Targeting the vascular endothelial growth factor (VEGF) pathway is crucial for antiangiogenesis therapy in treating cancers and diseases with abnormal blood vessel growth. Human umbilical vein endothelial cells (HUVECs) activated by VEGF are widely used for exploring the impact of antiangiogenic agents on cellular functions. In this study, seven quinolinone derivatives were successfully synthesized and structurally confirmed through 1H, 13C NMR, and HRMS spectra. Compounds 4 and 5 exhibited significant inhibition of VEGF-induced HUVEC proliferation, with IC50 values of 84.8 and 58.1 μM for 48 h. Compounds 3‒6 effectively suppressed VEGF-induced HUVEC migration and invasion, demonstrating potent inhibitory effects in the Matrigel tube formation assay. Compounds 4 and 5 directly bind to vascular endothelial growth factor receptor 2 (VEGFR2), thereby inhibiting VEGFR2-mediated downstream angiogenic signaling pathways (PI3K/Akt, ERK1/2/p38 MAPK, and FAK). Cell-cycle analysis revealed that compounds 4 and 5 induced substantial G2/M phase arrest in HUVECs, accompanied by increased p53 phosphorylation and upregulation of p21cip1 expression. Compounds 3‒6 also induced apoptosis in HUVECs, as evidenced by nuclear condensation, DNA laddering, and increased Annexin V/PI staining. Western blot analysis showed that compounds 4 and 5 significantly increased the levels of apoptosis-related proteins, particularly cleaved caspase-3 and PARP. Through in vivo experiments utilizing the chicken embryo chorioallantoic membrane (CAM) assay, a marked decline in newly formed microvessels was observed posttreatment with both compounds. These results suggest that compounds 4 and 5 show promise as antiangiogenic agents, warranting further investigation into their therapeutic efficacy in conditions characterized by abnormal angiogenesis.

A series of thiadiazole-based derivatives were synthesized and evaluated for their potential as VEGFR-2 inhibitors and anticancer agents. Among them, compound 7b demonstrated significant cytotoxic activity against MCF-7 breast cancer cells, with an IC50 value of 6.13 µM, surpassing that of the reference drug sorafenib (IC50: 7.26 µM). Compound 7b also exhibited potent VEGFR-2 inhibition with an IC50 of 40.65 nM, outperforming sorafenib (IC50: 53.32 nM). Further investigation into the mechanism of action revealed that compound 7b induced significant changes in the cell-cycle distribution of MCF-7 cells, causing G1 arrest and delaying progression through the G2/M phase. Apoptosis analysis demonstrated that compound 7b primarily induced late apoptosis (55.90%) and necrosis (21.81%), with only 22.26% of cells remaining viable. Treatment with 7b increased the expression of the proapoptotic gene BAX (4.19 ± 0.34-fold) and suppressed the expression of the antiapoptotic gene Bcl-2 (0.38 ± 0.02-fold), resulting in a dramatic increase in the BAX/Bcl-2 ratio (11.03 ± 1.66-fold). Additionally, caspase-8 and caspase-9 levels were elevated by 2.99 ± 0.22-fold and 4.13 ± 0.11-fold, respectively, confirming activation of both intrinsic and extrinsic apoptotic pathways. In conclusion, compound 7b is a potent VEGFR-2 inhibitor with promising anticancer activity, demonstrating cytotoxicity, inhibition of cell migration, and induction of apoptosis in MCF-7 cells. These results suggest that compound 7b has the potential to be developed as a therapeutic agent for breast cancer treatment, warranting further in vivo and mechanistic studies.

With the increasing use of programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) inhibitors in cancer treatment, hyponatremia has emerged as a notable adverse event associated with this class of drugs.

Multi-drug resistance (MDR) in cancer significantly hinders effective treatment, leading to poor patient outcomes. The study investigates the potential of natural compounds, Alisol B 23-acetate (B23) and Alisol A 24-acetate (A24), to reverse MDR through various mechanisms on cancer cell membranes.

