Sorafenib is a widely-adopted kinase inhibitor in anticancer therapy for advanced hepatocellular carcinoma (HCC) and the individualized pharmacological resistance to sorafenib is still an unresolved issue. Whether histone H3K9 methyltransferase SETDB1, which represses chromatin states and promotes various oncogenesis, modulate this process is still elusive. The analysis from both TCGA-LIHC cohort and our clinical HCC patient samples revealed that hepatic SETDB1 expression positively correlates with the prognosis of HCC patients receiving sorafenib therapy. Meanwhile, SETDB1 silencing diminished the cytotoxic effects of sorafenib in hepatoma cells. Mechanistically, SETDB1 knockdown led to mitochondrial dysfunction, including reduced mitochondrial membrane potential, mitochondria superoxide (mSOX), mitochondrial DNA (mtDNA) content, increased fission and DRP1S616 phosphorylation (pDRP1S616) in HepG2 cells. Not only did mSOX fluctuation modulate the sensitivity to sorafenib, but DRP1 activity-silenced counterpart pDRP1S616A inactivation also elevated the susceptibility to sorafenib and the corresponding mSOX and mtDNA content. Finally, pDRP1S616 IHC staining in clinical samples showed that hepatic pDRP1S616 level negatively correlates with the prognosis of HCC patients with sorafenib therapy as well. We first demonstrated that SETDB1 knockdown reduced the susceptibility to sorafenib through enhancing mitochondrial pDRP1S616 in hepatoma cells and hepatic SETDB1 expression might be a potential indicator for clinical HCC sorafenib therapy.

EGFR is critical for tumor angiogenesis and cancer progression, but existing treatments like erlotinib face limitations such as acquired resistance and side effects. To address these issues, this study employs structure-based drug design techniques including virtual screening, molecular docking, and molecular dynamics simulations to identify new small molecule inhibitors targeting the EGFR kinase domain. From an initial selection of 633,000 compounds from diverse databases, top candidates were identified based on their binding affinity and stability. The virtual screening and docking analyses revealed compounds with higher binding scores than erlotinib. Molecular dynamics simulations and Anisotropic Network Model (ANM) analysis uniquely report that EGFR undergoes significant conformational shifts: inward flap movements in the bound state stabilize a closed conformation, while outward movements in the free state result in a more open conformation. Among the identified inhibitors, compounds such as JFD00243, NPA015124, and others exhibited strong binding affinities and stable interactions with both active and inactive forms of EGFR. Notably, JFD00243 was effective in targeting EGFR in both active and inactive conformations. These findings suggest that the identified inhibitors could potentially overcome current treatment limitations and improve targeted cancer therapies by effectively inhibiting EGFR-mediated tumor angiogenesis.

Heat shock proteins (HSPs), particularly HSP70 and HSP90, are pivotal molecular chaperones implicated in cancer progression and resistance mechanisms. Dual inhibition of these chaperones represents a promising therapeutic approach. Here, we report the design and synthesis of a novel series of benzimidazole-carbazole hybrids aimed at targeting HSP70/90. Leveraging the kinase inhibitory properties of benzimidazole and the DNA interfering and apoptotic potential of carbazole, these hybrids were evaluated for their anticancer activity against breast (MCF-7) and colon (HCT-116) cancer cell lines. The most active compounds demonstrated submicromolar IC50 values and induced apoptosis through mitochondrial dysfunction and cytoskeletal disruption, confirmed via flow cytometry and fluorescence microscopy. Molecular docking revealed high binding affinities to HSP70 (PDB: 1S3X) and HSP90 (PDB: 1YC4), correlating with experimental outcomes. Furthermore, DNA interaction studies confirmed the compounds' ability to induce structural destabilization and fragmentation, providing insight into their mechanism of action. These findings highlight the potential of benzimidazole-carbazole hybrids as promising HSP inhibitors for overcoming cancer resistance.

