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To analyse the incidence and survival of patients with oligometastases (solitary and normal) when they are treated in centres that are experts in multidisciplinary approach to patients with sarcoma.Retrospective analysis of 414 patients with bone metastases secondary to carcinomas at Hospital Universitario La Paz and Hospital MD Anderson Cancer Centre (Madrid) between May 2006 and May 2019. Metastases located in the pelvis and axial skeleton were excluded, analyzing a total of 28 patients who met the criterion for solitary metastases or oligometastases with normal criteria. The study survival estimate was carried out following the Kaplan-Meier statistical method.The survival of the patients following the oligometastases criteria (solitary and normal) was 53%. Breast cancer was the most prevalent and had a survival rate of more than 70%. The average age of the patients was 58 years old.Systemic treatments in cancer treatment have managed to improve disease-free survival curves and lead us to redirect on the paradigm for the treatment of oligometastases, stating that treatment should be carried out in the centres that are experts in the treatment of sarcomas.The choice of surgical treatment for patients with oligometastases in the strict sense (solitary) and normal should be evaluated by multidisciplinary teams according to the prognoses of the patient, anatomical location and histotype of the neoplasm.

The systemic effects of physical activity are mediated by the release of IL-6 and other myokines from contracting muscle. Although the release of IL-6 from muscle has been extensively studied, the information on the cellular mechanisms is fragmentary and scarce, especially regarding the role of Ca2+ signals. The aim of this study was to characterize the role of the main components of Ca2+ signals in human skeletal muscle cells during IL-6 secretion stimulated by the Ca2+ mobilizing agonist ATP. Primary cultures were prepared from surgical samples, fluorescence microscopy was used to evaluate the Ca2+ signals and the stimulated release of IL-6 into the medium was determined using ELISA. Intracellular calcium chelator Bapta, low extracellular calcium and the Ca2+ channels blocker La3+ reduced the ATP-stimulated, but not the basal secretion. Secretion was inhibited by blockers of L-type (nifedipine, verapamil), T-type (NNC55-0396) and Orai1 (Synta66) Ca2+ channels and by silencing Orai1 expression. The same effect was achieved with inhibitors of ryanodine receptors (ryanodine, dantrolene) and IP3 receptors (xestospongin C, 2-APB, caffeine). Inhibitors of calmodulin (calmidazolium) and calcineurin (FK506) also decreased secretion. IL-6 transcription in response to ATP was not affected by Bapta or by the T channel blocker. Our results prove that ATP-stimulated IL-6 secretion is mediated at the post-transcriptional level by Ca2+ signals, including the mobilization of calcium stores, the activation of store-operated Ca2+ entry, and the subsequent activation of voltage-operated Ca2+ channels and calmodulin/calcineurin pathways.

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood–brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.

El uso de pajuelas para inseminación ha permitido aumentar la tasa de preñez en la especie bovina. El presente estudio tiene como objetivo evaluar la eficiencia del diluyente para la conservación de semen bovino. Para llevar a cabo la investigación se analizó parámetros como son, aptitud reproductiva del macho, evaluación funcional de la libido, prueba de capacidad de servicio, recolección del semen, evaluación macroscópica y microscópica del eyaculado. El semen obtenido presento color blanco cremoso, densidad lechosa y olor a yema de huevo, además se observó alta densidad, motilidad y movilidad de las células espermáticas.El diluyente más el semen dio un volumen de 17,5 mL, procesándose 35 pajuelas de 0,5mL, las que fueron almacenadas en nitrógeno l íquido. A fin de evaluar la viabilidad de las pajuelas, se descongeló una de ellas y se observó al microscopio el nivel de espermatozoides viables, determinándose que las pajuelas son óptimas para inseminación artificial.

Information of patients underwent the biopsy procedures.

Evaluation of RAD51 scores in CCA_PDXs and CCA patients. (A) RAD51 scores of CCA_PDXs and their matched originating biopsy samples. (B) RAD51 scores evaluated in PDX85 (IDH1mut) treated as for Figure 4C.

Purpose:Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%–50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.Experimental Design:We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.Results:This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.Conclusions:Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.

Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAFs also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGFβ/Snail1 signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis.Significance:Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues.

