Acadesine (AICAR) is a promising candidate for new drugs in Phase III clinical trials. The purpose of this study is to analyse the steps in the biosynthesis pathway of AICAR. Our previous study found that overexpression of veA, a gene encoding a global regulator, significantly increased AICAR production of endophytic Fusarium solani HB1-J1 and the anti-tumor activity of its extracts. Transcriptome and metabolome analysis of FsveAOE14, a veA overexpressing F. solani strain, revealed a 10-step AICAR synthesis pathway, with adenylosuccinate lyase PurB as a key enzyme. Generally, overexpressing purB (the gene encoding adenylosuccinate lyase) enhances AICAR synthesis. However, in FsveAOE14, despite down-regulation of purB, AICAR content increased, which is contradictory. Further studies revealed that expression levels of purB homologs gene, pro06469 and pro10879, were upregulated in FsveAOE14. This suggests that although veA overexpression leads to purB down-regulation, their up-regulation may compensate for the reduction of purB, thus affecting AICAR synthesis. Additionally, compared to the wild type, overexpressing purB significantly enhances the inhibitory activity of the strain's extracts against the nonsmall-cell lung cancer cell line A549. Furthermore, it also increases the metabolic levels of other anti-tumor compounds, including 3-methyladenine, taurine, and others. These results indicate that VeA regulates AICAR biosynthesis via key enzymes like PurB, enhancing AICAR and other anti-tumor compound production, thus increasing the anti-tumor activity of F. solani extracts.

Tumor immunotherapy, a novel and rapidly progressing cancer treatment, has experienced remarkable advancements over recent years. It focuses on augmenting the patient's immune defenses and remodeling the immune microenvironment (IME) of tumors, rather than directly targeting malignant cells. The efficacy of immunotherapy relies substantially on multiple components within the tumor microenvironment (TME), extending beyond adaptive immunity alone. Immune cells within the TME play critical roles in both promoting immune surveillance and facilitating immune evasion. This complexity emphasizes the importance of immune checkpoint regulation in immunotherapeutic interventions. Therapeutically targeting specific immune cell subsets and metabolic pathways in combination treatments can transform an immunosuppressive TME into one that is immunologically activated, facilitating enhanced immune cell infiltration and consequently improving immunotherapy efficacy. Nevertheless, comprehensive research remains necessary to fully elucidate the mechanisms underlying TME interactions and immune checkpoint regulation, ultimately enabling more effective immunotherapeutic approaches.

Drug-induced sarcoidosis-like reaction (DISR) is a rare adverse event associated with immunotherapy. Currently, there is no standardized treatment protocol for DISR linked to immune checkpoint inhibitors (ICIs). This study presents a case of an early-stage triple-negative breast cancer (TNBC) patient who developed hepatic sarcoidosis-like reactions during neoadjuvant pembrolizumab therapy. We provide an overview of ICI-induced sarcoidosis-like reactions in cancer patients, including incidence, mechanisms, clinical manifestations, treatment, and prognosis. Additionally, we discuss the significance of one-year adjuvant immunotherapy for early-stage TNBC patients who achieved pathological complete response after neoadjuvant therapy, offering insights for individualized therapeutic strategies in this population.

Multiple studies have demonstrated that adjuvant therapy with programmed death-1 (PD-1) inhibitors can enhance the recurrence-free survival of patients with hepatocellular carcinoma (HCC) following curative resection. This study aims to assess the efficacy and safety of adjuvant tislelizumab (a PD-1 inhibitor), with or without tyrosine kinase inhibitors, in HCC patients at high risk of recurrence.

