Search Results (322)

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

The generation of memory CD8⁺ T cells is essential for establishing protective T cell immunity against pathogens and cancers. However, the cellular and molecular mechanisms underlying memory CD8⁺ T cell formation remain incompletely understood. Reliance on specific pathogen-free (SPF) models, characterized by restricted microbial exposure, may limit our understanding of physiologically relevant immune memory development. This study reveals that CD1d-restricted NKT cells regulate central memory T cell (TCM) generation exclusively in a microbe-rich (“dirty”) environment. Under non-SPF housing, CD1d⁺/⁻ and Ja18⁺/⁻ mice exhibited enhanced TCM formation compared to NKT-deficient controls (CD1d⁻/⁻/Ja18⁻/⁻), demonstrating that microbial experience is required for NKT-mediated TCM regulation. Mechanistically, CD1d-restricted NKT cells increased IL-15Rα expression on CD4⁺ T cells in CD1d⁺/⁻ mice, potentiating IL-15 trans-presentation and thereby activating the IL-15/pSTAT5/Eomes axis critical for TCM maintenance. Functional validation through adoptive transfer of CFSE-labeled OT-1 memory cells revealed an NKT cell-dependent survival advantage in CD1d⁺/⁻ hosts. This provides direct evidence that microbiota-experienced niches shape immune memory. Collectively, these findings establish CD1d-restricted NKT cells as physiological regulators of TCM generation and suggest their potential utility as vaccine adjuvants to enhance protective immunity. Full article

Background: Ovarian clear cell carcinoma (OCCC) is characterized by chemoresistance and poor prognosis in advanced or recurrent cases. This study aimed to find specific prognostic markers for OCCC. Methods: We analyzed 169 OCCC patients for clinicopathological features. TERT promoter and PIK3CA mutations were assessed by Sanger sequencing, and immunohistochemistry for ARID1A, HDAC6, Cyclin E1, and p53 was performed on tissue microarrays. Survival analysis was conducted using Kaplan–Meier and Cox regression models. Results: The -124C>T TERT promoter mutation was associated with longer OS and PFS and was an independent predictor of favorable OS. This mutation correlated with lower CA125 levels and higher SNP frequency. p53 mutations indicated advanced disease, bilateral tumors, reduced Cyclin E1, and poor prognosis. Low HDAC6 expression was linked to worse PFS. Mutual exclusivity was observed between PIK3CA exon 20 mutations and SNPs. Conclusions: The -124C>T TERT promoter mutation may serve as a favorable prognostic marker in OCCC, while p53 mutations and reduced HDAC6 expression are associated with poor outcomes. Full article

Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We conducted a comprehensive literature analysis examining natural products tested in cancer organoids, immunomodulatory mechanisms from traditional models, technical advances in organoid-immune co-cultures, and standardization requirements for clinical translation. Our analysis reveals a critical research gap: no published studies have investigated natural product-mediated immunomodulation using organoid-immune co-culture systems. Even though compounds like curcumin, resveratrol, and medicinal mushroom polysaccharides show extensive immunomodulatory effects in two-dimensional (2D) cultures, and organoid technology achieves high clinical correlation for drug response prediction, all existing organoid studies focus exclusively on direct cytotoxicity. Technical challenges include compound stability, limited matrix penetration requiring substantially higher concentrations than 2D cultures, and maintaining functional immune populations in three-dimensional (3D) systems. The convergence of validated organoid-immune co-culture platforms, Food and Drug Administration (FDA) regulatory support through the Modernization Act 2.0, and extensive natural product knowledge creates unprecedented opportunities. Priority research directions include systematic screening of immunomodulatory natural products in organoid-immune co-cultures, development of 3D-optimized delivery systems, and clinical validation trials. Success requires moving beyond cytotoxicity-focused studies to investigate immunomodulatory mechanisms in physiologically relevant 3D systems, potentially unlocking new precision cancer immunotherapy approaches. Full article