Lung cancer (LC) is one of the leading causes of cancer-related mortality globally, and despite numerous available treatment modalities, the 5-year survival rate for LC patients remains approximately 20%. A large proportion of LC patients are diagnosed at advanced stages, and conventional treatments frequently exhibit poor efficacy and are often associated with numerous side effects. Therefore, there is an urgent need for innovative therapeutic strategies to meet the needs of LC patients. Recent advances in nanotechnology have opened new avenues for the diagnosis and treatment of LC, particularly through the use of nanoparticles (NPs) as a drug delivery system, which offer enhanced therapeutic potential. Due to their unique physicochemical properties, NPs are widely employed in LC drug delivery systems. They can efficiently load pharmaceuticals and specifically target cancer cells to enhance diagnostics and treatment. Additionally, NPs can encapsulate multiple therapeutic agents, including targeted molecules and photosensitive reagents. Despite the substantial promise of nanotechnology in LC treatment, several challenges remain in its clinical application. This review represents a comprehensive overview of LC, encompassing risk factors, types, stages, mechanisms, and traditional treatment strategies. Furthermore, we thoroughly emphasized the current nanotechnology-based diagnostics and therapies for LC. In summary, the ongoing advancement of drug delivery systems highlights the potential of nanotechnology to enhance traditional LC treatments and facilitate the development of new therapeutic strategies. Future research will focus on optimizing the unique properties of various NPs to enhance treatment outcomes and offer personalized therapeutic strategies, ultimately improving the prognosis and quality of life for LC patients.

Aggressive natural killer cell leukaemia (ANKL) is a rare form of NK cell lymphoma with a very low incidence and poor prognosis. While multi-agent chemotherapy including L-asparaginase has been used to treat ANKL patients, they often cannot receive adequate chemotherapy at diagnosis due to liver dysfunction. PPMX-T003, a fully human monoclonal antibody targeting the transferrin receptor 1, shows promise in treating ANKL by helping patients recover from fulminant clinical conditions, potentially enabling a transition to chemotherapy. This study aimed to evaluate the tolerability, safety, efficacy, and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with ANKL.

SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.

Background Low-dose radiotherapy (RT) is a promising treatment likely to increase the efficacy of immunotherapy, including programmed cell death ligand 1 (PD-L1) blockade, in cancer therapy. Further exploration and optimization of such combinatorial strategies are required. Notably, the ability of low-dose RT to enhance the efficacy of immune-checkpoint inhibitors (ICI) in distant, unirradiated tumors is debated. Methods We used a stepwise preclinical approach in immunocompetent mice bearing different murine tumor models (MC38 or CT26), with one or two tumors per mouse. Mice received tumor-only irradiation consisting of either low-dose RT (2x0.5 Gy to 2x2 Gy) or high-dose RT (2x6 Gy to 2x8 Gy) combined with anti-PD-L1. Tumor growth rate and survival were compared across the different conditions. The immune microenvironments of both irradiated and distant unirradiated tumors were characterized using single-cell RNA sequencing. Results We first demonstrated that low-dose RT 2×2 Gy combined with anti-PD-L1 is as effective as high-dose RT 2×6 Gy in delaying the growth of irradiated tumors. Subsequently, we showed that low-dose RT to one tumor enhances the efficacy of anti-PD-L1 consolidation therapy in a distant, unirradiated tumor, thereby inducing an abscopal effect comparable to that observed with high-dose RT. Single-cell RNA sequencing analysis highlighted the polarization of tumor-associated macrophages (TAMs) within distant unirradiated tumors towards a pro-inflammatory phenotype following low-dose RT and anti-PD-L1. Depleting TAMs in distant unirradiated tumors using liposomal clodronate abrogated the abscopal effect driven by low-dose RT combined with anti-PD-L1. Conclusion Our findings demonstrate the ability of low-dose RT to increase the efficacy of ICI in a distant tumor, resulting in a significant abscopal effect, and highlight the critical role of TAMs in the underlying mechanism, as well as a potential immune crosstalk between TAMs and activated lymphoid cells. These data propose low-dose RT as a potential strategy to improve the efficacy of immunotherapy in patients with metastatic solid tumors receiving anti-PD-L1.

