Search Results (303)

By 2030, millions of new cancer cases will be diagnosed, as well as millions of cancer-related deaths. Traditional drug delivery methods have limitations, so developing smart drug delivery systems (SDDs) has emerged as a promising avenue for more effective and precise cancer treatment. Nanotechnology, particularly nanomedicine, provides innovative approaches to enhance drug delivery, including the use of nanoparticles. One such type of SDD is thermosensitive nanoparticles, which respond to internal and external stimuli, such as temperature changes, to release drugs precisely at tumor sites and minimize off-target effects. On the other hand, hyperthermia is a cancer treatment mode that goes back centuries and has become popular because it can target cancer cells while sparing healthy tissue. This paper presents a comprehensive review of smart thermosensitive nanoparticles for cancer treatment, with a primary focus on organic nanoparticles. The integration of hyperthermia with temperature-sensitive nanocarriers, such as micelles, hydrogels, dendrimers, liposomes, and solid lipid nanoparticles, offers a promising approach to improving the precision and efficacy of cancer therapy. By leveraging temperature as a controlled drug release mechanism, this review highlights the potential of these innovative systems to enhance treatment outcomes while minimizing adverse side effects. Full article

Background/Objectives: Death-associated protein kinase 1 (DAPK1) is a serine/threonine kinase that plays a crucial role in cancer by regulating apoptosis through interactions with TP53. Aberrant expression of DAPK1 was shown in certain types of human cancer contributing to tumor progression and chemoresistance. This study aimed to investigate the role of DAPK1 in high-grade serous ovarian cancer (HGSOC) and to evaluate the therapeutic potential of restoring its kinase activity, including the use of truncated DAPK1 variants, to overcome chemoresistance and enhance tumor suppression. Methods: Gene expression analysis was performed on ovarian cancer tissues compared to benign controls to assess DAPK1 downregulation and its epigenetic regulation. Prognostic relevance was evaluated in a cohort of 1436 HGSOC patient samples. Functional restoration of DAPK1 was conducted in HGSOC cell lines and patient-derived primary tumor cells using vector-based expression or in vitro-transcribed (IVT) DAPK1 mRNA, including the application of truncated DAPK1 (ΔDAPK1) forms. To assess apoptosis, Caspase activation assays, 2D-colony formation assays, and cell survival assays were performed. To analyze the reactivation of DAPK1 downstream signaling, phosphorylation of p53 at Ser20 and the expression of p53 target proteins were examined. Chemosensitivity to Paclitaxel and Cisplatin was quantified by changes in IC₅₀ values. Results: DAPK1 expression was significantly downregulated in ovarian cancer compared to benign tissue, correlating with epigenetic silencing, and showed prognostic value in early-stage HGSOC. Restoration of DAPK1 activity, including ΔDAPK1 variants, led to phosphorylation of p53 Ser20, increased expression of p53 target proteins, and Caspase-dependent apoptosis. Reactivation of DAPK1 sensitized both established HGSOC cell lines and patient-derived ascites cells to Paclitaxel and Cisplatin. These effects occurred through both p53-dependent and p53-independent pathways, enabling robust tumor suppression even in p53-mutant contexts. Conclusions: Reactivation of DAPK1, particularly through truncated variants, represents a promising therapeutic strategy to overcome chemoresistance in HGSOC. The dual mechanisms of tumor suppression provide a strong rationale for developing DAPK1-based therapies to enhance the efficacy of standard chemotherapy, especially in patients with chemoresistant or p53-deficient tumors. Future work should focus on optimizing delivery approaches for DAPK1 variants and assessing their synergistic potential with emerging targeted treatments in clinical settings. Full article

ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, has emerged as a pivotal tumor suppressor altered in a broad range of human malignancies. Its frequent inactivation across diverse cancer types has revealed pleiotropic roles that intersect multiple Hallmarks of Cancer. In this review, we integrate current knowledge on how ARID1A loss influences cellular processes including proliferative signaling, resistance to cell death, genomic instability, metabolic reprogramming, immune evasion, and more. We discuss the context-specific consequences of ARID1A deficiency, its cooperation with other oncogenic events, and its implications for therapeutic vulnerability—particularly in the realm of synthetic lethality and immune modulation. By mapping ARID1A’s functional impact onto the established hallmarks framework, we highlight its centrality in cancer biology and underscore opportunities for biomarker-driven strategies and targeted interventions. Understanding ARID1A’s multifaceted roles offers a compelling lens through which to explore chromatin dysregulation in cancer and guide translational advances. Full article

