Search Results (42,073)

Background/Objectives: Histone deacetylase (HDAC) inhibitors have been shown to prime the response to immunotherapy (IMT) treatment by inducing immune activation and infiltration to target tumor cells. Many studies primarily focus on adaptive immune cells and their expression of pro-inflammatory markers, like somatostatin receptor 2 (SSTR2); however, macrophages are known to help mediate key tumor microenvironment changes. The goal of this study is to evaluate the effects of HDAC inhibitors and IMT on macrophages, their expression of SSTR2, and their impact on the treatment response in triple-negative breast cancer (TNBC). Methods: Cytotoxic effects of HDAC inhibitors on 4T1 mouse mammary carcinoma cells, including suberoylanilide hydroxamic acid (SAHA), were evaluated using flow cytometry. Bone marrow-derived macrophages (BMDMs) were stimulated to M1-like and M2-like phenotypes and treated with SAHA to explore the effects on SSTR2 expression in different macrophage phenotypes. 4T1-tumor-bearing BALB/c mice were used to evaluate the therapy response to four treatments: saline control, SAHA, anti-PD-1 + anti-CTLA-4 checkpoint blockade IMT, or a combination of SAHA + IMT. Additional cohorts of 4T1-tumor-bearing BALB/c mice and NOD SCID mice, which lack adaptive immune cells, were euthanized for early evaluation of tumor-associated macrophage (TAM) populations via flow cytometry and cytokine analysis. One-way independent ANOVAs and log-rank tests were used to compare group differences. Results: SAHA promotes SSTR2 expression on M1-like BMDMs in vitro. SAHA promotes M2-like TAMs in vivo and stimulates pro-inflammatory, anti-tumor cytokine production in combination with IMT. Conclusions: SAHA drives SSTR2 expression and anti-tumor innate immune responses with additive effects in combination with immunotherapy in preclinical TNBC. Full article

Background: ESKAPE constitutes a group of six nosocomial bacteria that can evade available antimicrobials due to their great potential to develop multi-drug resistance and biofilm-forming abilities. These pathogens often cause hospital-acquired infections and pose a serious threat to public health. The search for efficient innovative therapeutic strategies to fight ESKAPE bacteria have been intensively investigated topics. One promising approach to fight resistant pathogens and their biofilms is combination therapy, which allows the effectiveness against microorganisms to be increased while reducing the applied concentrations and risks of potential unwanted side effects. Objectives: The object of the study was to determine if there is an interaction of short lipopeptides ((C₁₀)₂-KKKK-NH₂, C₁₆-KK-NH₂) together with erythromycin and tetracycline against pathogens of the ESKAPE group (Acinetobacter baumannii, Enterobacter aerogenes, Enterococcus faecium Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus). Methods: The checkerboard assay was used to examine the activity of compounds applied in combinations against ESKAPE strains in planktonic cells and toward biofilms formed by Staphylococcus aures and Pseudomonas aeruginosa. Results: The lipopeptides demonstrated a great potential of their application as additives to conventional antimicrobials against Gram-negative bacteria, including microorganisms within biofilms. Full article