BackgroundCancer remains a leading cause of death worldwide, necessitating the development of affordable and innovative therapies to reduce its human and economic burden.ObjectivesIn this study, we aimed to develop a synergistic anticancer formula encapsulated in nanoliposomes to enhance efficacy and minimize side effects. Additionally, we explored the effect of aptamer conjugation on the efficacy and stability of the formula.MethodsThe Etoricoxib-β-cyclodextrin complex was prepared using the kneading method, and nanoliposomes were developed via thin film hydration. The AS1411 aptamer was conjugated to the nanoliposomes to target nucleolin, a protein overexpressed in cancer cells. The etoricoxib-β-cyclodextrin complex was characterized using proton nuclear magnetic resonance, and various liposome properties, including size, encapsulation efficiency, and stability, were optimized. The release profiles of the active compounds were evaluated using high-performance liquid chromatography, and their cytotoxicity was assessed in human cancer cell lines.ResultsThe nanoliposomes co-loaded with the three agents and their aptamer-conjugated counterpart showed optimal characteristics, with particle sizes of 133.3 ± 1.45 nm and 174.8 ± 4.78 nm, and zeta potentials of -15.26 ± 1.80 mV and -15.66 ± 2.57 mV, respectively. The encapsulation efficiencies were 88.63% (raloxifene), 41.73% (etoricoxib), and 39.26% (naringin) without the aptamer, and 81.99%, 36.66%, and 38.33%, respectively, with the aptamer. The IC50 of the formula for the three co-loaded agents was 167.4 µg/mL for A549 cells and 2.6 µg/mL for MCF-7 cells. Cytotoxicity was further enhanced using their aptamer conjugate, particularly against the MDA-MB-231 cell line.ConclusionThe novel triple-drug-loaded, aptamer-conjugated nanoliposome formula may be a future cancer treatment strategy.

The synthesis and characterization of a mini-library of cyclic triimidazo triazine (TT) derivatives functionalized with one, two, or three ethynyl-N-methyl-pyridinium moieties are reported here. These compounds were designed with the aim of targeting cancer-related DNA G-quadruplex structures. The newly synthesized compounds were tested for their ability to bind G-quadruplexes from both telomeric and oncogene promoter sequences using an affinity chromatography-based assay, spectroscopic and electrophoretic techniques, as well as molecular docking analysis. The obtained results demonstrated the effective capacity of the investigated compounds to specifically recognize the selected G-quadruplex models, with their TT cores targeting the outer G-quartets and their positively charged N-methyl-pyridinium groups interacting with the top edge of G-quadruplex grooves. Notably, the trisubstituted cyclic triimidazole compounds showed higher stabilizing properties than the related disubstituted derivatives, which in turn were stronger binders than their monosubstituted analogs. However, the mono- and disubstituted derivatives showed higher G-quadruplex versus duplex recognition selectivity compared with the trisubstituted ones. Altogether, the biophysical experiments, also in agreement with the biological assays, underlined the advantage of introducing an alkyne linker between the triimidazole core and the methylpyridinium group, proving to be beneficial to increase both the stabilizing effects on the G-quadruplexes and the anticancer activity compared with the analogs of the same family lacking the alkyne linker.

Most cancers, including head and neck squamous cell carcinoma (HNSCC), frequently exhibit an approximately 80% lack of response to immune checkpoint blockade (ICB) therapy, largely attributed to hypoxia-induced tumor immune suppression. Although hypoxia is known to upregulate PD-L1 expression, the key mechanisms by which it enhances PD-L1 membrane localization and high expression remain elusive.

Blockade of Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improves progression-free survival in patients with cancers, including melanoma. In addition to unleashing antitumor immunity, immune checkpoint inhibition (ICI) therapies disrupt immune regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Despite growing reports of cancer- and ICI-related cognitive impairments among survivors, our understanding of the pathophysiology of ICI-related neurodegenerative effects is limited.

The prognosis for patients with head and neck cancer (HNC) is usually poor, highlighting the need for new therapeutic strategies. To this end, this study aims to evaluate the antitumor efficacy of a combined treatment with low doses of different molecular targeted drugs, i.e. Y15, a FAK inhibitor, Afatinib (AFA) an ErbB inhibitor and TP-0903, an Axl inhibitor, on HNC. Human cell lines from salivary gland, tongue and pharynx HNC, cultured in 2D and 3D (spheroids) conditions, were used to evaluate the antitumor effects of Y15, AFA and TP-0903, alone or in combination. Cell survival, death and migration were evaluated. Western blotting and immunofluorescence analysis were performed to investigate the expression and activation of proteins involved in signal transduction and epithelial to mesenchymal transition. The combined treatment with low doses of Y15, AFA and TP-0903, was more effective than the individual and dual drug treatments in reducing survival, increasing cell death and reducing migration of HNC cells. The three inhibitors in combination had a synergistic effect in reducing survival of HNC cell lines in both 2D and 3D conditions. Moreover, as compared to the individual inhibitors and their pairwise combinations, the triple drug combination was the only able to simultaneously downregulate Axl, FAK, and N-cadherin while upregulating E-cadherin expression levels. The results reported herein provide compelling preliminary evidence supporting the combined use of Y15, AFA and TP-0903 as a novel therapeutic strategy for HNCs.

