Center for Research in Molecular Medicine and Chronic Diseases

Breast cancer stem cells (BCSCs) have been proposed as the cause of resistance to conventional treatments and of breast cancer recurrence and metastasis. This study provides compelling evidence for the role of the transcription factor POU1F1 in the increase of BCSC-like. Using POU1F1-overexpressing and knock-down breast cancer cell lines, as well as immunodeficient mouse models, our data demonstrate that POU1F1 induces a BCSC-like phenotype in breast tumor cells by deregulating markers such as CD24, CD44, CD133, and ALDH. These phenotypic modifications correlate with functional changes, i.e., increased clonogenicity, mammosphere formation, and glycolysis. In addition, we found that a subpopulation of MCF-7 cells with overexpression of POU1F1 and elevated ALDH expression exhibits both a high tumor-initiating capacity and increased resistance to chemotherapy and radiotherapy treatments. Mechanistically, these features are mediated by POU1F1 activation of the IL-6/JAK2/STAT3 pathway and up-regulation of ALDH. Janus kinase inhibitors and monoclonal anti-IL6 receptor antibodies significantly decrease ALDH expression, colony, and mammosphere formation, suggesting possible use of pharmacological inhibitors of the IL-6/JAK2/STAT3 pathway in breast tumors with elevated POU1F1 levels.

Melanostatin (MIF-1) is an endogenous tripeptide that acts as a positive allosteric modulator (PAM) of the dopamine D2 receptors (D2R), making it a valuable pharmacological lead for the treatment of dopamine-related disorders of the central nervous system (CNS). In this study, a novel series of MIF-1 derivatives was synthesized and pharmacologically evaluated to investigate the influence of ring flexibility and stereochemistry on PAM activity. For this purpose, the alicyclic β-amino acids (1R,2S)-2-aminocyclopentane-1-carboxylic acid (cispentacin) and its unsaturated precursor, (1R,2S)-2-aminocyclopent-3-ene-1-carboxylic acid, were used as proline surrogates. The results obtained showed that cispentacin-based derivatives 8b and 9b displayed PAM activity at 10 pM, significantly reducing the EC50 of dopamine by 4.34- and 4.22-fold, respectively (8b: EC50 = 20.08 ± 3.95 nM; 9b: EC50 = 20.61 ± 4.60 nM). At 1 nM, 8b further decreased the EC50 of dopamine by 9.20-fold (EC50 = 9.47 ± 5.02 nM) and, at higher concentrations (10 and 100 μM), it activated the D2R in the absence of dopamine, representing the first-in-class MIF-1-based ago-allosteric modulator of the D2R. Cytotoxicity assays in human dopaminergic-differentiated SH-SY5Y cells showed that neither 8b nor 9b exhibited cytotoxic effects at 100 μM, as assessed by both the MTT reduction and neutral red uptake assays, supporting their favorable toxicological profiles. Overall, these findings demonstrate that a fine-tuned interplay between ring flexibility and stereochemistry is a key determinant in generating effective PAM of the D2R, providing a framework for the future design of MIF-1-based modulators targeting Parkinson's disease and other dopamine-related CNS disorders.

Preclinical syngeneic tumor models are widely used to evaluate therapeutic responses in immunocompetent hosts, particularly for radiotherapy and radio-immunotherapy. Standard models, such as CT26.WT mouse colorectal carcinoma, have provided valuable insights into treatment efficacy and immune modulation. However, they often fail to reproduce the complexity of advanced human cancers, especially metastases, which differ from primary tumors in immunogenicity, antigen presentation, and tumor microenvironment (TME). Metastatic lesions are typically characterized by poor cytotoxic T cell infiltration and enrichment of immunosuppressive populations such as regulatory T cells and myeloid-derived suppressor cells, limiting the translational relevance of conventional approaches. To better model these features, we developed CT26.MtC3, a novel cell line derived from pulmonary metastases generated by systemic injection of CT26.WT cells into BALB/c mice. When implanted subcutaneously, CT26.MtC3 tumors displayed greater aggressiveness than parental CT26.WT. Immune profiling revealed a strongly immunosuppressive TME, with reduced CD8⁺ T cell infiltration and increased myeloid populations. Complementary in vitro analyses confirmed intrinsic differences, including higher migratory capacity, and significant upregulation of CAECAM-1a. Upon irradiation, CT26.MtC3 cells also showed altered expression of immune-regulatory molecules such as CD47, Fas, PD-L1, and PD-L2, potentially contributing to their immunoevasive phenotype in vivo. Together, these findings establish CT26.MtC3 as a clinically relevant model of metastatic, immune-resistant colorectal cancer. This model provides a robust platform for evaluating strategies to overcome tumor immunoresistance and for rigorously testing the potential of radio-immunotherapy combinations in settings that better reflect clinical reality.

