Abelson (ABL1) tyrosine kinase is an essential component of non-receptor tyrosine kinases and is associated with numerous cellular processes, including differentiation and proliferation. The structural features of ABL1 include a distinct N-terminal cap region, a C-terminal tail, a bilobed kinase, SH2, and SH3 domains. These domains enable its engagement in several signaling cascades and dynamic control. The pathophysiology of chronic myeloid leukemia (CML) is mainly driven by the BCR-ABL1 oncoprotein, arising from dysregulation of ABL1 kinase, namely through its fusion to the breakpoint cluster region (BCR) gene. ABL1 is a crucial target in the treatment of CML as the BCR-ABL1 fusion causes uncontrolled cellular proliferation and resistance to apoptosis. Tyrosine kinase inhibitors (TKIs) targeting the ABL1 tyrosine kinase are playing a critical role in the treatment of CML through the inhibition of persistently activated signaling pathways mediated by the BCR-ABL1 fusion protein. The article examines the structural characteristics of ABL1, how they relate to CML, and the interactions between ABL1 and the current FDA-approved TKIs, emphasizing the kinase's critical function in carcinogenesis and its possible target status for tyrosine kinase inhibitors.

The PD-L1/PD-1 pathway is crucial for immune regulation and has become a target in cancer immunotherapy. However, in order to improve patient selection for immune checkpoint blockade (ICB) therapies, better selection criteria are needed. This study explores how the N-glycosylation of PD-L1 affects its interaction with PD-1 and ICB efficacy, focusing on its four N-linked glycosylation sites: N35, N192, N200, and N219.

Lung cancer, the deadliest malignancy worldwide, causes 2.2 million cases and 1.8 million deaths annually, accounting for 18% of cancer deaths. Limited early detection, unaffordable treatments, and drug resistance lead to low survival rates, highlighting the urgent need for developing effective, resistance-proof therapies. In this study, we docked the DrugBank library against Lung Cancer Oxidoreductase, Chaperone, Transferase, and Hydrolase Proteins to identify a multitargeted drug candidate, resulting in identifying a promising drug candidate named Indenopyrazole with docking and MM\GBSA scores ranging from -7.337 to -11.62 and -17.82 to -60.38 kcal/mol, respectively. We also evaluated the interaction pattern of the drug candidate with Molecular Interaction Fingerprints and found that the most interacting residues with its counts are 4TRP, 3ASP, 3GLN, 3GLU, 3LYS, 3PHE, and 3TYR. The pharmacokinetics and comparison with standard values supported the candidate, followed by the density functional theory computations. The study was also validated for the WaterMap for water thermodynamics, and its role in binding pockets has also supported the idea that Indenopyrazole has a multitargeted potency. Further, we extended our studies with 100ns MD Simulation in water to analyse the deviations, fluctuations, and intermolecular interactions, and all the 1000 trajectories were evaluated for total complex energy and binding free energy with MM\GBSA concluding wonderful promising results in support of Indenopyrazole as a multitargeted drug candidate-however, its efficacy needs to be experimentally validated.

The rising global incidence of bladder cancer and chemotherapy resistance necessitate novel therapies. Plant-derived compounds, owing to their diverse biological activities and favorable safety profiles, are considered promising candidates for cancer treatment. In this study, we investigated Bousigonine D, a monoterpene indole alkaloid isolated from the roots of Bousigonia mekongensis, for its potential as a therapeutic agent for bladder cancer. Our results show that Bousigonine D effectively inhibits cell proliferation and clonogenic formation, and induces cell cycle arrest at the G0/G1 phase in murine and human bladder cancer cells. Furthermore, Bousigonine D significantly promotes apoptosis in these cells, surpassing the apoptosis-inducing efficacy of cisplatin. Mechanistically, Bousigonine D enhances the generation of reactive oxygen species, disrupts calcium homeostasis, and impairs mitochondrial function, leading to cytoskeletal collapse and caspase-dependent apoptotic cell death. In vivo, Bousigonine D effectively suppresses tumor growth in an orthotopic MB49 mouse model, and importantly, it retains strong anti-tumor efficacy in cisplatin-resistant bladder cancer. Notably, Bousigonine D exhibits low toxicity in major organs, similar to cisplatin, underscoring its potential as a safe and effective treatment for bladder cancer. This study highlights the promising role of plant-derived compounds in cancer therapy and supports further development of Bousigonine D as a novel therapeutic option for bladder cancer.