Antimicrobial peptides (AMPs) are natural bioactive peptides produced by all organisms—from plants to insects, microbes and animals—and constitute a first line of defense. As they exhibit a broad spectrum of activity (antibacterial, antiviral, antifungal, antiparasitic, anticancer), strong efforts are being made to integrate AMPs into clinical use. AMPs are also being investigated as anticancer agents to overcome the side effects and/or resistance associated with current chemotherapies. In this context, we identified the natural AMP chionodracine from a new biological source: an Antarctic fish. Starting from the fragmentation of a chionodracine mutant peptide, a rational modular design approach was applied to develop three very short peptides (Pep-A, Pep-B and Pep-C), which were further modified with an N-terminal myristic acid lipid tail. The anticancer activity of the three N-myristoylated short peptides (Myr-A, Myr-B and Myr-C) was explored against the human cervical cancer HeLa cell line. The rationale behind this study is based on the previously reported antifungal activity of these myr peptides and on their ability to interact selectively with biological membrane-mimicking synthetic phospholipids without being particularly hemolytic or cytotoxic towards normal cells. We first demonstrated that myr peptides had cytotoxic activity against HeLa cells (IC₅₀ from 32 to 47 μM) but spared healthy primary human fibroblasts, whereas the corresponding non-myr peptides failed to kill cancer cells. The peptide with no hemolytic activity and a low IC₅₀, labeled Myr-B, was selected for subsequent analyses. Lactate dehydrogenase (LDH) assay and scanning electron microscopy (SEM) analysis revealed membrane damage and predominantly necrotic cell death in HeLa cells exposed to IC₅₀ doses of the Myr-B peptide, compared with cells treated with Pep-B. To thoroughly investigate the molecular effects of Myr-B in HeLa cells, we employed high-resolution label-free shotgun quantitative proteomics coupled with bioinformatics. Our results showed that exposing HeLa cells to Myr-B led to the under-expression of proteins belonging to the “apoptosis- and splicing-associated protein complex”, potentially influencing the alternative splicing process and consequently leading to a possible susceptibility to programmed cell death. These findings indicate that modifying natural AMPs may be a promising strategy for developing selective anticancer drugs and pinpoint Myr-B as an interesting target for future studies. Full article

Adipogenesis is a critical factor in causing obesity, which is a global health problem associated with metabolic disorders, such as insulin resistance and cardiovascular diseases. Natural compounds with anti-adipogenic activity may represent potential approaches for modulating adipocyte function. However, despite increasing interest in natural products, the anti-adipogenic potential of acridone alkaloids, particularly prenylated derivatives, remains largely unexplored. This study examined the effects of N-methylatalaphylline (NMA), a prenylated acridone alkaloid, on adipocyte differentiation, lipid accumulation, and glucose uptake. NMA exhibited anti-adipogenesis, particularly toward preadipocytes, and significantly reduced lipid accumulation in murine 3T3-L1 and human PCS-210-010 adipocytes at nontoxic doses (1.5–6 µM). At 3–6 µM, NMA downregulated adipogenic regulators, including PPARγ, C/EBPα, and SREBP1, along with adipogenic effectors, such as FABP4, adiponectin, LPL, PLIN1, and FAS. Mechanistic studies indicated that NMA treatment was associated with reduced phosphorylation of AKT, ERK, and p38, accompanied by cell-cycle arrest and inhibition of mitotic clonal expansion. Meanwhile, activation of AMPK-ACC signaling, which may contribute to suppression of adipogenesis and reduced glucose uptake, was observed in differentiated 3T3-L1 cells after treatment with 6 µM NMA for 48 h. Additionally, molecular docking and molecular dynamics simulations suggested potential interaction between NMA and ERK1, supported by hydrogen bonding and hydrophobic contacts. Overall, these findings suggest that NMA exerts anti-adipogenic effects in vitro by modulating adipocyte proliferation, differentiation, and lipid metabolism. These findings highlight NMA as a promising acridone alkaloid scaffold for anti-adiposity applications, warranting further in vivo validation. Full article

Background: Microfibrillar-associated protein 2 (MFAP2) is implicated in various malignancies, yet its specific role and molecular mechanisms in glioblastoma (GBM) progression remain poorly understood. Methods: We analyzed MFAP2 expression in human clinical specimens and murine models. Functional impacts were assessed in U251 cells via gain- and loss-of-function assays. Mechanistic studies explored the interplay between autophagic flux and Wnt/β-catenin signaling. An orthotopic GL261 syngeneic orthotopic model validated these findings in vivo. Results: MFAP2 was significantly overexpressed in GBM, correlating with poor patient prognosis. In vitro, MFAP2 markedly enhanced U251 viability, migration, and invasion while suppressing apoptosis. Mechanistically, MFAP2 triggered autophagic flux, subsequently activating the Wnt/β-catenin cascade and its downstream targets (MMP9, c-Myc, Cyclin D1). Pharmacological inhibition of either autophagy or Wnt signaling effectively abrogated these oncogenic phenotypes. In vivo, MFAP2 knockdown reduced tumor volume by 62.4% and suppressed the autophagy–Wnt axis. Conclusions: MFAP2 is an oncogenic regulator in glioblastoma models that links autophagy activity to Wnt/β-catenin signaling. Our findings support MFAP2 as a candidate prognostic biomarker and a potential therapeutic target; however, additional validation in larger molecularly annotated clinical cohorts and multiple GBM models is warranted. Full article

