Resultados de investigación

Figure 1. WAPOSAL regions containing the wave power density information based on satellite high-resolution observations (CryoSat-2 and Sentinel-3 A/B) - https://waposal.tecnico.ulisboa.pt/index.php/regions/ - https://waposal.tecnico.ulisboa.pt/ - https://eo4society.esa.int/projects/waposal/ - https://opensciencedata.esa.int/products/waposal-waves/collection - https://esa-earthcode.github.io/tutorials/waposal/, The WAPOSAL project has developed a novel database derived from high-resolution OCRE EO satellite altimetry data, comprising 11 years of reprocessed Cryosat-2 and Sentinel-3 A/B data, and serving as a proof of concept for the regions depicted below in Figure 1. The objective of WAPOSAL (Wave Power & Satellite Altimetry) is to create a new-generation database of wave power density, its variability, and the trend of the wave resource, based on high-resolution observations, This research was funded by the European Space Agency (ESA) Open Call (FUTURE EO-1 SEGMENT 2 OPEN CALL FOR PROPOSAL FOR EO INNOVATION) contract ESA Co. 4000144113/24/I-DT-bgh given for the WAPOSAL Project. We are grateful to ESA. https://eo4society.esa.int/projects/waposal/, This work contributes to the Institut de Ciències del Mar "Severo Ochoa Centre of Excellence" accreditation CEX2024-001494-S funded by AEI 10.13039/501100011033 of the Spanish Ministry of Science and Innovation, Peer reviewed

Activation of PPARδ initiates invasiveness and metastasis. A,PPARD mRNA expression upon 24 to 48 hours of treatment with MCM, etomoxir (Eto), and 5 μmol/L of the PPARδ agonist GW0742. Pooled data of PDAC-215, 253, and 354 cells (n = 4–7). B, Representative Western blot after 48 hours of treatment in PDAC-354 cells. C, PPARδ activity, measured as binding to the PPAR response element, following stimulation with MCM, etomoxir, and the PPARδ agonist GW0742 for 24 hours (n = 5). D, CUT&Tag analysis of PPARδ protein binding at the UCP1, PGC1A, and SNAI2 loci. WashU Epigenome browser tracks showing CUT&Tag signals at the mentioned loci with the indicated transcription start site (TSS). Blue signals represent PPARδ binding in control (Ctrl) conditions, and red signals represent PPARδ binding upon 24 hours of etomoxir treatment in PDAC-002 cells. E, Lipidomics analyses for PDAC-215 and PDAC-253 cells treated for 24 hours with MCM and etomoxir. OPLS-DA analysis showing the most represented lipids common for PDAC-215 and 253 for each experimental conditions vs. the control condition (n = 3). F, Venn diagram indicating the number of lipid species for each experimental group. The four common upregulated lipids for all four conditions are indicated in the square. G, Invasive capacity of cells treated for 48 hours with the PPARδ agonists L-165 and GW0742 (5 μmol/L). Cells were placed in modified Boyden invasion chambers containing 20% FBS in the lower compartment, and the number of invasive cells was assessed after 16 hours (n = 4–8). H, Experimental metastasis assay of PDAC-354-GFP-Luc cells pretreated with GW0742 for 48 hours. After intrasplenic injection, mice received three more daily doses of GW0742 (0.3 mg/kg i.v.). IVIS imaging (left) and quantification of the total CK-19 area in the livers 9 weeks after implantation (right). All data are represented as the mean ± SEM. *, P < 0.05; **, P < 0.01. See also Supplementary Figs. S7–S9., European Commission National Natural Science Foundation of China Associazione Italiana per la Ricerca sul Cancro Instituto de Salud Carlos III Worldwide Cancer Research Fundación Científica Asociación Española Contra el Cáncer Fundación Fero Cancer Council NSW (Australia) National Health and Medical Research Council (Australia) German Research Foundation Shanghai Municipal Education Commission Ministero della Salute, Peer reviewed