Drug resistance poses a significant challenge in cancer therapy, contributing to rapid recurrence, disease progression, and high patient mortality. Despite its critical impact, few reliable predictors for cancer drug response or failure have been established for clinical application. Tumor heterogeneity and the tumor microenvironment (TME) are pivotal factors influencing cancer drug efficacy and resistance. Tumor heterogeneity leads to variable therapeutic responses among patients, while dynamic interactions between cancer cells and the TME enhance tumor survival and proliferation, underscoring the urgent need to identify cellular hallmarks for predicting drug response and resistance. Single-cell and spatial omics technologies provide high-resolution insights into gene expression at the individual cell level, capturing intercellular heterogeneity and revealing the underlying pathologies, mechanisms, and cellular interactions. This review delves into the principles, methodologies, and workflows of single-cell and spatial omics in cancer drug research, highlighting key hallmarks involving tumor heterogeneity, TME reprogramming, cell-cell interactions, metabolic modulation, and signaling pathway regulation in drug treatment at single-cell and spatial levels. Furthermore, we synthesize predictive cellular biomarkers for cancer drug response and resistance across 25 cancer types, paving the way for advancements in cancer precision medicine.

Natural plant products represent one of the most productive sources of innovative lead drugs for the treatment of a wide range of ailments. Dolichos kilimandischaricus (Harms) ex Taub. (Fabaceae) root extracts have been traditionally used for the treatment of HPV-related cancers. The extracts from the plant have been previously shown to have antiproliferative effects on cancer cell lines. This study aimed to isolate, purify, and analyze the phytochemicals from the leaves of D. kilimandischaricus.

This study investigated the impact of anticancer treatment on the oral microbiome in pediatric patients and its association with oral mucositis (OM).

Cancer is one of the biggest challenges for health concerns in the world. There are so many drugs available, but they have a lack of specificity, poor safety, side effects, and the development of resistance. Therefore, there is an urgent need for much safer and more targeted anticancer treatments. Nitrogen-containing heterocycles play an important role in the development of drugs. Recently, imidazole and phenothiazine rings are well known for their antiproliferative and anticancer activities. This study employs the molecular hybridisation method to link these bioactive scaffolds and develop novel N-substituted imidazole-phenothiazine (N-IPTZ) hybrids. All the synthesised hybrids were characterised by using analytical techniques such as 1H-NMR,13C-NMR, mass spectrum, and FT-IR. Furthermore, the DFT analysis under the B3LYP/6-311G(d, p) level in gas phase to optimise and correlate the structures of the synthesised hybrids was also performed. The optimised structure was used to determine the energies of frontier molecular orbitals (HOMO-LUMO), quantum chemical descriptors (QCD), and molecular electrostatic potentials (MEP). Additionally, in silico approaches such as ADMET, BOILED-Egg, and bioactivity radar were also performed to evaluate the oral bioavailability of the synthesised hybrids. Molecular docking and MD simulation studies were also conducted to assess the interaction profile of the synthesised hybrids with cancer target receptors like EGFR, IGF, VEGFR1, VEGFR2, and PARP-2. It was found through docking studies that the synthesised N-IPTZ(a-c) hybrids might interact with amino acids such as GLY695, SER696, GLY697, ALA698, PHE699, LYS721, GLY772, CYS773, THR766, GLN767, LEU768, MET769, ARG817, ASN818, and THR830. Additionally, it reveals hydrogen bonding with ASP831, with binding energies of - 7.23, - 6.11, and - 5.93 kcal/mol. Moreover, all the synthesised hybrids were also analysed for their anti-cancer activity against the human liver cancer cell line (HepG2) by MTT assay. Obtained results revealed that N-IPTZ(c) exhibited anticancer activity with an IC50 value of 35.3 µg/mL.

To evaluate the short-term treatment outcomes of 80% dose photodynamic therapy (PDT) combined with intravitreal aflibercept injection (IVA) for symptomatic pachychoroid neovasculopathy (PNV) in a working-age population. We retrospectively reviewed a total of 137 eyes of 128 patients (108 males and 20 females) with PNV who were treated with combination therapy. All patients were working-age individuals, and the mean age was 49.0 ± 7.3 (range 33-65) years. Reduced-PDT (80% dose) was performed within 1 week of IVA. The presence of subretinal fluid  (SRF) at 1 month and changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), and fundus autofluorescence findings were assessed between at baseline and 1 month. One month after the combination therapy, SRF was resolved in 128 eyes (93.4%). The median (interquartile range) BCVA was 0.0 (- 0.08, 0.10)/- 0.08 (- 0.18, 0.05) (p < 0.001), the mean CRT was 374 ± 112/221 ± 36 (p < 0.001), and the mean SFCT was 416 ± 89/371 ± 92 (p < 0.001) at baseline and 1 month, respectively. Hypoautofluorescence, indicating macular atrophy was observed in 1 eye, and 1 eye developed transient visual loss at posttreatment. In terms of the rapid resolution of SRF and the improvement in VA, reduced-PDT combined with IVA can be a treatment option for PNV in the working-age population.