Rituximab is frequently used to treat B-cell lymphomas. The major adverse effect of rituximab is infusion-related reaction (IRR). The standard of care for IRR is not well established. We explored the incidence, risk factors, and impact on outcome of IRR in our institution. In total, 254 patients with B-cell lymphomas diagnosed from January 2016 to March 2018 were retrospectively reviewed. The median age was 61 (range 18-91). Diffuse large B-cell lymphoma (DLBCL) (71.3%) was the most common subtype of lymphomas. IRR occurred in 55 patients (21.7%). Incidence of IRR was significantly higher for follicular lymphoma (46.4%) than DLBCL (18.8%). Fifty patients (19.7%) experienced IRR at the first treatment cycle. Six of them had another IRR in subsequent treatment. Five patients had IRR ≥ grade 3. Two patients did not complete the treatment courses due to IRR. Rituximab-associated IRR is manageable by a slower infusion rate and administration of steroids and antihistamines. Patients experiencing IRR should not be excluded from subsequent rituximab treatment. Incidence of IRR is higher in follicular lymphoma than DLBCL. IRR is not predicted by any risk factors and do not affect the clinical outcome of patients with B-cell lymphomas.

Ovarian cancer (OV) is the most prevalent and lethal gynecologic malignancy globally. Cisplatin remains the first-line chemotherapeutic regimen for OV; however, chemotherapy resistance poses a persistent clinical challenge in gynecologic oncology. Parthenolide, a naturally derived phytochemical, exhibits broad-spectrum antitumor activity. Recent studies suggest that parthenolide may reverse cisplatin-resistance in OV when used in combination therapy. This study aims to elucidate the molecular targets and mechanisms underlying parthenolide-mediated reversal of cisplatin-resistance by integrating network pharmacology and molecular docking approaches.

Cancer represents a form of unregulated cellular proliferation, persisting as a significant challenge to global health. Despite the progress made in therapeutic interventions, challenges such as inadequate drug selectivity, systemic toxicity, and the development of drug resistance continue to pose considerable obstacles. In response to these barriers, we prepared pH (Stimuli)-responsive gelatin (GA) nanocapsules (NCs) that encapsulate 5-fluorouracil (5-FU)-coated CuO-ZnO nanoparticles (NPs) to achieve a combined effect in anticancer activity. The CuO-ZnO nanoparticles have been chosen for their combined antitumor efficacy of CuO and ZnO NPs. CuO-ZnO NPs synthesized through an environmentally friendly approach utilizing Trichosanthes dioica fruit extract demonstrated a size of 35.79 ± 6.04 nm. The drug-coated NPs were encapsulated within a gelatin matrix, which was stabilized with poloxamer 188 (Po) through modified emulsion techniques. Various characterizations were conducted using FTIR, XRD, TEM, and XPS, yielding valuable insights into the structural integrity and morphology of CuO-ZnO NPs and NCs. The NCs' average size was found to be 331.4 ± 38.7 nm with an average zeta potential of -15.6 ± 4.98 mV. Studies found drug release is sensitive to acidic pH 5.6, with a more rapid release than pH 7.4 (~25% 48 h), increasing tumor delivery selectivity. The assessment of cytotoxicity (MTT assay) on HeLa cells revealed a markedly reduced IC50 (13.71 ± 2.6 µg/mL) for nanocapsules in comparison with CuO-ZnO NPs and 5-Fu, suggesting a combined interaction. The confirmation of the apoptosis feature was achieved via AO/EtBr staining. The results underscore the promise of PoGA-5Fu(CuO-ZnO) nanocapsules as a targeted approach to cancer therapy, demonstrating improved efficacy while minimizing systemic toxicity.

