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Juan Marco Figueira‐Gonçalves,1,2 Miguel Ángel García-Bello,3,4 Yolanda Ramallo‐Fariña,3– 5 Raúl Méndez,6– 9 Ana Latorre Campos,6,7 Paula González-Jiménez,6,7,9 Germán Peces-Barba,10 María Molina-Molina,11 Pedro Pablo España,12 Estela García,13 Santiago de Jorge Domínguez-Pazos,14 Marta García Clemente,15 Carolina Panadero,16 David de la Rosa-Carrillo,17 Oriol Sibila,18 María Dolores Martínez-Pitarch,19 Nuria Toledo-Pons,20 Cecilia López-Ramirez,21 Wanda Almonte-Batista,22 Abigail Macías-Paredes,23 Diana Badenes-Bonet,24 Eli Nancy Pérez-Rodas,25 Javier Lázaro,26 Sarai Quirós Fernández,27 Rosa Cordovilla,28 Irene Cano-Pumarega,8,29 Antoni Torres,8,18 Rosario Menendez6– 9 On behalf of RECOVID1Pneumology and Thoracic Surgery Service, Unit for Patients with Highly Complex COPD, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 2University Institute of Tropical Disease and Public Health of the Canary Islands, University of La Laguna, Santa Cruz de Tenerife, Spain; 3Evaluation Unit (SESCS), Canary Islands Health Research Institute Foundation (FIISC), Tenerife, Spain; 4Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Tenerife, Spain; 5Health Services Research on Chronic Patients Network (REDISSEC), Madrid, Spain; 6Pneumology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 7Respiratory InFections, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; 8CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; 9Medicine Department, University of Valencia, Valencia, Spain; 10Pulmonology Department, Hospital Fundación Jiménez Díaz, Madrid, Spain; 11ILD Unit, Respiratory Department, Hospital de Bellvitge, Hospitalet de Llobregat, Spain; 12Respiratory Service, Hospital de Galdakao-Usansolo, Galdakao, Spain; 13Respiratory Service, Hospital de Cabueñes, Gijón, Spain; 14Respiratory Service, Hospital Universitario de A Coruña, A Coruña, Spain; 15Respiratory Service, Hospital Universitario Central de Asturias, Oviedo, Spain; 16Respiratory Service, Hospital de Getafe, Getafe, Spain; 17Respiratory Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 18Respiratory Service, Hospital Clínic, Barcelona, Spain; 19Respiratory Service, Hospital Lluís Alcanyís, Játiva, Spain; 20Respiratory Service, Hospital Son Espases, Palma, Spain; 21Medical Surgical Unit of Respiratory Diseases, Hospital Virgen del Rocío, Sevilla, Spain; 22Respiratory Service, Hospital de Albacete, Albacete, Spain; 23Respiratory Service, Hospital de Sant Jaume, Calella, Spain; 24Respiratory Service, Hospital del Mar, Barcelona, Spain; 25Respiratory Service, Hospital Municipal de Badalona, Badalona, Spain; 26Respiratory Service, Hospital Royo Villanova, Zaragoza, Spain; 27Respiratory Service, Hospital Basurto, Bilbao, Spain; 28Respiratory Service, Hospital de Salamanca, Salamanca, Spain; 29Respiratory Service, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, SpainCorrespondence: Juan Marco Figueira‐Gonçalves, Pneumology and Thoracic Surgery Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain, Tel +34654959246, Email juanmarcofigueira@gmail.comBackground: Chronic obstructive pulmonary disease (COPD) has been associated with worse clinical evolution/survival during a hospitalization for SARS-CoV2 (COVID-19). The objective of this study was to learn the situation of these patients at discharge as well as the risk of re-admission/mortality in the following 12 months.Methods: We carried out a subanalysis of the RECOVID registry. A multicenter, observational study that retrospectively collected data on severe acute COVID-19 episodes and follow-up visits for up to a year in survivors. The data collection protocol includes general demographic data, smoking, comorbidities, pharmacological treatment, infection severity, complications during hospitalization and required treatment. At discharge, resting oxygen saturation (SpO2), dyspnea according to the mMRC (modified Medical Research Council) scale and long-term oxygen therapy prescription were recorded. The follow-up database included the clinical management visits at 6 and 12 months, where re-admission and mortality were recorded.Results: A total of 2047 patients were included (5.6% had a COPD diagnosis). At discharge, patients with COPD had greater dyspnea and a greater need for prescription home oxygen. After adjusting for age, sex and Charlson comorbidity index, patients with COPD had a greater risk of hospital re-admission due to respiratory causes (HR 2.57 [1.35– 4.89], p = 0.004), with no significant differences in survival.Conclusion: Patients with COPD who overcome a serious SARS-CoV2 infection show a worse clinical situation at discharge and a greater risk of re-admission for respiratory causes.Keywords: chronic obstructive pulmonary disease, COPD, COVID-19, coronavirus disease 2019, RECOVID, Spanish COVID-19 registry, SARS-CoV2, severe acute respiratory syndrome coronavirus 2, SEPAR, respiratory failure