Visnaga daucoides (Desf.) Celak. (Apiaceae) is a plant known for its medicinal properties, but its phenolic content and biological activities remain underexplored, especially in relation to samples from different geographical regions. Exploring how environmental conditions may influence the plant's bioactive profile can provide valuable insights for its potential medicinal use. This study investigates the phenolic profile, antioxidant, anticholinesterase, and antiproliferative activities of V. daucoides collected from Iraq and Türkiye. In this study, the phenolic composition of Visnaga daucoides was determined by LC-MS/MS analysis. Antioxidant status was evaluated using TAS, TOS and OSI analyses, while antiproliferative activity was evaluated by MTT method on A549 lung cancer cells. Anticholinesterase activity was measured using Ellman method and antimicrobial activity was tested using agar dilution analysis. LC-MS/MS analysis revealed significant phenolic compounds, including acetohydroxamic acid, kaempferol, quercetin, gallic acid, and resveratrol, with geographical differences observed between the two regions. The plant exhibited potent antioxidant activity, as demonstrated by variations in total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), which were determined using Rel Assay diagnostic kits. Furthermore, V. daucoides displayed notable antiproliferative effects, particularly against A549 lung cancer cells, and strong anticholinesterase activity, with inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These findings suggest that V. daucoides is a promising source of bioactive compounds with potential applications in cancer therapy, neuroprotection, and oxidative stress management. The study also emphasizes the influence of environmental factors on the chemical composition and biological activities of the plant, warranting further investigation into its pharmacological potential for therapeutic use.

Chemotherapeutic drugs induce DNA damage, including double-strand breaks (DSBs), interstrand cross-links (ICLs), and DNA-protein cross-links (DPCs), to inhibit cancer cell proliferation. Understanding the relative contributions of these damages is essential for optimizing therapeutic strategies. To achieve physiologically relevant conditions, we determined the LD20 for four classes of chemotherapeutic agents and treated HeLa cells accordingly. Topoisomerase inhibitors (CPT, ETO) primarily induced DSBs and DPCs, whereas platinum-based agents (CisPt, OXA) predominantly caused DPCs and ICLs. The DNMT inhibitor AzadC was strongly associated with DPC formation. Although both L-PAM and MMC are bifunctional alkylating agents, their cytotoxic mechanisms differed; L-PAM induced DSBs, DPCs, and ICLs, while MMC primarily caused ICLs. DPCs were consistently detected across all drug treatments except MMC, with a half-life of 4.7 to 8.4 h, suggesting their prolonged impact on cytotoxicity. To assess apoptosis induction, we performed Annexin-V assays, which revealed significant apoptotic responses in all treated cells. CPT exhibited the highest proportion of early apoptotic cells (~ 80%) at 24 h, with all drug treatments shifting from early to late apoptosis over time. By 48 h, late apoptotic fractions exceeded 60% in CPT-, ETO-, and AzadC-treated cells. These findings highlight the critical role of DPCs in chemotherapeutic cytotoxicity and suggest that targeting apoptotic pathways could enhance cancer treatment efficacy.