Video showing migration of activated CAFs toward the Gln-rich compartment when cultured in Gln-high conditions (2 mM)

PDF file - 196KB, Table 1. Estimated aMT6s mesor (circadian mean) and acrophase (peak time) by night shift work (shift status, night shift workers' diurnal preference, nights worked over the past 2 weeks and total years worked in night shift). Table 2. Estimated aMT6s mesor (circadian mean) and acrophase (peak time) by light exposure among night shift workers (tertiles of mean light exposure from 24:00 to 05:00 h and over the night shift). Figure 1. Directed Acyclic Graph (DAG) for the selection of confounders (ancestor of exposure and outcome) using DAGitty (http://www.dagitty.net) for the association between night shift work and aMT6s (levels and time of peak).

Supplemental Tables 1-5 and Figures 1-2. Supplemental Table 1. Inter-assay precision of the GC-MS method for each sex hormone calculated as the coefficient of variation (CV) after analyzing 15 replicates (3 replicates in 5 different days). Supplemental Table 2. Estimated geometric mean (GM), geometric mean ratio ratio (GMR) and 95% confidence interval (CI) of 24-h mean metabolite levels (mesor) and peak time (acrophase) in night workers compared to day workers in premenopausal women (n=32) by menstrual cycle. Supplemental Table 3. Peak time (acrophase) of metabolite production (hh:mm) in day and night workers among men and women (geometric mean (GM) and 95% confidence intervals (CI)) Supplemental Table 4. Correlations between 6-sulfatoxymelatonin (aMT6s) and sex hormone 24-h mean levels (mesor) and peak time (acrophase) in all subjects, men and women (Pearson correlation coefficients). Supplemental Table 5. Correlations between 6-sulfatoxymelatonin (aMT6s) and sex hormones 24-h mean levels (mesor) and peak time (acrophase) in all, day and night workers (Pearson correlation coefficients). Supplemental Figure 1. Directed acyclic graph (DAG) used for the selections of confounders for the association between night shift work and urinary sex steroid metabolites. Supplemental Figure 2. Scatterplots and correlation coefficients (r) between log-tranformed 24-h mean levels (mesor) and peak time (acrophase) of 6-sulfatoxymelatonin and estradiol, estrone, pregnanediol and testosterone in men and women.

Supplementary Information containing supplementary methods, eight supplementary figures with legends and one supplementary table.

Background: Light-at-night has been shown in experimental studies to disrupt melatonin production but this has only partly been confirmed in studies of night shift workers. In this cross-sectional study, we examined the circadian variation of melatonin in relation to shift status, individual levels of light-at-night exposure, and diurnal preference, an attribute reflecting personal preference for activity in the morning or evening.Methods: One hundred and seventeen workers (75 night and 42 day) of both sexes, ages 22 to 64 years, were recruited from four companies. Participants collected urine samples from all voids over 24 hours and wore a data logger continuously recording their light exposure. Sociodemographic, occupational, lifestyle, and diurnal preference information were collected by interview. Concentrations of urinary 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, were measured.Results: Mean aMT6s levels were lower in night [10.9 ng/mg creatinine/hour; 95% confidence interval (CI), 9.5–12.6] compared with day workers (15.4; 95% CI, 12.3–19.3). The lowest aMT6s levels were observed in night workers with morning preference (6.4; 95% CI, 3.0–13.6). Peak time of aMT6s production occurred 3 hours later in night (08:42 hour, 95% CI, 07:48–09:42) compared with day workers (05:36 hour, 95% CI, 05:06–06:12). Phase delay was stronger among subjects with higher light-at-night exposure and number of nights worked.Conclusions: Night shift workers had lower levels and a delay in peak time of aMT6s production over a 24-hour period. Differences were modified by diurnal preference and intensity of light-at-night exposure.Impact: Night shift work affects levels and timing of melatonin production and both parameters may relate to future cancer risk. Cancer Epidemiol Biomarkers Prev; 23(7); 1176–86. ©2014 AACR.

Background: Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes.Methods: We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers.Results: Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17–2.32] and androgens (GMR: 1.44; 95% CI, 1.03–2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46).Conclusions: We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers.Impact: The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers. Cancer Epidemiol Biomarkers Prev; 24(5); 854–63. ©2015 AACR.

