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Cecilia Castillo,1 Natalia Camejo,1 Monika Rondan,1 Florencia Savio,1 Guadalupe Herrera,2 Gabriel Krygier,1 Lucia Delgado1 1Department of Clinical Oncology, School of Medicine, University of Uruguay, Montevideo, Uruguay; 2Department of Quantitative Methods, School of Medicine, University of Uruguay, Montevideo, UruguayCorrespondence: Cecilia CastilloDepartment of Clinical Oncology, School of Medicine, University of Uruguay, Avenida Italia s/n, Montevideo, 11600, UruguayTel +59824872075Email cascecilia@gmail.comIntroduction: Increases in disease-free survival and overall survival (OS) with the use of adjuvant chemotherapy in early breast cancer (BC) are widely known; however, the optimal time to initiate treatment with adjuvant chemotherapy remains controversial.Objective: To evaluate the time elapsed between surgery and the initiation of adjuvant chemotherapy and its possible impact on OS in patients diagnosed with BC stages I–III.Materials and Methods: This retrospective study included 112 patients diagnosed with BC stages I–III who received adjuvant chemotherapy at the Mastology Unit of the Hospital de Clínicas in Uruguay from 2009 to 2019. OS was estimated using the Kaplan–Meier method, and a Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals.Results: No statistically significant association was found between the time from surgery to the initiation of chemotherapy and the described variables. OS was worse for patients initiating chemotherapy more than 90 days after breast surgery (n = 19) (HR 7.63; p = 0.004) and between 61 and 90 days after surgery (n = 46) (HR 4.58; p = 0.040) compared to those who started before 30 days (n = 23). Controlling by type of surgery and stage, the prognosis of patients who started chemotherapy between 61 and 90 days after surgery was similar to that of patients who underwent chemotherapy within the first 30 days, controlling for surgery (HR 4.10; p = 0.056) and controlling for stage (HR 3.76; p = 0.075). Prognosis was worse for patients with stage III disease (p = 0.022) who underwent a mastectomy and/or axillary lymph node dissection (p = 0.025).Conclusion: Patients who started chemotherapy more than 90 days following surgery and those with stage III disease or underwent mastectomy and/or axillary lymph node dissection who initiated it between 61 and 90 days had a worse OS. Multiple factors are involved in the time between surgery and the initiation of chemotherapy, and further studies are needed to evaluate which of these factors influence the delay of chemotherapy in order to design strategies to avoid such delays and their negative impact on survival.Keywords: time, adjuvant chemotherapy, breast cancer, survival

Made available in DSpace on 2022-04-28T19:44:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-01 Agencia Nacional de Investigación e Innovación Comisión Sectorial de Investigación Científica Fondo Nacional de Desarrollo Científico y Tecnológico The molecular evolution of life on earth along with changing environmental, conditions has rendered mankind susceptible to endemic and pandemic emerging infectious diseases. The effects of certain systemic viral and bacterial infections on morbidity and mortality are considered as examples of recent emerging infections. Here we will focus on three examples of infections that are important in pregnancy and early childhood: SARS-CoV-2 virus, Zika virus, and Mycoplasma species. The basic structural characteristics of these infectious agents will be examined, along with their general pathogenic mechanisms. Coronavirus infections, such as caused by the SARS-CoV-2 virus, likely evolved from zoonotic bat viruses to infect humans and cause a pandemic that has been the biggest challenge for humanity since the Spanish Flu pandemic of the early 20th century. In contrast, Zika Virus infections represent an expanding infectious threat in the context of global climate change. The relationship of these infections to pregnancy, the vertical transmission and neurological sequels make these viruses highly relevant to the topics of this special issue. Finally, mycoplasmal infections have been present before mankind evolved, but they were rarely identified as human pathogens until recently, and they are now recognized as important coinfections that are able to modify the course and prognosis of various infectious diseases and other chronic illnesses. The infectious processes caused by these intracellular microorganisms are examined as well as some general aspects of their pathogeneses, clinical presentations, and diagnoses. We will finally consider examples of treatments that have been used to reduce morbidity and mortality of these infections and discuss briefly the current status of vaccines, in particular, against the SARS-CoV-2 virus. It is important to understand some of the basic features of these emerging infectious diseases and the pathogens involved in order to better appreciate the contributions of this special issue on how infectious diseases can affect human pregnancy, fetuses and neonates. Laboratory of Ion Channels Biological Membranes and Cell Signaling Department of Biophysics Faculty of Medicine Universidad de la República Department of Infectious Diseases Faculty of Medicine Universidad de la República Cellular and Molecular Physiology Laboratory (CMPL) Department of Obstetrics Division of Obstetrics and Gynaeology School of Medicine Faculty of Medicine Pontificia Universidad Católica de Chile Department of Physiology Faculty of Pharmacy Universidad de Sevilla Medical School (Faculty of Medicine) São Paulo State University (UNESP) University of Queensland Centre for Clinical Research (UQCCR) Faculty of Medicine and Biomedical Sciences University of Queensland Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen (UMCG) Department of Molecular Pathology The Institute for Molecular Medicine Medical School (Faculty of Medicine) São Paulo State University (UNESP) Fondo Nacional de Desarrollo Científico y Tecnológico: 1190316

