Imiquimod (IQM), an imidazoquinoline derivative, is an immunomodulator that activates an adaptive immune response. IQM is applied topically for genital warts and actinic keratosis. Programmed cell death-1 (PD-1) suppresses activated T cells by binding to programmed cell death-ligand 1 and programmed cell death-ligand 2, braking antitumor immunity. Anti-PD-1 therapy has been used for various malignant neoplasms including renal cell carcinoma (RCC). Whether combination therapy with transcutaneous administration of IQM cream and intraperitoneal administration of anti-PD-1 monoclonal antibody (mAb) suppresses mouse RCC cells growing in subcutaneous tissue was investigated.

High-Grade Serous Ovarian Carcinoma (HGSOC) represents the most prevalent and lethal subtype of ovarian cancer, with approximately 225,000 new cases reported globally each year and a five-year survival rate of merely 49.1%. The clinical management of HGSOC encounters substantial challenges, primarily attributable to its intricate drug resistance mechanisms, which involve multiple biological processes, including tumor cell heterogeneity, microenvironment remodeling, gene mutations, and drug efflux. This study systematically reviews the most recent advancements in HGSOC drug resistance research, concentrating on the molecular biological foundations of resistance mechanisms, innovative detection strategies, and potential therapeutic approaches. The research indicates that HGSOC drug resistance constitutes a complex process characterized by multifactorial interactions, involving aberrant cell signaling pathways, dynamic alterations in the tumor microenvironment, and specific expressions of molecular markers. In this review, we systematically analyzed and investigated the intricate biological behaviors associated with HGSOC drug resistance, which not only enhances the understanding of disease progression but also provides essential theoretical foundations for the development of more precise and effective targeted therapies. This review firstly illustrated the detailed drug resistance cellular and molecular mechanisms underlying HGSOC chemotherapy, which can pave the way for future studies in HGSOC drug resistance practices.

Dedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center.

Motivated by the anti-leukemic synergy between histone deacetylase (HDAC) inhibitors and the FDA-approved BCL-2 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster the anti-leukemic efficacy of the clinical drug by grafting HDAC1-selective or HDAC6-selective inhibitor motifs onto a solvent-accessible domain of venetoclax. We discovered multiple polypharmacological agents that both retained the potent BCL-2 inhibitory activity of venetoclax and effectively inhibited either HDAC1 or HDAC6 with excellent (up to 80-fold) selectivities for the desired HDAC isoform. In addition, relative to parental venetoclax, two of our lead compounds, BD-4-213 and AMC-4-154, exhibited superior activities against the acute myeloid leukemia cell line MV4;11 and an MV4;11 cell line engineered to overexpress BCL-2. Annexin-V assay results confirmed an on-target mechanism of apoptosis for these novel chimeric molecules. Efforts to further boost the HDAC1 or HDAC6 binding affinities and/or selectivities proved unsuccessful due to synthetic chemistry challenges and solubility problems, which may underscore the difficulties of polypharmacology approaches involving a large inhibitor, such as venetoclax.

There is growing interest in the production and characterization of bacterial exopolysaccharides (EPS) because of their diverse range of applications. This study aimed to examine the production of EPS by Pseudomonas aeruginosa AG01, to characterize the produced EPS and its application as antioxidant, antimicrobial, antibiofilm, antitumor, and antiviral activity. The results indicated that the ideal conditions for achieving the highest production of EPS included an incubation period of 96 h, a pH level of 6, and a temperature of 32 °C in a nutrient broth medium. The most efficient sources of carbon and nitrogen for the formation of EPS were found to be galactose, glucose, yeast extract, and peptone. Several functional groups were confirmed to be present by Fourier transform infrared spectroscopy including amino groups, amides, carboxylic acids, hydroxyl groups, and phosphates. In the same respect, EPS has antioxidant activity. Moreover, EPS produced by Pseudomonas aeruginosa AG01 demonstrated antibacterial activity against various Gram-positive, Gram-negative bacteria, and yeast, besides antibiofilm activity about 98.93%, 98.86%, 98.63%, and 97.19% for Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli, respectively as well as anticancer activity against prostate cancer (PC3) and breast cancer (MCF7) cells with IC50 values of 156.41 and 156.41 µg/ml, respectively. Flow cytometry analysis revealed that MCF7 cells treated with EPS at a concentration of 500 µg/ml for 48 h showed a reduction in the percentage of cells in both the G0/G1 and S phases compared to the untreated control MCF7 cells. EPS resulted in apoptosis induction in MCF7 cells using the Annexin V-FITC PI staining method. The findings indicate that EPS demonstrates significant antiviral activity against both the herpes simplex virus (HSV-1) and the hepatitis A virus (HAV). In conclusion, EPS has great potential to be developed as a natural antioxidant or used in medicine and pharmaceuticals.