Background/Objectives: Engineered nanomaterials, particularly silver nanoparticles (AgNPs), have emerged as promising tools in oncology due to their ability to enhance tumor targeting and minimize off-target effects. This study investigates the cytotoxic effects of two different types of AgNPs—citrate-coated (AgNPs-cit) and EG₆OH-coated (AgNPs-EG₆OH)—on colorectal cancer (CRC) cell lines and healthy colonocytes, aiming to assess their potential as selective therapeutic agents. Methods: AgNPs-cit and AgNPs-EG₆OH were synthesized and characterized for size and surface properties. LoVo (microsatellite instability-high) and HT-29 (microsatellite stable) CRC cell lines, along with primary colonocyte cultures from healthy mucosal tissues, were exposed to these nanoparticles. Cytotoxicity was assessed through MTT assays, while morphological changes were observed using fluorescence microscopy. Internalization of the nanoparticles was evaluated by confocal microscopy. Results: AgNPs-cit exhibited significant cytotoxicity in LoVo cells, reducing viability and inducing morphological changes indicative of programmed cell death, especially after 48 h of exposure. In contrast, AgNPs-EG₆OH showed minimal effects on LoVo cells and no significant toxicity on HT-29 cells or primary colonocytes. Confocal microscopy confirmed nanoparticle internalization, with surface functionalization influencing the distribution patterns within cells. Conclusions: This study demonstrates that surface functionalization significantly influences the cytotoxicity of AgNPs, with citrate-coated nanoparticles showing selective effects on microsatellite instability-high CRC cells. These findings underscore the potential of surface-modified nanoparticles for targeted cancer therapy and highlight the importance of tailoring nanoparticle design to optimize therapeutic efficacy while minimizing off-target effects. Full article

Background: While Bacillus Calmette-Guérin (BCG) remains the first-line therapy for high-risk bladder cancer, 30–40% of patients develop treatment resistance necessitating radical cystectomy, some are not suitable candidates for this procedure. This underscores the critical need for novel therapeutic approaches. Emerging clinical evidence has increasingly supported the therapeutic potential of oncolytic viruses in bladder cancer treatment. Based on this clinical foundation, we investigated the anti-tumor effects of KD01, a novel type 5 recombinant oncolytic adenovirus previously developed by our team engineered to express truncated BID (tBID), in bladder cancer. Methods: The cytotoxic effects and anti-tumor efficacy of KD01 were systematically evaluated across human bladder cancer cell lines, and cell death pathways were investigated by RNA sequencing and validated. Combination therapy studies with cisplatin employed cytotoxic testing. In the final stage, the safety of KD01 bladder instillation was evaluated. Results: KD01 induced bladder cancer cell death through multiple mechanisms, including oncolysis, immunogenic cell death, and mitochondrial apoptosis. At higher doses, KD01 combined with cisplatin synergistically inhibited cancer cell proliferation and induced apoptosis. Additionally, KD01 amplified damage-associated molecular patterns (DAMPs) release and immune activation; the combination with cisplatin further enhanced the process. Safety evaluations showed favorable tolerance to intravesical perfusion with KD01. Conclusions: The dual action of KD01 in directly killing tumor cells and activating anti-tumor immunity underscores its potential as a therapeutic agent. These findings highlight the preclinical efficacy and safety of KD01, informing the design of clinical trials. Full article

The genetic diversity of influenza A virus is a major obstacle that makes vaccine effectiveness variable and unpredictable. Objectives: Current vaccines induce strain-specific immunity that oftentimes fail to protect against divergent strains. Our previous research explored synthetic centralized consensus (CC) vaccines to minimize immunogen-strain divergence and focused on the viral glycoprotein hemagglutinin. Methods: Recently, emerging evidence of neuraminidase (NA)-mediated immunity has shifted vaccine strategies, prompting our development of a CC NA type 1 (N1CC) vaccine based on ancestral N1 sequences and delivered using a human adenovirus type 5 vector Results: The N1CC vaccine elicited antibody responses with NA inhibition activity and induced NA-specific T-cell responses. In lethal influenza challenge models, N1CC fully protected mice from death against human, swine, and avian influenza H1N1 and H5N1 strains. Conclusions: These findings support NA as a protective immunogen and demonstrate the power and efficacy of a centralized consensus NA design. Full article

