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Purpose: To evaluate the efficacy and safety of first-line therapy with palbociclib in a Spanish cohort treated after palbociclib approval. Methods: PALBOSPAIN is an observational, retrospective, multicenter study evaluating real-world patterns and outcomes with 1 L palbociclib in men and women (any menopausal status) with advanced HR+/HER2– BC diagnosed between November 2017 and November 2019. The primary endpoint was real-world progression-free survival (rw-PFS). Secondary endpoints included overall survival (OS), the real-world response rate (rw-RR), the clinical benefit rate, palbociclib dose reduction, and safety. Results: A total of 762 patients were included. The median rw-PFS and OS were 24 months (95% CI 21–27) and 42 months (40-not estimable [NE]) in the whole population, respectively. By cohort, the median rw-PFS and OS were as follows: 28 (95% CI 23–39) and 44 (95% CI 38-NE) months in patients with de novo metastatic disease, 13 (95% CI 11–17) and 36 months (95% CI 31–41) in patients who experienced relapse < 12 months after the end of ET, and 31 months (95% CI 26–37) and not reached (NR) in patients who experienced relapse > 12 months after the end of ET. rw-PFS and OS were longer in patients with oligometastasis and only one metastatic site and those with non-visceral disease. The most frequent hematologic toxicity was neutropenia (72%; grade ≥ 3: 52.5%), and the most common non-hematologic adverse event was asthenia (38%). Conclusion: These findings, consistent with those from clinical trials, support use of palbociclib plus ET as 1 L for advanced BC in the real-world setting, including pre-menopausal women and men. Trial registration number: NCT04874025 (PALBOSPAIN). Date of registration: 04/30/2021 retrospectively registered. [ABSTRACT FROM AUTHOR]

Effluents from urban wastewater treatment plants (UWWTPs) discharged into water bodies such as the sea or ocean, offer a potential source of renewable energy through the salinity gradient (SGE) between seawater and treated water. The European project Life-3E: Environment-Energy-Economy aims to demonstrate an innovative process integrating renewable energy production with water reclamation. Using reverse electrodialysis (RED) technology, SGE can power tertiary wastewater treatment processes in coastal UWWTPs, offsetting energy costs associated with water regeneration and reuse. This study pioneers a pilot-scale RED system with a 20.125 m 2 membrane area at a coastal UWWTP in Comillas, Spain. The initial tests with synthetic solutions in the up-scaled RED module have reached a peak power density of 1.39 W/m 2 . Under real environmental conditions, using natural seawater and treated water at ambient temperatures (289 ± 0.5 K), the system achieved a peak power density of 0.95 W/m 2 , outperforming previous setups in stability and efficiency. The results show competitive energy metrics, with an energy efficiency of 1.9 W/m 2 ·m³LC and up to 38.2 Wh/m³LC generated. The treated water, with an inlet conductivity to the RED stack of <1 mS/cm, exits the pilot with a conductivity of around 4 mS/cm (measured under a load of 2A and a flow rate of 500 L/h), maintaining the quality standards for urban reuse. This study demonstrates the effective integration of RED technology into water reclamation stages, creating a self-sustained energy loop and enhancing the efficiency in water management. By harnessing blue energy and supporting sustainable water reuse, this research contributes to the global shift toward a circular water economy and critical sustainability goals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The chemical potential difference at the discharge points of coastal Wastewater Treatment Plants (WWTPs) uncovers the opportunity to harness renewable salinity gradient energy (SGE). This work performs an upscaling assessment of reverse electrodialysis (RED) for SGE harvesting of two selected WWTPs located in Europe, quantified in terms of net present value (NPV). For that purpose, a design tool based on an optimization model formulated as a Generalized Disjunctive Program previously developed by the research group has been applied. The industrial scale-up of SGE-RED has already proven to be technically and economically feasible in the Ierapetra medium-sized plant (Greece), mainly due to a greater volumetric flow and a warmer temperature. At the current price of electricity in Greece and the up-to-date market cost of membranes of 10 EUR/m 2 , the NPV of an optimized RED plant in Ierapetra would amount to EUR117 thousand operating with 30 RUs in winter and EUR 157 thousand for 32 RUs in summer, harnessing 10.43 kW and 11.96 kW of SGE for the winter and summer seasons, respectively. However, in the Comillas facility (Spain), this could be cost-competitive with conventional alternatives, namely coal or nuclear power, under certain conditions such as lower capital expenses due to affordable membrane commercialization (4 EUR/m 2 ). Bringing the membrane price down to 4 EUR/m 2 would place the SGE-RED's Levelized Cost of Energy in the range of 83 EUR/MWh to 106 EUR/MWh, similar to renewable sources such as solar PV residential rooftops.