Events that occur during fetal and perinatal life can have consequences on the health and disease of the offspring. The pioneering work on the "Fetal Programming Hypothesis" focused on pregnant women exposed to a great famine that occurred in the Netherlands at the end of World War II. The intrauterine environment of the babies during that famine caused them to low birthweight and determined the appearance of cardiovascular diseases in themselves when they reached adulthood, a risk that was transmitted even to the following generation. In addition to the general stress that a pregnant woman may suffer as a result of the death of a family member, suffering a war or natural disaster such as the SARS-CoV-2 coronavirus, there is another specific type of stress that refers exclusively to the pregnancy process; this is the pregnancy specific-stress. Pregnancy-specific stress is capable of sensitively predicting negative maternal and neonatal outcomes. This type of stress refers to the specific stress of pregnant women related to medical problems, the health of the newborn, the changes that the pregnancy will produce in their social relationships, prematurity, physical changes of pregnancy and fear of labor and birth. The objective of this article was to offer an updated information on pregnancy-specific stress and its consequences for maternal and neonatal health. Thus, we also proposed to offer strategies that midwives and psychologists can use to reduce pregnancy-specific stress levels. In conclusion, midwives and psychologists can work together to reduce pregnancy-specific stress levels.

Background: Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC., Methods: Through kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo., Results: Complete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts., Conclusions: ATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard of care but shows very limited antitumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response, plays a central role in safeguarding cells from replication stress and can therefore limit the efficacy of antimetabolite drug therapies. We investigated the ability of the ATR inhibitor, AZD6738, to prevent the gemcitabine-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell-cycle arrest, and restrained RRM2 accumulation, leading to the strong induction of replication stress markers only with the combination. Moreover, synergistic growth inhibition was identified in a panel of 5 mouse and 7 human PDAC cell lines using both Bliss Independence and Loewe models. In clonogenic assays, the combination abrogated survival at concentrations for which single agents had minor effects. In vivo , AZD6738 in combination with gemcitabine was well tolerated and induced tumor regression in a subcutaneous allograft model of a Kras G12D ; Trp53 R172H ; Pdx-Cre (KPC) mouse cancer cell line, significantly extending survival. Remarkably, the combination also induced regression of a subgroup of KPC autochthonous tumors, which generally do not respond well to conventional chemotherapy. Altogether, our data suggest that AZD6738 in combination with gemcitabine merits evaluation in a clinical trial in patients with PDAC. Mol Cancer Ther; 17(8); 1670-82. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesized that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modeling and single-cell assays distinguished the synergy kinetics of WEE1 inhibitor (WEE1i) from CHEK1 inhibitor (CHK1i) by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumor cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumor control compared with single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitization, leading to the rational development of a tolerable multitherapeutic regimen. Significance: Multiple lines of mechanistic insight regarding DNA damage response inhibitors rationally guide the preclinical development of a tolerable multitherapeutic regimen. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/11/3054/F1.large.jpg Cancer Res; 78(11); 3054-66. ©2018 AACR ., (©2018 American Association for Cancer Research.)