Background/Objectives: RNA interference (RNAi) is a promising strategy for mitigating diseases at the molecular level. However, RNAi is limited by its instability in biological fluids and impermeability to cellular membranes. In response, our lab has previously patented a non-ionizable lipid nanoparticle (LNP) platform (R8-PLP) for RNAi therapeutic delivery. This formulation incorporates 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) to improve particle stability and drug retention. However, long-anchored PEGylated lipids like DSPE-PEG may impair internalization and stimulate immune responses. The literature suggests substituting short-anchored PEGylated-lipids like 1,2-dimyristoyl-rac-glycero-3-[methoxy(polyethylene glycol)-2000] (DMG-PEG) to attenuate these effects. Here, we evaluated whether substituting DMG-PEG for DSPE-PEG in our R8-PLP would improve in vitro cellular delivery and gene transfection without compromising in vitro critical quality attributes (CQAs) or increasing cytotoxicity. Methods: CQAs [encapsulation efficiency (EE%), particle size (nm), homogeneity (polydispersity index; PDI), and membrane zeta-potential] were assessed at assembly and after storage for up to 28 days at 4 °C. Additionally, in-serum stability at 4 °C and serum release kinetics at 37 °C were assessed. Human aortic smooth muscle cells (HASMCs) were treated with R8-PLPs and analyzed for cellular uptake (fluorometry), cytotoxicity (LIVE/DEAD stain), and gene modulation (qPCR). Results: DMG-PEG incorporation at variable mol% did not alter R8-PLP size, homogeneity, or siRNA EE% at assembly or after long-term storage, but did accelerate siRNA release kinetic profiles compared to DSPE-PEG controls. DMG-PEG substitution enhanced cellular uptake compared to DSPE-PEG R8-PLPs without increasing cytotoxicity. DMG-PEG incorporation also achieved significant silencing versus non-treated controls but did not improve gene silencing compared to DSPE-PEG R8-PLPs. Conclusions: Thus, DMG-PEG substitution did not enhance R8-PLP in vitro gene modulation efficacy despite improving cellular uptake and maintaining CQAs. Full article

Decarbonizing heavy-duty road freight transportation requires efficient energy management in zero-emission powertrains. This study investigates energy management strategies (EMSs) for a heavy-duty Fuel Cell Plug-in Hybrid Electric Vehicle (FC-PHEV). Rather than the typical charge-sustaining operation, these strategies are designed for charge-depleting operation, in which each route begins with a charged battery and ends at a lower state of charge (SOC), leveraging the vehicle’s plug-in capability. The EMSs are evaluated primarily in terms of energy consumption, while battery C-rate and fuel cell ramp rate are used as simple stress indicators for comparative analysis. A backward-facing vehicle model is developed to test several EMSs, including both optimization- and rule-based strategies. The Equivalent Consumption Minimization Strategy (ECMS) emerged as a promising option, motivating further testing with a forward-facing model and additional drive cycles. The simulation results show that ECMS consumed only 1.1% more energy than the global optimal solution found by Pontryagin’s Minimum Principle (PMP) and 7.5% less energy than a simple rule-based strategy, on average across five drive cycles. These results show that ECMS can be effective for a heavy-duty FC-PHEV operating in charge-depleting mode, extending its demonstrated applicability beyond charge-sustaining and light-duty vehicles. Full article