Background: Since 2011, re-emerging pseudorabies virus (PRV) variant strains have been widespread in swine herds immunized with the classical PRV vaccine in China, suggesting that it is necessary to develop a new vaccine against these PRV variant strains. Methods: Here, based on a PRV mutant strain isolated in Jinmen (JM), two recombinant strains were constructed using CRISPR/Cas9 technology, including PRV-JM-ΔEK with the deletion of the gE and TK genes and PRV-JM-ΔEI92K with the deletion of the gE, gI, US2, US9, and TK genes. Results: A one-step growth curve and plaque assay revealed that the cell-to-cell transmission ability of PRV-JM-ΔEI92K was lower than that of PRV-JM-ΔEK. However, the replication ability of PRV-JM-ΔEI92K was approximately 10 times higher than that of PRV-JM-ΔEK, similar to wild-type PRV-JM. The intramuscular injection of 10⁶ TCID₅₀ of PRV-JM-ΔEK or PRV-JM-ΔEI92K could not cause death in mice, and both could produce specific antibodies against gB and gD. The survival rate of mice immunized with both recombinant viruses was 100% when the mice were challenged by the PRV-JM strain. Histopathological sections from the PRV-JM-ΔEK group showed milder pathological changes compared to the PRV-JM-ΔEI92K group, proving that PRV-JM-ΔEK provided more effective protection. In pigs injected with 10⁶ TCID₅₀ of PRV-JM-ΔEK or PRV-JM-ΔEI92K, their body temperature did not rise, and their weight gain was not affected. Both recombinant viruses could induce the production of gB- and gD-specific antibodies and neutralizing antibodies. After the challenge of the PRV-JM virus, neutralizing antibody production was rapidly induced and lasted for at least 3 weeks. Pigs immunized with both PRV-JM-ΔEI92K and PRV-JM-ΔEK had a 100% survival rate, demonstrating that both recombinant viruses could provide effective protection. Conclusions: Compared with PRV-JM-ΔEK, PRV-JM-ΔEI92K had better safety. In conclusion, we constructed two PRV recombinant viruses, which have the potential to be used as a live carrier vaccine. Full article

Background/Objectives: Yersinia pestis is an important zoonotic pathogen responsible for the rare but deadly disease of people with bubonic, septic, or pneumonic forms of plague. The emergence of multidrug-resistant Y. pestis strains has attracted more and more researchers’ attention to the search for molecular targets for antivirulence therapy, including anti-nutritional-virulence therapy. The glnALG operon plays a crucial role in regulating the nitrogen content within a bacterial cell. This operon codes for three genes: the structural gene glnA and the two regulatory genes glnL and glnG. In this study, we tested the effect of the deletion of glnA and glnALG on the pathogenic properties of Y. pestis. Methods: To assess the contribution of nitrogen metabolism to Y. pestis virulence, knockout mutants ΔglnA and ΔglnALG were constructed. The former was unable to synthesize glutamine, while the latter was not only defective in glutamine synthesis but also lacked the two-component sensor–transcriptional activator pair GlnL and GlnG, which could partially compensate for the decrease in intracellular glutamine concentrations by transporting it from the host or by catabolic reactions. For vaccine studies, immunized mice and guinea pigs were injected s.c. with 200 LD₁₀₀ of the wild-type Y. pestis strain. Results: A single knockout mutation in the glnA gene did not affect the virulence of Y. pestis in mice and guinea pigs. Knockout of the entire glnALG gene cluster was required for attenuation in these animals. The ΔglnALG strain of Y. pestis did not cause death in mice (LD₅₀ > 10⁵ CFU) and guinea pigs (LD₅₀ > 10⁷ CFU) when administered subcutaneously and provided 100% protection of animals when subsequently infected with 200 LD₁₀₀ of the Y. pestis virulent wild-type strain 231. Conclusions: Y. pestis, defective in both the glutamine synthetase GlnA and the two-component sensor–transcriptional activator pair GlnL-GlnG, completely lost virulence and provided potent protective immunity to mice and guinea pigs subsequently challenged with a wild-type Y. pestis strain, demonstrating the potential use of the glnALG operon as a new molecular target for developing a safe and efficient live plague vaccine. Full article