Bombyx mori silk is one of the most extensively studied types of silk due to its unique mechanical properties and biocompatibility, which have enabled its Utilization in medical applications Including surgical sutures since the second century. In the present study, a new method for the biosynthesis of silver nanoparticles (AgNPs) was explored by applying Bombyx mori cocoon extract as a sustainable and eco-friendly biological source. Unlike previous studies that primarily utilized plant or microbial extracts, this approach offers a more efficient alternative due to the unique protein and polyphenol content of silk cocoons, which enhances the stability and biological properties of the biosynthesized nanoparticles. The resulting AgNPs exhibited significant antibacterial, antioxidant, anti-inflammatory, and cytotoxic properties, opening new avenues for their therapeutic applications. This study expands the range of biological materials used in AgNP synthesis and provides deeper insight into how different bioactive components influence their functional properties. In this study, AgNPs were biosynthesized by mechanically processing extracted raw silk material with silver nitrate (AgNO₃). The synthesized nanoparticles were characterized by implementing several physicochemical techniques, including UV-visible spectrophotometry, FTIR, and XRD, and their morphology was examined through Transmission Electron Microscopy (TEM). The obtained AgNPs displayed a distinct absorption peak at 420 nm, with a particle size ranging between 5 and 25 nm, and displayed characteristic FTIR and XRD patterns typical of silver nanoparticles. The biosynthesized AgNPs demonstrated significant antimicrobial activity against Staphylococcus aureus (ATCC25923), Staphylococcus haemolyticus (ATCC29968), Escherichia coli (ATCC8739), and Klebsiella pneumoniae (ATCC2146). The antioxidant potential, assessed via the DPPH assay, yielded an IC50 value of 4.94 µg/ml, while the anti-inflammatory effect, evaluated using the membrane stabilization technique, showed an IC50 of 7.14 µg/ml. Additionally, AgNPs exhibited notable cytotoxic properties against Caco-2 and PANC1 cell lines, with IC50 values of 177.24 ± 2.01 µg/ml and 208.15 ± 2.79 µg/ml, respectively. Conversely, their impact on normal HFB-4 cells was minimal, with an IC50 of 582.33 ± 6.37 µg/ml, indicating a favorable safety profile. These observations highlight the multifunctional potential of silk-derived AgNPs, suggesting their applicability in various biomedical fields.

Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC); however, innate and acquired resistance is clinically seen in many patients. Hence, a combinatorial approach with novel therapeutic agents to overcome chemoresistance is a promising option for improving patient outcomes. We investigated the combinational anticancer efficacy of cisplatin and narciclasine in three-dimensional NSCLC tumor spheroids.