Advances in the understanding of atopic dermatitis (AD) pathogenesis have driven the development of innovative systemic therapies targeting key immunologic pathways. This systematic review summarizes current evidence on the impact of biologic agents, Janus kinase (JAK) inhibitors, and other emerging treatments on AD-related biomarkers and their correlation with clinical outcomes. A comprehensive literature search was conducted across PubMed, Embase, Scopus, and Web of Science for studies published between 2014 and 2024. Eighty studies met the inclusion criteria. Dupilumab was the most extensively investigated therapy, followed by tralokinumab, JAK inhibitors, and novel agents such as amlitelimab, stapokibart, and tezepelumab. Across drug classes, consistent reductions in CCL17/TARC, LDH, and total IgE levels were observed, generally paralleling clinical improvement in EASI and SCORAD scores. Transcriptomic and proteomic analyses revealed normalization of Th2/Th22 inflammatory signatures and restoration of barrier-related gene expression, while microbiome studies showed a reduction in Staphylococcus aureus colonization. Despite these advances, the heterogeneity of study designs and analytical techniques limits the comparability of results. CCL17 and LDH currently represent the most reliable biomarkers associated with disease severity and treatment response, although their limited specificity restricts clinical applicability. Future research should aim to validate integrated biomarker panels combining immunologic, transcriptomic, and microbiomic data to enable precision medicine approaches in atopic dermatitis management.

New arylbenzofuran derivatives were designed, synthesized, and evaluated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Five hybrid compounds (31–35) feature a 2-phenylbenzofuran core linked via a heptyloxy spacer to an N-methylbenzylamine moiety, to enhance interactions within the active site of BChE. Biological evaluation revealed that brominated derivatives 34 and 35 showed the highest cholinesterases (ChE) inhibition compared to their chlorinated analogs, with compound 34 showing the highest activity for both AChE (IC50 = 27.7 μM) and BChE (IC50 = 0.7 μM). These compounds proved to be non-cytotoxic and demonstrated significant antioxidant activity in SH-SY5Y cells exposed to hydrogen peroxide (H2O2), highlighting their potential to mitigate oxidative stress: a key pathological factor in Alzheimer’s disease. Structural activity analysis suggests that bromine substitution at position 7 and the presence of a seven-carbon linker are critical for dual ChE inhibition and selectivity towards BChE. ADMET prediction indicates favorable pharmacokinetic properties, including drug-likeness and oral bioavailability. Overall, these findings highlight the potential of the 2-arylbenzofuran as a promising scaffold for multitarget-directed ligands in Alzheimer’s disease therapy.

The increase in thermal conductivity, κ, at small period lengths in covalently bonded semiconductor and oxide epitaxial superlattices (SLs) is a hallmark of coherent phonon transport and a route for improving heat dissipation in the thin limit. Here, we show that, on the contrary, the phonon coherence length remains shorter than the minimum SL period in van der Waals (vdW) SLs. We measured the cross-plane κz of epitaxial Bi2Se3/β-In2Se3 vdW SLs grown by molecular beam epitaxy; our results show that κ decreases monotonically with increasing interface density down to the two-layer period limit. This suggests that the weak interface vdW bonding of these SLs results in diffusive phonon transport over the whole period range. We discuss further reduction to single-layer SLs and its effects on crystal and interface quality. The results presented in this paper highlight a constraint for thermal management in vdW-based nanoelectronic and thermoelectric devices.

