The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells

Funding: This research was partly funded by the Research Center grant ToxOmics (UIDB/00009/2020 and UIDP/0009/2020), from the Portuguese Fundação para a Ciência e a Tecnologia—FCTThe altered activity of drug metabolism enzymes (DMEs) is a hallmark of chemotherapy resistance. Cytochrome P450s (CYPs), mainly CYP3A4, and several oxidoreductases are responsible for Phase I metabolism of doxorubicin (DOX), an anthracycline widely used in breast cancer (BC) treatment. This study aimed to investigate the role of Phase I DMEs involved in the first stages of acquisition of DOX-resistance in BC cells. For this purpose, the expression of 92 DME genes and specific CYP-complex enzymes activities were assessed in either sensitive (MCF-7 parental cells; MCF-7/DOXS) or DOX-resistant (MCF-7/DOXR) cells. The DMEs genes detected to be significantly differentially expressed in MCF-7/DOXR cells (12 CYPs and eight oxidoreductases) were indicated previously to be involved in tumor progression and/or chemotherapy response. The analysis of CYP-mediated activities suggests a putative enhanced CYP3A4-dependent metabolism in MCF-7/DOXR cells. A discrepancy was observed between CYP-enzyme activities and their corresponding levels of mRNA transcripts. This is indicative that the phenotype of DMEs is not linearly correlated with transcription induction responses, confirming the multifactorial complexity of this mechanism. Our results pinpoint the potential role of specific CYPs and oxidoreductases involved in the metabolism of drugs, retinoic and arachidonic acids, in the mechanisms of chemo-resistance to DOX and carcinogenesis of BC.publishersversionpublishe

Septic Pulmonary Embolism Case Report: Optimal Outcome after Insertion of an Inferior Vena Cava Filter in a Patient with Staphylococcus aureus Bacteraemia

A 14-year-old patient presented with bilateral pneumonia and pleural effusions, septic arthritis of the hip, deep venous thrombosis, and pulmonary thromboembolism. Methicillin-sensitive Staphylococcus aureus (S. aureus) containing the Panton Valentine Leukocidin (PVL) genes was isolated. Contraindication to anticoagulation prompted inferior vena cava filter placement. He completed 4 weeks of treatment with flucloxacillin, with good clinical outcome. S. aureus containing PVL genes should be sought in cases of necrotizing pneumonia as it seems to increase the risk of severe multifocal infection and thrombotic complications. There are few reports of placement of filters during S. aureus sepsis and bacteraemia. This case highlights that when anticoagulation is not feasible, an inferior vena cava filter can be inserted safely, even in patients with active sepsis and high risk for seeding of the filter. Long-term follow-up confirmed a successful outcome with sterilization of the septic thrombosis with no further pulmonary embolism or additional sepsis episodes

Controlo químico de infestantes

Uma planta é considerada infestante quando nasce espontaneamente num local e momento indesejados, podendo interferir negativamente com a cultura instalada. As infestantes competem com as culturas para o espaço, a luz, água e nutrientes, podendo atrasar e prejudicar as operações de colheita, depreciar o produto final e assegurarem a reinfestação nas culturas seguintes. Dado o modo de propagação diferenciado das diversas espécies de infestantes, com as anuais a propagarem-se por semente e as perenes ou vivazes a assegurarem a sua propagação através de órgãos vegetativos (rizomas, bolbos, tubérculos, etc.), assim, também o seu controlo quer químico, quer mecânico terá que ser diferenciado, ou seja, para controlar infestantes anuais será suficiente destruir a sua parte aérea, enquanto para controlar infestantes perenes teremos que destruir os seus órgãos reprodutivos. O controlo de infestantes poderá ser químico, através da utilização de herbicidas, ou mecânico pela utilização de alfaias agrícolas, tais como a charrua de aivecas, a charrua de discos, a grade de discos, o escarificador e a fresa. Quando a técnica utilizada na instalação das culturas é a sementeira directa, o controlo das infestantes terá que ser obrigatoriamente químico, enquanto se o recurso à mobilização do solo for a técnica mais utilizada (sistema de mobilização tradicional ou sistema de mobilização reduzida), o controlo das infestantes tanto poderá ser químico como mecânico. Neste trabalho iremos abordar apenas, o controlo químico de infestantes