The remarkable biophysical properties of metastatic migrating cells, such as their exceptional motility and deformability, enable them to migrate through physical confinements created by neighboring cells or extracellular matrix. This study explores the adaptive responses of breast cancer (BC) cell sublines derived from the highly aggressive, metastatic triple-negative MDA-MB-231 and the non-metastatic MCF7 human BC cell lines, after undergoing three rounds of confined migration (CM) stress. Our findings demonstrate that CM elicits common and cell-type specific adaptive responses in BC cell sublines. In particular, both cell sublines exhibit a similar enhancement of clonogenicity and nanoparticle (NP) uptake activity, indicating tumorigenic potential. We have, for the first time, shown that stimulation with CM induces a hybrid epithelial-to-mesenchymal transition (EMT) phenotype of MDA-MB-231 cells. This transition is characterized by a significant rise in the expression of stage-specific embryonic antigen-4 (SSEA4), alongside a substantial decline in the population of CD133+ cells and a marked reduction in Ki67 expression in the MDA-MB-231-derived subline following Cis-Platin treatment. These changes are likely associated with heightened resistance of this subline to cisplatin. In contrast, CM induces far fewer such alterations in the MCF7-derived counterpart with a notable increase of CD133+ population, which seems to be insufficient to change cell susceptibility to cisplatin exposure. This study contributes to our understanding of the adaptive mechanisms underlying metastasis and drug resistance in breast cancer, emphasizing the need for personalized approaches in cancer treatment that consider the heterogeneous responses of different cancer subtypes to environmental stresses.

Hepatocellular carcinoma (HCC) is characterized by poor prognosis and remains a leading cause of cancer mortality worldwide. Advanced HCC is managed with several first-line therapies, including tyrosine kinase inhibitors (TKI) and immunotherapy (mAb-PD-1 and mAb-VEGF). However, the efficacy of HCC therapeutics is often short-lived. Recent studies have demonstrated that the activation of the Nrf2-Bcl-xL pathway contributes to poor prognosis in a subset of HCC patients. Here, we found that dimethyl fumarate (DMF), a drug used for treating psoriasis and multiple sclerosis, regulates the Nrf2-Bcl-xL signaling axis to inhibit HCC growth in a mice xenograft model. Mechanistically, the downregulation of the Nrf2-Bcl-xL axis led to mitochondria stress and apoptosis in vitro and in vivo. Enforced Nrf2 or Bcl-xL expression in HCC cells markedly reversed the antitumor effects of DMF in HCC cells. Importantly, DMF enhanced sorafenib's antitumor effects. Collectively, our results demonstrate new mechanism insights into the antitumor effects of DMF and that Nrf2-targeted therapy might improve HCC treatment outcomes.

In recent decades, despite advancements in conventional cancer therapies, their serious side effects on both healthy and tumor cells remain a major concern. Aiming to address indiscriminate drug distribution, unwanted toxicity, and high chemotherapy doses, this study explores the targeted delivery of zinc oxide nanoparticles (ZnO NPs). ZnO NPs were synthesized and coated with bovine serum albumin (BSA) and tetraethoxysilane (TEOS) to control cellular uptake and enhance anticancer activity. Characterized by UV-visible spectroscopy, DLS, FTIR, XRD, and TEM, ZnO, ZnOB, and ZnOT particles displayed sizes of 140 ± 13.6 nm, 342 ± 8.4 nm, and 145 ± 23.8 nm, respectively, with ZnOT showing a positive charge of + 19.3 ± 4.16 mV, enhancing stability and cellular interaction. Cytotoxicity assays revealed ZnO's potent anticancer effect in Caco-2 cells with an IC50 of 219 µg/ml, while ZnOB and ZnOT showed moderate toxicity (IC50 values of 308 µg/ml and 235 µg/ml). HepG2 cells maintained viability close to 100%, highlighting ZnO NPs' selectivity for Caco-2 cells. Flow cytometry and confocal microscopy indicated differential uptake, with ZnOB showing the highest uptake in Caco-2 cells after 24 h at 37 °C, increasing fluorescence intensity by over 80% compared to ZnO. ZnOT notably increased late apoptotic cells by 65% in Caco-2 lines and caused a 40% rise in G2/M phase arrest. Mitochondrial function assays showed that ZnO reduced mitochondrial membrane potential by over 30%, indicating stress induction. These results support the potential of ZnO-based nanoparticles in colorectal cancer treatment, offering selective cytotoxicity, enhanced cellular uptake, and clear apoptotic activity, making them a promising alternative to conventional chemotherapy.

