This study aimed to compare adverse event (AE) profiles between Avastin and bevacizumab biosimilars to support clinical decision-making, given the limited availability of real-world data.

Spider silk is highly attractive material because of its superior mechanical properties and excellent biocompatibility, enabling it to self-assemble into a wide range of morphological structures for drug delivery system. However, most spider silk particles developed as drug carriers are based on complex repetitive domains of spider silk proteins and exhibit relatively large particle sizes (> 300 nm), which limits their biomedical applications. In this study, we engineered a novel recombinant spider silk protein (NC-iRGD) by integrating terminal domains derived from major ampullate silk and the tumor-penetrating peptide iRGD. The silk particles were generated by mixing with a high-concentration potassium phosphate buffer and exhibited an average particle size of approximately 170 nm, which is smaller than that of other reported spider silk particles. Under incubation of silk particles in the drug solution, a 90% loading efficiency for the peptide drug (ChMAP-28) were determined. The cytotoxicity result showed that NC-iRGD particles displayed excellent biocompatibility and high drug loading efficiency in the neutral pH and low ionic strength. The release of ChMAP-28 was shown to be dependent on the ionic strength and pH of the release buffer. Additionally, NC-iRGD demonstrated enhanced tumor penetration and greater cytotoxicity against cancer cells compared to NC particles due to its iRGD sequence. Overall, the high drug loading capacity, controlled-release capability, and improved tumor penetration of NC-iRGD particles make them a promising novel drug delivery system for targeting polypeptide therapeutics to tumor microenvironments.

This phase I trial aimed to assess the pharmacokinetics (PK), safety, and preliminary efficacy of a single dose of HR20013 (mixed formulation of fosrolapitant and palonosetron) plus dexamethasone in patients with malignant solid tumors.

Anticancer drug therapy-induced immunosuppression increases the incidence of treatment-resistant infectious diseases in cancer patients. Combining antibacterial and anticancer capabilities into a single medication can potentially enhance the treatment outcomes. In this light, the current study focused on developing innovative 5-arylidene-3-phenyl-2-thioimidazolones 1a-e and evaluated them as antimicrobial candidates against a panel of Gram-positive and Gram-negative bacterial and fungal isolates. Compounds 1e and 2d exhibited the most potent microbial activity, with MIC values ranging from 24 ± 0.5 to 12 ± 0.20 µg/ml in comparison with streptomycin and cycloheximide as reference standards. Using the colon cancer cell line (HCT 116) as a representative example, the novel compounds were assessed as anticancer agents. Compounds 1e and 2d appeared to be the most effective candidates, with IC50 values of 7.25 ± 1.03 and 44.3 ± 3.28 µg/ml, respectively, when compared to doxorubicin (IC50 = 4.12 ± 0.50 µg/ml). Therefore, we extended the anticancer study of both 1e and 3b to include the other three cancer cells, PC3, A549, and MCF-7, and the normal Vero cell line. 1e was the most effective anticancer compound, exhibiting IC50 values ranging from 5.2 ± 0.09 to 8.1 ± 0.11 µg/mL and demonstrating a promising safety profile against the BJ1 normal cell line. In vitro enzyme screening assay of 1e against CDK-2, EGFR, HER-2, and VEGFR-2 enzymes investigated its promising multitargeting inhibiting activity (IC50 = 0.314 ± 0.031, 0.183 ± 0.014, 0.197 ± 0.024, and 0.235 ± 0.028 µM, respectively). A molecular docking study was carried out to discover the probable interactions of compound 1e with the active sites of the assessed kinases. Additionally, in silico ADMET studies were carried out for 1e, which represented its good oral absorption, good drug-likeness characteristics, and low toxicity risks.

