Search Results (23,761)

Human coronavirus 229E (HCoV-229E) is an endemic coronavirus responsible for approximately one-third of “common cold” cases. To infect target cells, HCoV-229E first binds to its receptor on the cell surface and then can follow different pathways, entering by direct fusion or by taking advantage of host cell mechanisms such as endocytosis. Based on the role of clathrin, the process can be classified into clathrin-dependent or -independent endocytosis. This study characterizes the role of clathrin-mediated endocytosis (CME) in HCoV-229E infection of the human hepatoma cell line Huh-7. Using specific CME inhibitory drugs, we demonstrated that blocking CME significantly reduces HCoV-229E infection. Additionally, CRISPR/Cas9-mediated knockout of the µ subunit of adaptor protein complex 2 (AP-2) further corroborated the role of CME, as KOs showed over a 50% reduction in viral infection. AP-2 plays an important role in clathrin recruitment and the maturation of clathrin-coated vesicles. Our study also confirmed that in Huh-7 cells, HCoV-229E requires endosomal acidification for successful entry, as viral entry decreased when treated with lysomotropic agents. Furthermore, the colocalization of HCoV-229E with early endosome antigen 1 (EEA-1), only present in early endosomes, suggested that the virus uses an endosomal route for entry. These findings highlight, for the first time, the role of CME in HCoV-229E infection and confirm previous data of the use of the endosomal route at a low pH in the experimental cell model Huh-7. Our results provide new insights into the mechanisms of entry of HCoV-229E and provide a new basis for the development of targeted antiviral therapies. Full article

Background: Urothelial carcinoma (UC) is one of the most common cancers diagnosed worldwide. However, minority populations, such as female, elder, and Black patients, may have disparate outcomes and are commonly neglected in randomized prospective trials. This review aims to study the relationship between age, sex, and race on urothelial cancer prognosis, particularly focusing on contemporary therapy and its effect on overall survival. Methods: Phase III prospective trials since 2016 of immune checkpoint inhibitors, antibody-drug conjugates, or targeted therapies in urothelial carcinoma were identified from PubMed. Trials that did not report on survival by race, sex, or age distribution were excluded, and remaining trials (n = 17) were compared by subgroup. Results: Women were reported to have inferior OS on investigational agents compared to men in 9/17 trials. In a meta-analysis, women had inferior OS to men (OR 0.89 [95% CI: 0.78–0.99]; p = 0.04). Asian/Pacific Islander patients had inferior outcomes to White patients on investigational agents in 3/5 trials. In a meta-analysis, OS was not significant by race (OR 1.18 [0.90–1.46], p = 0.38). Black patients composed <2% of all trial patients, and no subgroup data were reported. Both 65 (n = 7) and 75 (n = 2) were reported as age cut-offs in trial subgroups, and survival data were mixed. Conclusions: Women in UC trials may have inferior survival outcomes to men. Racial diversity was poor and thus limited any conclusions on survival disparities. Full article

Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods: A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results: While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions: This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy. Full article

Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug–drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug–drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug–drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug–drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making. Full article

Despite advances in vaccination and therapies for coronavirus disease, challenges remain due to reduced antibody longevity and the emergence of virulent variants like Omicron (BA.1) and its subvariants (BA.1.1, BA.2, BA.3, and BA.5). This study explored the potential of adoptive immunotherapy and harnessing the protective abilities using virus-specific T cells (VSTs). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) VSTs were generated by stimulating donor-derived peripheral blood mononuclear cells with spike, nucleocapsid, and membrane protein peptide mixtures. Phenotypic characterization, including T-cell receptor (TCR) vβ and pentamer analyses, was performed on the ex vivo-expanded cells. We infected human leukocyte antigen (HLA)-partially matched human Calu-3 cells with various authentic SARS-CoV-2 strains in a Biosafety Level 3 facility and co-cultured them with VSTs. VSTs exhibited a diverse TCR vβ repertoire, confirming their ability to target a broad range of SARS-CoV-2 antigens from both the ancestral and mutant strains, including Omicron BA.1 and BA.5. These ex vivo-expanded cells exhibited robust cytotoxicity and low alloreactivity against HLA-partially matched SARS-CoV-2-infected cells. Their cytotoxic effects were consistent across variants, targeting conserved spike and nucleocapsid epitopes. Our findings suggest that third-party partial HLA-matching VSTs could counter immune-escape mechanisms posed by emerging variants of concern. Full article