Video showing migration of activated CAFs toward the Gln-rich compartment when cultured in a Gln-concentration gradient (0.2-2 mM)

Whether basal metabolic activity in sperm has any influence on their fertilising capacity has not been explored. Using the pig as a model, the present study investigated the relationship of energetic metabolism with sperm quality and function (assessed through computer-assisted sperm analysis and flow cytometry), and fertility (in vitro fertilisation (IVF) outcomes). In semen samples from 16 boars, levels of metabolites related to glycolysis, ketogenesis and Krebs cycle were determined through a targeted metabolomics approach using liquid chromatography-tandem mass spectrometry. High-quality sperm are associated to greater levels of glycolysis-derived metabolites, and oocyte fertilisation and embryo development are conditioned by the sperm metabolic status. Interestingly, glycolysis appears to be the preferred catabolic pathway of the sperm giving rise to greater percentages of embryos at day 6. In conclusion, this study shows that the basal metabolic activity of sperm influences their function, even beyond fertilisation.

The ATP-binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6-hydroxymelatonin, and 6-sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK-II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild-type and Abcg2-/- mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2-/- mice was between 1.5 and 6-fold higher compared to the wild-type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6-sulfatoxymelatonin in Abcg2-/- mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild-type compared with Abcg2-/- lactating female mice. In addition, melatonin metabolites showed a higher milk-to-plasma ratio in wild-type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity. The authors thank Dr. A. H. Schinkel (The Netherlands Cancer Institute, Amsterdam, The Netherlands) who provided parental MDCK-II cells and its murine Abcg2 and human ABCG2-transduced subclones, as well as Abcg2 knockout mice. We are grateful to Prof. James McCue for assistance with language editing. This work was supported by the research project RTI2018-100903-B-I00 and PID2021-125660OB-I00 (MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa”) and by predoctoral grants (FPU19/04169 grant to LAF) from the Spanish Ministry of Education, Culture and Sport.

The exchange of phosphorus (P) and carbon (C) between plants and arbuscular mycorrhizal fungi (AMF) is a major determinant of their mutualistic symbiosis. We explored the C dynamics in tomato (Solanum lycorpersicum) inoculated or not with Rhizophagus irregularis to study their growth response under different NaHPO concentrations (Null P, 0 mM; Low P, 0.065 mM; High P, 1.3 mM). The percentage of AMF colonization was similar in plants under Null and Low P, but severely reduced under High P. However, the AMF mass biomarker 16:1ω5 revealed higher fungal accumulation in inoculated roots under Low P, while more AMF spores were produced in the Null P. Under High P, AMF biomass and spores were strongly reduced. Plant growth response to mycorrhiza was negative under Null P, showing reduction in height, biovolume index, and source leaf (SL) area. Under Low P, inoculated plants showed a positive response (e.g., increased SL area), while inoculated plants under High P were similar to non-inoculated plants. AMF promoted the accumulation of soluble sugars in the SL under all fertilization levels, whereas the soluble sugar level decreased in roots under Low P in inoculated plants. Transcriptional upregulation of SlLIN6 and SlSUS1, genes related to carbohydrate metabolism, was observed in inoculated roots under Null P and Low P, respectively. We conclude that P-limiting conditions that increase AMF colonization stimulate plant growth due to an increase in the source and sink strength. Our results suggest that C partitioning and allocation to different catabolic pathways in the host are influenced by AMF performance., Funding information Consejo Nacional de Ciencia y Tecnología, Grant/Award Number: 732373; Coordinación de la Investigación Científica, Grant/Award Number: 5872608. The authors wish to acknowledge I. E. Maldonado-Mendoza and M. López-Meyer for the kind donation of the in vitro monoxenic cultured spores of R. irregularis (DAOM 197198), which we propagated to generate the inoculum used in this work. I. A. S.-S. received a scholarship (732373) granted by the Consejo Nacional de Ciencia y Tecnonogía (CONACYT). To conduct this research, A. T. C.-B. provided funding from Coordinación de la Investigación Científica (Universidad Michoacana de San Nicolás de Hidalgo), project (5872608).

