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PARP1 inhibitors are FDA-approved for BRCA1/2-mutated breast cancer but show limited efficacy in wild-type cancers and face resistance issues. To overcome these, we designed novel 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-based compounds integrating PARP1 inhibitor pharmacophores with the ATR inhibitor AZD6738 scaffold. Substituent modifications influenced PARP1 and ATR selectivity, yielding dual inhibitors or selective PARP1 inhibitors. Compound 38a, the lead candidate, exhibited potent dual inhibition (IC50 < 20 nM) and strong antitumor effects in MDA-MB-231 (IC50 < 0.048 μM) and MDA-MB-468 (IC50: 0.01 μM) cell lines in vitro. Mechanistically, 38a arrested cell cycle progression, induced apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair pathways, outperforming combined Niraparib and AZD6738. These findings underscore the therapeutic potential of PARP1/ATR dual inhibitors for breast cancer and support further investigation.

The fungal priority pathogen and basidiomycete, Cryptococcus neoformans (Cn), causes lung and brain infection in predominantly immuno-compromised individuals and there is an urgent need for new treatment options. The pyrazolopyrimidine-based cyclin dependent kinase (CDK)7 inhibitor, BS-181, has anticancer properties, but its antifungal activity has not been investigated. We show that cryptococcal CDK7 more closely resembles the human enzyme than that of ascomycetes, and that BS-181 inhibits its activity. BS-181 inhibited growth of both Cn and Cryptococcus gattii (Cg), but not ascomycete fungi and delayed progression through the G2/M phase of the cell cycle. Transcriptomic analysis revealed that BS-181 induces splicing defects leading to elevated intron retention within the transcriptome and also suppresses translational processes. BS-181 displayed additive or synergistic activity with licensed antifungals against laboratory and clinical Cn and Cg strains, most notably with amphotericin B where synergy (2-4-fold reduction in the amphotericin B MIC) was achieved using low-sub micromolar concentrations of BS-181. Compared with either drug alone, BS-181-AmB combination therapy provided greater protection against Cn infection in a wax moth model (p ≤ 0.032) and extended survival of Cn-infected mice. These findings demonstrate that CDK7 inhibitors, already of interest as anticancer agents, could be repurposed to prevent or treat opportunistic fungal infections in cancer patients when combined with licensed antifungals limited by either toxicity or resistance.

The growing burden of multimorbidity challenges the healthcare system due to increased healthcare utilization and uncoordinated care. Identifying patients with multimorbidity who have high healthcare utilization is essential to improve management and reduce pressure on the healthcare system. This study aims to identify and characterize clusters of patients with multimorbidity based on both their chronic conditions and healthcare utilization patterns. A weighted K-means method was applied to a population of 1,184,334 individuals with two or more out of 33 chronic conditions, defined using diagnostic algorithms based on ICD-10 and ATC codes. Sociodemographic variables were applied to describe the identified clusters. Four clusters were identified based on chronic conditions and healthcare utilization. Cluster 1 had the highest healthcare utilization and a high burden of both somatic and mental conditions, combined with low social status. Cluster 2, consisting primarily of younger women with mental conditions, showed high use of psychological services, and few somatic conditions. The largest cluster, cluster 3, had low healthcare utilization and consisted of individuals with common, manageable conditions, and relatively high social status. Cluster 4 was defined by older individuals with complex somatic conditions requiring frequent contact with general practitioners and specialists. The identified clusters showed varying chronic condition patterns and levels of healthcare utilization. The findings underscore the importance of tailored strategies, particularly for multimorbidity patients with mental conditions taking social status into account, in order to improve care and manage resource use more effectively.