Background/Objectives: Uterine sarcoma, a rare cancer originating in the smooth muscle of the uterus, exhibits high rates of recurrence and metastasis. It represents one of the most challenging types of cancer due to its chemorefractory nature, showing little response to conventional chemotherapy methods and displaying a relative survival rate of 30–40%. A potentially promising approach for treating uterine sarcoma involves combination therapy with paclitaxel (PAC), a microtubule-targeting agent, and seliciclib (SEL), a cyclin-dependent kinase inhibitor. SEL has been identified as a drug that can enhance the effectiveness of PAC through synergistic effects. To further refine this treatment strategy, an efficient analytical tool capable of simultaneously measuring the concentrations of PAC and SEL in blood plasma is needed. This tool would make it easier to study the pharmacokinetic interactions of potential drugs and assist in monitoring therapy when administering this combination treatment. Regrettably, a method meeting these specific requirements has not been documented in the existing literature. Methods: This article introduces the first HPLC technique employing a PDA detector to concurrently measure PAC and SEL levels in plasma. The methodology underwent validation in accordance with the ICH standards for validating bioanalytical methods. Results: The method exhibited linearity in the concentrations ranging from 0.8 to 100 µg mL⁻¹ for both PAC and SEL. The limits of quantification were determined and found to be 1.34 and 1.25 µg mL⁻¹ for PAC and SEL, respectively. All the other validation criteria conformed to the ICH validation standards. The HPLC-PDA method was successfully employed to quantify both PAC and SEL in plasma samples with a high level of reliability (in terms of accuracy and precision). The eco-friendliness of the approach was verified using three thorough assessments. This technique serves as a valuable asset in establishing the correct dosage and administration schedule for the combined treatment involving PAC and SEL, ensuring the desired therapeutic effects and safety in managing uterine sarcoma. Conclusions: The proposed HPLC-PDA method is the first reliable and eco-friendly method developed to simultaneously determine PAC and SEL in high-throughput plasma samples in clinical laboratories. Full article

Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment (TME), all of which present new opportunities for targeted therapies. However, studying these metabolic networks is challenging in traditional 2D cell cultures, which often fail to replicate the three-dimensional architecture and dynamic interactions of real tumors. To address this, organoid models have emerged as powerful tools. Tumor organoids are 3D cultures, often derived from patient tissue, that more accurately mimic the structural and functional properties of actual tumor tissues in vivo, offering a more realistic model for investigating cancer metabolism. This review explores the unique metabolic adaptations of breast cancer and discusses how organoid models can provide deeper insights into these processes. We evaluate the most advanced tools for studying cancer metabolism in three-dimensional culture models, including optical metabolic imaging (OMI), matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and recent advances in conventional techniques applied to 3D cultures. Finally, we explore the progress made in identifying and targeting potential therapeutic targets in breast cancer metabolism. Full article

Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In search of signal transduction pathways with a potential impact in glioma growth and immunotherapy, the Slit guidance ligands (Slits) and their Roundabout (Robo) family of receptors have been revealed as key regulators of tumor cells and their microenvironment. Recent evidence indicates the implication of the Slit/Robo signaling pathway in inflammation, cell migration, angiogenesis, and immune cell infiltration of gliomas, suppressing or promoting the expression of pivotal proteins, such as cell adhesion molecules, matrix metalloproteinases, interleukins, angiogenic growth factors, and immune checkpoints. Herein, we discuss recent data on the significant implication of the Slit/Robo signaling pathway in glioma pathology along with the respective targeting options, including immunotherapy, monoclonal antibody therapy, and protein expression modifiers. Full article