Coumarin is a natural benzopyrone compound known for its diverse pharmacological activities, including anticancer, anti-inflammatory, and antioxidant properties. But its derivatives' exploration in cancer, specially PI3K-AKT-mTOR pathways-based cancer activity not explored yet. This review aims to evaluate the anticancer potential of coumarin derivatives' by exploring their modulatory effects on the PI3K-AKT-mTOR signaling pathway across diverse cancer types. This review adopted a systematic literature approach, emphasizing studies across various cancer types and focusing on coumarin's mechanisms and therapeutic potential. Results reveal that coumarin derivatives suppress PI3K-AKT-mTOR pathway activity across cancers, such as liver, breast, and colorectal, with IC50 values ranging from 4 µM to > 200 µM in vitro and confirmed effects in vivo. The modulation of other pathways, including NF-κB and MAPK, underscores their multi-targeted anticancer action. Despite promising preclinical efficacy, challenges like low bioavailability, potential hepatotoxicity, and systemic toxicity persist. Structure-activity relationship (SAR) studies suggest that introducing specific functional groups can enhance selectivity, reduce toxicity, and improve therapeutic outcomes. The conclusion reinforces the potential of coumarin derivatives as novel anticancer agents, advocating for structural optimizations and clinical investigations to overcome pharmacokinetic barriers and maximize therapeutic benefits. This exploration offers a strategic perspective on utilizing coumarin-based molecules in advancing cancer therapeutics.

Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women and the most lethal gynaecological malignancy. The high mortality rate is primarily due to late diagnosis and the lack of targeted therapies. The gold standard treatment consists of debulking surgery followed by platinum/taxane-based chemotherapy, which is initially effective in approximately 75% of patients. However, most women experience relapse and develop chemoresistance. To date, no therapy has proven to be decisive, underscoring the need for research into second-line or alternative treatments to overcome chemoresistance and prevent relapses. Auranofin (AF) is a promising repositioned anticancer agent with a multifaceted mode of action both cancer cell type- and dose-dependent. The current study evaluated AF's cytotoxicity on multicellular tumour spheroids derived from three ovarian cancer cell lines (SKOV3, A2780, and A2780 cisplatin-resistant). Results demonstrated that AF inhibited spheroid formation and growth by inducing apoptosis. Furthermore, we showed that AF's mode of action involves the PI3K/Akt and NF-κB pathways, and we highlighted differences in drug responses between cisplatin-sensitive, resistant, and primary ovarian cancer cells. Finally, by examining the efficacy of AF and cisplatin in combination, we identified differential sensitivities among the cell lines and primary ovarian cancer cells.

A significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) are ineligible for immune checkpoint inhibitors (ICIs) because of low programmed cell death protein-ligand 1 (PD-L1) expression. The therapeutic potential of B7-H4 (VTCN1) was investigated using immunohistochemistry (IHC) and spatial transcriptomics (ST).

This study aims to investigate the potential of Salvianic acid A (SAA) to enhance the efficacy of anti-PD-1 immunotherapy in triple-negative breast cancer (TNBC), with a focus on elucidating the mechanisms.

Chromatin modifiers, owing to their enzymatic activities and frequent overexpression or hyperactivation in cancer, have emerged as promising therapeutic targets. Among these, the nuclear receptor-binding SET domain (NSD) family of proteins catalyzes lysine methylation-a key histone post-translational modification that is implicated in diverse biological processes, primarily through the regulation of transcription. Previous studies have demonstrated that NSD proteins are often overexpressed, mutated, or involved in chromosomal translocations in both hematologic malignancies and solid tumors, thereby regulating tumor initiation and progression. Motivated by these insights, a range of NSD-targeting agents, including targeted protein degraders such as proteolysis-targeting chimeras (PROTACs), have been developed and have exhibited notable anti-cancer activities. In this review, we provide an overview of the NSD family of protein, highlighting their roles in regulating anti-tumor immunity and their implications for immunotherapy response and resistance. We further assess the current landscape of NSD-targeted protein degrader-based therapeutics and their potential utility as anti-cancer agents.