Lead is a heavy metal pollutant that constitutes frequent exposomes. It is nonbiodegradable and has a nonsafe limit of exposure. It has multisystemic effects, and most of the cardiac effects have been discovered to be indirect. There are strong similarities between Ca2+ and Pb2+ in their chemistry. Because cardiac function is dramatically dependent in extracellular Ca2+, as well as in precise control of intracellular Ca2+, we tested if Pb2+ could antagonize Ca2+-dependent effects in a short amount of time. Acute exposure of isolated hearts showed a negative inotropic effect. In guinea pig isolated cardiomyocytes loaded with a Pb2+-specific dye (Leadmium green), our results showed that there was an associated increment in fluorescence related to extracellular stimulation blocked by 1–5 µM DHP. Calcium currents were partially blocked by extracellular Pb2+, though currents seemed to last longer after a fast inactivation. Charge movement from gating currents was slightly hastened over time, giving an appearance of a slight reduction in the Cav1.2 gating currents. Action potentials were prolonged in Pb2+ compared with Ca2+. In isolated cardiomyocytes loaded with Ca2+-sensitive dyes, Ca2+ variations promoted by extracellular stimuli were affected in space/time. As Pb2+ could interfere with Ca2+-sensitive dyes, we measured contraction of isolated cardiomyocytes under extracellular stimuli in Pb2+. In both Ca2+ dye fluorescence and contractions, Pb2+ disorganizes the pattern of contraction and intracellular Ca2+ homeostasis. Our results suggest that (1) Pb2+ enters to cardiomyocytes through Cav1.2 channels, and (2) once it enters the cell, Pb2+ may substitute Ca2+ in Ca2+-binding proteins. In addition to these direct mechanisms related to Pb2+ competition with Ca2+-binding sites, we cannot discard a direct contribution of Pb2+ redox properties.

Cancer and cardiovascular diseases are the main causes of death in Uruguay and developed countries. In clinical practice, there is often the need to administrate chemotherapy with cisplatin (CTP) to patients with cardiovascular comorbidities. The aim of this work is to characterize the possible detrimental effects in cardiac function by the acute exposition to CPT using isolated heart and cardiomyocytes from guinea pigs (Cavia porcellus). All the procedures regarding animal experimentation were performed following approved protocols by the university ethics committee. Isolated hearts were placed in a Langendorff system and perfused with Tyrode 1.8 mM Ca2+ as control medium, or with extracellularly added CPT (0–100 µM). Tension was recorded with a gauge force transducer attached to the papillary muscle and electrical responses were measured with Ag-AgCl electrodes placed in surface extremes near the papillary muscle. Cardiomyocytes were isolated by enzymatic methods. Data were obtained by patch clamp and confocal microscopy with Rhodamine and Fluo dyes sensitive to Ca2+ binding. Non-parametric t tests were used for data comparison. The best fit of Hill’s equation to dose–response curves was done using nonlinear regression methods. In isolated hearts, CPT showed a biphasic effect over the development of tension, increasing up to 5–10 µM to decrease at higher concentrations. In isolated cardiomyocytes, Ca2+ currents were stimulated and inhibited by CPT in a similar dose. Confocal microscopy showed an increment and a reduction of relative fluorescence of the calcium-sensitive dyes with CPT as well. Our results suggest that CPT may affect cardiac contraction and automatism upon acute exposure of the heart, presumably by blocking L-type (Cav1.2) calcium channels and interference with molecules involved in maintaining the homeostasis of intracellular Ca2+.