Naturally derived carbon quantum dots (CQDs) are novel carbon-based nanomaterials with excellent traits. It is highly demanded to develop CQDs from biowaste that have excellent photostability, a simple synthesis approach, and an appealing output so that they can be used widely in various fields. Herein, highly fluorescent CQDs were synthesized hydrothermally using artichoke leaves. The CQDs were synthesized and analyzed for their structure, optical properties, antimicrobial, and anticancer activities. The CQDs exhibited antimicrobial action against a single fungus strain in addition to Gram-positive and Gram-negative cells; also, the cytotoxicity against the MCF-7 cell line was evaluated as 96.5 µg/mL. The findings indicated that the spherical dots have a semi-spherical shape with the smallest size of 2.88 nm, and a zeta potential value of 37.31 V, thus confirming that the synthetic CQDs are in an outstanding colloidal state. When photoexcited at 320 nm, the dots were found to show blue fluorescence at 398 nm with a fluorescence quantum yield of 3.32%, long fluorescence decay time, high photostability, and good sensing for hydrogen peroxide. Additionally, the effect of ionic strength was evaluated.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality, with limited therapeutic options available for advanced stages of the disease. Treatment strategies for HCC are multimodal and largely depend on the disease stage, liver function, and individual patient factors. Based on the WHO's VigiAccess database, this study employed a retrospective descriptive analysis of adverse drug reaction (ADR) reports associated with four widely used tyrosine kinase inhibitors (TKIs) for HCC, including Sorafenib, Cabozantinib, Lenvatinib, and Regorafenib. The analysis included demographic data such as patient age, gender, and geographical distribution, alongside clinical information on the systems and symptoms associated with ADR reports. A total of 112,975 ADR reports related to the four TKI-targeted drugs were identified. Sorafenib exhibited the highest ADR reporting rate (30.7%), followed by Cabozantinib (29.4%), Lenvatinib (24.5%), and Regorafenib (15.4%). The odds ratio method was employed to assess the statistical correlation between the use of these targeted drugs and the occurrence of ADRs. Notably, Sorafenib (3,746) and Regorafenib (2,496) served to have the highest number of reported palmar-plantar erythrodysaesthesia syndrome. Chi-square analyses suggested that ADRs related to Lenvatinib were reported significantly more frequently in female patients compared to their male counterparts. The findings of this study can enhance public awareness of drug-related adverse events and provide an evidence-based foundation for prioritizing the management of ADRs associated with TKIs in second-line HCC therapy.

Colorectal cancer is one of the most common malignant tumors, and its drug resistance poses a huge challenge and a serious threat to people's health. In previous studies, we have found that the combination of paclitaxel and BEZ235 has synergistic anti-colon cancer effects, particularly in drug-resistant colorectal cancer, demonstrating excellent anti-tumor effects. Therefore, this study aims to investigate the preparation of the nanoemulsification of paclitaxel and BEZ235 (NEs-PTX-BEZ235) and to explore the potential key parameters for its clinical translation. This study aims to provide a new therapeutic strategy for colorectal cancer, especially for drug-resistant colorectal cancer. The nanomaterials were prepared by low energy self-emulsification method, and analyzed by Malvern laser particle size analyzer. Cell drug uptake was observed under fluorescence microscope. CCK8, Western blot and flow cytometry were used to compare the anti-cancer effects and mechanisms of different experimental groups on ordinary and drug-resistant colon cancer cells. Human colon cancer primary cells were extracted to verify the anti-tumor effect of drugs. Finally, we found that NEs-PTX-BEZ235 significantly killed colon cancer cells, especially drug-resistant cells, and performed better than Nab-PTX. It may play a synergistic role in reducing drug resistance, inhibiting tumor stemness and inducing apoptosis of colon cancer cells by inhibiting drug resistance proteins.