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

Nucleolin (NCL), an RNA-binding protein which regulates critical cellular processes, is frequently dysregulated in human cancers, including breast cancer, making it an attractive therapeutic target. However, molecular details of the RNA-NCL interaction have not been investigated yet. A tRNA fragment named tRF3E, displaying tumor suppressor roles in breast cancer, was found to bind NCL with high affinity displacing NCL-controlled transcripts. Here, we investigated the determinants and cooperativity of tRF3E-NCL interaction by Electrophoretic Mobility Shift Assays and in silico docking analysis, using wild-type or mutated tRF3E. We found that NCL, through its RNA-binding domains (RBD1–2 and RBD3–4), binds simultaneously two tRF3E molecules, giving rise to an energetically favored complex. Instead, a mutant form of tRF3E (M19–24), in which the NCL recognition element in position 19–24 has been disrupted, contacts NCL exclusively at RBD3–4, causing the loss of cooperativity among RBDs. Importantly, when expressed in MCF7 breast cancer cells, tRF3E significantly reduced cell proliferation and colony formation, confirming its role as tumor suppressor, but tRF3E functional properties were lost when the 19–24 motif was mutated, suggesting that cooperativity among multiple domains is required for the NCL-mediated tRF3E antitumor function. This study sheds light on the dynamic of RNA-NCL interaction and lays the foundations for using tRF3E as a promising NCL-targeted biodrug candidate. Full article

Background: Medullary thyroid cancer (MTC), a neuroendocrine tumor originating from thyroid parafollicular C-cells, presents therapeutic challenges, particularly in advanced stages. While RET proto-oncogene mutations are known drivers, a comprehensive understanding of the broader somatic mutation landscape is needed to identify novel therapeutic targets and improve prognostication. This study leveraged the extensive AACR Project GENIE dataset to characterize MTC genomics. Methods: A retrospective analysis of MTC samples from GENIE examined recurrent somatic mutations, demographic/survival correlations, and copy number variations using targeted sequencing data (significance: p < 0.05). Results: Among 341 samples, RET mutations predominated (75.7%, mostly M918T), followed by HRAS (10.0%) and KRAS (5.6%), with mutual exclusivity between RET and RAS alterations. Recurrent mutations included KMT2D (5.3%), CDH11 (5.3%), ATM (5.0%), and TP53 (4.1%). NOTCH1 mutations were enriched in metastatic cases (p = 0.023). Preliminary associations included sex-linked mutations (BRAF/BRCA1/KIT in females, p = 0.028), and survival (ATM associated with longer survival, p = 0.016; BARD1/BLM/UBR5/MYH11 with shorter survival, p < 0.05), though limited subgroup sizes warrant caution. Conclusions: This large-scale genomic analysis confirms the centrality of RET and RAS pathway alterations in MTC and their mutual exclusivity. The association of NOTCH1 mutations with metastasis suggests a potential role in disease progression. While findings regarding demographic and survival correlations are preliminary, they generate hypotheses for future validation. This study enhances the genomic foundation for understanding MTC and underscores the need for integrated clinico-genomic datasets to refine therapeutic approaches. Full article

Introduction: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Even though surgery and chemotherapy are the mainstay of treatment, immunotherapy, and more specifically anti-tumor vaccination, has gained popularity over the past years due to the lower related toxicity and fewer long-term side effects. Dendritic cell (DC) vaccines have been shown to induce tumor specific cytotoxic T-cell (CTL) responses both in vitro and in vivo; however, due to the nature of the disease, resistance to immunotherapy is often developed. Various modifications, such as the implementation of viral vectors, tumor RNA, or even tumor-specific peptides (neoantigens), have been studied as a means to avoid resistance and enhance the effectiveness of the vaccines. In this review, we aim to assess the effects of neoantigen-loaded DC vaccines (naDCVs) on the immune response against gastric cancer cells. Materials and methods: A thorough literature search was conducted on PubMed and clinicaltrials.gov for studies assessing the efficacy of naDCVs against gastric cancer both in vivo and in vitro. The studies were assessed for eligibility by two independent reviewers based on predetermined inclusion and exclusion criteria. The search was completed following the PRISMA guidelines. Results: Eleven studies were included in our systematic review. In five of the studies, the effects of the naDCVs were tested in vitro; in two and in four they were examined both in vitro and in vivo. The in vitro studies showed that the naDCVs resulted in a more robust immune response against the cancer cells in the study groups compared to the control groups. The in vivo studies conducted on mice showed that tumor volume was reduced in the groups treated with the naDCV compared to the untreated groups. What is more, the cytotoxic effect of CTLs against tumor cells was also increased in the vaccine groups. One of the studies was conducted on humans as a phase I study. The results show increased CTL proliferation and cytokine production in the vaccinated group compared to the control, but no difference regarding the tumor size was observed. Conclusions: Neoantigen-loaded DC vaccines can stimulate a strong immune response against specific gastric cancer cell peptides and enhance tumor cell lysis, therefore hindering or even reversing disease progression, offering great potential for the treatment of patients with gastric cancer. Full article