Made available in DSpace on 2022-04-28T19:47:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Agencia Nacional de Investigación e Innovación CA Technologies Comisión Sectorial de Investigación Científica Fondo Nacional de Desarrollo Científico y Tecnológico FP7 International Cooperation Rijksuniversiteit Groningen University of South Alabama Lead and mercury are heavy metals that are highly toxic to life forms. There are no known physiological processes that require them, and they do not have a particular threshold concentration to produce biologic damage. They are non-biodegradable, and they slowly accumulate in the environment in a dynamic equilibrium between air, water, soil, food, and living organisms. Their accumulation in the environment has been increasing over time, because they were not banned from use in anthropogenic industrial production. In their +2 cationic state they are powerful oxidizing agents with the ability to interfere significantly with processes that require specific divalent cations. Acute or chronic exposure to lead and mercury can produce multisystemic damage, especially in the developing nervous systems of children and fetuses, resulting in variety of neurological consequences. They can also affect the cardiovascular system and especially the heart, either directly through their action on cardiomyocytes or indirectly through their effects on innervation, humoral responses or blood vessel alterations. For example, heart function modified by these heavy metals are heart rate, contraction, excitability, and rhythm. Some cardiac molecular targets have been identified and characterized. The direct mechanisms of damage of these heavy metals on heart function are discussed. We conclude that exposome to these heavy metals, should be considered as a major relevant risk factor for cardiac diseases. Laboratory of Ion Channels Biological Membranes and Cell Signaling Department of Biophysics Faculty of Medicine Universidad de la República, Gral. Flores, CP 11800 Cellular and Molecular Physiology Laboratory (CMPL) Department of Obstetrics Division of Obstetrics and Gynaecology Universidad Católica de Chile, 8330024 Department of Physiology Faculty of Pharmacy Universidad de Sevilla Medical School (Faculty of Medicine) São Paulo State University (UNESP) University of Queensland Centre for Clinical Research (UQCCR) Faculty of Medicine and Biomedical Sciences University of Queensland, QLD 4029 Department of Pathology and Medical Biology University of Groningen University Medical Center Groningen Department of Molecular Pathology The Institute for Molecular Medicine, 16731 Gothard St. Huntington Beach Medical School (Faculty of Medicine) São Paulo State University (UNESP)

Lead ions (Pb2+) possess characteristics similar to Ca2+. Because of this and its redox capabilities, lead causes different toxic effects. The neurotoxic effects have been well documented; however, the toxic effects on cardiac tissues remain allusive. We utilized isolated guinea pig hearts and measured the effects of Pb2+ on their contractility and excitability. Acute exposure to extracellular Pb2+ had a negative inotropic effect and increased diastolic tension. The speed of contraction and relaxation were affected, though the effects were more dramatic on the speed of contraction. Excitability was also altered. Heart beat frequency increased and later diminished after lead ion exposure. Pro-arrhytmic events, such as early after-depolarization and a reduction of the action potential plateau, were also observed. In isolated cardiomyocytes and tsA 201 cells, extracellular lead blocked currents through Cav1.2 channels, diminished their activation, and enhanced their fast inactivation, negatively affecting their gating currents. Thus, Pb2+ was cardiotoxic and reduced cardiac contractility, making the heart prone to arrhythmias. This was due, in part, to Pb2+ effects on the Cav1.2 channels; however, other channels, transporters or pathways may also be involved. Acute cardiotoxic effects were observed at Pb2+ concentrations achievable during acute lead poisoning. The results suggest how Cav1.2 gating can be affected by divalent cations, such as Pb2, and also suggest a more thorough evaluation of heart function in individuals affected by lead poisoning.