BackgroundCognitive frailty (CF) is defined as the simultaneous presence of physical frailty (PF) and cognitive impairment in the absence of dementia or other brain disorders. CF is considered reversible in the presence of physical pre‐frailty (PPF) and Subjective Cognitive Decline (SCD), and potentially reversible in the presence of PF and Mild Cognitive Impairment (MCI). Previous studies have related CF with neuroimaging biomarkers (Facal et al., 2021), however the relationship between FC and plasma biomarkers specific to AD, such as NfL, Ab42, Ab40, t‐Tau, p‐tau181 and p‐tau217, has been less studied.MethodThe sample consisted of 325 participants from the CompAS who successfully completed cognitive and functional assessment and plasma analysis. Of these, 78 (24%) were non‐frail, 66 (20.3%) had PPF without cognitive decline, 84 (25.8%) reversible cognitive pre‐frailty (RCPF), 81 (24.9%) potentially reversible cognitive pre‐frailty (PRCPF), 2 (0.6%) PF without cognitive decline, 7 (2.2%) reversible CF, and 7 (2.2%) potentially reversible CF. Participants in the PF without cognitive impairment, reversible PF, and potentially reversible PF groups were rare and were excluded from the analyses.The concentrations (pg/mL) of NfL, Aβ‐40, Aβ‐42, tau, p‐tau217, and p‐tau181 were quantified using the ultra‐sensitive Single Molecule Array (SIMOA) technology on the Simoa SR‐X platform (Quanterix). The corresponding commercial kits (PCs. 104073, 101995, 104570, and 104111) were used in strict accordance with the manufacturer's protocol. Group‐comparisons were carried out considering non‐frail, PPF without cognitive decline, RCPF and PRCPF participants.ResultsSignificant differences were found in NfL and p‐Tau217 (Table 1), with lower levels in the group of PPF without cognitive decline compared with the group with PRCPF (Bonferroni test p < 0.05).ConclusionThe differences between the group of PPF without cognitive decline and the group with PRCPF seem to indicate that the presence of plasma AD markers is higher related to the cognitive status of the participants than to their functional status. Further investigation of this relationship would require regression models with CF status as the dependent variable and plasma AD biomarkers and functional markers as predictors.

Land-use/land-cover (LULC) is a critical driver of ecosystem dynamics globally. Arid regions are particularly vulnerable to global change factors, and comprehensive LULC assessments are crucial for evaluating the environmental stability of these areas. Despite considerable developments of remote sensing (RS) data/products and classification algorithms, the available multi-scale maps fail to represent the complex heterogeneity of LULC in these areas. The major limitation resides not on the improvements in data resolutions or the complexity of algorithmic decisions, but rather on the lack of approaches prioritizing detailed categorization of LULC in arid regions. Therefore, we propose an integrative multi-classification approach of LULC based on RS techniques and in-situ data for general application in arid regions, using the north-western Saudi Arabia as pilot area. Using in-situ data (N = 7523) and a Landsat-8 time-series, we applied a supervised classification of non-dynamic classes representing regional geodiversity, combined with a clustering analysis of dynamic harmonic regression model coefficients to categorize ecologically dynamic classes. The map was obtained with high accuracy for non-dynamic classes (Kappa≈0.84; overall accuracy≈0.87; overall producer's accuracy≈0.86; overall user's accuracy≈0.89) and dynamic classes (combined overall accuracy≈0.76). The final map presents a total of 15 classes, considerably improving the available categorical resolution for the study area. The approach is transferable to other arid regions, having the potential to integrate other finer-scale RS data and classification algorithms. We urge for increased efforts in data collection and the implementation of approaches considering the prominent diversity of LULC in arid regions. • We propose an approach of land-use/land-cover (LULC) classification in arid regions. • Multi-classification of LULC based on groups of non-dynamic and dynamic classes. • Final LULC map with high overall and class-wise accuracy measures. • The approach improved the LULC categorization in north-western arid Saudi Arabia. • Improved data collection efforts and target-based approaches needed in arid regions.