This study evaluated the antibacterial and anticancer properties of S. mauritianum fruit components through LC-QTOF-MS/MS metabolomic profiling. The samples were extracted, and the antibacterial activity was conducted using a standard Resazurin microtiter assay. The minimum inhibitory concentrations (MICs) of the crude extracts were evaluated against reference pathogenic bacterial isolates. The anticancer activity of the extracts was tested against U-87 MG glioblastoma and A549 lung carcinoma cells (ATCC cancer cell lines). The real-time toxicity assay and comprehensive metabolomic profiling were evaluated for the crude extracts. Results revealed that the ripe fruit coat exhibited the richest chemical diversity, with 15 unique metabolites, while the unripe fruit had 5. Detailed classification of the identified metabolites showed that alkaloids accounted for 33.3%, followed by terpenoids (21.2%). The extracts of the fruit components had significant antibacterial activity against the referenced pathogens of public health importance. Extracts from the ripe fruit coat demonstrated significant cytotoxicity on U-87 MG glioblastoma cell viability, suggesting potential anticancer activity, while the effect on A549 lung carcinoma cells showed high viability across all treatments. The real-time cytotoxicity assays further highlighted the dose-dependent inhibition of glioblastoma cells by crude extracts from the ripe fruit coat, emphasizing its therapeutic potential.

The impact of concomitant medications on immune-related adverse events (irAEs) and immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC) remains unclear. Benzodiazepine receptor agonists (BZRAs), commonly prescribed for anxiety and insomnia in cancer care, may influence antitumor immunity via γ-aminobutyric acid (GABA) signaling. Here, we retrospectively analyzed medical records of NSCLC patients treated with ICIs.

The scarcity of human biopsies available for drug testing is a paramount challenge for developing therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective, and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories.

Breast cancer is a major cause of death in women, and various drug therapies are used for its treatment. However, current therapies have many side effects and limitations. Propolis, a resinous product of bee hives, possesses a variety of biological activities, including anticancer and chemo-protective properties. The present study aimed to investigate the potential suitability of propolis-derived compounds to inhibit matriptase (MT-SP1), a potential protein target for breast cancer treatment, through comprehensive computational analysis. The MT-SP1 protein structure (PDB ID: 1EAX) was retrieved, energy-minimized, and validated. Five propolis-derived compounds with the highest binding energies to MT-SP1 were selected after virtual screening. Molecular docking of these selected ligands revealed binding energies ranging from -8.4 to -9.1 kcal/mol. Stable complex formation was validated by an additional 250 ns of molecular dynamics simulations. The HOMO-LUMO and DFT characteristics provided further evidence of the chemical reactivity and stability of these five ligands at the MT-SP1 active site. Screening of compounds for drug-likeness, pharmacokinetics (ADMET profiles), and toxicity identified two promising small molecules (PubChem IDs of ligands 72307 and 129827386) as potential drug candidates for inhibiting MT-SP1. However, experimental validation through in vitro or in vivo studies is necessary to confirm these computational findings and explore their therapeutic potential for breast cancer treatment.

Trial no. NCT04821778 registered in ClinicalTrials.gov.

This study focuses on the development and optimization of S11a-0000168202, a novel LIMK1 inhibitor with potential therapeutic applications in gastric cancer. Through scaffold hopping and structural modification of HIT100844099, S11a-0000168202 demonstrated enhanced binding stability and stronger interactions with key LIMK1 residues, including GLU-414, ILE-416, and HIS-464. Molecular dynamics simulations and MMGBSA analyses confirmed the compound's stability, while ADMET evaluation revealed favorable properties such as moderate lipophilicity, good human intestinal absorption, and low P-glycoprotein inhibition. Despite the promising computational results, the lack of experimental validation remains a limitation. Future studies should focus on in vitro and in vivo testing to confirm S11a-0000168202's efficacy, pharmacokinetics, and safety. This compound holds significant potential as a therapeutic agent for LIMK1-targeted gastric cancer treatment.

A phase II study evaluated a corticosteroid-free regimen (olanzapine, netupitant, and palonosetron) for the treatment of chemotherapy-induced nausea and vomiting. The results showed control rates comparable to those of standard protocols, demonstrating its feasibility without dexamethasone. ■ Evaluation of a corticosteroid-free antiemetic regimen. ■ Primary endpoint: 46% nausea control. ■ Secondary endpoint: 68% emesis control. ■ Comparable to standard four-drug protocols.