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

INNOVA Research Journal

El (Censos, 2016) (INEC), en su encuesta nacional de empleo, desempleo y subempleo en el Ecuador, de marzo de 2016, informó que el 68,6% de las personas en edad de trabajar se considera económicamente activo; de éstos, el 94,3% se consideran con empleo, el 5,7% no cuenta con empleo formal o independiente. De las personas en edad de trabajar 31,4% forman parte de la población económicamente inactiva. El emprendimiento se presenta como una solución que permite generar empleo. A la luz de nuevas investigaciones sobre el consumo de carnes y productos procesados. Está evolucionando las percepciones de la población y se están modificando sus hábitos. Se cuestionan más sobre los efectos en su salud y sobre el impacto ambiental, es mayor la demanda de productos en cuya elaboración se genere un menor nivel de impacto ambiental. Siendo la responsabilidad ambiental, un factor que a las empresas competitivas globales y locales las ha llevado no sólo a cumplir con las disposiciones legales, sino a crear ventajas competitivas a partir de la promoción del trabajo realizado en favor de la protección del medio ambiente. El fomento de emprendimientos con responsabilidad ambiental, mediante el uso de fibras sintéticas y pieles artificiales ayudará a generar herramientas para incrementar el empleo, generando valor con responsabilidad ambiental

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Emotions under the skin: autonomic reactivity to emotional pictures in insecure attachment

Author’s personal copy (e-offprint)The present study examined physiological reactivity to emotional stimuli as a function of attachment style. Skin conductance responses (SCRs) and heart rate (HR) changes were simultaneously recorded while participants engaged in a visual attentional task. The task included positive, neutral, and negative emotional pictures, and required the identification of a target (neutral picture rotated 90 to the left or right), among a stream of pictures in which an emotional distracter (positive or negative) was presented. Participants additionally rated each of the emotional distracters for valence and arousal. Behavioral results on the attentional task showed that positive pictures facilitated overall target detection for all participants, compared to negative and neutral pictures, and that anxiously attached participants had significantly lower accuracy scores, relative to the other groups. Affective ratings indicated that positive pictures were rated as being more pleasant than negative ones, although no differences were found in HR changes to picture valence. In contrast, negative pictures were evaluated as being highly arousing. Consistent with this, negative pictures elicited larger SCRs in both insecure anxious and avoidant groups, especially for the anxious while the secure group showed SCRs unaffected by stimuli’s arousal. Present results show that individuals with different attachment styles reveal distinct patterns of attentional bias, appraisal, and physiological reactivity toward emotionally arousing stimuli. These findings further highlight the regulatory function of the attachment system.Portuguese Ministry of Science and Technology, FCT-MCTES grants (SFRH/BD/30355/2006 and SFRH/BPD/80910/ 2011)info:eu-repo/semantics/publishedVersio

Probability distribution of copy number alterations along the genome: an algorithm to distinguish different tumour profiles

Copy number alterations (CNAs) comprise deletions or amplifications of fragments of genomic material that are particularly common in cancer and play a major contribution in its development and progression. High resolution microarray-based genome-wide technologies have been widely used to detect CNAs, generating complex datasets that require further steps to allow for the determination of meaningful results. In this work, we propose a methodology to determine common regions of CNAs from these datasets, that in turn are used to infer the probability distribution of disease profiles in the population. This methodology was validated using simulated data and assessed using real data from Head and Neck Squamous Cell Carcinoma and Lung Adenocarcinoma, from the TCGA platform. Probability distribution profiles were produced allowing for the distinction between different phenotypic groups established within that cohort. This method may be used to distinguish between groups in the diseased population, within well-established degrees of confidence. The application of such methods may be of greater value in the clinical context both as a diagnostic or prognostic tool and, even as a useful way for helping to establish the most adequate treatment and care plans