Bladder cancer remains a major clinical challenge due to high recurrence rates, metastatic potential, and the development of drug resistance driven by complex gene regulation. Targeting the PI3K/AKT/mTOR pathway is a promising strategy, as its dysregulation promotes tumor growth and survival. Rapamycin, Everolimus, Temsirolimus and Other ATP-competitive inhibitors work by binding to the mTOR protein and preventing it from activating downstream signaling pathways that control cell growth and division. However, the therapeutic potential of Rapamycin, an mTORC1 inhibitor, is limited by poor solubility, low bioavailability, and non-specific distribution. This study explores the use of poly (lactic-co-glycolic acid) nanoparticles to encapsulate Rapamycin for enhanced delivery and controlled release in bladder cancer therapy. Drug release followed the Korsmeyer-Peppas model, indicating sustained release behavior. In vitro cytotoxicity assays demonstrated that Rapa-PLGA NPs significantly reduced the IC50 compared to free Rapamycin in T24 bladder cancer cells. Wound healing assays revealed substantial inhibition of cancer cell migration. Gene expression analysis showed that Rapa-PLGA NPs effectively downregulated mTOR, HIF-α, BCL-2, and ABCC1, while upregulating FOXO1 and MAPK, promoting apoptosis and reducing drug resistance. These findings highlight the potential of Rapa-PLGA NPs to enhance Rapamycin's therapeutic efficacy by integrating nanotechnology-driven delivery with gene regulatory mechanisms. This nanoparticle-based system presents a promising strategy for improving targeted bladder cancer therapy and overcoming drug resistance, warranting further in vivo investigation.

Despite the introduction of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, the number of deaths from lung cancer remains high, and further improvements in response rates are necessary. Recently, the gut microbiota has been reported to be involved in the therapeutic effects of ICIs; however, only a few studies have examined patients with lung cancer in this context. In the current study, we aimed to explore the association between the gut microbiota before therapy and the efficacy of ICIs in patients with advanced non-small cell lung cancer (NSCLC). The a-diversity of the intestinal microbiota in patients who responded to ICI treatment (responders) was significantly higher than that in those who did not respond to ICIs (non-responders). Additionally, the abundance of Bifidobacteriaceae was significantly higher in the responders than in the non-responders. Furthermore, patients with a high abundance of Bifidobacteriaceae had significantly longer overall survival than those with a low abundance. Counts of Levilactobacillus brevis were significantly higher in responders than in non-responders. Our findings suggest that a higher diversity of the gut microbiota and an abundance of Bifidobacterium and/or L. brevis are distinctive features of the microbiota in patients with NSCLC who respond to ICI treatment.

Peripheral T cell lymphomas (PTCL) is a group of non-Hodgkin lymphomas characterized by substantial molecular heterogeneity, rapid progression, poor therapeutic response, and unfavorable outcomes. In recent clinical studies, antithymocyte globulin (ATG)-based allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the prognosis and survival of patients with PTCL. This study aimed to explore whether ATG has toxic effects on PTCL cells and evaluate whether ATG combined with chemotherapy has a synergistic antitumor effect. Our research revealed that ATG significantly inhibited PTCL cell growth by suppressing cell proliferation and colony formation. Moreover, ATG treatment decreased cell invasion; however, it had no effect on cell cycle arrest in PTCL cells. ATG-induced PTCL cell apoptosis, which was partially reversed by pan-caspase inhibitor and caspase 8 inhibitor. Additionally, ATG was able to induce complement-dependent cytotoxicity in PTCL cells. Of note, the combination of ATG and doxorubicin exhibited an enhanced antitumor effect against PTCL in xenograft mouse models in vivo. The addition of ATG into the chemotherapy regimen may be a beneficial way for treating PTCL.

Carotenoids, a diverse group of naturally occurring pigments, have gained attention for their potential anticancer properties. Among them, bacterioruberin (BR), a rare C50 carotenoid, has shown promising bioactivities. This study evaluates the antiproliferative and cytotoxic effects of a bacterioruberin-rich carotenoid extract (BRCE) derived from Haloferax (H.) mediterranei on myeloid leukaemia (ML) cell lines, including chronic myelogenous leukaemia (CML) and acute myelogenous leukaemia (AML) models. Using MTT assay, Annexin V/PI and AO/EtBr staining, CFDA-SE proliferation assay, PI-based cell cycle analysis, and H2DCF-DA for reactive oxygen species (ROS) quantification, we demonstrate that BRCE significantly reduces cell viability, induces apoptosis, causes G2/M cell cycle arrest, and increases ROS levels in leukaemia cell lines. Notably, BRCE exhibited selective cytotoxicity, with minimal effects on normal PBMCs from healthy donors, suggesting its potential for tumour-specific targeting. Additionally, we analysed the morphological features of the cells treated with BRCE, observing significant changes such as cell blebbing, clumping, and the formation of apoptotic bodies, which are indicative of the induction of apoptosis. Overall, this research underscores an antitumoural therapeutic potential of BRCEs from H. mediterranei, providing a basis for future studies on their application in leukaemia treatment. Further investigation is needed to fully understand the molecular mechanisms involved and optimize BRCE for clinical use.