The use of arbuscular mycorrhizal (AM) fungi has great potential, being used as biostimulants, biofertilizers and bioprotection agents in agricultural and natural ecosystems. However, the application of AM fungal inoculants is still challenging due to the variability of results when applied in production systems. This variability is partly due to differences in symbiosis establishment. Reducing such variability and promoting symbiosis establishment is essential to improve the efficiency of the inoculants. In addition to strigolactones, flavonoids have been proposed to participate in the pre-symbiotic plant-AM fungus communication in the rhizosphere, although their role is still unclear. Here, we studied the specific function of flavonoids as signaling molecules in AM symbiosis. For that, both in vitro and in planta approaches were used to test the stimulatory effect of an array of different subclasses of flavonoids on Rhizophagus irregularis spore germination and symbiosis establishment, using physiological doses of the compounds. We show that the flavone chrysin and the flavonols quercetin and rutin were able to promote spore germination and root colonization at low doses, confirming their role as pre-symbiotic signaling molecules in AM symbiosis. The results pave the way to use these flavonoids in the formulation of AM fungal-based products to promote the symbiosis. This can improve the efficiency of commercial inoculants, and therefore, help to implement their use in sustainable agriculture., This work was supported by grants PY20_00400 from the Consejería de Transformación Económica, Industria, Conocimiento y Universidad (Junta de Andalucía), RTI2018- 094350-B-C31 from the Spanish National R&D Plan of the Ministry of Science, Innovation and Universities (MICIU), and the European Regional Development Fund (ERDF) ‘a way a making Europe’. JL was supported by PhD fellowship BES-2016- 077850 and LE-L by fellowship AND21_EEZ_M2_042 from the Garantí Juvenil Andalucía 2021 program.

Arbuscular mycorrhizal fungi (AMF) are obligate biotrophs that supply mineral nutrients to the host plant in exchange for carbon derived from photosynthesis. Sucrose is the end‐product of photosynthesis and the main compound used by plants to translocate photosynthates to non-photosynthetic tissues. AMF alter carbon distribution in plants by modifying the expression and activity of key enzymes of sucrose biosynthesis, transport, and/or catabolism. Since sucrose is essential for the maintenance of all metabolic and physiological processes, the modifications addressed by AMF can significantly affect plant development and stress responses. AMF also modulate plant lipid biosynthesis to acquire storage reserves, generate biomass, and fulfill its life cycle. In this review we address the most relevant aspects of the influence of AMF on sucrose and lipid metabolism in plants, including its effects on sucrose biosynthesis both in photosynthetic and heterotrophic tissues, and the influence of sucrose on lipid biosynthesis in the context of the symbiosis. We present a hypothetical model of carbon partitioning between plants and AMF in which the coordinated action of sucrose biosynthesis, transport, and catabolism plays a role in the generation of hexose gradients to supply carbon to AMF, and to control the amount of carbon assigned to the fungus., I.A.S.-S. received a scholarship granted by the Consejo Nacional de Ciencia y Tecnología (CONACYT), México (732373). Funding support was provided to A.T.C.-B. from Coordinación de la Investigación Científica Project 5872608, Universidad Michoacana de San Nicolás de Hidalgo.

The aim of this study was to evaluate, in male Long-Evans rats, whether a restricted-cafeteria diet (CAFR), based on a 30% calorie restriction vs continuous ad libitum cafeteria (CAF) fed animals, administered alone or in combination with moderate treadmill exercise (12 m/min, 35 min, 5 days/week for 8 weeks), was able to ameliorate obesity and the associated risk factors induced by CAF feeding for 18 weeks and to examine the changes in circadian locomotor activity, hypothalamic-pituitary-adrenal (HPA) axis functionality, and stress response elicited by this dietary pattern. In addition to the expected increase in body weight and adiposity, and the development of metabolic dysregulations compatible with Metabolic Syndrome, CAF intake resulted in a sedentary profile assessed by the home-cage activity test, reduced baseline HPA axis activity through decreased corticosterone levels, and boosted exploratory behavior. Both CAFR alone and in combination with exercise reduced abdominal adiposity and hypercholesterolemia compared to CAF. Exercise increased baseline locomotor activity in the home-cage in all dietary groups, boosted exploratory behavior in STD and CAF, partially decreased anxiety-like behavior in CAF and CAFR, but did not affect HPA axis-related parameters. This research was funded by the Spanish Ministerio de Economía, Industria y Competitividad, grant number PSI2016-77234-R. A.A-M. is granted by the Universitat Autònoma de Barcelona, grant PIF-UAB2018. A.S.-G. is granted by the Ministerio de Ciencia e Innovación, grant number BES-2017–081939. This work was also financially supported by the Catalan Government through the funding grant ACCIÓ-EURECAT. The funding sources had no involvement in study design, collection, analysis and interpretation of data, the writing of the report and the decision to submit the article for publication.

Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30\\%–50\\% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA\_PDX). The CCA\_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA\_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA\_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.This collection of CCA\_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA\_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA\_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA\_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials. The authors would like to thank the patients and their families for their support. This work was supported by grants from the Fundaci o Marat o TV3 awarded to T. Macarulla, M. Mel e, and S. Peir o; BeiGene research grant awarded toT. Macarulla and S. Peir o; AECC (INVES20036TIAN), Ram on y Cajal investigator program (RYC2020-029098-I), Proyecto de IþDþi (PID2019-108008RJ-I00), and FERO Foundation grant awarded to T.V. Tian; Proyecto de Investigaci on en Salud from the Instituto de Salud Carlos III (ISCIII) (PI20/00898) awarded to T. Macarulla; FIS/FEDER from the Instituto de Salud Carlos III (ISCIII) (PI12/01250; CP08/00223; PI16/00253 and CB16/12/00449) awarded to S. Peir o; and Ram on y Cajal investigator program (RYC-2017-22249) awarded to M. Mel e. Q. Serra-Camprubí is a recipient of the Ph.D. fellowship from La Caixa Foundation (LCF/PR/PR12/51070001). A. LlopGuevara was supported by the AECC (INVES20095LLOP) and V. Serra by the ISCIII (CPII19/00033). E.J. Arenas was funded by the AECC (POSTD211413AREN).J. Arribas is funded by the Instituto de Salud Carlos III (AC15/00062, CB16/12/00449, and PI22/00001). This publication is based upon the work of COST Action CA18122, European Cholangiocarcinoma Network, supported by the COST (European Cooperation in Science and Technology, www.cost.eu), a funding agency for research and innovation networks. The authors would like to thank Dr. V.A. Raker for manuscript editing and Drs. N. Herranz and J. Mateo for scientific discussions. The authors acknowledge the infrastructure and support of the FERO Foundation, La Caixa Foundation, and the Cellex Foundation. Peer Reviewed "Article signat per 31 autors/es: Queralt Serra-Camprubí; Helena Verdaguer; Winona Oliveros; Núria Lupión-Garcia; Núria Lupión-Garcia;Alba Llop-Guevara; Cristina Molina; Maria Vila-Casadesús; Anthony Turpin; Cindy Neuzillet; Joan Frigola; Jessica Querol; Mariana Yáñez-Bartolomé; Florian Castet; Carles Fabregat-Franco; Carmen Escudero-Iriarte; Marta Escorihuela; Enrique J. Arenas; Cristina Bernadó-Morales; Noemí Haro; Francis J. Giles; Óscar J. Pozo; Josep M. Miquel ; Paolo G. Nuciforo; Ana Vivancos; Marta Melé; Violeta Serra ; Joaquín Arribas; Josep Tabernero; Sandra Peiró; Teresa Macarulla; Tian V. Tian"

Stress and anxiety are frequent occurrences among pregnant women. We aimed to evaluate the effects of a Mediterranean diet intervention during pregnancy on maternal stress, well-being, and sleep quality throughout gestation. In a randomized clinical trial, 1221 high-risk pregnant women were randomly allocated into three groups at 19–23 weeks’ gestation: a Mediterranean diet intervention, a Mindfulness-Based Stress Reduction program, or usual care. All women who provided self-reported life-style questionnaires to measure their anxiety (State Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS)), well-being (WHO Five Well Being Index (WHO-5)), and sleep quality (Pittsburgh sleep quality index (PSQI)) at enrollment and at the end of the intervention (34–36 weeks) were included. In a random subgroup of 106 women, the levels of cortisol and related metabolites were also measured. At the end of the intervention (34–36 weeks), participants in the Mediterranean diet group had significantly lower perceived stress and anxiety scores (PSS mean (SE) 15.9 (0.4) vs. 17.0 (0.4), p = 0.035; STAI-anxiety mean (SE) 13.6 (0.4) vs. 15.8 (0.5), p = 0.004) and better sleep quality (PSQI mean 7.0 ± 0.2 SE vs. 7.9 ± 0.2 SE, p = 0.001) compared to usual care. As compared to usual care, women in the Mediterranean diet group also had a more significant increase in their 24 h urinary cortisone/cortisol ratio during gestation (mean 1.7 ± SE 0.1 vs. 1.3 ± SE 0.1, p < 0.001). A Mediterranean diet intervention during pregnancy is associated with a significant reduction in maternal anxiety and stress, and improvements in sleep quality throughout gestation.