Background and Clinical Significance: Lung cancer, a leading cause of global cancer diagnoses, maintains the highest mortality risk despite advances in treatment. Immunotherapy agents, such as anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1), have revolutionized care for non-small cell lung cancer (NSCLC). However, the success is tempered by the emergence of immune-mediated adverse reactions, including the rare onset of type I diabetes. The incidence of diabetes mellitus increased during the SARS-CoV-2 pandemic. While there are several cases of new-onset diabetes after COVID-19 and COVID-19 vaccination, no case of new-onset type 1 diabetes after COVID-19 was described in an immune checkpoint inhibitor (ICI)-treated patient. Case Presentation: A 57-year-old male with stage IV NSCLC (brain and liver metastases) who had been treated with nivolumab for 4 years appeared positive for SARS-CoV-2 infection at a routine check. After two weeks, he was admitted to our clinic with severe fatigue, hyperglycemia, hyponatremia, and hyperkalemia. HbA1c level was normal and serum peptide C was undetectable. Nivolumab treatment was ceased, and the patient became fully dependent on basal–bolus insulin. After 3 months, the patient showed a complete imagistic remission. Conclusions: The case presented significant challenges due to the unclear etiology of newly onset diabetes and the uncommon age at which type 1 diabetes is developed. The outcome suggests that anti-PD-1 and SARS-CoV-2 infection can act synergistically. Full article

Myocardial infarction remains a leading cause of death worldwide due to the heart’s limited regenerative capability and the current lack of viable therapeutic solutions. Therefore, there is an urgent need to develop effective treatment options to restore cardiac function after a heart attack. Stem cell-derived cardiac cells have been extensively utilised in cardiac tissue regeneration studies. However, the use of Matrigel as a substrate for the culture and maturation of these cells has been a major limitation for the translation of this research into clinical application. Hydrogels are emerging as a promising system to overcome this problem. They are biocompatible and can provide stem cells with a supportive scaffold that mimics the extracellular matrix, which is essential for repairing damaged tissue in the myocardium after an infarction. Thus, hydrogels provide an alternative and reproducible option in addressing myocardial infarction due to their unique potential therapeutic benefits. This review explores the different types of natural and synthetic polymers used to create hydrogels and their various delivery methods, the most common being via injection and cardiac patches and other applications such as bioprinting. Many challenges remain before hydrogels can be used in a clinical setting, but they hold great promise for the future of cardiac tissue regeneration. Full article

Pyroptosis is an inflammatory programmed cell death recently identified as a crucial cellular process in various diseases, including cancers. Unlike other forms of cell death, canonical pyroptosis involves the specific cleavage of gasdermin by caspase-1, resulting in cell membrane damage and the release of the pro-inflammatory cytokines IL-1β and IL-18. Initially observed in innate immune cells responding to external pathogens or internal death signals, pyroptotic cell death has now been observed in numerous cell types. Recent studies have extensively explored different ways to trigger pyroptotic cell death in solid tumors, presenting a promising avenue for cancer treatment. This review outlines the mechanisms of both canonical and noncanonical pyroptosis pertinent to cancer and primarily focuses on various biomolecules that can induce pyroptosis in malignancies. This strategy aims not only to eliminate cancer cells but also to promote an improved tumor immune microenvironment. Furthermore, emerging research indicates that targeting pyroptotic pathways may improve the effectiveness of existing cancer treatments, making them more potent against resistant tumor types, offering new hope for overcoming treatment resistance in aggressive malignancies. Full article

Background/Objectives: The COVID-19 pandemic resulted in 675 million cases and 6.9 million deaths by 2022. Despite substantial declines in case fatalities following widespread vaccination campaigns, the threat of future coronavirus outbreaks remains a concern. Current treatments for COVID-19 have been repurposed from existing therapies for other infectious and non-infectious diseases. Emerging evidence suggests a role for genetic factors in both susceptibility to SARS-CoV-2 infection and response to treatment. However, comprehensive studies correlating clinical outcomes with genetic variants are lacking. The main aim of our study is the identification of host genetic biomarkers that predict the clinical outcome of COVID-19 pharmacological treatments. Methods: In this study, we present findings from GWAS and candidate gene and pathway enrichment analyses leveraging diverse patient samples from the Spanish Coalition to Unlock Research of Host Genetics on COVID-19 (SCOURGE), representing patients treated with immunomodulators (n = 849), corticoids (n = 2202), and the combined cohort of both treatments (n = 2487) who developed different outcomes. We assessed various phenotypes as indicators of treatment response, including survival at 90 days, admission to the intensive care unit (ICU), radiological affectation, and type of ventilation. Results: We identified significant polymorphisms in 16 genes from the GWAS and candidate gene studies (TLR1, TLR6, TLR10, CYP2C19, ACE2, UGT1A1, IL-1α, ZMAT3, TLR4, MIR924HG, IFNG-AS1, ABCG1, RBFOX1, ABCB11, TLR5, and ANK3) that may modulate the response to corticoid and immunomodulator therapies in COVID-19 patients. Enrichment analyses revealed overrepresentation of genes involved in the innate immune system, drug ADME, viral infection, and the programmed cell death pathways associated with the response phenotypes. Conclusions: Our study provides an initial framework for understanding the genetic determinants of treatment response in COVID-19 patients, offering insights that could inform precision medicine approaches for future epidemics. Full article

