Unveiling potentially convergent key events related to adverse outcome pathways induced by silver nanoparticles via cross-species omics-scale analysis.

The adverse effects of silver nanoparticles (AgNPs) have been studied in various models. However, there has been discordance between molecular responses across the literature, attributed to methodological biases and the physicochemical variability of AgNPs. In this study, a gene pathway meta-analysis was conducted to identify convergent and divergent key events (KEs) associated with AgNPs and explore common patterns of these KEs across species. We performed a cross-species analysis of transcriptomic data from multiple studies involving various AgNPs exposure. Pathway enrichment analysis revealed a set of pathways linked to oxidative stress, apoptosis, and metabolite and lipid metabolism, which are considered potentially conserved KEs across species. Subsequently, experiments confirmed that oxidative stress responses could be early KEs in both Caenorhabditis elegans and HepG2 cells. Moreover, AgNPs preferentially impaired the mitochondria, as evidenced by mitochondrial fragmentation and dysfunction. Furthermore, disruption of amino acids, nucleotides, sulfur compounds, glycerolipids, and glycerophospholipids metabolism were in good agreement with gene pathway shreds of evidence. Our findings imply that, although there may be organism-specific responses, potentially conserved events could exist regardless of species and physicochemical factors. These results provide valuable insights into the development of adverse outcome pathways of AgNPs across species and the regulatory toxicity of AgNPs.

CervixFormer: A Multi-scale swin transformer-Based cervical pap-Smear WSI classification framework.

BACKGROUND AND OBJECTIVES: Cervical cancer affects around 0.5 million women per year, resulting in over 0.3 million fatalities. Therefore, repetitive screening for cervical cancer is of utmost importance. Computer-assisted diagnosis is key for scaling up cervical cancer screening. Current recognition algorithms, however, perform poorly on the whole-slide image (WSI) analysis, fail to generalize for different staining methods and on uneven distribution for subtype imaging, and provide sub-optimal clinical-level interpretations. Herein, we developed CervixFormer-an end-to-end, multi-scale swin transformer-based adversarial ensemble learning framework to assess pre-cancerous and cancer-specific cervical malignant lesions on WSIs. METHODS: The proposed framework consists of (1) a self-attention generative adversarial network (SAGAN) for generating synthetic images during patch-level training to address the class imbalanced problems; (2) a multi-scale transformer-based ensemble learning method for cell identification at various stages, including atypical squamous cells (ASC) and atypical squamous cells of undetermined significance (ASCUS), which have not been demonstrated in previous studies; and (3) a fusion model for concatenating ensemble-based results and producing final outcomes. RESULTS: In the evaluation, the proposed method is first evaluated on a private dataset of 717 annotated samples from six classes, obtaining a high recall and precision of 0.940 and 0.934, respectively, in roughly 1.2 minutes. To further examine the generalizability of CervixFormer, we evaluated it on four independent, publicly available datasets, namely, the CRIC cervix, Mendeley LBC, SIPaKMeD Pap Smear, and Cervix93 Extended Depth of Field image datasets. CervixFormer obtained a fairly better performance on two-, three-, four-, and six-class classification of smear- and cell-level datasets. For clinical interpretation, we used GradCAM to visualize a coarse localization map, highlighting important regions in the WSI. Notably, CervixFormer extracts feature mostly from the cell nucleus and partially from the cytoplasm. CONCLUSIONS: In comparison with the existing state-of-the-art benchmark methods, the CervixFormer outperforms them in terms of recall, accuracy, and computing time.

ω3-polyunsaturated fatty acids induce cell death through apoptosis and autophagy in glioblastoma cells: In vitro and in vivo.

