Metformin-induced preferential killing of breast cancer initiating CD44+CD24−/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts

Trastuzumab-refractory breast cancer stem cells (CSCs) could explain the high rate of primary resistance to single-agent trastuzumab in HER2 gene-amplified breast cancer patients. The identification of agents with strong selective toxicity for trastuzumab-resistant breast CSCs may have tremendous relevance for how HER2+ breast cancer patients should be treated. Using the human breast cancer cell line JIMT-1, which was established from the pleural metastasis of a patient who was clinically resistant to trastuzumab ab initio, we examined whether preferential killing of the putative CD44+CD24 −/low breast CSC population might be sufficient to overcome primary resistance to trastuzumab in vivo. Because recent studies have shown that the anti-diabetic biguanide metformin can exert antitumor effects by targeted killing of CSC-like cells, we explored whether metformin's ability to preferentially kill breast cancer initiating CD44+CD24 −/low cells may have the potential to sensitize JIMT-1 xenograft mouse models to trastuzumab. Upon isolation for breast cancer initiating CD44+CD24 −/low cells by employing magnetic activated cell sorting, we observed the kinetics of metformin-induced killing drastically varied among CSC and non-CSC subpopulations. Metformin's cell killing effect increased dramatically by more than 10-fold in CD44+CD24 −/low breast CSC cells compared to non-CD44+CD24 −/low immunophenotypes. While seven-weeks treatment length with trastuzumab likewise failed to reduce tumor growth of JIMT-1 xenografts, systemic treatment with metformin as single agent resulted in a significant two-fold reduction in tumor volume. When trastuzumab was combined with concurrent metformin, tumor volume decreased sharply by more than four-fold. Given that metformin-induced preferential killing of breast cancer initiating CD44+CD24 −/low subpopulations is sufficient to overcome in vivo primary resistance to trastuzumab, the incorporation of metformin into trastuzumab-based regimens may provide a valuable strategy for treatment of HER2+ breast cancer patients

Understanding the self-assembly of TCNQ on Cu(111): a combined study based on scanning tunnelling microscopy experiments and density functional theory simulations

Two polymorphic structures of TCNQ on Cu(111) can be formed by varying the deposition conditions.</p

Sex-Specific Relationships of Physical Activity and Sedentary Behaviour with Oxidative Stress and Inflammatory Markers in Young Adults

This study aims to analyse sex-specific associations of physical activity and sedentary behaviour with oxidative stress and inflammatory markers in a young-adult population. Sixty participants (21 women, 22.63 ± 4.62 years old) wore a hip accelerometer for 7 consecutive days to estimate their physical activity and sedentarism. Oxidative stress (catalase, superoxide dismutase, glutathione peroxidase, glutathione, malondialdehyde, and advanced oxidation protein products) and inflammatory (tumour necrosis factor-alpha and interleukin-6) markers were measured. Student t-tests and single linear regressions were applied. The women presented higher catalase activity and glutathione concentrations, and lower levels of advanced protein-oxidation products, tumour necrosis factor-alpha, and interleukin-6 than the men (p < 0.05). In the men, longer sedentary time was associated with lower catalase activity (β = −0.315, p = 0.04), and longer sedentary breaks and higher physical-activity expenditures were associated with malondialdehyde (β = −0.308, p = 0.04). Vigorous physical activity was related to inflammatory markers in the women (tumour necrosis factor-alpha, β = 0.437, p = 0.02) and men (interleukin−6, β = 0.528, p < 0.01). In conclusion, the women presented a better redox and inflammatory status than the men; however, oxidative-stress markers were associated with physical activity and sedentary behaviours only in the men. In light of this, women could have better protection against the deleterious effect of sedentarism but a worse adaptation to daily physical activity.This work was partly supported by Universidad de Cádiz (grant number PR2016-051 and PR2019-054), by Instituto de Investigación e Innovación Biomédica de Cádiz (LI19/21IN-CO09), and by the Spanish Ministry of Science and Innovation (Ministerio de Ciencia e Innovación) (MCIN/AEI/ 10.13039/501100011033), grants PID2019-110063RA-I00 and PID2020-120034RA-I00. J.C.-P. is supported by a predoctoral grant from the Spanish Ministry of Education (Ministerio de Educación) (grant number FPU19/02326). D.V.-D is funded by the Margarita Salas Postdoctoral Program from European Union Next GenerationEU and University of Cádiz. Partial funding for open access charge: Universidad de Málag

Fabrication and Actuation of Magnetic Shape-Memory Materials

Soft actuators are deformable materials that change their dimensions and/or shape in response to external stimuli. Among the various stimuli, remote magnetic fields are one of the most attractive forms of actuation, due to their ease of use, fast response and safety in biological systems. Composites of magnetic particles with polymer matrices are the most common material for magnetic soft actuators. In this paper, we demonstrate the fabrication and actuation of magnetic shape-memory materials based on hydrogels containing field-structured magnetic particles. These actuators are formed by placing the pregel dispersion into a mold of the desired on-field shape and exposing this to a homogeneous magnetic field until the gel point is reached. At this point the material may be removed from the mold and fully gelled in the desired off-field shape. The resultant magnetic shape-memory material then transitions between these two shapes when subjected to successive cycles of a homogeneous magnetic field, acting as a large deformation actuator. For actuators that are planar in the off-field state, this can result in significant bending to return to the on-field state. In addition, it is possible to make shape-memory materials that twist under the application of a magnetic field. For these torsional actuators, both experimental and theoretical results are given.Departamento de Física AplicadaGrupo FQM144Ministerio de Ciencia, Innovación y UniversidadesAgencia Estatal de InvestigaciónDeutsche Forschungsgemeinschaft (DFG

IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations

Using non-small cell lung carcinoma (NSCLC) cells harboring the erlotinib-sensitizing Epidermal Growth Factor Receptor (EGFR) exon 19 mutation delE746-A750, we developed erlotinib-refractory derivatives in which hyperactive Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling associated with enrichment in epithelial-to-mesenchymal transition (EMT)-related morphological and transcriptional features. We then explored whether an IGF-1R/EMT crosstalk was sufficient to promote erlotinib refractoriness in the absence of second-site EGFR mutations, MET and AXL hyperactivation. Transforming Growth Factor-beta1 (TGF beta 1)-induced mesenchymal trans-differentiation was sufficient to impede erlotinib functioning in the presence of drug-sensitive delE746-A750 EGFR mutation. Pharmacological blockade of IGF-1R fully prevented the TGF beta 1's ability to activate an EMT protein signature [E-cadherin low/vimentin high]. The sole presence of erlotinib was capable of rapidly activate an IGF-1R-dependent, vimentin-enriched mesenchymal-like phenotype in delE746-A750-mutated epithelial cells. Even if transient, NSCLC cells' intrinsic plasticity to undergo crosstalk between IGF-1R and EMT signaling pathways can sufficiently eliminate the erlotinib-sensitizing effect of highly prevalent EGFR mutations and suggests the urgent need for dual IGF-1R/EMT-targeting strategies to circumvent erlotinib resistance