The aim of this research was to prepare a different particle sizes of zinc oxide nanostructures by two different methods. The zinc oxide nanoparticle (ZnO NPs) was successfully prepared by a green synthesis technique but the zinc oxide quantum dot (ZnO QDs) was successfully prepared by a chemical method. The structure, composition and morphology of the prepared different shapes of ZnO nanostructures have been characterized by the means of X-ray diffractograms (XRD), high resolution transmission electron microscope (HRTEM), Energy Dispersive x-ray (EDX), UV-Vis spectroscopy and Fourier transform infrared spectroscopy (FTIR). From UV-Vis spectroscopy studies we noticed that the optical band gap energy of ZnO nanostructures was decreased by increasing an irradiation time. The removal of complex organic contaminants and pollutants from water, the heterogeneous photocatalytic degradation of methylene blue (MB), Fluorescein and Rhodamine 6G (Rh 6G) dyes were studied using ZnO NPs and ZnO QDs as a derived catalyst. We had studied the impact of ZnO NPs and ZnO QDs as a catalyst to enhance the photocatalytic activity of different organic dyes under UV-Vis irradiation and we observed that the photodegradation percentage of organic dyes was rapidly increased by increasing UV irradiation time in both two shapes of ZnO nanostructures. ZnO QDs behave as the best photocatalyst for successfully photodegraded due to the smallest size of ZnO QDs has a higher photocatalytic activity than the large particle size of ZnO NPs. So, it is better to use the ZnO QDs as a removal dyes and pollutants in the wastewater application. Also, we have assessed the cytotoxicity of ZnO NPs and ZnO QDs against two cell lines, (T-47) breast cancer carcinoma, and (DU-145) prostate cancer cell compared to Human skin fibroblast (HSF). The proliferation of cancer cells using MTT assay clarified that both cancer cells (T-47), (DU-145) as well as (HSF) normal cell line are regularly inhibited as they grow on different concentrations of ZnQ QDs and ZnQ NPs. The maximum inhibitory effect of both were recorded at concentration of 100 µg/ml (62.63, 79.72 and 42.59% and 72.68, 83.28, 18.12 µg/ml) in case of ZnQ QDs and ZnQ NPs respectively. It was cleared that ZnQ NPs was more potent for test cancer cell lines, this was confirmed by IC50, since it was (18.12,13.3,74.86) in ZnO NPs compared with (42.59,17.05 and 76.4) in ZnQ QDs respectively. Finally, it was proved that the ZnO NPs behave as a good anticancer nanomaterial than ZnO QDs. This means ZnO NPs are superior for anticancer applications if compared with ZnO QDs.

Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.

Cancer immunotherapy targeting the PD-1/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other 'checkpoint inhibitors' targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance-but not redundancy-of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.

Cancer is an age-related disease that affects one in two Japanese individuals, placing a significant burden on both patients and caregivers due to its clinical characteristics, high treatment costs, and associated adverse events (AEs). Consequently, cancer treatment remains a major public concern. In recent years, patient-centered medical care has gained increasing attention and is strongly desired in cancer treatment. Companion diagnostics (CDx) are expected to facilitate personalized treatment; however, their current status remains unclear. In this study, we evaluated the role of CDx in anticancer drug treatment based on data available at the time of drug approval. Our analysis revealed that the benefit-risk ratio, defined as the objective response rate of an anticancer drug divided by the incidence of severe AEs, was significantly higher for anticancer drugs requiring CDx (wCDx) in Japanese patients (1.54-fold, p < 0.0135) than for anticancer drugs not requiring CDx. Although the objective response rate did not differ between the 2 groups, the incidence of severe AEs was lower in the wCDx group. These findings suggest that CDx helps identify patients who are better suited for specific anticancer treatments and/or that active pharmaceutical ingredients in wCDx therapies carry a lower risk of severe AEs. To further promote patient-centered medical care, the active development of CDx alongside new anticancer drugs should be encouraged, despite the higher development hurdles, through regulatory support, particularly since drug pricing does not differ between the 2 groups.

Pigmentation is one of the most prominent side effects caused by anticancer drugs, especially in female patients, as these changes in appearance can decrease QOL. A typical drug causing such pigmentation is 5-fluorouracil (5-FU); we have previously shown that 5-FU-induced pigmentation is associated with increased adrenocorticotropic hormone (ACTH) and reactive oxygen species (ROS) levels. In male Hos:HRM-2 mice, 5-FU administration resulted in pigmentation appearing in the genital area, accompanied by elevations in neutrophils, ACTH, and ROS. By contrast, female mice showed increases in neutrophils and noradrenaline, but not in ACTH or ROS levels; furthermore, they did not develop pigmentation. In addition, estradiol levels were markedly decreased in female mice, which may have enhanced neutrophil apoptosis and suppressed ROS production. In addition, noradrenaline reflects the stress response and may contribute to the decrease in estradiol, suggesting the hypothalamus-pituitary-adrenal axis and sex hormones may interact in the formation of sex differences. These results suggest that sex differences exist in the development of 5-FU-induced hyperpigmentation and that fluctuations in estradiol and associated changes in neutrophils, ROS, and ACTH may underlie this phenomenon.