The individual effects of iprovalicarb, mepanipyrim, and tetraconazole on the volatile composition and aromatic profile of Monastrell-based wines were evaluated. To date, no studies about the effect of these fungicides on Monastrell-based wines are available, and the effect on other grape varieties is also unknown. Fungicides were added separately in the cellar to the grape must at two concentration levels (4 and 10 mg/kg for iprovalicarb and mepanipyrim and 1 and 2.5 mg/kg for tetraconazole). The aromatic composition of the final wines was analysed by gas chromatography using flame ionisation and ion trap mass selective detectors. In the presence of fungicides, the most significant variations were observed for isoamyl acetate and 2-phenylethyl acetate (increasing between 20 and 43% compared with the control wine) and ethyl caprate and caprylate (increasing between 12 and 68%). Consequently, treated wines showed a higher global odourant intensity, with increased fresh fruit notes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The effect of two commercial formulations (incorporating mepanipyrim and tetraconazole as active substances) on the metabolism of Saccharomyces cerevisiae Lalvin T73™, growing on a synthetic grape must, and their influence on the alcoholic fermentation course and the biosynthesis of volatiles derived from phenylalanine catabolism was studied. No relevant effects were observed for mepanipyrim except for glycerol production. On the contrary, in the presence of tetraconazole many genes and some proteins related to cell cycle progression and mitosis were repressed. This fact could explain the lower biomass concentration and the lower sugar consumption registered for tetraconazole at the end of the study. However, the biomass-to-ethanol yield was higher in connection with the overexpression of the ADH1 gene. The presence of tetraconazole residues seems to accelerate the Ehrlich pathway. These results agree with the overexpression of several genes (BAT1, PDC1, PDC5, ADH1, SFA1, ATF2, PFK1, PFK2 and ARO3) and a higher abundance of two proteins (Gap1p and Atf2p) involved in this metabolic pathway., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The impact of fungicides mepanipyrim (Mep) and tetraconazole (Tetra) and their corresponding commercial formulations (Mep-Form and Tetra-Form) on the aroma composition of wines was assessed. Fungicide residues can affect the biotransformation of aroma precursors from grapes and/or the yeast metabolism. The results confirmed that both maximum residue levels (MRL and 2xMRL) of Mep promoted benzyl alcohol and 4-vinylguaiacol contents; while MRL and 2xMRL of Mep-Form promoted benzene derivatives (benzyl alcohol, benzaldehyde, and trans-isoeugenol), 2-phenylethanol and γ-nonalactone. The addition of Tetra (2xMRL) and Tetra-Form (MRL and 2xMRL) release higher contents of cis-3-hexen-1-ol and ethyl vanillate and affected yeast metabolism related to phenylacetaldehyde, 2-phenylethanol, methionol, capric acid, ethyl 2-methylbutyrate, ethyl isovalerate, ethyl monosuccionate, diethyl succinate and γ-butyrolactone production. Fungicide residues did not display higher variations in global odour activity values with respect to control wines, although some variations on the "floral", "fruity", "spicy" and "lactic" nuances could be sensed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The 9p21 gene cluster, harboring growth suppressive genes p14 ARF , p15 INK4b , and p16 INK4a , is one of the major aberration hotspots in head and neck cancers. We try to elucidate specific aberrations affecting this region, throughout methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. Methylation of the gene was investigated by MS-MLPA in a well-characterized series of 27 laryngeal squamous cell carcinomas and 20 samples of healthy mucosa. Aberrant promoter hypermethylation was confirmed using and methylation-specific. All samples studied except 3 (11 %) presented losses at 9p21 segment. The most common finding was the small deletion (exon 1α) of the p16 INK4a locus (44 %). Deletion of the 9p21 gene cluster was identified in 5 cases (18 %). We only found methylation in 8 samples (30 %) for p15 IK4b -exon 1. Promoter methylation of p14 ARF , p15 IK4b and p16 INK4a was not detected in any tumor sample. Methylation-specific polymerase chain reaction confirmed the results. Our data indicate that there may be a subgroup of patients in which epigenetic regulation of 9p21 segment might have little relevance. Nevertheless, MS-MLPA could not be suitable for the study of methylation at this region and further research is required.

