty acid synthesis, bioenergetics, HIF-1 signaling pathway, antioxidation, nucleic acid synthesis, and other pathways. Among them, rewiring of glycerophospholipid (including phosphatidylcholine, -serine and -inositol) metabolism and increased arginine metabolism have not been reported yet. Conclusions: Rewired glycerophospholipid and arginine metabolism were identified as components of BRCA1-induced metabolic reprogramming in breast cancer cells. The study helps to identify metabolites that are candidate biomarkers of the BRCA1 genotype and metabolic pathways that can be exploited in targeted therapies. Full article

Background/Objectives: The whole cell pertussis vaccine was introduced in the United States in the 1940s and switched to the acellular pertussis vaccine partially in 1992 and completely in 1997. This study examines the relationship between the resurgence of pertussis in the United States and the change in the type of pertussis vaccines. Methods: Pertussis cases from 1922 to 2024 were obtained from the CDC’s national notifiable disease surveillance system, and vaccination coverage was obtained from the WHO. A trend analysis and Pearson’s correlation test were conducted between the incidence of cases and the coverage of the third and fourth doses of the pertussis vaccine. An ANOVA test and multivariable linear regression were performed to assess the association between the type of vaccine and the number of pertussis cases. Results: The number of cases increased from 4083 in 1992 to 35,435 in 2024, with cyclical outbreaks in 2010, 2012–2014, and 2024. The third and fourth doses of pertussis vaccine coverage had mild and moderate correlations with the number of pertussis cases. The vaccine type had a significant association with the number of pertussis cases and stayed significant after adjusting for vaccination coverage. Conclusions: The switch in pertussis vaccine has impacted the epidemiology of pertussis outbreaks in the United States. A combination of factors, such as different types of immune response to vaccines, waning of immunity, and selection of non-vaccine bacterial strains, may explain the observed results. Further research on newer, improved vaccinations or alternative schedules in children needs to be conducted to address the resurgence of pertussis in this study. Full article

Hydrogen offers an effective pathway for the large-scale storage of renewable energy. For a tourist city located in a plateau region rich in renewable energy, hydrogen shows great potential for reducing carbon emissions and utilizing uncertain renewable energy. Herein, the wind–solar–hydrogen stand-alone and grid-connected systems in the plateau tourist city of Lijiang City in Yunnan Province are modeled and techno-economically evaluated by using the HOMER Pro software (version 3.14.2) with the multi-criteria decision analysis models. The system is composed of 5588 kW solar photovoltaic panels, an 800 kW wind turbine, a 1600 kW electrolyzer, a 421 kWh battery, and a 50 kW fuel cell. In addition to meeting the power requirements for system operation, the system has the capacity to provide daily electricity for 200 households in a neighborhood and supply 240 kg of hydrogen per day to local hydrogen-fueled buses. The stand-alone system can produce 10.15 × 10⁶ kWh of electricity and 93.44 t of hydrogen per year, with an NPC of USD 8.15 million, an LCOE of USD 0.43/kWh, and an LCOH of USD 5.26/kg. The grid-connected system can generate 10.10 × 10⁶ kWh of electricity and 103.01 ton of hydrogen annually. Its NPC is USD 7.34 million, its LCOE is USD 0.11/kWh, and its LCOH is USD 3.42/kg. This study provides a new solution for optimizing the configuration of hybrid renewable energy systems, which will develop the hydrogen economy and create low-carbon-emission energy systems. Full article

Lactoferrin (LF) is an 80 kDa iron-binding glycoprotein primarily found in milk, saliva, tears, and nasal secretions. LF is well known for its antibacterial and immunomodulatory effects. However, the extraction of LF from milk is inadequate for large-scale therapeutic applications, presenting a challenge for economic mass production. Recombinant protein expression systems offer a solution to overcome this challenge and efficient production of LF. This review discusses recent progress in the translational research of LF gene transfer and biopharming, focusing on different expression systems such as bacteria, yeast, filamentous fungi, transgenic crops, and animals as well as purification methods. The optimization of expression yields, prospects for genetic engineering, and biotechnology to enhance LF production for biomedical applications are emphasized. This review systematically sourced the literature from 1987 to 2025 from leading scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. Despite ongoing debates, progress in this field indicates a viable path towards the effective use of LF in therapeutic settings. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