The location of nasopharyngeal carcinoma (NPC) is relatively hidden. Most patients are diagnosed at the middle or late stage of the disease, having missed the best time for treatment.

Individuals diagnosed with Fanconi anemia (FA) present an incidence of 500- to 700-fold higher to develop head and neck squamous carcinomas (HNSCCs) compared to the general population. Effective anticancer treatments for FA-HNSCCs are missing. Several studies demonstrated that FA-HNSCCs overexpress the epithelial growth factor receptor (EGFR) and their viability is highly dependent on this pathway, as FA-HNSCCs cells are highly sensitive to EGFR inhibitors such as afatinib in preclinical models, which led to an orphan drug designation by EMA in 2018.

Several small molecules have been approved for cancer treatment, but the continuously growing cancer cases have further encouraged the identification of new anticancer drug compounds. Experimental methods are costly and time-consuming, thus rapid and cost-effective alternative method is much required. The effective identification of anticancer compounds using machine learning (ML) offers a promising solution, reducing both time and cost. In this study, small molecules with known inhibitory activities, both anticancer and non-anticancer were considered to train classification models. Molecular descriptors were calculated, and multistep feature selection was applied to identify significant features. Multiple ML algorithms were employed to build classification models and evaluated their performance using independent test and external datasets. The tree-based ensemble model, particularly Light Gradient Boosting Machine (LGBM), achieved the highest prediction accuracy of 90.33%, with an area under the receiver operating characteristic curve (AUROC) of 97.31%. Consequently, LGBM model was implemented in our proposed method, ACLPred. The ACLPred demonstrated superior prediction accuracy with good generalizability compared to existing methods. SHapley Additive exPlanations (SHAP) analysis provided model interpretability and revealed that topological features made major contributions to decision-making. ACLPred is available as an open-source, user-friendly graphical interface at https://github.com/ArvindYadav7/ACLPred for the screening of potential anticancer compounds.

Wet age-related macular degeneration (AMD) causes vision loss when vascular endothelial growth factor (VEGF) stimulates blood vessel growth into the light-sensitive retina. Anti-VEGF treatments such as ranibizumab are currently administered to treat wet AMD via intravitreal injections, which are unpleasant, expensive, and risk complications. We explored the efficacy of topically administered ranibizumab, with cell-penetrating peptides (CPPs).

Three-dimensional (3D) culture models, particularly multi-spheroid models, are becoming increasingly essential in cancer drug discovery, particularly in stem cell and cancer stem cell (CSC) research. However, analytical methods for 3D multi-spheroid models, especially for single-cell and single-spheroid analysis in CSC research, remain limited. To address this gap we developed 3D multi-spheroid cholangiocarcinoma models that incorporate a CSC live-cell biosensor and a novel analysis method, 3D Surface Integrative Spheroid Profiling (3D-SiSP), utilizing high-content confocal imaging. 3D-SiSP quantifies spheroid area, allowing for both high- and low-throughput analyses. We demonstrate three key applications of 3D-SiSP. First, it outperformed traditional length-based methods for in vitro tumorigenesis measurements, offering greater precision. Second, 3D-SiSP enabled the calculation of individual spheroid areas along with real-time CSC biosensor signals, revealing larger spheroids had more undifferentiated cells. Lastly, 3D-SiSP facilitated simultaneous, real-time quantification of CSC content during anti-cancer drug testing in individual spheroids, providing evaluation of drug responses. Drug response differences across treatments were also quantified. Overall, 3D-SiSP provides a flexible and effective methodology for characterizing cancer cells and CSCs while evaluating anti-cancer drugs, applicable in both high- and low-throughput contexts. This approach enhances our understanding of CSC dynamics and supports the development of anti-CSC therapies.