This study conducts a comparative analysis of cystamine (RSSR), a disulfide, and cysteamine (RSH), its thiol monomer, to evaluate their efficacy as radioprotectors and antioxidants under high linear energy transfer (LET) and high-dose-rate irradiation conditions. It examines their interactions with reactive primary species produced during the radiolysis of the aqueous ferrous sulfate (Fricke) dosimeter, offering insights into the mechanisms of radioprotection and highlighting their potential to enhance the therapeutic index of radiation therapy, particularly in advanced techniques like FLASH radiotherapy. Using Monte Carlo multi-track chemical modeling to simulate the radiolytic oxidation of ferrous to ferric ions in Fricke-cystamine and Fricke-cysteamine solutions, this study assesses the radioprotective and antioxidant properties of these compounds across a variety of irradiation conditions. Concentrations were varied in both aerated (oxygen-rich) and deaerated (hypoxic) environments, simulating conditions akin to healthy tissue and tumors. Both cystamine and cysteamine demonstrate radioprotective and strong antioxidant properties. However, their effectiveness varies significantly depending on the concentration employed, the conditions of irradiation, and whether or not environmental oxygen is present. Specifically, excluding potential in vivo toxicity, cysteamine substantially reduces the adverse effects of ionizing radiation under aerated, low-LET conditions at concentrations above ~1 mM. However, its efficacy is minimal in hypoxic environments, irrespective of the concentration used. Conversely, cystamine consistently offers robust protective effects in both oxygen-rich and oxygen-poor conditions. The distinct protective capacities of cysteamine and cystamine underscore cysteamine’s enhanced potential in radiotherapeutic settings aimed at safeguarding healthy tissues from radiation-induced damage while effectively targeting tumor tissues. This differential effectiveness emphasizes the need for personalized radioprotective strategies, tailored to the specific environmental conditions of the tissue involved. Implementing such approaches is crucial for optimizing therapeutic outcomes and minimizing collateral damage in cancer treatment. Full article

The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior. Full article

The landscape of pharmacological treatment for Alzheimer’s disease (AD) has undergone significant transformations with the advent of disease-modifying therapies (DMTs) targeting β-Amyloid (Aβ) accumulation, one of the hallmark pathologies of AD. The approval and market introduction of monoclonal antibodies mark the dawn of a new era in AD therapeutics as well. Furthermore, considerable progress has also been made in the development of new drugs targeting non-Aβ and non-Tau protein pathways. These advancements are key in tackling the root causes of AD, offering hope for treatments that both relieve symptoms and slow disease progression, improving patient outcomes and quality of life. This review aims to provide a comprehensive update on the advances in drug development and application for AD, including those currently in clinical trials and those already approved for the market to treat patients. Full article

Coronary aneurysms are typically defined as sections of a coronary artery where the diameter is more than 1.5 times that of an adjacent normal segment. In rare circumstances, these aneurysms can become exceedingly large, leading to the classification of giant coronary artery aneurysms. Despite their occurrence, there is no clear consensus on the precise definition of giant coronary artery aneurysms, and their etiology remains somewhat ambiguous. Numerous potential causes have been suggested, with atherosclerosis being the most prevalent in adults, accounting for up to 50% of cases. In pediatric populations, Kawasaki disease and Takayasu arteritis are the primary causes. Although often discovered incidentally, coronary artery aneurysms can lead to severe complications. These complications include local thrombosis, distal embolization, rupture, and vasospasm, which can result in ischemia, heart failure, and arrhythmias. The optimal approach to medical, interventional, or surgical management of these aneurysms is still under debate and requires further clarification. This literature review aims to consolidate current knowledge regarding coronary artery aneurysms’ pathophysiology, emphasizing their definition, causes, complications, and treatment strategies. Recent research has begun to explore the molecular mechanisms involved in the formation and progression of coronary artery aneurysms. Various molecules, such as matrix metalloproteinases (MMPs), inflammatory cytokines, and growth factors, play crucial roles in the degradation of the extracellular matrix and the remodeling of vascular walls. Elevated levels of MMPs, particularly MMP-9, have been associated with the weakening of the arterial wall, contributing to aneurysm development. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6) have been implicated in promoting inflammatory responses that further degrade vascular integrity. Additionally, growth factors such as vascular endothelial growth factor (VEGF) may influence angiogenesis and vascular remodeling processes. Understanding these molecular pathways is essential for developing targeted therapies aimed at preventing the progression of coronary artery aneurysms and improving patient outcomes. Full article

Monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy, offering unprecedented specificity and diverse mechanisms to combat malignant cells. These biologic agents have emerged as a cornerstone in targeted cancer treatment, binding to specific antigens on cancer cells and exerting their therapeutic effects through various mechanisms, including inhibition of signaling pathways, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). The unique ability of mAbs to engage the immune system and directly interfere with cancer cell function has significantly enhanced the therapeutic armamentarium against a broad spectrum of malignancies. mAbs were initially studied in oncology; however, today, treatments have been developed for eye diseases. This review discusses the current applications of mAbs for the treatment of ocular diseases, discussing the specificity and the variety of mechanisms by which these molecules exhibit their therapeutic effects. The benefits, drawbacks, effectiveness, and risks associated with using mAbs in ophthalmology are highlighted, focusing on the most relevant ocular diseases and mAbs currently in use. Technological advances have led to in vitro production methods and recombinant engineering techniques, allowing the development of chimeric, humanized, and fully human mAbs. Nowadays, many humanized mAbs have several applications, e.g., for the treatment of age-related macular disease, diabetic retinopathy, and uveitis, while studies about new applications of mAbs, such as for SARS-CoV-2 infection, are also currently ongoing to seek more efficient and safe approaches to treat this new ocular disease. Full article

Anterior myocardial infarction is a critical condition with significant implications for cardiac function and patient prognosis. Despite advancements in reperfusion therapies, optimizing recovery during the early phases of myocardial infarction remains challenging. Anterior myocardial infarction can lead to substantial long-term effects on a patient’s health due to extensive damage to the heart muscle, particularly the left ventricle, impacting both quality of life and overall prognosis. Vericiguat, a soluble guanylate cyclase stimulator, has shown promise in heart failure, but its role in early anterior myocardial infarction has not yet been fully explored. By enhancing soluble guanylate cyclase activity, vericiguat may increase cyclic guanosine monophosphate production, leading to vasodilation, inhibition of platelet aggregation, and potential cardioprotective effects. Currently, treatment options for anterior myocardial infarction primarily focus on reperfusion strategies and managing complications. However, there is a critical need for adjunctive therapies that specifically target the pathophysiological changes occurring in the early phases of myocardial infarction. Vericiguat’s mechanism of action offers a novel approach to improving vascular function and myocardial health, potentially contributing to innovative treatment strategies that could transform the care and prognosis of patients with anterior myocardial infarction. Full article

Background/Objectives: Patients with endometriosis still respond poorly to progestins due to progesterone resistance associated with microRNAs (miRNAs). The aim of this study was to investigate the expression of selected miRNAs, estrogen receptor (ER)α, ERβ, progesterone receptor (PR)-A and PR-B and to determine the target genes of upregulated miRNAs in endometriosis. Methods: In this study, 18 controls, 18 eutopic and 18 ectopic samples were analysed. Profiling and validation of miRNAs associated with functions of endometriosis were performed using next-generation sequencing (NGS) and qRT-PCR. At the same time, the expression of ERα, ERβ, PR-A and PR-B was also determined using qRT-PCR. Target prediction was also performed for miR-199a-3p, miR-1-3p and miR-125b-5p using StarBase. Results: In this study, NGS identified seven significantly differentially expressed miRNAs, of which six miRNAs related to the role of endometriosis were selected for validation by qRT-PCR. The expression of miR-199a-3p, miR-1-3p, miR-146a-5p and miR-125b-5p was upregulated in the ectopic group compared to the eutopic group. Meanwhile, ERα and ERβ were significantly differentially expressed in endometriosis compared to the control group. However, the expressions of PR-A and PR-B showed no significant differences between the groups. The predicted target genes for miR-199a-3p, miR-1-3p and miR-125b-5p are SCD, TAOK1, DDIT4, LASP1, CDK6, TAGLN2, G6PD and ELOVL6. Conclusions: Our findings demonstrated that the expressions of ERα and ERβ might be regulated by miRNAs contributing to progesterone resistance, whereas the binding of miRNAs to target genes could also contribute to the pathogenesis of endometriosis. Therefore, miRNAs could be used as potential biomarkers and for targeted therapy in patients with endometriosis. Full article