PD-(L)1-based immune checkpoint inhibitor therapies have profoundly impacted the treatment of many solid malignancies. Although the addition of CTLA-4 checkpoint inhibitors can enhance anticancer activity, it also significantly increases the rate of immune-related adverse events. Therefore, there has been much interest in identifying additional immune checkpoints to improve the outcomes seen with PD-1-based therapy while minimizing additional side effects. One such target, lymphocyte-activation gene 3 (LAG-3), has long been recognized as an important inhibitor of T-cell function via modulation of the T-cell receptor pathway. Several drugs targeting LAG-3 have been developed, including most prominently the monoclonal antibody relatlimab. To date, the most significant demonstration of efficacy in targeting LAG-3 has been the use of relatlimab with the PD-1 inhibitor nivolumab in the treatment of advanced melanoma. The combination of nivolumab plus relatlimab is more efficacious compared to PD-1 inhibition alone, as has been previously seen with the combination of CTLA-4 inhibitor ipilimumab with nivolumab. However, nivolumab plus relatlimab offers a potentially more favorable toxicity profile. Here, the authors review the mechanism of the LAG-3 pathway and its rationale as a target for anticancer therapy as well as currently available data regarding the use of LAG-3 agents in treating melanoma and other solid tumors. Other investigational agents that target LAG-3 via novel mechanisms are also reviewed.

Artificial intelligence (AI) is a revolutionary tool yet to be fully integrated into several health care sectors, including medical imaging. AI can transform how medical imaging is conducted and interpreted, especially in cardio-oncology.

The aim of this study is to better characterize the clinical characteristics and outcomes of patients diagnosed with Immune checkpoint Inhibitor (ICI) pneumonitis and propose predictive models.

Drug repurposing may be an efficient strategy for identifying new cancer treatments. Tranexamic acid (TXA), an antifibrinolytic agent that affects the plasminogen-plasmin pathway, may have potential anticancer effects by influencing tumor cell proliferation, angiogenesis, inflammation, immune response, and tissue remodeling-all crucial processes contributing to tumor progression and metastasis.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. By releasing blocks (checkpoints) on the immune system, they elicit powerful antitumor effects. Despite improving survival, ICIs are associated with serious cardiac toxicities. Previous reports have focused on advanced cancer; cardiotoxicity data are therefore limited in the curative setting. We evaluated ICI cardiotoxicity in the non-metastatic setting, where long-term cardiac safety is a growing public health concern.

Platinum-based chemotherapeutics, particularly cisplatin, are crucial in the treatment of various malignancies due to their strong antitumor effects. However, a significant side effect of cisplatin is muscle atrophy, which severely impairs physical strength, diminishes quality of life and complicates cancer therapy. Cisplatin-induced muscle wasting arises from a complex interplay of enhanced proteolysis, reduced muscle protein synthesis and systemic inflammation. Understanding the underlying molecular mechanisms of muscle atrophy is vital for identifying new therapeutic targets. This review systematically explores molecular-based therapies and plant-derived natural compounds, providing a comprehensive overview of their efficacy in vivo and in vitro for preventing cisplatin-induced muscle atrophy. Both molecular-based therapies and plant-derived natural compounds present promising strategies for mitigating cisplatin-induced muscle atrophy. Ghrelin, growth hormone secretagogues and testosterone stimulate anabolic pathways and reduce muscle degradation, whereas natural compounds like capsaicin and naringenin exert protective effects by reducing inflammation and oxidative stress. A better understanding of the pathophysiology of muscle atrophy, combined with optimized therapeutic applications, may facilitate the clinical translation of these interventions to improve outcomes for cancer patients undergoing chemotherapy.

Immunotherapy using immune checkpoint inhibitors (ICIs) represents a promising therapeutic approach for canine cancer patients. Similar to human cancer patients, the concurrent use of corticosteroids may attenuate the efficacy of immune checkpoint inhibitors in dogs. In this study, we evaluated the impact of corticosteroid therapy on canine peripheral blood mononuclear cell (cPBMC) composition and the in vitro response to Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) axis blockade and recombinant human Interleukin-12 (rhIL-12) stimulation.

