Under the European Cosmetic Regulation, safety assessments of cosmetics and their ingredients must be conducted without the use of animals. This regulatory requirement poses a number of challenges, as validated alternative methods are only available for some of the toxicological endpoints that are typically considered in standard human health risk assessments. Despite significant progress since the ban in 2013, particularly in the development of New Approach Methodologies (NAMs) for local and acute toxicity, and for mutagenicity/genotoxicity, there remains an urgent need for non-animal test methods to assess systemic toxicity, which often becomes evident after repeated or long-term exposure. Currently, no validated animal-free alternatives are available for assessing sub-acute, sub-chronic and chronic toxicity, carcinogenicity, developmental/reproductive toxicity, or for a major part of toxicokinetics. In response to these challenges, the Methodology Working Group of the Scientific Committee on Consumer Safety organised a dedicated workshop in December 2024 to discuss advances in the application of Next Generation Risk Assessment (NGRA) as a strategic animal-free approach for the safety assessment of cosmetic ingredients. The workshop focused on a number of important key issues for the practical application of NAMs and NGRA, their regulatory acceptance and identification of possible (partial) solutions to overcome existing limitations.

Amyloid-beta 1-40 peptide (Aβ40) has recently emerged as a blood-based biomarker of cardiovascular disease (CVD). However, whether plasma levels of Aβ40 are associated with metabolic traits in humans without established CVD remains poorly understood. Aβ40 was measured in plasma by ELISA and metabolic traits (waist circumference, fasting triglycerides, fasting HDL cholesterol and fasting glucose) were determined in a general population (n = 449) of individuals who did not have clinically overt CVD. Triglyceride-glucose index (TyG) was used to calculate the risk for insulin resistance. BARD score was used to calculate the risk for metabolic liver disease. Aβ40 levels were associated with the presence of metabolic syndrome (OR: 1.41 95% CI: 1.13-1.76, p = .003), and with higher odds for increasing incidence of metabolic syndrome components, characterized by decreased HDL-C levels (OR: 1.31 95% CI: 1.03-1.58, p = .017) and increased triglyceride levels (OR: 1.30 95% CI: 1.04-1.57, p = .033) after adjustment for traditional cardiovascular risk factors. Further, Aβ40 levels were associated with increased odds for TyG (OR: 1.26 95% CI: 1.03-1.57, p = .042) and increased odds for the presence of diabetes mellitus (OR: 1.35 95% CI: 1.04-1.76, p = .018) after adjustment for age and sex, smoking status, hypertension and dyslipidemia. Increased Aβ40 levels were associated with increased odds for BARD score ≥2 (OR: 1.41 95% CI: 1.04-2.04, p = .045) after adjustment for traditional cardiovascular risk factors. Our findings suggest that Aβ40 peptide is associated with metabolic traits and risk for metabolic disease. Future longitudinal studies are warranted to determine the prognostic value of Aβ40 for the development and progression of metabolic diseases.

Modulation of extracellular matrix (ECM) turnover is a critical prerequisite process underlying the onset of melanoma metastasis. ECM proteases are involved in the degradation of matrix components during ECM turnover, which is associated with melanoma cell growth, migration, invasion, extravasation, metastasis, and modulation of melanoma tumor immunogenicity. During these processes, fluctuations in ECM protease activities and concentrations occur in response to complex regulatory mechanisms acting at both the transcriptional and post-transcriptional levels of protease gene expression. In this review, we examine the major factors of epigenetic machinery, specifically protease-regulating microRNAs (miRNAs), with respect to their ability to directly target ECM protease transcripts and influence melanoma progression. Furthermore, given that dysregulation of the intestinal microbiota has been identified as an etiological factor in melanoma resistance to contemporary immunotherapies, this review examines evidence linking gut dysbiosis-induced changes in matrix metalloproteinase-targeting miRNA profiles to the progression of melanoma. In conclusion, we evaluate the therapeutic potential of approaches involving modifications of gut microbiota populations, alongside direct miRNA targeting of ECM proteases. The integration of these strategies may facilitate the development of innovative adjuvant therapies aimed at overcoming resistance to current inhibitor checkpoint immunotherapies.

Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in chemoimmunotherapy-treated patients remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early endpoint, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each, p=0.4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median, 3.3 versus 8.8 years; HR 2.8, p=0.0036) and OS (HR 2.6, p=0.036) compared to CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS: 71% versus 86%; HR 3.1, p=0.005) and higher mortality (SMR 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR 1.1). In conclusion, BR is effective, irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Non-POD24 patients represent a cohort with distinctly favorable outcome.

The Methana volcanic center, located on the northwestern edge of the Aegean volcanic arc, formed due to the Hellenic subduction zone. Submarine volcanic activity northwest of the Methana Peninsula has created the Paphsanias volcanic field, comprising six volcanic edifices of varying morphology and heights of up to 185m. These edifices lie within the eastern Epidavros Basin, a tectonic graben defined by WNW-ESE, NE-SW, and NW-SE trending faults, filled with 250-500m of Plio-Quaternary sediments. Newly acquired 5m resolution bathymetric data revealed a link between these submarine structures and onshore volcanism, through detailed morphometric analysis highlighting the initiation of NE-SW faulting and a subsequent tectonic phase characterised by E-W-trending faults. The orientation and distribution of the submarine edifices suggest a connection to extensional fault systems and magma ascent, with a general growth trend to the north. Moreover, between Methana and Agistri Island, a hummocky area with scattered and aligned blocks marks a multi-phase failure event. These debris avalanche deposits exhibit moderate mobility, differing from the high-mobility avalanches seen in other Aegean volcanic arc regions, such as Santorini and Nisyros.