Background: Zoonotic infection with Mycobacterium bovis continues to occur, particularly in regions lacking bovine tuberculosis surveillance and where the consumption of unpasteurized dairy products, including artisanal cheeses, is common. We describe the clinical and microbiological characteristics, diagnostic procedures, and treatment outcomes of individuals with HIV with M. bovis infection. Methods: We conducted a retrospective study analyzing sociodemographic, clinical, microbiological, and computed tomography (CT) data, as well as treatment outcomes, in 12 patients with HIV with confirmed M. bovis infection. These findings were compared with those of 14 individuals with HIV diagnosed with Mycobacterium tuberculosis infection during the same period. Results: Consumption of unpasteurized dairy products was significantly associated with M. bovis. Patients with M. bovis infection had higher CD4+ T-cell counts compared to those with M. tuberculosis infection (p = 0.01, r = 0.45). All M. bovis cases presented with extrapulmonary disease. CT imaging in M. bovis infection more frequently demonstrated retroperitoneal lymphadenopathy, hepatosplenomegaly, and splenic abscesses compared to M. tuberculosis infection. Microbiological identification was exclusively from extrapulmonary sites in all M. bovis cases. Surgical interventions, including abscess drainage or splenectomy, were significantly more common among M. bovis patients. Conclusions: M. bovis infection in individuals with HIV is characterized by consistent extrapulmonary, often abdominal, involvement. Surgical procedures are frequently required for both diagnosis and management. Targeted efforts to identify M. bovis are warranted, particularly in high-burden regions where unpasteurized dairy consumption remains prevalent. Full article

Virus-like nanoparticles (VNPs) based on Moloney murine leukemia virus represent a well-established platform for the expression of heterologous molecules such as cytokines, cytokine receptors, peptide MHC (pMHC) and major allergens, but their application for inducing protective anti-viral immunity has remained understudied as of yet. Here, we variably fused the wildtype SARS-CoV-2 spike, its receptor-binding domain (RBD) and nucleocapsid (NC) to the minimal CD16b-GPI anchor acceptor sequence for expression on the surface of VNP. Moreover, a CD16b-GPI-anchored single-chain version of IL-12 was tested for its adjuvanticity. VNPs expressing RBD::CD16b-GPI alone or in combination with IL-12::CD16b-GPI were used to immunize BALB/c mice intramuscularly and subsequently to investigate virus-specific humoral and cellular immune responses. CD16b-GPI-anchored viral molecules and IL-12-GPI were well-expressed on HEK-293T-producer cells and purified VNPs. After the immunization of mice with VNPs, RBD-specific antibodies were only induced with RBD-expressing VNPs, but not with empty control VNPs or VNPs solely expressing IL-12. Mice immunized with RBD VNPs produced RBD-specific IgM, IgG_2a and IgG₁ after the first immunization, whereas RBD-specific IgA only appeared after a booster immunization. Protein/peptide microarray and ELISA analyses confirmed exclusive IgG reactivity with folded but not unfolded RBD and showed no specific IgG reactivity with linear RBD peptides. Notably, booster injections gradually increased long-term IgG antibody avidity as measured by ELISA. Interestingly, the final immunization with RBD–Omicron VNPs mainly enhanced preexisting RBD Wuhan Hu-1-specific antibodies. Furthermore, the induced antibodies significantly neutralized SARS-CoV-2 and specifically enhanced cellular cytotoxicity (ADCC) against RBD protein-expressing target cells. In summary, VNPs expressing viral proteins, even in the absence of adjuvants, efficiently induce functional SARS-CoV-2-specific antibodies of all three major classes, making this technology very interesting for future vaccine development and boosting strategies with low reactogenicity. Full article