Exosomes are membranous vesicles that play a crucial role as intercellular messengers. Cells secrete exosomes, which can be found in a variety of bodily fluids such as amniotic fluid, semen, breast milk, tears, saliva, urine, blood, bile, ascites, and cerebrospinal fluid. Exosomes have a distinct bilipid protein structure and can be as small as 30–150 nm in diameter. They may transport and exchange multiple cellular messenger cargoes across cells and are used as a non-invasive biomarker for various illnesses. Due to their unique features, exosomes are recognized as the most effective biomarkers for cancer and other disease detection. We give a review of the most current applications of exosomes derived from various sources in the prognosis and diagnosis of multiple diseases. This review also briefly examines the significance of exosomes and their applications in biomedical research, including the use of aptamers and antibody–antigen functionalized biosensors. Full article

Electrospun nanofibrous membranes have gained considerable attention in bone tissue engineering due to their ability to mimic the extracellular matrix and provide a suitable environment for cell attachment and proliferation. This study investigates the fabrication, characterization, and biocompatibility of poly(L-lactic acid) (PLA)-based membranes enhanced with periclase (MgO) and gold nanoparticles (AuNPs). The membranes were fabricated using an optimized electrospinning process and subsequently characterized using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), Fourier-transform infrared spectroscopy (FT-IR), and contact angle measurements. Additionally, in vitro biodegradation studies in simulated body fluid (SBF) and cytocompatibility tests with osteoblast-like cells were conducted. The results demonstrated that the incorporation of MgO and AuNPs significantly influenced the structural and chemical properties of the membranes, improving their wettability and bioactivity. SEM imaging confirmed uniform fiber morphology with well-distributed nanoparticles. FT-IR spectroscopy indicated successful integration of bioactive components into the PLA matrix. Cytocompatibility assays showed that modified membranes promoted higher osteoblast adhesion and proliferation compared to pristine PLA membranes. Furthermore, biodegradation studies revealed a controlled degradation rate suitable for guided bone regeneration applications. These findings suggest that electrospun PLA membranes enriched with MgO and AuNPs present a promising biomaterial for GBR applications, offering improved bioactivity, mechanical stability, and biocompatibility. Full article

The rapid adoption of electric vehicles (EVs) has driven a strong need for optimizing locations of electric vehicle charging stations (EVCSs). Previous methods for locating EVCSs rely on statistical and optimization models, but these methods have limitations in capturing complex nonlinear relationships and spatial dependencies among factors influencing EVCS locations. To address this research gap and better understand the spatial impacts of urban activities on EVCS placement, this study presents a spatially aware machine learning (SAML) method that combines a multi-layer perceptron (MLP) model with a spatial loss function to optimize EVCS sites. Additionally, the method uses the Shapley additive explanation (SHAP) technique to investigate nonlinear relationships embedded in EVCS placement. Using the city of Wuhan as a case study, the SAML method reveals that parking site (PS), road density (RD), population density (PD), and commercial residential (CR) areas are key factors in determining optimal EVCS sites. The SAML model classifies these grid cells into no EVCS demand (0 EVCS), low EVCS demand (from 1 to 3 EVCSs), and high EVCS demand (4+ EVCSs) classes. The model performs well in predicting EVCS demand. Findings from ablation tests also indicate that the inclusion of spatial correlations in the model’s loss function significantly enhances the model’s performance. Additionally, results from case studies validate that the model is effective in predicting EVCSs in other metropolitan cities. Full article