Objectives: This study aimed to investigate the biological role and molecular mechanism of the RNA m⁵C methyltransferase NSUN4 in cervical cancer progression, with a focus on its involvement in ferroptosis regulation. Methods: Differential expression and survival analyses were performed using TCGA and GEPIA datasets. Functional enrichment and GSEA identified pathways associated with NSUN4 dysregulation. NSUN4 expression was validated in clinical tissues by qRT-PCR, Western blot, and immunohistochemistry. Gain- and loss-of-function assays, including CCK-8, colony formation, and Transwell assays, were conducted to assess cell proliferation and invasion. Furthermore, a nude mouse subcutaneous xenograft model was established to validate the oncogenic role of NSUN4 in vivo. Ferroptosis was evaluated using specific inhibitors and measurement of GSH and ferroptosis-related proteins. RIP, m⁵C-RIP, RNA stability, and dual-luciferase assays were performed to explore the underlying mechanism. Results: NSUN4 was markedly upregulated in cervical cancer tissues and correlated with poor prognosis. Functionally, NSUN4 enhanced tumor cell growth, migration, and invasion while inhibiting ferroptosis. Mechanistically, NSUN4 bound to and stabilized C-MYC mRNA via m⁵C methylation, activating the PI3K/Akt signaling pathway and promoting ferroptosis resistance. Conclusions: NSUN4 promotes cervical cancer progression by stabilizing C-MYC mRNA through m⁵C modification, leading to PI3K/Akt activation and suppression of ferroptosis. These findings identify NSUN4 as a novel oncogenic regulator and potential therapeutic target in cervical cancer. Full article

Background: Recent studies strongly suggest that low intracranial pressure (ICP) may be involved in the pathogenesis of glaucomatous optic neuropathy. As retinal ganglion cells (RGCs) are highly susceptible to mitochondrial dysfunction, mitochondrial injury may be associated with optic neuropathy related to reduced ICP. In this study, aquaporin-1 (AQP1)-null mice were used to investigate whether reduced ICP is associated with alterations in mitochondrial structure and the release of optic atrophy type 1 (OPA1) and cytochrome c from mitochondria. Methods: Intraocular pressure (IOP) and ICP were measured in AQP1-null mice, and mitochondrial structural changes were examined using transmission electron microscopy (TEM). Total OPA1 and cytochrome c protein levels were evaluated using immunocytochemistry and Western blotting. Cytosolic and mitochondrial fractions were extracted from retinal tissues, and the subcellular distribution of OPA1 and cytochrome c was further analyzed by Western blotting. Bax and Bcl-2 expression levels were also detected. Results: TEM revealed mitochondrial fission, matrix swelling, and abnormal cristae depletion in the retinas of 1-, 3-, and 6-month-old AQP1-null mice. Morphometric quantification further confirmed significantly reduced mitochondrial length across all age groups and increased mitochondrial width at 1 and 6 months in AQP1-null mice compared with wild-type controls. Decreased retinal OPA1 immunoreactivity and protein expression were observed across all age groups of AQP1-null mice compared with age-matched C57BL/6 control mice. Subcellular fractionation showed increased mitochondrial release of OPA1 (at 3 and 6 months) and cytochrome c (at 1, 3, and 6 months) in the retinas of AQP1-null mice. Altered Bax expression was also detected in the retinas of AQP1-null mice with reduced ICP at all examined ages. Conclusions: Mitochondrial ultrastructural abnormalities, including fission and cristae depletion, altered OPA1 distribution, increased mitochondrial release of OPA1 and cytochrome c, and upregulated Bax expression were observed in the retinas of AQP1-null mice with reduced ICP. These concurrent changes indicate a close association between reduced ICP and retinal mitochondrial dysfunction. Maintaining mitochondrial integrity may therefore serve as a potential protective strategy against optic nerve degeneration in patients with chronic low ICP. Full article

