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Cancer represents a significant challenge to people's health and safety. Tumor biomarker detection plays a vital role in the precise diagnosis of cancer and finds widespread applications in cancer screening and pathological diagnosis. Existing methods for tumor biomarker detection have drawbacks such as susceptibility to false positives, complexity of operation, and high costs. As a molecular-level fingerprint spectrum, Raman spectroscopy holds promise as a rapid and accurate method for tumor biomarker protein detection. This paper presents a high-confidence Raman spectra collection method for tumor biomarker proteins based on experimental and theoretical cross-validation. On the one hand, through ultrafiltration purification of protein samples, high-confidence spectra for four tumor biomarker proteins of breast cancer were experimentally acquired. On the other hand, using first-principles Density Functional Theory (DFT), the Raman spectra of the proteins were calculated theoretically. Experimental and theoretical spectra were mutually validated, confirming differences in spectral peak characteristics and their assignments for the four biomarker proteins. We also demonstrate improvement in AI-based protein classification through theoretical-experimental cross-validation, with 7.62% accuracy gain. The method proposed in this paper is well-suited for integration with high-throughput spectral analysis algorithms based on artificial intelligence. It holds the potential for developing deep learning models constrained by biological knowledge in the field of cancer screening and tissue biopsy pathological diagnosis in the future.

The rapid and accurate differentiation of bacteremia, focal bacterial infections (FBI), and viral illnesses in febrile immunocompromised patients is a critical unmet clinical need that directly impacts antibiotic stewardship. While host-response diagnostics are increasingly applied in clinical practice, most current approaches cannot reliably differentiate systemic from localized bacterial infections and do not offer mechanistic, biochemically interpretable signatures underlying their classifications. This study introduces a unified platform for Fourier-transform infrared (FTIR) spectroscopy and machine learning that balances diagnostic performance and biochemical explainability. Using white blood cells from 457 pediatric oncology episodes (69 bacteremia, 90 FBI, 178 viral, and 120 control), the platform was evaluated on key diagnostic challenges. It achieved high accuracy in distinguishing bacteremia from FBI (94.6%) and bacteremia from viral infections (93.5%). Crucially, it also demonstrated robust performance in the critical comparison of FBI versus viral infections, a common diagnostic dilemma. To elucidate the biochemical basis of this performance, we identified interpretable spectral biomarkers for each etiology. Bacteremia exhibited systemic inflammatory signatures in carbohydrate/phosphodiester regions (∼1160 cm-1), while FBI showed features in amide II and lipid regions (∼1580-1560, ∼1430 cm-1). This work establishes a diagnostic platform that successfully resolves fine-grained infection etiologies and directly links its high accuracy to underlying, explainable immunometabolic host responses, offering a powerful tool for combating antimicrobial resistance.

Based on the surface plasmon resonance (SPR) technique, the proposed biosensor is investigated as an SPR-based sensing platform for detecting breast cancer cells, specifically MCF-7 and MDA-MB-231 cells. Developed biosensor features an octagonal cylinder-shaped resonator design composed of two novel materials: an octagon-shaped structure made of gold (Au) and a cylinder-shaped structure made of silver (Ag). Graphene is also integrated to achieve high sensitivity in the detection for the two breast cancer cell lines based on the refractive index values, within the wavelength range of 1650-1700 nm, yielding sensitivity rates of 714.28 nm/RIU (MCF-7) and 785.71 nm/RIU (MDA-MB-231). The proposed Graphene Octagonal Cylinder-Shaped Surface Plasmon Resonance (GOCSPR) biosensor consists of two layers, with a ceramic substrate made of aluminum nitride (AlN), and exhibits good quality factors of 560 for MCF-7 and 557 for MDA-MB-231. The analysis of layer height and cylinder radius, along with optimization using a Linear Regression machine learning algorithm and the corresponding R2 values, is also presented in the manuscript. The designed graphene-based structure can be used for detecting breast cancer cell with high efficiency for medical applications.