HIF2α is aberrantly upregulated in some renal cell carcinomas due to VHL mutations, supporting HIF2α inhibition as a compelling therapeutic approach for such cases. Therefore, the six compounds (designated as Compounds 1-6) were screened from the Maybridge database based on the constructed pharmacophore model and molecular docking. Subsequently, the docking models of Compounds 1-6 with HIF2α were analysed. Affinity assays revealed that both Compound-4 and Compound-5 exhibited robust affinity towards human recombinant HIF2α. MD simulations displayed that Compound-4 and Compound-5 stably bound to the active pocket of HIF2α. Cell experiments demonstrated that Compound-4 effectively inhibited the growth of the 786-O human renal cell carcinomas line (IC50 = 1.35 ± 0.06 μM). This study demonstrates that Compound-4 may serve as a potential candidate compound for renal cell carcinomas therapy.

The hypothesis-generating case study aimed at identifying those who are sensitive to anti-PD-L1 and TGF-β bifunctional fusion proteins and exploring potential mechanisms in the treatment of recurrent cervical cancer. We report that recurrent cervical cancer treated with anti-PD-L1 and TGF-β bifunctional fusion proteins in Qilu Hospital of Shandong University show distinct clinical therapeutic outcomes. We describe the clinical course, characteristics, and genetic characteristics of the patients and analyzed the differentially expressed genes (DEGs) following treatment. The elevation of peripheral blood lymphocytes after treatment may predict response to anti-PD-L1 and TGF-β bifunctional fusion proteins, since partial response (PR) and progressive disease (PD) exhibit different trends. A total of 4,844 DEGs were selected between PR and PD patients during the anti-PD-L1 and TGF-β bifunctional fusion protein treatments, which are believed to be involved in the regulation of the immune response. We demonstrated that changing-fate genes continuously change during treatment fostering the IL 17 signaling pathway and TGF-β signaling pathways. Finally, we identified the prognostic genes and validated that high expression levels of PMEPA1, FSTL3, SERPINE1, CXCL1, CXCL8, and low expression levels of JUND，MAP2K2 were significantly associated with poor prognosis of cervical cancer patients using the TCGA database. Anti-PD-L1 and TGF-β bifunctional fusion proteins are feasible and effective for recurrent cervical cancer through the IL 17 signaling pathway and TGF-β signaling pathways. A novel immune infiltration-based gene signature consisting of PMEPA1, FSTL3, SERPINE1, CXCL1, CXCL8, JUND, and MAP2K2 plays a crucial role in recurrent cervical cancer patients with anti-PD-L1 and TGF-β bifunctional fusion proteins.

Docetaxel (DTX) resistance is the main cause of treatment failure in castration-resistant prostate cancer (CRPC). Pyrroline-5-carboxylic acid reductase 1 (PYCR1) is an enzyme involved in proline metabolism. It is highly expressed in various cancers and promotes malignant progression, yet its role in DTX resistance in prostate cancer remains unclear. In this study, bioinformatics analyses and in vitro/vivo experiments demonstrated that interfering with PYCR1 expression modulates the sensitivity of prostate cancer cells to DTX. Subsequently, via structure-based virtual screening, molecular dynamics simulations, and cellular thermal shift assay (CETSA), emodin-an anthraquinone compound-was identified as a PYCR1-targeting agent. Collectively, these findings suggest that PYCR1 may serve as a key target mediating DTX resistance in prostate cancer, and the emodin-DTX combination provides a promising potential clinical strategy to overcome such resistance. Finally, its functions and safety were also verified through in vitro experiments.

Although FGFR2 is a well-validated oncogenic target, no selective FGFR2 inhibitors have been approved for clinical use. In this study, we report the discovery of 2H-pyrazolo[3,4-d]pyrimidin-4-amine derivative as novel, irreversible FGFR2 inhibitors. The optimal compound, PLW559, potently inhibited FGFR2 with an IC50 value of 13.59 nM and demonstrated exceptional selectivity over FGFR1, FGFR3, and FGFR4. Covalent binding to the target was confirmed by mass spectrometry. In cellular models, PLW559 exhibited potent and selective antiproliferative effects against FGFR2-driven cancer cells, effectively suppressed downstream FGFR2 signalling and induced cancer cell apoptosis. Notably, it showed minimal activity in non-FGFR2-dependent cells. This work presents a new class of selective FGFR2 inhibitors based on a novel scaffold, offering promising lead compounds for the development of FGFR2-target therapies.