Obesity is considered a global pandemic. In Mexico, 7/10 adults, 4/10 adolescents, and 1/3 children are overweight or obese, and it is estimated that 90% of cases of type 2 diabetes (T2D) are attributable to these pathologies. Visceral adipose tissue (VAT) presents increased lipolysis, lower insulin sensitivity, and greater metabolic alterations. Glucagon-like peptide-1 (GLP-1) is a polypeptide incretin hormone that stimulates insulin secretion dependent on the amount of oral glucose consumed, reduces plasma glucagon concentrations, slows gastric emptying, suppresses appetite, improves insulin synthesis and secretion, and increases the sensitivity of β cells to glucose. Liraglutide is a synthetic GLP-1 analog that reduces VAT and improves the expression of Glucose transporter receptor type 4 (GLUT 4R), Mitogen-activated protein (MAP kinases), decreases Fibroblast growth factor type β (TGF-β), reactivates the peroxisome proliferator-activated receptor type ɣ (PPAR-ɣ) pathway, and decreases chronic inflammation. Currently, there are many studies that explain the decrease in VAT with these medications, but there are no studies that compare the decrease in patients with obesity and prediabetes vs. obesity and type 2 diabetes to know which population obtains a greater benefit from treatment with this pharmacological group; this is the reason for this study. The primary objective was to compare the difference in the determination of visceral adipose tissue in people with obesity and type 2 diabetes vs. obesity and prediabetes treated with liraglutide. Methods: A quasi-experimental, analytical, prolective, non-randomized, non-blinded study was conducted over a period of 6 months in a tertiary care center. A total of 36 participants were divided into two arms; group 1 (G1: Obesity and prediabetes) and group 2 (G2: Obesity and type 2 diabetes) for 6 months. Inclusion criteria: men and women ≥18 years with type 2 diabetes, prediabetes, and obesity. Exclusion criteria: Glomerular filtration rate (GFR) < 60 mL/min/1.73 m² elevated transaminases (>5 times the upper limit of normal), and use of non-weight-modifying antidiabetic agents. Conclusions: No statistically significant difference was found in the decrease in visceral adipose tissue when comparing G1 (OB and PD) with G2 (OB and T2D). When comparing intragroup in G2 (OB and T2D), greater weight loss was found [(−3.78 kg; p = 0.012) vs. (−3.78 kg; p = 0.012)], as well differences in waist circumference [(−3.9 cm; p = 0.049) vs. (−3.09 cm; p = 0.017)], and glucose levels [(−1.75 mmol/L; p = 0.002) vs. (−0.56 mmol/L; p = 0.002)], A1c% [(−1.15%; p = 0.001) vs. (−0.5%; p = 0.000)]. Full article

Skin cancer, including melanoma and non-melanoma cancers (basal and squamous cell carcinomas), is the most common type of cancer. UV radiation, family history, and genetic predisposition are the main risk factors. Although surgical excision is the standard treatment, essential oils are attracting growing interest for their anti-cancer effects. This study tested the effects of Juniperus excelsa M. Bieb. (Cupressaceae), Lavandula vera DC. (Lamiaceae), and Salvia fruticosa (Mill). (Lamiaceae) essential oils extracted from Middle Eastern medicinal plants on HaCaT (normal), A5 (benign), and II4 (low-grade malignant) keratinocytes. Essential oils were extracted from Juniperus excelsa, Lavandula vera, and Salvia libanotica using steam distillation and then were chemically analyzed. The oils were sterilized, dissolved in DMSO, and prepared at concentrations of 0.75, 0.5, and 0.25 mg/mL. Human keratinocyte (HaCaT), benign (A5), and malignant (II4) cell lines were cultured in DMEM and treated with the essential oils for 24 or 48 h. Cell viability was assessed using the Trypan Blue Exclusion Test, while cell proliferation was evaluated using the MTT assay. Statistical analysis was performed using ANOVA with appropriate post hoc tests, considering p < 0.05 as significant. The results show that J. excelsa is cytotoxic but lacks selectivity, limiting its efficacy. In contrast, L. vera and S. fruticosa preferentially target malignant cells, particularly at low concentrations, while sparing normal cells. These oils have dose-dependent anticancer effects, with L. vera efficacy increasing as the concentration increases. In conclusion, L. vera and S. fruticosa are promising candidates for the treatment of skin cancer, although further in vivo studies are required. Full article