To investigate the efficacy of PD-L1 blockade in restoring humoral immune response against HBV.

Immune checkpoint inhibitors (ICIs) have become a standard treatment for various cancers, but their use is often associated with immune-related adverse events (irAEs), including cutaneous irAEs (cirAEs). Here, we report a rare case of subacute cutaneous lupus erythematosus (SCLE) induced by sintilimab, a PD-1 inhibitor, in a 30-year-old woman undergoing neoadjuvant chemo-immunotherapy for gastric cancer. The patient presented with erythema, macules, papules, and vesicles, with positive ANA (108U/mL) and strongly positive anti-SSA/Ro. After discontinuation of sintilimab and treatment with corticosteroids, hydroxychloroquine, and intravenous immunoglobulin (IVIG), her symptoms improved. This case represents the first reported instance of drug-induced lupus caused by sintilimab and emphasizes the importance of distinguishing between paraneoplastic lupus and ICI-induced lupus.

Over the past few years, immune checkpoint inhibitors resulted in magnificent and durable successes in treating cancer; however, only a minority of patients respond favorably to the treatment due to a broad-spectrum of tumor-intrinsic and tumor-extrinsic factors. With the recent insights gained into the mechanisms of resistance, combination treatment strategies to overcome the resistance and enhance the therapeutic potential of immune checkpoint inhibitors are emerging and showing promising results in both pre-clinical and clinical settings. This has been derived through multiple interconnected mechanisms such as enhancing tumor immunogenicity, improving neoantigen processing and presentation in addition to augmenting T cell infiltration and cytotoxic potentials. In the clinical settings, several avenues of combination treatments involving immune checkpoint inhibitors were associated with considerable improvement in the therapeutic outcome in terms of patient's survival and tumor growth control. This, in turn, increased the spectrum of cancer patients benefiting from the unprecedented and durable effects of immune checkpoint inhibitors leading to their adoption as a first-line treatment for certain cancers. Moreover, the significance of precision medicine in cancer immunotherapy and the unmet demand to develop more personalized predictive biomarkers and treatment strategies are also highlighted in this review.

Leptomeningeal metastasis (LM) is a fatal complication of malignant tumors with limited treatment options. Finding more effective therapeutic strategies is of significant importance. This case reports an LM patient from breast cancer treated with intrathecal pemetrexed (15 mg) combined with PD-1 inhibitors (40 mg). The pemetrexed dosing regimen included an induction phase (twice weekly for 2 weeks), a consolidation phase (once weekly for 4 weeks), and a maintenance phase (once monthly). The PD-1 inhibitor dosing regimen included an induction phase (once every 2 weeks for 6 weeks) and a maintenance phase (once monthly). The patient showed good tolerance, with no severe adverse events observed, and achieved favorable therapeutic outcomes, including complete resolution of neurological symptoms, negative conversion of cerebrospinal fluid cytology, and significant reduction of imaging-detected lesions. This case provides a new approach to the treatment of LM, suggesting that intrathecal immunotherapy combined with intrathecal chemotherapy may be a safe and effective treatment option, offering valuable insights for future clinical applications.

A new series of N-decyl-N'-benzylbenzimidazolium N-heterocyclic carbene (NHC) precursors and their mononuclear silver(I)-NHC complexes were synthesised and characterised. The benzyl group was functionalised with various para substituents (H, CH3, F, Cl, Br, CN, NO2). The effect of these substituents on cytotoxicity and cell line selectivity against human cervical cancer (HeLa), oestrogen-positive human breast cancer (MCF-7), and normal skin fibroblasts (Hs-27) was investigated. All compounds exhibited significant growth inhibition against the tested cell lines. The activity and selectivity of the compounds were influenced by the para substituents and the type of cell line. The electron-donating methylated NHC precursor and its silver complex generally demonstrated higher growth inhibition potentials than the analogues with electron-withdrawing groups, except in two cases where the fluorinated compounds were more potent against Hs-27 and HeLa, while the chlorinated NHC precursor was more active against MCF-7. Notably, all compounds, particularly the silver(I)-NHC complexes, were more active towards MCF-7 but less toxic towards Hs-27. The methyl-, bromo-, and cyano-containing silver(I)-NHC complexes broadened the safety windows against MCF-7 (selectivity indices ≥ 3). The most selective (against MCF-7) chlorinated NHC precursor and its silver(I)-NHC exhibited ROS-mediated proapoptotic activity, which indicated that these compounds promoted cell death by inducing intracellular ROS formation and accumulation. Our findings highlight the potential use of silver(I)-NHC complexes in the design and development of safe and selective anticancer agents.