Supplementary Figure S1 | IPATHER trial design. aPatients could be pre-screened before or during induction treatment with chemotherapy and dual anti-HER2 blockade regimen. Patients who were HER2-positive and harbored a PIK3CA mutation, identified in archival or fresh tumor tissue samples (from primary breast, local recurrence, or metastatic lesions) or in ctDNA, qualified for the study. ctDNA, circulating tumor DNA; EOT, end of treatment; ER, estrogen receptor; HR, hormone receptor; MBC, metastatic breast cancer; PO, oral administration; PR, progesterone receptor; SC, subcutaneous., The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP. Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%–58.5%], clinical benefit rate 84.6% (95% CI, 53.7%–97.3%), and median progression-free survival 16.4 months (95% CI, 9.4–NR); 47.3% of patients were progression free at 18 months. These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut., Peer reviewed

We investigate how microbial diversity loss affects the degradation of five commercial plastics with varying biodegradability under contrasting nutrient regimes (oligotrophic and eutrophic) in marine sediments. We conducted a six-month laboratory experiment in which plastics were exposed to a gradient of decreasing microbial diversity using the dilution-to-extinction approach., This study forms part of the ThinkInAzul programme and was supported by MICIU with funding from European Union NextGenerationEU (PRTR-C17.I1) and by Generalitat Valenciana (GVA-THINKINAZUL/2021/041; principal investigators: C. Sanz-Lázaro, A. Beltrán-Sanahuja, University of Alicante). This manuscript is published as part of the project “Viable, safe and sustainable PHBV value chain for food packaging applications (ViSS)” under a CreativeCommon Public Domain Dedication. ViSS was Co – Funded by the European Union, grant number 101081931. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union, REA or UKRI. Neither the European Union nor the granting authorities can be held responsible for them, No

Supplementary Figs. 1–6 and Table 1 Reporting Summary Peer Review File, Peer reviewed

PPARδ controls the balance between OXPHOS and glycolysis, linked to EMT and metastasis. A,In vitro invasion in PDAC-215, 253, and 354 cells stably transduced with inducible lentiviral vectors expressing either a nontargeting short hairpin RNA (NT shRNA) or three different shRNAs against PPARD (sh#1, sh#2, and sh#3). Transduced cells were pretreated with doxycycline for 24 hours, then incubated with MCM, etomoxir (Eto), or L-165 for 48 hours, and finally plated in modified Boyden chambers for 16 hours (n = 7). B, Top, ZsGreen expression by RT-qPCR in liver homogenates from an in vivo metastasis assay of PDAC-354 cells stably expressing either the NT or the sh#1 against PPARD. Cells were pretreated with doxycycline and/or 20 μmol/L etomoxir for 48 hours. After intrasplenic implantation, mice were treated with oral doxycycline (2 mg/mL; drinking water) and etomoxir (15 mg/kg, i.p. daily) for 7 days, when splenectomies were performed. Bottom, numbers indicate the percentage and total number of micrometastases in each experimental group. C, PDAC-215, 253, and 354 transduced cells as in A were pretreated with doxycycline for 24 hours, then incubated with MCM, etomoxir, or L-165, and then tested for ATP-linked respiration (top) and glycolytic capacity (bottom) after additional 24 hours (n = 8). D, Mitochondrial stress test (top row) and glycolysis test (bottom row) following treatment with control (Ctrl) or the PPARδ agonists L-165 or GW0742. Left column, representative OCR and extracellular acidification rate (ECAR) profiles for PDAC-253. Right column, pooled data for PDAC-215, 253, and 354 cells (n = 6–9). Glyco, glycolytic; Max res, maximum respiration; O, ATP synthase inhibitor oligomycin; F, mitochondrial OXPHOS uncoupler FCCP [carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone]; A+R, complex III inhibitor antimycin A + electron transport change inhibitor rotenone. G, glucose; 2DG, glycolysis inhibitor 2-deoxy-glucose. E, ATP-linked respiration (left) and maximal respiration (right) for control vs. GW0742-treated cells following treatment with or without palmitate-BSA (FAO assay). PDAC-354 cells were treated with 10 μmol/L GW0742 for 48 hours prior to the assay (n = 5). In A, C, and D, the bars represent pooled data from PDAC-215, 253, and 354, showing individual data points corresponding to each PDX. All data are represented as the mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. control, ###, P < 0.001 vs. palmitate., European Commission National Natural Science Foundation of China Associazione Italiana per la Ricerca sul Cancro Instituto de Salud Carlos III Worldwide Cancer Research Fundación Científica Asociación Española Contra el Cáncer Fundación Fero Cancer Council NSW (Australia) National Health and Medical Research Council (Australia) German Research Foundation Shanghai Municipal Education Commission Ministero della Salute, Peer reviewed