Herein, we report the discovery of APO-50815 (14), a potent and selective thietane-3-ol WEE1 inhibitor. When tested against TP53-mutated colorectal cancer (CRC) patient-derived organoids (PDOs) grown from peritoneal and liver metastases, 14 exhibited outstanding anticancer efficacy, surpassing previously reported branched alkane counterpart 3, as well as clinical candidates AZD1775 (1) and ZN-c3 (2). Against primary CRC organoids with diverse TP53, BRAF and KRAS mutation profiles compared with patient-matched normal colon organoids, 14 exhibited selectively potent activity, yielding exceptionally high TI values (129-238) that highlight a substantial therapeutic window for potential cancer treatment. Against primary CRC PDOs (TP53-WT, BRAF-V600E, KRAS-WT), 14 profoundly elevated DNA damage and replication stress compared to 1, while amplifying cellular apoptosis, confirming a broadly similar but superior mode of action. Owing to its highly selective and exemplary anticancer efficacy, 14 represents a valuable tool compound for drug testing investigations against primary and metastatic CRCs, especially in the context of PDOs.

Targeting autophagy initiation represents a promising strategy to disrupt the metabolic resilience of cancer cells. In this study, we identified ATI-1 as a novel small-molecule inhibitor that selectively blocks the early stages of autophagosome formation. Importantly, we discovered that ATI-1-mediated de novo inhibition of autophagy initiation leads to a synergistic surge in cell death under nutrient-deprived conditions, revealing a critical, context-specific vulnerability in autophagy-dependent malignancies. Mechanistically, ATI-1 appears to target valosin-containing protein (VCP/p97) and disrupt its interaction with the UFM1-specific E3 ligase UFL1. This disruption may promote the polyubiquitination and subsequent degradation of Beclin1, thereby contributing to the inhibition of autophagy initiation. Furthermore, ATI-1 demonstrates potent antitumor efficacy in xenograft models with minimal overt toxicity. This work collectively suggests that the VCP-UFL1-Beclin1 axis may represent a potentially targetable node in autophagy regulation, and identifies ATI-1 as a potential small-molecule modulator of this pathway, thereby providing a promising therapeutic lead for cancer treatment.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking the ER, PR, and HER2 receptors, with limited treatment options and poor prognosis. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic strategy for TNBC. Glutathione peroxidase 4 (GPX4) is a key ferroptosis suppressor, and its inhibition sensitizes TNBC cells to oxidative damage. To discover and characterize DA-5, a novel 3,5-disubstituted azaindole derivative inspired by compounds from the traditional Chinese medicine Shuganning injection (SGNI), as a potent GPX4 inhibitor to induce ferroptosis in TNBC cells. Molecular docking and structural optimization were used to design DA-5. Its binding affinity (Kd) and enzymatic inhibitory activity (IC50) against GPX4 were evaluated. In vitro assays assessed DA-5's ability to induce ferroptosis in TNBC cells through lipid peroxidation while sparing normal mammary epithelial cells. In vivo studies evaluated the efficacy and safety of DA-5 in TNBC xenograft models via oral administration. Pharmacokinetic profiles were also analyzed. DA-5 demonstrated high-affinity binding to GPX4 (Kd = 10.04 μM) and effectively suppressed its enzymatic activity (IC50 = 10.90 μM). In TNBC cells, DA-5 promoted lipid peroxidation and induced ferroptosis, which was rescued by ferroptosis inhibitors and by iron chelators. Oral administration of DA-5 significantly inhibited TNBC xenograft growth in vivo without systemic toxicity, supported by favorable pharmacokinetic and safety profiles. These findings identify DA-5 as a novel azaindole-based GPX4 inhibitor capable of inducing ferroptosis through GPX4-targeted lipid peroxidation. This breakthrough offers a promising targeted therapy for TNBC.