T cell phenotypes and kinetics are emerging as crucial factors associated with immunotherapeutic responses in a wide range of solid cancer types. However, challenges remain in understanding the spatial and temporal profiles of T cells with differential phenotypes due to difficulties in single-cell analysis with preserved tissue structures. Here, we provide an optimized 12-marker multiplex immunohistochemical (IHC) panel and single-cell-based quantitative assessment to identify the spatial distributions of T cell phenotypes in formalin-fixed paraffin-embedded sections. This panel revealed differential T cell populations with spatial localizations in human tonsil tissue, where the percentages of CD8⁺ T cell-expressing programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin domain 3 (TIM3), and other T cell phenotypic markers vary by tonsillar tissue components such as follicles, parenchyma, and epithelium. A specimen from salivary gland adenocarcinoma during hyper-progression, followed by anti-PD-1 treatment, exhibited the exclusion of CD8⁺ T cells from the intratumoral regions. Although the vast majority of peritumoral CD8⁺ T cells exhibited proliferative effector T cell phenotypes with PD-1⁻TIM3⁻Ki67⁺CD45RA⁺, intratumoral CD8⁺ T cells showed exhausted phenotypes with PD-1⁺TIM3⁻ and increased Eomes expression, which might be related to poor therapeutic response in this case. To verify these findings in the context of temporal changes, we analyzed six longitudinal samples from a single patient with maxillary sinus cancer, observing increased T cell exhaustion along with metastasis and progression. Together, highly multiplexed IHC can be applied to analyze the spatiotemporal phenotypes of T cells, potentially contributing to the understanding of the mechanisms of resistance to immunotherapy. Full article

In 2025, gynecological cancers are projected to account for approximately 10% of cancer-related deaths in women. High-grade serous ovarian carcinoma (HGSC) and serous endometrial carcinoma (SEC) are the most lethal gynecological cancer subtypes. Both malignancies commonly have TP53 mutations, alterations of the RB1 pathway, and numerous secondary mutations. Both carcinoma types consist of poorly differentiated and highly heterogeneous cell populations at the time of detection. Latent development and rapid progression of HGSC and SEC impede the identification of definitive cells of origin and genetic drivers. Here, we review our current knowledge about cancer-prone cell states and genetic drivers. We also discuss how emerging transcriptomic and genetic tools applied to contemporary model systems may facilitate the identification of novel targets for timely detection and therapeutic intervention. Full article

N6-methyladenosine (m6A) is the most prevalent internal chemical modification in eukaryotic messenger RNA (mRNA), significantly impacting its lifecycle through dynamic and reversible processes involving methyltransferase, demethylase, and binding proteins. These processes regulate mRNA stability, splicing, nuclear export, translation, and degradation. Programmed cell death (PCD), a tightly controlled process encompassing apoptosis, pyroptosis, ferroptosis, autophagy, and necroptosis, plays a crucial role in maintaining cellular homeostasis, tissue development, and function. Recently, m6A modification has emerged as a significant research area due to its role in regulating PCD and its implications in cardiovascular diseases (CVDs). In this review, we delve into the intricate relationship between various PCD types and m6A modification, emphasizing their pivotal roles in the initiation and progression of CVDs such as myocardial ischemia-reperfusion (I/R), atherosclerosis (AS), pulmonary hypertension (PH), cardiomyopathy, doxorubicin (Dox)-induced cardiotoxicity (DIC), heart failure (HF), and myocardial infarction (MI). Our findings underscore the potential of elucidating the roles of m6A and PCD in CVD to pave new pathways for prevention and treatment strategies. Full article