Breast cancer is the uncontrolled growth of breast cells in the lobules or the inner lining of milk ducts due to dysfunction of regulatory genes. The drugs currently used in breast cancer treatment have severe limitations. The study aimed to test 10 new synthetic forms of pyrazole clubbed pyrazoline thiazole derivatives for their ability to kill tumor cells, reduce inflammation, fight free radicals, and other important factors linked to breast cancer. The study involved computational models to assess ligand-binding affinities and pharmacokinetic properties. Later, we evaluated cytotoxicity using a human breast cancer cell line, MCF-7. In a preclinical model, the levels of vital cytokines like Transforming Growth Factor-β (TGF-β), Tumor Necrosis Factor alpha (TNF-α), and Interleukin- 6 were used to test the anticancer activity. The antioxidant activity is evaluated by malondialdehyde (MDA) levels. Changes in body weight, tumor weight and volume, inflammatory cytokine concentrations, and histology were among the measurements taken in rats. In result, we found compound 5E [5-(2-fluorophenoxy)-4-(3-(4-fluorophenyl)-1-(4-(4-fluorophenyl)thiazol-2-yl)-4,5-dihydro-1 H-pyrazol-5-yl)-3-methyl-1-phenyl-1 H-pyrazole] has best antitumor activity by decreasing the levels of TNF-α, IL-6, MDA, and TGF-β. It was observed that compound 5E contains potential in vitro and in vivo anticancer activity.

Osteosarcoma (OS) is the most frequent primary bone sarcomas with high recurrence and poor prognosis. Emerging evidence indicates that membraneless organelles stress granules (SGs), whose assemblies are driven by scaffold protein G3BP1, are extensively involved in tumor, especially in OS. However, how SGs behave and communicate with organelles, particularly nucleoli and mitochondria, during drug challenges remain unknown. This study revealed that chemotherapeutic drugs activated the cysteine protease asparagine endopeptidase (AEP) to specifically cleave the SG core protein G3BP1 at N258/N309 in OS and malignant glioma. tG3BP1-Ns modulated SG dynamics by competitively binding to full-length G3BP1. Strikingly, tG3BP1-Cs, containing a conserved RNA recognition motif CCUBSCUS, sequestered mRNAs of ribosomal proteins and oxidative phosphorylation genes in the nucleoli and mitochondria to repress translation and oxidative stress. Moreover, the inhibition of AEP promoted the tumor-suppressing effect of chemotherapeutic drugs, whereas AEP-cleaved G3BP1 rescue reversed the effect in both OS and glioma models. Cancerous tissues exhibited high levels of AEP and G3BP1 truncations, which were strongly associated with poor prognosis. Accordingly, this study proposed a new paradigm and potential therapeutic targets to address chemotherapy sensitivity conferred by AEP-cleaved G3BP1-mediated SGs/nucleoli/mitochondria coordination.

Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population (n = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65-1.35; p = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation.

Data on long-term outcomes of antivascular endothelial growth factor therapy in retinopathy of prematurity (ROP) are still rare. We present 5-year post-treatment ophthalmological and paediatric outcomes of the prospective, multicentre, randomised, double-blinded, controlled pilot study CARE-ROP (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity).

The current research involves the preparation of novel thiazole derivatives, which was carried out via one-pot three-component reaction utilizing conventional and microwave irradiation (MW) methods. The MW method reduced the reaction time and allowed the reactions to be carried out with higher yields. 1H NMR, 13C NMR, EI-MS and FT-IR techniques were employed for the characterization of synthesized compounds. All compounds exhibited anti-cancer activity ranging from 0.190 to 0.273 µg/mL against SaOS-2 cell line and the best activity was shown by compound 4i which exhibited IC50 value = 0.190 ± 0.045 µg/mL. It is evident that the concentration of these compounds is a critical factor in determining their biological efficacy. This dose-dependent relationship highlights the importance of optimizing compound concentrations to achieve maximal therapeutic benefits while minimizing potential side effects. Moreover, these findings demonstrated the potential of thiazole derivatives as promising candidates for anti-cancer drug development and warrant further investigation into their mechanisms of action and therapeutic applications. Molecular modelling was utilized to predict potential interactions of the synthesized compounds that exhibited inhibitory effects. The analyses revealed that compound 4i exhibited strong inhibitory effects against EGFR (docking score: -6.434, MM-GBSA energy: -53.40 kcal/mol) in in silico studies.

The continuation or discontinuation of oncological care is a critical consideration, particularly due to its implications for quality of life at the end of life. We evaluated the management of cancer patients during the final 90 days of life by measuring the intensity of care and assessing its overall impact.