Micronuclei serve as a biomarker of cancer cell due to genetic mutations and an indicator of deoxyribonucleic acid (DNA) damage. The aim of this study to examine the effect of hexadecanoic acid in Musa paradisiaca (MP) as anticancer by reducing the frequency of micronuclei and inducing apoptosis.. Twenty male rats were divided into five groups. Negative control was given aquades orally (K-) and positive control was induced with 0.5% DMBA (K+). In addition, the treatment groups were induced with 0.5% DMBA and given ethanol extract of MP (EEMP) at doses of 1 mg/kgBW/day (EEMP1), 2 mg/kgBW/day (EEMP2), and 4 mg/kgBW/day (EEMP3), respectively. DMBA was applied to the buccal mucosa for 14 weeks, followed by the administration of EEMP orally after nodules appeared for 10 days. MN examination was carried out using the papanicolaou method, while apoptosis was assessed using the TUNEL assay. Oral administration of EEMP at a dose of 4 mg/kg BW for 10 days in rats showed a lower frequency of MN compared to other groups with significant difference at p=0.000 (p<0.05). In addition, EEMP dose of 4 mg/kgBW increased apoptosis of epithelial cell that transformed towards malignancy, as showed by green-stained epithelial cell (TdT) with significant different at p=0.000 (p<0.05), and the green-stained cell exhibited a linear increase with the increasing dose. The administration of EEMP could reduce the frequency of MN in DMBA-induced precancerous lesions of the buccal mucosa. The decrease in MN was caused by EEMP through the enhancement of apoptosis, which prevented oral cancer.

Durable clinical responses to immune checkpoint inhibitors (ICI) are limited to a minority of patients, and molecular pathways that modulate their efficacy remain incompletely defined. We have recently shown that activation of the innate RNA-sensing receptor RIG-I and associated apoptotic tumor cell death can facilitate tumor immunosurveillance and -therapy, but the mechanism that drives its immunogenicity remained unclear. We here show that intratumoral activity of the pore-forming protein gasdermin E (GSDME) links active RIG-I signaling and apoptotic cell death in tumor cells to inflammatory pyroptosis. Activation of tumor-intrinsic RIG‑I triggered cleavage of GSDME, pore formation, loss of cell membrane integrity and leakage of cytosolic components from dying tumor cells. Tumor antigen cross-presentation by dendritic cells and subsequent expansion of cytotoxic T cells strongly relied on tumor-intrinsic GSDME activity. In preclinical murine cancer models, defective GSDME signaling rendered tumors resistant to ICI therapy. Epigenetic reprogramming with upregulation of Gdsme enhanced the susceptibility of tumor cells to inflammatory cell death and immunotherapy. In humans, transcriptome analysis of melanoma samples showed strong correlation between genetic activity of the RIG-I and pyroptosis pathways. In melanoma patients, high transcriptional activity of a pyroptosis gene set was associated with prolonged survival and beneficial response to ICI therapy. In summary, our data show that GSDME links RIG-I and apoptotic signaling to inflammatory cell death, thereby driving its immunogenicity and responsiveness to ICI. A deeper understanding of these pathways may allow for the development of novel combined modality approaches to improve ICI treatment responses in cancer patients.

Immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), significantly improving survival outcomes and offering renewed hope to patients. However, the presence of interstitial lung abnormalities (ILAs) in patients with NSCLC presents unique challenges, especially due to the elevated risk of immune checkpoint inhibitor (ICI)-related pneumonitis, which can result in treatment interruptions and adversely affect prognosis. ILAs, often detected incidentally on computed tomography imaging, are associated with an increased risk of progression to interstitial lung disease and have been identified as a potential predictor of poor clinical outcomes in patients with NSCLC receiving immunotherapy. This review offers an overview of the current understanding of the interaction between ILAs and ICI therapy, discussing prevalence, radiological features, risk stratification, and management strategies. Additionally, it highlights the need for prospective, multicenter studies to establish optimal treatment modalities for patients with NSCLC having ILAs, to ensure safer and more effective immunotherapy.