Systemic chemotherapy is a common method for treatment of metastatic lymph nodes (LNs), but it has low tissue selectivity and high toxicity. Lymphatic drug delivery system (LDDS) is a novel approach to treat and prevent LN metastases. In a previous study, it was found that the increase of osmotic pressure with varied viscosity of the drug reagent enhances drug retention in the LNs. Here, we optimized the administration conditions to achieve a long-term therapeutic response by varying the dosages and injection rate, using the optimized osmotic pressure and varied viscosity of drug reagent for LDDS. A metastatic LN mouse model was created with MXH10/Mo/lpr mice. Luciferase labelled FM3A mouse mammary carcinoma cells were inoculated in subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). 4 days post tumor cell inoculation, carboplatin (CBDCA) was injected into the tumor-bearing SiLN under different administration conditions. Superior drug retention was observed in the group that received two-doses of CBDCA solution adjusted to an osmotic pressure and viscosity of 1897 kPa and 12 mPa·s, at an injection rate of 10 µL/min. Furthermore, this effect persisted for 42 days. This effect was accompanied by an upregulated expression of CD8, IL-12a, and IFN-γ in the spleen. These results suggest that dual-dose administration at 10 µL/min with hyper-osmotic and high viscosity formulation is optimal and can improve the long-term therapeutic efficacy of LN metastasis.

This work presents a multifaceted mechanism of the anticancer action of a 2-styrylquinazoline derivative. Extensive analysis of various aspects related to tyrosine kinase inhibition and effects on cellular targets at both the gene and protein levels revealed the potential of this IS20 compound for future research. This study presents a detailed analysis of the relationship between ABL and SRC kinase affecting the inhibition of the EGFR/mTOR signaling pathway in a non-obvious manner. The study was supported by experiments using various molecular biology techniques to confirm the induction of oxidative stress, inhibition of the cell cycle in the G2/M phase and the triggering of cell death via both the apoptosis and autophagy pathways. The cell models included those with different p53 protein status, which affected the cellular response in the form of altered Ndrg1 expression. Finally, the appropriate physicochemical properties of IS20 for adequate bioavailability and toxicity to the body were observed in an in vivo model.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults, characterized by the accumulation of dysfunctional lymphocytes. Ibrutinib, a first-generation Bruton tyrosine kinase (BTK) inhibitor, has significantly improved CLL treatment but is associated with adverse cardiovascular events such as atrial fibrillation (AF) and hypertension (HTN). Second-generation BTK inhibitors (BTKi) such as acalabrutinib were developed to have greater selectivity for BTK to reduce off-target effects and improve safety. Comparative real-world data between ibrutinib and second-generation BTKi are limited. This study analyzed data from the TriNetX Global Collaborative Network to compare cardiovascular outcomes in CLL patients who received ibrutinib or acalabrutinib. The two groups were well-balanced using propensity score matching. The outcomes examined included new-onset AF, HTN, reported heart failure, ventricular arrhythmias, bleeding, and all-cause mortality. The incidence of AF/flutter was lower for acalabrutinib compared to ibrutinib [5.8% vs. 11.7%; HR 0.59 (95% CI 0.43-0.83); p = 0.002]. The incidence of HTN was also lower in the acalabrutinib cohort [15% vs. 26.3%; HR 0.65 (95% CI 0.53-0.81); p < 0.05]. The incidence of heart failure, ventricular arrhythmia, bleeding events, or all-cause mortality did not differ after 3 years of treatment with acalabrutinib or ibrutinib, respectively. Our findings indicate that acalabrutinib has a more favorable cardiovascular toxicity profile compared to ibrutinib; therefore, validating the ELEVATE-RR trial in a real-world setting.