Background: The escalating prevalence of food allergies, alongside the global call for environmentally sustainable dietary transitions, has drawn attention to plant-based dietary models—particularly those inspired by the EAT-Lancet Commission. These frameworks not only reduce reliance on animal-sourced foods, benefiting planetary health, but may also play a role in modulating immune tolerance and allergic responses. Methods: This scoping review followed PRISMA guidelines and included 53 peer-reviewed studies published between 2000 and 2024, retrieved from PubMed, Scopus, and Google Scholar. Eligible articles were classified into two thematic domains: prevention of food allergy onset (n = 31) and modulation of allergic symptoms in sensitized individuals (n = 22). Included studies comprised randomized controlled trials (n = 6), observational studies (n = 17), systematic reviews and meta-analyses (n = 11), and narrative/scoping reviews (n = 19). Results: Sustainable plant-based diets were consistently associated with a lower incidence of allergic sensitization and reduced symptom severity. These effects were partly due to the exclusion of common allergens (e.g., dairy, eggs, and shellfish) but more importantly due to immunomodulatory mechanisms. Fermentable fibers can enhance short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium prausnitzii), elevating butyrate and acetate levels, which interact with G-protein-coupled receptors 43 and 109A (GPR43 and GPR109A) to induce regulatory T cells (Tregs) and reinforce epithelial integrity via tight junction proteins such as occludin and claudin-1. Polyphenols (e.g., quercetin and luteolin) can inhibit Th2-driven inflammation by stabilizing mast cells and downregulating IL-4 and IL-1. Conclusions: Following sustainable dietary guidelines such as those proposed by the EAT-Lancet Commission may confer dual benefits: promoting environmental health and reducing the burden of allergic diseases. By emphasizing plant-based patterns rich in fiber and polyphenols, these diets support microbiota-mediated immune education, mucosal barrier function, and immunological tolerance. When properly supervised, they represent a promising tool for allergy prevention and symptom management. Larger randomized trials and long-term population studies are needed to confirm and operationalize these findings in clinical and public health contexts. Full article

Background/Objectives: While sublobar resection (SLR) is accepted for selected small, early non-small-cell lung cancers (NSCLCs), its efficacy for tumors with visceral pleural invasion (VPI) remains debated. This study aimed to compare lung-cancer-specific survival (LCSS) between SLR and lobectomy in pT2a (tumor ≤ 3 cm with VPI) N0M0 NSCLCs from a nationwide population-based database. Methods: This retrospective study utilized Taiwan Cancer Registry data from 2011 to 2018, selecting patients with pT2a (tumor ≤ 3 cm with VPI) N0M0 NSCLC that underwent SLR or lobectomy, with specific exclusion criteria. Propensity score matching (1:1) was performed using a greedy algorithm with a 0.01 caliper width. LCSS was compared using Kaplan–Meier analysis with log-rank tests and Cox proportional hazards models before and after matching. Results: In the 2460-patient cohort (624 SLR, 1836 lobectomy) before matching, lobectomy was associated with significantly better overall (p = 0.01) and PL1 VPI subgroup (p = 0.009) LCSS. In the matched cohort (523 pairs), no significant difference in LCSS was observed between SLR and lobectomy, either overall (p = 0.21) or when stratified by PL1 (p = 0.11) or PL2 (p = 0.94) status. Multivariate Cox analysis in the matched cohort confirmed no significant association between surgery type and LCSS (adjusted HR 0.75, 95% CI 0.52–1.08, p = 0.124), but older age (>75 years), PL2 VPI, and lymphovascular invasion were independent predictors of worse LCSS (all p < 0.001). Conclusions: This large population-based study, after rigorous adjustment for confounders, found that SLR and lobectomy provided comparable LCSS. SLR may be an alternative for selected patients, but prospective validation is recommended. Full article

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor. Doxorubicin (DOX) is extensively used in OS chemotherapy, yet improving patient outcomes remains challenging. This study investigated the effect of free DOX combined with inductive moderate hyperthermia (IMH) on Saos-2 human OS cells. Methods: Cell viability was assessed by trypan blue exclusion. Flow cytometry analyzed apoptosis, necrosis, and reactive oxygen species (ROS) in cells exposed to control (no treatment), IMH (42 MHz frequency, 500 μT magnetic field induction, 564 V/m electric field strength, 15 W output power, and 30 min duration) alone, DOX (0.06 μg/mL) alone, or DOX combined with IMH. The expression of p14^ARF tumor suppressor and epidermal growth factor receptor (EGFR) was evaluated by immunocytochemistry. Spatial autocorrelation analysis quantified the heterogeneity of p14^ARF and EGFR distributions in acquired images. Results: The half maximal inhibitory concentration (IC₅₀) of DOX in Saos-2 cells had minimal variation between 48 h (0.060 ± 0.01 μg/mL) and 72 h (0.055 ± 0.003 μg/mL). DOX + IMH resulted in a 15% increase in early apoptosis and a 20% elevation in ROS levels compared with DOX alone. Immunocytochemical analysis revealed a 37% increase in p14^ARF and a 32% reduction in EGFR expression following combined treatment in comparison to DOX alone. Image analysis showed that DOX + IMH treatment caused the highest Moran’s index values for p14^ARF and EGFR, reflecting less heterogeneous spatial distributions (p < 0.05). Conclusions: IMH enhanced DOX-induced cytotoxicity in Saos-2 cells by initiating ROS-mediated apoptosis and reducing heterogeneity of cellular responses. Full article