The purpose of this study was to evaluate the relationship between retinal blood flow and oxygen saturation during intravitreal aflibercept treatment for central retinal vein occlusion (CRVO) using OxymapT1 and laser speckle flowgraphy (LSFG).

This study reports the design, synthesis, and antimicrobial evaluation of novel thiazole-based benzylidene thiazolidinones. Starting from 4-thiazolidinone intermediates (3a and 3b), benzylidene derivatives (5a-l, 7a,b) and bis-derivatives (9a,b) were synthesized via condensation with aromatic aldehydes. In vitro antimicrobial screening against Gram-positive and Gram-negative bacteria, yeast, and fungi showed several compounds-especially 5 f and 5 h-exhibited significant activity comparable to gentamicin and fluconazole. Molecular docking against the Staphylococcus aureus gyrase-DNA complex further supported the experimental results, revealing strong binding affinities for select compounds, particularly 9b. These findings suggest the synthesized thiazolidinones are promising candidates for developing new antimicrobial agents targeting resistant pathogens.

The use of activated neutrophils has emerged as a promising antineoplastic method in oncology. However, challenges, including a short lifespan, susceptibility to the tumor microenvironment, and protumorigenic risks, limit their clinical application. While artificial neutrophils have several limitations, few tumor-related studies have been conducted with constraining factors, including specific targeting inefficiency, immunogenicity and manufacturing challenges. Neutrophil elastase (ELANE), a key antitumor effector in activated neutrophils, is functionally mimicked by porcine pancreatic elastase (PPE), which exhibits selective cancer cytotoxicity. However, PPE triggers protective autophagy in hepatocellular carcinoma (HCC), limiting its therapeutic effectiveness. Methods: To overcome this resistance, we sensitized PPE by the autophagy inhibitor 3-methyladenine (3MA), which is codelivered via tumor-targeting liposomes. This system protects drugs and improves therapeutic efficacy both in vitro and in vivo. Results: 3MA enhanced iron-related ROS-mediated cell destruction induced by PPE while suppressing prosurvival autophagy. The autophagy inhibitor-sensitized artificially activated neutrophils (asAN-P/3) showed precise tumor targeting, excellent therapeutic efficacy, prolonged survival and favorable biocompatibility. Conclusions: We established a precise neutrophil-related tumor therapeutic method (asAN-P/3) and elucidated the mechanistic insights into PPE-mediated therapeutic limitations in HCC. Our study provides a substantial framework for the development of neutrophil-derived antitumor therapeutic strategies in oncology.

The tumor microenvironment (TME) is often characterized by distinctive features such as hypoxia, low pH, the overexpression of extracellular matrix-degrading enzymes, and increased redox reactions. These attributes create a specialized internal environment that promotes tumor cell survival and proliferation, thereby facilitating tumor development, metastasis, and the emergence of drug resistance. These challenging aspects pose significant hurdles to the efficacy of traditional cancer therapies. However, they also offer unique opportunities for the development of responsive nanomedicines that specifically target the TME to improve treatment outcomes for cancer patients when combined with photothermal therapy (PTT). This review provides an overview of the predominant features of the TME and delves into recent advancements in the field of nanomedicine, with a special focus on TME-responsive nanomedicines. Each type of TME-responsive nanomedicine is reviewed for its potential value in drug delivery in combination with PTT and chemotherapy, which may enable effective multimodal antitumor therapy. Finally, the review discusses the challenges and opportunities associated with the use of TME-responsive nanomaterials in PTT, highlighting the potential for these innovative strategies to overcome current therapeutic limitations and improve patient outcomes.