Background: Hepatic ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation (LTx) and hepatectomy. Previous studies identified a 12/15-lipoxygenase (12/15-LOX)-driven lipid peroxidation cascade promoting cell death, whereas glutathione peroxidase 4 (GPx4)-dependent metabolism acts antagonistically. This study investigated whether tacrolimus protects against hepatic IRI through this redox axis. Methods: Male C57BL/6 mice underwent 65% partial hepatic warm ischemia and reperfusion with or without tacrolimus preconditioning. Liver tissue and serum were analyzed by spectral photometry, Western blotting, TUNEL assay, and serum enzyme measurement. Results were statistically analyzed and compared with previously published results of 12/15-LOX inhibition by baicalein pretreatment and its carrier DMSO. Also, the combination of both tacrolimus and baicalein was investigated. Results: Tacrolimus increased the oxidative glutathione activity quotient (GSSG/GSH) by 75.1% (p = 0.0302), attenuated MAPK signaling, reduced SAPK/JNK by 84.6% (p = 0.0059), with ERK1/2 showing a downward trend, decreased Caspase-3 activation by 66.9% (p < 0.001) and PARP cleavage by 59.9% (p = 0.0330), and lowered TUNEL-positive cell death by 61.8% (p = 0.0015). Tacrolimus achieved hepatoprotection comparable to 12/15-LOX inhibition, but without hepatotoxicity, whereas combined treatment conferred no additional benefit yet bore toxic properties. Conclusions: Tacrolimus preconditioning mitigates hepatic IRI through a glutathione-linked redox–signaling–cell death axis and exerts cytoprotective effects beyond immunosuppression. Full article

Background: Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with distinct clinical and biological features compared to rarer entities such as primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECTCL). Although recurrent genomic alterations in CTCL have been described, comparative analyses at the pathway level across biologically divergent subtypes remain limited. Here, we leveraged a conversational artificial intelligence (AI) platform for precision oncology to enable rapid, integrative, and hypothesis-driven interrogation of publicly available genomic datasets. Methods: We conducted a secondary analysis of somatic mutation and clinical data from the Columbia University CTCL cohort accessed via cBioPortal. Cases were stratified into SS (n = 26) and PCAECTCL (n = 13). High-confidence coding variants were curated and mapped to biologically relevant signaling pathways and functional gene categories implicated in CTCL pathogenesis. Pathway-level mutation frequencies were compared using Fisher’s exact tests, with effect sizes quantified as odds ratios. Tumor mutational burden (TMB) was compared using the Wilcoxon rank-sum test. Subtype-specific co-mutation patterns were evaluated using pairwise association analyses and visualized through oncoplots and network heatmaps. A conversational AI agent, AI-HOPE, was used to iteratively refine cohort definitions, prioritize pathway-level signals, and contextualize findings. Results: TMB was comparable between SS and PCAECTCL (p = 0.96), indicating no significant difference in global mutational load. In contrast, pathway-centric analyses revealed marked qualitative differences. SS demonstrated enrichment of alterations in epigenetic regulators, tumor suppressor and cell-cycle control pathways, NFAT signaling, and DNA damage response mechanisms, consistent with transcriptional dysregulation and immune modulation. PCAECTCL exhibited relatively higher frequencies of alterations involving epigenetic regulators and MAPK pathway signaling, suggesting distinct oncogenic dependencies. Co-mutation analysis revealed a more constrained and focused interaction landscape in SS, whereas PCAECTCL displayed broader and more heterogeneous co-mutation networks, indicative of divergent evolutionary trajectories. Notably, ERBB2 mutations were significantly enriched between subtypes (p = 0.031), highlighting a potential subtype-specific therapeutic vulnerability. Conclusions: This study demonstrates that SS is distinguished from PCAECTCL not by increased mutational burden but by distinct pathway-level architectures, particularly involving epigenetic regulation, immune signaling, and transcriptional control. These findings generate biologically grounded, testable hypotheses for subtype-specific therapeutic targeting and underscore the value of conversational AI as a scalable framework for accelerating discovery in translational cancer genomics. Full article