NPS-2143, as a CaSR allosteric antagonist, performs an important role in diverse cancers. However, the function and mechanism of NPS-2143 in human retinoblastoma have not been reported. Cell viability was evaluated by using cell counting kit-8, flow cytometry was used for apoptosis detection and western blotting was carried out to detect the expression of target genes. Small interference RNA (siRNA) was used to reduce CaSR expression. Bortezomib was used to suppress the NF-κB pathway. NPS-2143 (16.5 µM) suppressed the proliferation of Y-79 cells, and increased the apoptosis of Y-79 cells. NPS-2143 treatment inhibited the protein patterns of p-P65 NF-κB and p-IκBα. Additionally, si-CaSR transfection obviously decreased the proliferation of Y-79 cells, and increased the apoptosis of Y-79 cells. Moreover, the protein patterns of p-P65 NF-κB and p-IκBα were obviously decreased after si-CaSR transfection. Bortezomib treatment increased the apoptosis of Y-79 cells, and CaSR overexpression suppressed the apoptosis of Y-79 cells. The whole data indicated that NPS-2143 inhibited the viability of Y-79 cells, and induced apoptosis by modulating the NF-κB signaling pathways. Therefore, NPS-2143 has potential anti-retinoblastoma effect.

Teclistamab, a BCMA-directed bispecific antibody, received regulatory approval for relapsed/refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. Despite the fact that myeloma is primarily a cancer of elderly adults, only 15% of MajesTEC-1 participants (n = 24) were ≥75 years old. In this multicenter retrospective study, we report real-world outcomes of a large cohort of older RRMM patients treated with teclistamab. Of 385 analyzed patients, 83 (22%) were in the older group (age ≥75) and 302 (78%) in the younger group (age <75). Compared to the younger group, the older group had less adverse baseline disease characteristics, including a lower incidence of high-risk cytogenetics (44.6% vs. 57.9%, p = 0.03) and extramedullary disease (22% vs. 40%, p = 0.02). There were no significant differences in rates of any-grade CRS (52% vs. 59%, p = 0.27), any-grade ICANS (19% vs. 13%, p = 0.12), and overall response rate (62% vs. 53%, p = 0.17) between the older and younger groups. In multivariable analysis, age was not significantly associated with survival outcomes. Our findings suggest that teclistamab is safe and efficacious in well-selected patients ≥75 years old, and advanced age alone should not preclude teclistamab administration.

Immune checkpoint inhibitors (ICIs) of programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell immune responses against tumor cells. For many patients, these therapies fail because the development of spontaneous immune responses is often compromised, as the tumor microenvironment (TME) lacks proinflammatory signals resulting in suboptimal activation of antigen-presenting cells (APCs). Necroptosis is a special form of programmed cell death associated with leakage of inflammatory factors that can lead to APC maturation. However, it is unclear to which extent functional necroptosis in tumor cells contributes to ICI immunotherapy.

Understanding the mechanisms through which anticancer drugs interact with multiple protein targets is crucial for optimizing drug design and enhancing the efficacy of chemotherapy. This study focuses on doxorubicin, a broad-spectrum anticancer drug recognized for its multi-target mechanisms of action. We initially screened 363 doxorubicin-binding proteins using protein microarrays; of these, 166 proteins with known PDB (Protein Data Bank) structures were selected for molecular docking to evaluate their binding energies. The binding energy distribution and residue enrichment analyses revealed that doxorubicin preferentially binds to specific residues at its binding sites, including serine, glycine, arginine, glutamic acid, lysine, aspartic acid, and leucine. These residues stabilize doxorubicin binding through hydrogen bonds, hydrophobic interactions, and electrostatic interactions. In addition, RUVBL1 (RuvB-like AAA ATPase 1) exhibited the highest integrated score from the protein microarray and molecular docking analyses. Furthermore, PPI (protein-protein interaction) network analysis and centrality calculations identified key proteins with potential regulatory roles, with MAPK1 (mitogen-activated protein kinase 1) exhibiting the highest betweenness centrality in the PPI network. Finally, molecular dynamics simulations of the RUVBL1- and MAPK1-doxorubicin complexes were conducted to evaluate the binding mechanisms. The simulations revealed key binding residues, including Ile56, Lys59, Leu87, Pro296, and Ile326 in RUVBL1 and Asp88, Ile89, Pro93, Phe354, and Ala92 in MAPK1 that mediate stable interactions with doxorubicin. This study presents a comprehensive analytical approach for investigating the interactions between doxorubicin and multiple protein targets, providing a reference framework for understanding the molecular mechanisms of anticancer drugs and for future analyses of similar data sets.

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.