Spread through air spaces (STAS) is recognized as an aggressive pattern of invasion in lung cancer and has been associated with poorer survival outcomes. However, STAS is frequently overlooked or misdiagnosed during routine pathological diagnosis. We analyzed 129 pathological slides from 91 STAS-positive patients with non-small cell lung cancer (NSCLC). An artificial intelligence framework consisting of a tumor region segmentation algorithm and an object detection algorithm was developed. The segmentation algorithm was first used to isolate the main tumor region, followed by STAS detection using an improved object detection model. The segmentation module achieved a Jaccard similarity of 0.846. The proposed object detection algorithm demonstrated superior performance with a precision of 0.738, recall of 0.747 and average precision (AP) of 0.784 and F1 score of 0.742, outperforming other object detection methods. Both segmentation and detection results met diagnostic requirements, with higher accuracy observed in lung adenocarcinoma (LUAD) than in lung squamous cell carcinoma (LUSC). In external validation, the model achieved a precision of 0.670, recall of 0.705 and AP of 0.732 and F1 score of 0.687. Additionally, the AI-derived STAS counts showed substantial agreement with pathologists (interclass correlation coefficient = 0.703). Kaplan-Meier survival analysis revealed that the number of STAS events was significantly associated with disease-free survival (DFS) in stage I LUAD (p < .05). We propose a deep learning-based artificial intelligence framework for automated STAS detection and quantification in digital whole-slide images of NSCLC. This model holds promising potential to assist pathologists in achieving more comprehensive and accurate diagnosis of STAS.

In this study, we report the Pictet-Spengler enabled synthesis of a series of eighteen carboxamide-substituted imidazo[1,2-a]quinoxaline derivatives (JRC-1-JRC-18) targeting epidermal growth factor receptor (EGFR) and tubulin. Compounds JRC-2 and JRC-6 exhibited potent antiproliferative effects against MCF-7 breast cancer cells, with IC50 values of 4.59 ± 0.23 µM and 4.01 ± 0.14 µM, respectively, outperforming erlotinib (IC50 = 9.39 ± 0.16 µM). In enzymatic assays, JRC-2 and JRC-6 inhibited wild-type EGFR with IC50 values of 294.45 nM and 383.90 nM, respectively. Notably, JRC-6 displayed microtubule-stabilising activity comparable to that of paclitaxel and induced ROS generation, mitochondrial membrane depolarisation, and G2/M phase cell cycle arrest. Molecular docking and molecular dynamics simulations confirmed stable binding of compounds at the EGFR ATP-binding site and the tubulin taxol-binding site.

Utilising drug design methodologies including bioisosteric modification and substituents variation, sets of 4,5,6,7-tetrahydrobenzo[b]thiophene carboxamides were synthesised, by conventional heating and eco-friendly microwave-assisted techniques, as CDK-2 inhibitors. These entities were assessed for their antitumor effects against hepatic HepG-2 and breast MCF-7 and MDA-MB-231 carcinomas, in which dimethoxy 5 and dimethyl-bearing analogues 6 and 11 demonstrated significant cytotoxicity and selectivity against the examined cancer cells. Consequently, they were chosen for further assays to determine their mechanism. The findings suggest that these compounds may exert cytotoxicity by inhibiting CDK-2. Compound 11 displayed the highest CDK-2 inhibition, exceeding roscovitine by nearly threefold. Besides, it arrested the MDA-MB-231 cell cycle at the G0/G1 phase by apoptotic stimulation. Molecular modelling showed strong binding of the bioactive analogues to the active pocket of CDK-2 receptor, suggesting their potential as lead inhibitors.