Background: This study investigated how chronic heat stress affects meat quality and post-slaughter muscle acidification in slow-growing yellow-feathered broilers, focusing on the roles of ALDOB and HSP90B1 in glycometabolism. Methods: From 100 to 120 days of age, broilers were kept either under thermoneutral conditions (25 ± 1 °C, N group) or cyclic heat stress (32 ± 1 °C for 9 h/day, H group). Meat quality traits (pH, shear force, drip loss, color) were measured at 0, 24, and 48 h of refrigeration (4 °C). Free amino acid and fatty acid profiles were analyzed. DF-1 cells were exposed to 43 °C for functional assays of ALDOB and HSP90B1. Results: Chronic heat stress reduced body weight, altered flavor precursors, and induced PSE-like characteristics (lower pH, higher shear force, increased drip loss, paler color), especially in leg muscles. ALDOB and HSP90B1 were upregulated in both tissues and cells. ALDOB overexpression promoted glucose consumption, while HSP90B1 suppressed lactic acid production. Conclusions: Chronic heat stress impairs growth and flavor precursors and exacerbates post-slaughter muscle acidification (primarily driven by ATP hydrolysis, with lactic acid as a secondary contributor). ALDOB and HSP90B1 may dually regulate glycometabolism under heat stress. Full article

Perineural spread (PNS) from cutaneous squamous cell carcinoma (cSCC) to the skull base is increasingly recognised as a route of cancer spread. Management historically involved definitive radiotherapy to treat PNS at the skull base. In the endemic region with modern magnetic resonance neurogram (MRN) and skull base surgical expertise, the outcome has improved over the years. With the advent of immunotherapy, the outcome may be maintained while preserving critical organs in the head and neck region. We conducted a critical review of the literature to establish the treatment outcomes and pattern of failure as practice evolved. Furthermore, we described our skull base surgical and radiotherapy management guideline and outlined the emerging paradigm shift in the immunotherapy era. Full article

Background: Trichosporon japonicum is a rare but highly lethal pathogen causing fungemia in immunocompromised patients. With the expanding use of chimeric antigen receptor T (CAR-T) cell therapy, the spectrum of opportunistic fungal infections is changing, yet data on T. japonicum infections in this setting remain scarce. Case Presentation: A 69-year-old man with diffuse large B-cell lymphoma developed catheter-associated fungemia after CAR-T cell reinfusion. He initially presented with neck pain and white oral mucosal patches, followed by fever four days later. T. japonicum was isolated from both peripheral blood and central venous catheter tip cultures, identified by microscopic examination, mass spectrometry, and molecular sequencing. Antifungal prophylaxis was initiated before fever onset based on close monitoring of white blood cell count, procalcitonin, interleukin-6, and C-reactive protein; treatment was subsequently adjusted according to species identification and antifungal susceptibility results. Infection was controlled within two weeks after catheter removal and immune recovery. The patient remained well at six-month follow-up. Conclusion: This case adds to the limited literature on T. japonicum fungemia in patients receiving CAR-T therapy. Our experience, together with a review of the literature, underscores that successful management requires prompt catheter removal, immune restoration, and combination therapy with voriconazole and amphotericin B, as echinocandin monotherapy should be avoided. Awareness of this pathogen in immunocompromised patients is critical. Full article

The cornea of the dromedary camel is essential for maintaining ocular clarity and protecting the eye in dry, dusty, and thermally stressful environments. Aquaporins are membrane channels that facilitate water transport, and AQP1 has been widely implicated in corneal fluid homeostasis in several species. The present work investigated, for the first time, the regional distribution of AQP1 in the camel cornea. Corneas collected from twelve healthy adult camels after slaughter were divided into nine anatomical regions: central (C), middle dorsal (MD), middle ventral (MV), middle nasal (MN), middle temporal (MT), peripheral dorsal (PD), peripheral ventral (PV), peripheral nasal (PN), and peripheral temporal (PT). Histological examination and immunohistochemistry were combined with digital morphometry to assess corneal layer thickness and AQP1 localization. AQP1 labeling was identified in the corneal epithelium, stromal keratocytes, and endothelium. Epithelial staining differed among regions and was most pronounced in the peripheral nasal region, whereas stromal keratocytes and endothelial cells showed strong and relatively uniform immunoreactivity. These findings indicate that AQP1 is broadly expressed in the camel cornea and likely contributes to regional control of hydration and tissue maintenance in an arid-adapted species. Full article