Short-chain per-fluoroalkyl substances (PFAS) have replaced long-chains in many applications, however the toxicity and its mode of action and interactions due to the large number of these compounds and their mixtures is still poorly understood. The paper aims to compare the effects on mouse liver organoids (target organ for bioaccumulation) of two long-chain PFAS (perfluorooctane sulfonate -PFOS-, perfluorooctanoic acid -PFOA) and two short-chain PFAS commonly utilized in the industry (heptafluorobutyric acid -HFBA-, Pentafluoropropionic anhydride-PFPA) to identify the mode of action of these classes of contaminants. Cytomorphological aberrations and ALT/GDH enzyme disruption were identified but no acute toxicity endpoint neither apoptosis was detected by the two tested short-chain PFAS. After cytomorphological analysis, it is evident that short-chain PFAS affected organoid morphology inducing a reduction of cytostructural complexity and aberrant cytological features. Conversely, EC50 values of 670 ± 30 µM and 895 ± 7 µM were measured for PFOS and PFOA, respectively, together with strong ALT/GDH enzyme disruption, caspase 3 and 7 apoptosis activation and deep loss of architectural complexity of organoids in the range of 500–1000 µM. Eventually, biochemical markers and histology analysis confirmed the sensitivity of organoid tests that could be used as a fast and reproducible platform to test many PFAS and mixtures saving time and at low cost in comparison with in vivo tests. Organoids testing could be introduced as an innovative platform to assess the toxicity to fast recognize potentially dangerous pollutants.

A new class of palladium–indenyl complexes characterized by the presence of one bulky alkyl isocyanide and one aryl phosphine serving as ancillary ligands has been prepared, presenting high yields and selectivity. All the new products were completely characterized using spectroscopic and spectrometric techniques (NMR, FT-IR, and HRMS), and, for most of them, it was also possible to define their solid-state structures via X-ray diffractometry, revealing that the indenyl fragment always binds to the metal centre with a hapticity intermediate between ƞ³ and ƞ⁵. A reactivity study carried out using piperidine as a nucleophilic agent proved that the indenyl moiety is the eligible site of attack rather than the isocyanide ligand or the metal centre. All complexes were tested as potential anticancer agents against three ovarian cancer cell lines (A2780, A2780cis, and OVCAR-5) and one breast cancer cell line (MDA-MB-231), displaying comparable activity with respect to cisplatin, which was used as a positive control. Moreover, the similar cytotoxicity observed towards A2780 and A2780cis cells (cisplatin-sensitive and cisplatin-resistant, respectively) suggests that our palladium derivatives presumably act with a mechanism of action different than that of the clinically approved platinum drugs. For comparison, we also synthesized Pd-ƞ³-allyl derivatives, which generally showed a slightly higher activity towards ovarian cancer cells and lower activity towards breast cancer cells with respect to their Pd-indenyl congeners.

Phosphorylated ACC (pACC), a downstream effector of the LKB1/AMPK pathway, may support tumor bioenergetics and exert a tumor-promoting role in glioblastoma (GBM). In the randomized REGOMA trial, pACC expression was associated with improved overall survival (OS) in GBM patients treated with regorafenib, but its validity in large cohorts is unclear. This study aimed to characterize pACC and phosphorylated AMPK (pAMPK) expression in a real-world GBM cohort and to assess their prognostic and predictive value in patients receiving second-line regorafenib or fotemustine/lomustine. In this retrospective, multicenter translational study, pACC and pAMPK were assessed by immunohistochemistry on FFPE tumor sections from 174 IDH-wild-type GBM patients treated with regorafenib (n = 84) or fotemustine/lomustine (n = 90). Staining was performed with a validated anti-pACC monoclonal antibody and quantified by digital pathology. Survival analyses included univariable and multivariable Cox proportional hazards models, with interaction testing. pACC and pAMPK were expressed in 85.6% and 95.4% of samples, respectively, with heterogeneous spatial patterns. Neither marker was significantly associated with OS in the univariable analyses, and neither retained independent prognostic value in multivariable analysis. Regorafenib was associated with significantly longer OS than alkylating agents (10.4 vs. 6.3 months; p = 0.0021). However, the treatment-by-pACC interaction test was not statistically significant (adjusted p = 0.610), providing no formal evidence of a differential treatment effect by pACC status. Although pACC-positive expression was enriched among patients experiencing longer overall survival under regorafenib, formal treatment-by-biomarker interaction was non-significant. These exploratory findings indicate that pACC is not an established predictive biomarker and warrant prospectively powered evaluation.

Marine brown algae are an important source of bioactive metabolites with promising anticancer potential. Scytosiphon lomentaria has repeatedly shown selective antitumor activity, although the active metabolite associated with its lipophilic fractions had not previously been identified. Here, five solvent extracts were screened and a bioassay-guided primary and secondary fractionation approach, using the less-active related species Scytosiphon dotyi as a comparator, was combined with high-resolution mass spectrometry to identify the oxylipin (E)-6-hydroxyoctadec-4-enoic acid (NP-011548) as a metabolite endowed with significant antitumor activity. The pure compound selectively reduced the viability of human breast (MDA-MB-231) and ovarian (Kuramochi) cancer cells while exhibiting limited toxicity towards normal fibroblasts. Comparative testing with the structural analogs 6-hydroxystearic acid (6-HSA) and 6-oxostearic acid (6-OSA) further indicated that the C4 double bond and the C6 hydroxy group may contribute to the selective activity of NP-011548. NP-011548 induced delayed reactive oxygen species accumulation without activating caspase-3/7 and caused extensive mitochondrial degeneration, lysosomal accumulation, chromatin condensation and plasma membrane alterations, supporting the involvement of a caspase-independent cell death. These findings identify NP-011548 as a candidate metabolite underlying the antitumor activity of S. lomentaria, expanding the biological relevance of marine oxylipins and supporting their potential as a source of novel anticancer agents.