Supplementary data S3. Analysis outputs., The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP. Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%–58.5%], clinical benefit rate 84.6% (95% CI, 53.7%–97.3%), and median progression-free survival 16.4 months (95% CI, 9.4–NR); 47.3% of patients were progression free at 18 months. These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut., Peer reviewed

Root-knot nematodes (RKNs) cause major yield losses in horticultural systems worldwide. With increasing restrictions on chemical nematicides, environmentally sustainable alternatives such as entomopathogenic nematodes (EPNs) and derivatives of their symbiotic bacteria are gaining attention. However, it remains unclear how EPNs and their bacterial products might influence RKN behavior. This study investigated the behavioral responses of the RKN Meloidogyne incognita to EPN-derived treatments, testing the hypothesis that these cues induce directional avoidance when RKNs are given a choice, and that such responses may be modulated by plant presence. Experiments were conducted using two-choice horizontal tube systems filled with moistened sand with and without tomato seedlings ( Solanum lycopersicum cv. Moneymaker). Three EPN Steinernema species were assessed: S. feltiae , S. carpocapsae , and S. riojaense . Treatments included (i) EPN infective juveniles (IJs), (ii) EPN-infected Galleria mellonella cadavers, and (iii) bacterial cell-free supernatant (CFS) derived from Xenorhabdus spp. After inoculation of 1500 M. incognita second-stage juveniles (J2s) into the central tube section, nematode movement was quantified after seven days. Although overall J2 mobility was generally low, with most individuals remaining near the inoculation point, clear patterns still emerged: J2 showed a significant avoidance of EPNs and their derivatives, with the strongest responses observed for cadaver and CFS treatments. Plant presence did not markedly change J2 behavioral patterns; repellency occurred regardless of plant cues, although the presence of plants slightly amplified the effect. These findings advance our understanding of how EPNs and by-products influence RKN behavior, revealing early behavioral barriers that may shape rhizosphere interactions., Ministry of Science and Innovation, grant PID2022-136487OB-I00 (MCIN/AEI/10.13039/50110001103 and and by “ERDF A way of making Europe"). The use of the entomopathogenic nematodes described in this study was conducted under permit reference number ESNC 273, corresponding to the Internationally Recognized Certificate of Compliance (IRCC) with unique identifier ABSCH-IRCC-ES-281207-1 RBP is funded by the Consejería de Innovación (Government of La Rioja, Spain, (Resolution 198/2025, call 2025–2028) MMGT was awarded a FPI-CAR-2022 fellowship (University of La Rioja, Spain), Peer reviewed

Supplementary Data S2. Study Protocol., The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP. Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%–58.5%], clinical benefit rate 84.6% (95% CI, 53.7%–97.3%), and median progression-free survival 16.4 months (95% CI, 9.4–NR); 47.3% of patients were progression free at 18 months. These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut., Peer reviewed

Supplementary Data S1. Detailed description of the experimental and analytical methods used in this study., The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP. Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%–58.5%], clinical benefit rate 84.6% (95% CI, 53.7%–97.3%), and median progression-free survival 16.4 months (95% CI, 9.4–NR); 47.3% of patients were progression free at 18 months. These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut., Peer reviewed