The effects of four fungicides commonly used for the control of fungal diseases in vines and grapes in the course of winemaking were tested. The concentration of fungicide residues was monitored throughout the process to establish their kinetics of dissipation. In all cases the percentages of dissipation were >68%, which shows the detoxificant effect of the winemaking process. On the other hand, the effect of the fungicide residues on the aroma composition of Tempranillo red wines was tested. To evaluate possible modifications on the aroma profile of wines, seven odorant series (ripe fruits, fresh fruits, lactic, floral, spicy, vinous, and herbaceous) were built from the odor activity values (OAVs) obtained for each volatile compound. Ripe fruits and fresh fruits were the major aromatic attributes in all Tempranillo red wines. These two odorant series registered the highest variations in their total OAVs with respect to the control wine, especially with the application of boscalid + kresoxim-methyl into vines, leading to a decrease in the ripe fruit and fresh fruit nuances of the resulting wines. Moreover, when the effect of these fungicides on the aroma of Tempranillo red wines was compared throughout two years (2012 and 2013), wines elaborated from grapes treated in the field with boscalid + kresoxim-methyl in 2013 displayed the highest variation in aroma profile with respect to control wine.

The effect of two antifungals (boscalid+kresoxim-methyl and metrafenone) applied onto vines under Good Agricultural Practices (GAPs) on the volatile composition of Tempranillo and Graciano red wines was studied. Changes in aroma profile in the wines were assessed from the combined odour activity values (OAVs) for the volatile compounds in each of seven different odorant series (viz., ripe fruits, fresh fruits, lactic, floral, vinous, spicy and herbaceous). Graciano wines obtained from grapes treated with the antifungals exhibited markedly increased concentrations of varietal volatile compounds (monoterpenes and C13-norisoprenoids) and aldehydes, and decreased concentrations of acetates and aromatic alcohols. By contrast, the concentrations of volatile compounds in Tempranillo wines showed different changes depending on the fungicide applied. Also, the aroma profiles of wines obtained from treated grapes were modified, particularly the ripe fruit nuances in Graciano wines. The OAV of this odorant series underwent an increase by more than 60% with respect to the control wine as a result of the increase of β-damascenone concentration (which imparts wine a dry plum note). The aroma profile of Tempranillo red wines containing metrafenone residues exhibited marked changes relative to those from untreated grapes.

Objectives: Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay is a method that has rarely been exploited in DNA methylation profiling of laryngeal squamous cell carcinoma (LSCC)., Material and Methods: Methylation of the gene was investigated by MS-MLPA in a well-characterized series of 53 LSCC and 30 samples of healthy mucosa. Aberrant promoter hypermethylation was confirmed using bisulfite pyrosequencing, and methylation-specific., Results: Promoter hypermethylation was observed in 36 of the 53 patients (68%). CDKN2B (28%), APC (17%), RARβ (15%), DAPK1 (11%) and CHFR (11%) were most frequently hypermethylated. Aberrant methylation of CHFR was mainly a late-stage event. Methylation-specific polymerase chain reaction and bisulfite pyrosequencing confirmed aberrant methylation for CDKN2B, APC and DAPK1., Conclusion: Promoter methylation profiling of LSCC using MS-MLPA identified CDKN2B, DAPK1, RARβ, APC, and CHFR as frequent epigenetic events. The clinical implications of these genes as biomarkers are highly relevant as attractive targets for cancer therapy, given the reversible nature of epigenetic gene silencing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Type 2 diabetes mellitus (DM2) is a disease with high prevalence and significant impact in terms of mortality and morbidity. The increased prevalence of the disease requires the implementation of new strategies to promote patient self-management. The Spanish Diabetes Self-Management Program (SDSMP) has proven to be effective in other settings. The objective of this study is to assess its effectiveness in terms of care for DM2 patients in primary care settings within the Basque Health Service - Osakidetza (Spain)., Method/design: This is a randomised clinical trial in which patients diagnosed with DM2, 18-79 years of age, from four health regions within the Basque Health Service will be randomised into two groups: an intervention group, who will follow the SDSMP, and a control group, who will receive usual care in accordance with the clinical guidelines for DM2 and existing regulations in our region. The intervention consists of 2,5 hour-group sessions once a week for six weeks. The sessions cover target setting and problem solving techniques, promotion of physical exercise, basic knowledge of nutrition, proper use of medication, effective communication with relatives and health professionals, and basic knowledge about DM2 and its complications. This content is complemented by educational material: books, leaflets and CDs. The primary outcome measure will be the change in glycated haemoglobin (HbA1c), and secondary outcome measures will include changes in levels of physical activity and intake of fruit and vegetables, cardiovascular risk, quality of life, self-efficacy, number of consultations and drug prescriptions. The results will be analysed 6, 12 and 24 months after the intervention., Discussion: If the intervention were to be effective, the programme should be spread to the entire diabetic population in the Basque Country and it could also be applied for other diseases., Trial Registration: ClinicalTrials.gov identifier NCT01642394.