The phyto-synthesis of ternary CuO/ Mn3O4/ZnO nanocomposite was achieved by the utilization of an eco-friendly, straightforward approach that involved the extract of Nigella sativa seeds. Our ternary nanocomposite appears to include equal amounts of CuO, Mn3O4, and ZnO based on the atomic percentages. The results indicate that a robust and thermally stable CuO/Mn3O4/ZnO nanocomposite was developed in stable nanosuspensions. The CuO/Mn3O4/ZnO nanocomposites showed antimicrobial capabilities against multidrug-resistant human pathogens. The highest biofilm reduction in viable planktonic populations of all human pathogens investigated was significantly reduced by the CuO/Mn3O4/ZnO ternary nanocomposites with a value of 18.5 µg/mL. The unique, enhanced, and triple-combined properties enabled the nanocomposite to have strong antimicrobial ability. The CuO/Mn3O4/ZnO nanocomposite exhibited strong anticancer activity against A549, MDA, HCT-116, and HepG2 cells, with selectivity index values ​​ranging from 24.72 to 41.96. The CuO/Mn3O4/ZnO nanocomposite appeared to induce selective dose-dependent nuclear condensation and cell shrinkage in the treated cancer cells, significantly inducing the apoptosis mechanism to combat cancer progression. The phytosynthetic CuO/Mn3O4/ZnO nanocomposite appears to induce selective dose-dependent nuclear condensation and cell shrinkage in treated cancer cells, significantly triggering apoptotic mechanisms to combat cancer progression. This apoptotic pathway was confirmed by the strong affinity of CuO/Mn3O4/ZnO nanocomposites for ErbBs and VEGF with potent antioxidant activity to scavenge ABTS and DPPH radicals at EC50 values ​​of 236.6 µg/mL and 134.8 µg/mL, respectively.

Datura metel, a common plant in the Solanaceae family, is known for its valuable medicinal properties. The metabolites created by its rhizosphere bacterium, Sphingomonas sanguinis DM, have garnered interest for their potential biological effects. This study will discuss the steps involved in fermenting and processing a bacterial strain to extract potent secondary metabolites. The ethyl acetate extract of the propagated strain was subjected to fractionation and purification through various chromatographic techniques. The purified compound was characterized through multiple spectroscopic methods for structure elucidation, including UV, MS, 1D, and 2D-NMR. Its cytotoxic activity was assessed on malignant skin cells (A-431) using the MTT test compared with normal melanocytes (HFB 4). Furthermore, A-431 cells were double-stained with PI and annexin V-FITC and analyzed by flow cytometry to detect Apoptosis. Molecular investigations include PCR screening to detect genes related to the biosynthesis of bioactive metabolites, such as NRPS and lipopeptide ItuD genes. A prospective effective strategy to overcome tumor plasticity in melanoma is to target the Wnt signaling pathways. Molecular docking studies were conducted in the different proteins (Fz4-CRD, LRP6, GSK3β) of the Wnt signaling pathway and Protein Kinase B/Akt for the isolated compound to investigate the possible pathway to inhibit melanoma. Sphingomonas sanguinis DM produced bis (2-methylheptyl) benzene-1,4-dicarboxylate isolated for the first time from a natural source. It was cytotoxic against the A-431 human skin carcinoma cell line (IC50 = 191.61 µg/mL) but less effective against HFB 4 human normal melanocytes (IC50 = 416.23 µg/mL; selectivity index = 2.17). The A-431 cells showed a significant increase in early Apoptosis and a moderate rise in late Apoptosis. PCR amplification confirmed genes encoding A domain and Iturin A. Bacterial sequences are available in NCBI GenBank with accession codes OR597597 and OR597598. Consequently, Sphingomonas sanguinis DM synthesized a cytotoxic natural terephthalate diester derivative, along with the host specificity of the strain.