Lignin used in this work was isolated from sapele (Entandrophragma cylindricum) wood through a hybrid pulping process using soda/ethanol as pulping liquor and denoted soda-oxyethylated lignin (SOL). SOL was mixed with a polyethylene glycol (PEG)–glycerol mixture (80/20 v/v) as liquefying solvent with 98% wt. sulfur acid as catalyst, and the mixture was taken to boil at 140 °C for 2, 2.5, and 3 h. Three bio-polyols LBP1, LBP2, and LBP3 were obtained, and each of them exhibited a high proportion of -OH groups. Lignin-based polyurethane foams (LBPUFs) were prepared using the bio-polyols obtained with a toluene diisocyanate (TDI) prepolymer by the one-shot method. Gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), and carbon-13 nuclear magnetic resonance spectroscopy (¹³C NMR) were used characterize lignin in order to determine viscosity, yield, and composition and to characterize their structure. The PEG-400–glycerol mixture was found to react with the lignin bio-polyols’ phenolic -OHs. The bio-polyols’ viscosity was found to increase as the liquefaction temperature increased, while simultaneously their molecular weights decreased. All the NCO groups were eliminated from the samples, which had high thermal stability as the liquefaction temperature increased, leading to a decrease in cell size, density, and crystallinity and an improvement in mechanical performance. Based on these properties, especially the presence of some aromatic rings in the bio-polyols, the foams produced can be useful in automotive applications and for floor carpets. Full article

Advanced therapy medicinal products (ATMPs), especially effective against cancer, remain costly due to their reliance on genetically modified T cells. Contamination during production is a major concern, as traditional quality control methods involve samplings, which can themselves introduce contaminants. It is therefore necessary to develop methods for detecting contamination without sampling and, if possible, in real time. In this article, we present a white light spectroscopy method that makes this possible. It is based on shape analysis of the absorption spectrum, which evolves from an approximately Gaussian shape to a shape modified by the 1/λ component of bacterial absorption spectra when contamination develops. A warning value based on this shape descriptor is proposed. It is demonstrated that a few hours are sufficient to detect contamination and trigger an alarm to quickly stop the production. This time-saving should reduce the cost of these new drugs, making them accessible to as many people as possible. This method can be used regardless of the type of contaminants, provided that the shape of their absorption spectrum is sufficiently different from that of pure T cells so that the shape descriptor is efficient. 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

The evolutionary loss of ednrb2 in specific vertebrate lineages, such as mammals and cypriniform fish, raises fundamental questions about its functional necessity and potential redundancy or synergy with paralogous endothelin receptors in pigment cell development. In teleosts possessing both ednrb1a and ednrb2 (e.g., Nile tilapia), their respective and combined roles in regulating neural crest-derived pigment cell precursors remains unresolved. Using CRISPR/Cas9, we generated single and double ednrb mutants to dissect their functions. We demonstrated that ednrb1a and ednrb2 synergistically govern the differentiation and migration of iridophore precursors. While ednrb1a is broadly essential for iridophore development, ednrb2 plays a unique and indispensable role in the colonization of iridophores in the dorsal iris. Double mutants exhibit near-complete iridophore loss; severe depletion of melanophores, xanthophores, and erythrophores; and a striking, fertile, transparent phenotype. Crucially, this iridophore deficiency does not impair systemic guanine synthesis pathways. mRNA rescue experiments confirmed mitfa as a key downstream effector within the Ednrb signaling cascade. This work resolves the synergistic regulation of pigment cell fates by Ednrb receptors and establishes a mechanism for generating transparent ermplasm. Full article

Skin aging is closely related to mitochondrial dysfunction and cell cycle abnormalities, and developing intervention strategies targeting mitochondrial quality control is an important direction for anti-aging research. In this study, we investigated the anti-aging mechanism of Camellia japonica flower (CJF) extract and its active ingredient hyperoside based on a doxorubicin (DOX)-induced endogenous senescence model in human skin fibroblasts (HSFs). LC-MS proteomics analysis revealed that CJF extract and hyperoside specifically activated the FUNDC1-mediated mitochondrial autophagy pathway, significantly ameliorated the DOX-induced decrease in mitochondrial membrane potential and the accumulation of reactive oxygen species (ROS), and alleviated the cellular S-phase blockade and reversed the high expression of senescence-associated β-galactosidase (SA-β-gal). Further studies showed that the two cleared damaged mitochondria by enhancing mitochondrial autophagy and restoring cellular energy metabolism homeostasis while promoting type III collagen and elastin synthesis and repairing the expression of Claudin 1 related to skin barrier function. For the first time, the present study reveals the molecular mechanism of CJF extract in delaying skin aging by regulating the FUNDC1-dependent mitochondrial autophagy pathway, which provides a theoretical basis and a candidate strategy for developing novel anti-aging agents targeting mitochondrial quality control. Full article

Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-β signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy. Full article