Ubiquitin-specific protease 7 (USP7) is a key member of the deubiquitinating enzyme family. It is abnormally overexpressed in various malignancies, including breast cancer, chronic lymphocytic leukemia, and prostate cancer. By regulating pathways such as the p53-MDM2 signaling axis, USP7 promotes tumorigenesis and progression, making it a highly promising therapeutic target for anticancer treatment. Although multiple USP7 inhibitors have been reported, existing screening and evaluation assays exhibit limitations: the ubiquitin-phospholipase A2 (Ub-PLA2) assay frequently produces false-positive results, while the ubiquitin-rhodamine (Ub-Rho) assay is susceptible to interference from compound autofluorescence. To address this challenge, we developed a fluorescence polarization (FP) assay. This employs a rationally designed strategy that exhibits excellent characteristics, making it a simple-to-operate and cost-effective method, suitable for the evaluation of compound bioactivity against USP7. To further validate the practicality and reliability of this FP assay, we conducted a structure-based drug design campaign involving two rounds of systematic structural optimization, yielding 51 novel derivatives featuring pyrazolo[4,3-d]pyrimidine and piperidol scaffolds. Following FP evaluation and Ub-Rho enzyme activity validation, we performed a comprehensive structure-activity relationship (SAR) analysis. Ultimately, in vitro cellular assays identified three compounds (LC-U7-44, LC-U7-48, and LC-U7-50) that exhibit potent USP7 inhibitory activity alongside favorable cellular anti-proliferative effects. Overall, the established FP assay in this study closes a methodological gap in the evaluation of USP7 inhibitors, and the detailed SAR analysis provides a foundation for the further development of potent USP7 inhibitors.

PI3Kα plays a key role in a variety of cellular processes, and its gene mutations are closely related to the occurrence and development of many types of cancer. Although two orthosteric PI3Kα inhibitors including Alpelisib and Inavolisib have been launched onto market, they often cause toxic and side effects due to insufficient selectivity for PIK3CA mutant protein. The development of allosteric PI3Kα inhibitors provides new ideas for overcoming these problems. Our research focuses on optimizing a novel series of allosteric PI3Kα inhibitors derived from STX-478. By integrating scaffold hopping and comprehensive structural modification strategies, we obtained the lead compound allosteric PI3Kα inhibitor 11f with a benzothiophene scaffold. The inhibitor demonstrates high selectivity for PIK3CA mutant protein, low hERG inhibition, minimal CYP inhibition, excellent in vivo efficacy, good safety and no impact on insulin balance. Collectively, these findings confirm that compound 11f is a highly promising drug candidate for the targeted therapy of PIK3CA H1047R mutant HR+/HER2-breast cancer.

Glioblastoma multiforme (GBM) counts as one of the highly deadly primary intracranial malignancies, posing a significant challenge to clinical management. Focal Adhesion Kinase (FAK) has been identified as a pivotal molecular target implicated in GBM pathogenesis, modulating key processes such as tumor cell proliferation, invasion, and therapeutic resistance. Despite the considerable number of FAK inhibitors advancing to clinical evaluation, their efficacy against GBM remains inadequately documented. In this study, a cyclization strategy was served for discovering novel FAK inhibitors, which was employed TAE-226 as the molecular scaffold. Among the synthesized derivatives, compound 16c distinguished itself as a highly potent inhibitor, showing an IC50 value of 5.8 nM against FAK and robust antiproliferative activities in U87-MG (IC50 = 6.6 nM) and U118-MG (IC50 = 4.3 nM) GBM cell lines. Additionally, 16c exhibited favorable blood-brain barrier penetration, markedly promoted apoptotic cell death, and induced G2/M cell cycle arrest in U87-MG cells. Furthermore, compound 16c exhibited significant inhibitory activity against 25 kinases, which indicated that it could be a promising multi-targeted kinase inhibitor. Importantly, the oral bioavailability of 16c reached 18.7% at a dose of 10 mg/kg, and 16c displayed pronounced antitumor efficacy in the absence of detectable systemic toxicity in a U87-MG xenograft model. These results collectively highlight the promise of FAK inhibition as a therapeutic strategy for GBM.