Among brain tumors, glioblastoma (GBM) is the most aggressive type and is associated with the lowest patient survival rate. Numerous lines of evidence have established that omega-3-polyunsaturated fatty acids (ω3-PUFAs) have potential for the prevention and therapy of several types of cancers. Docosahexaenoic acid (DHA), an ω3-PUFA, was reported to inhibit growth and induce apoptotic and autophagic cell death in several cancer cell lines; however, its effects on GBM cells are still unknown. in the present study, we examined the cytotoxic effect of DHA on the GBM cell lines, D54MG, U87MG, U251MG and GL261. Treatment of GBM cells with DHA induced PARP cleavage, increased the population of sub-G1 cells, and increased the number of TUNEL-positive cells, which are all indicative of apoptosis. Furthermore, treatment of GBM cells with DHA resulted in a significant increase in autophagic activity, as revealed by increased LC3-II levels, GFP-LC3 puncta, and autophagic flux activation, accompanied by activation of 5'-AMP-activated protein kinase (AMPK) and decreases in phosphorylated Akt (p-AktSer473) levels and mTOR activity. In vivo, endogenous expression of Caenorhabditis elegans ω3-desaturase, which converts ω6-PUFAs to ω3-PUFAs, in fat-1 transgenic mice yielded a significant decrease in tumor volume following subcutaneous injection of mouse glioma cells (GL261), when compared with wild-type mice. TUNEL-positive cell numbers and LC3-II levels were elevated in tumor tissue from the fat-1 transgenic mice compared with tumor tissue from the wild-type mice. In addition, p-Akt levels were decreased and p-AMPK levels were increased in tumor tissue from the fat-1 transgenic mice. These results indicate that ω3-PUFAs induce cell death through apoptosis and autophagy in GBM cells; thus, it may be possible to use ω3-PUFAs as chemopreventive and therapeutic agents for GBM.

Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors.

The Hedgehog (Hh) signaling pathway is associated with diverse aspects of cellular events, such as cell migration, proliferation, and differentiation throughout embryonic development and tissue patterning. An abnormal Hh signaling pathway is linked to numerous human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB), lung cancer, prostate cancer, and ovarian cancer, and it is therefore a promising target in cancer therapy. Using a structure-hopping approach, we designed new Hh signaling pathway inhibitors with isoindolinone or quinazolinone moieties, which were synthesized and biologically evaluated using an 8xGli-luciferase (Gli-Luc) reporter assay in NIH3T3 cells. Compounds 9-11 and 14 with isoindolinone scaffolds demonstrated moderate Hh inhibitory activity; whereas quinazolinone derivatives 24, 29, 32, 34, and 35 exhibited good potency with submicromolar IC50 values and the analog 28 showed nanomolar IC50 value. Although sonidegib shows a decrease in inhibitory effect on vismodegib resistance-conferring Smo mutants, the structurally modified new compounds not only possess the pharmacophoric properties of Hh pathway inhibition but also preserve the suppressive potency in drug-resistant Smo mutants. Mechanistically, quinazolinone derivatives 28 and 34 suppress Hh signaling by blocking Smo and Gli translocation into the cilia, similar to vismodegib and sonidegib. Additionally, the human microsomal stability of the representative analogs 28 and 34 were determined to be comparable to that of the reference compound sonidegib. Thus, these new scaffolds can serve as a platform for the development of novel cancer therapeutics targeting the Hh pathway.

Chemical biology approach for the development of hypoxia inducible factor (HIF) inhibitor LW6 as a potential anticancer agent.

Intratumoral hypoxia has long been considered to be a driving force in tumor progression as well as a negative prognostic factor in human cancers. The discovery of hypoxia inducible factors (HIFs), which mediate transcriptional responses to changes in oxygen levels, has renewed enthusiasm for drug discovery and the development of targeted therapies in this field. LW6 represents an important new class of small molecules that inhibit HIF-1; it has been major source for diverse lead compounds including HIF-1α inhibitors. Through a chemical biology approach, LW6-derived chemical probes were successfully utilized for the identification of the direct targeting of a protein in cancer. LW6 provides a valuable platform for the discovery and development of small molecule inhibitors of HIF-1α-dependent tumor progression, metabolic reprogramming, and angiogenesis.