The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

[EN]GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway

Deleterious Effects of Lard-enriched Diet on Tissues Fatty Acids Composition and Hypothalamic Insulin Actions

Altered tissue fatty acid (FA) composition may affect mechanisms involved in the control of energy homeostasis, including central insulin actions. In rats fed either standard chow or a lard-enriched chow (high in saturated/low in polyunsaturated FA, HS-LP) for eight weeks, we examined the FA composition of blood, hypothalamus, liver, and retroperitoneal, epididymal and mesenteric adipose tissues. Insulin-induced hypophagia and hypothalamic signaling were evaluated after intracerebroventricular insulin injection. HS-LP feeding increased saturated FA content in adipose tissues and serum while it decreased polyunsaturated FA content of adipose tissues, serum, and liver. Hypothalamic C20:5n-3 and C20:3n-6 contents increased while monounsaturated FA content decreased. HS-LP rats showed hyperglycemia, impaired insulin-induced hypophagia and hypothalamic insulin signaling. The results showed that, upon HS-LP feeding, peripheral tissues underwent potentially deleterious alterations in their FA composition, whist the hypothalamus was relatively preserved. However, hypothalamic insulin signaling and hypophagia were drastically impaired. These findings suggest that impairment of hypothalamic insulin actions by HS-LP feeding was not related to tissue FA composition.

Nature-based solutions to climate change mitigation and adaptation in urban areas: perspectives on indicators, knowledge gaps, barriers, and opportunities for action

Nature-based solutions promoting green and blue urban areas have significant potential to decrease the vulnerability and enhance the resilience of cities in light of climatic change. They can thereby help to mitigate climate change-induced impacts and serve as proactive adaptation options for municipalities. We explore the various contexts in which nature-based solutions are relevant for climate mitigation and adaptation in urban areas, identify indicators for assessing the effectiveness of nature-based solutions and related knowledge gaps. In addition, we explore existing barriers and potential opportunities for increasing the scale and effectiveness of nature-based solution implementation. The results were derived from an inter- and transdisciplinary workshop with experts from research, municipalities, policy, and society. As an outcome of the workshop discussions and building on existing evidence, we highlight three main needs for future science and policy agendas when dealing with nature-based solutions: (i) produce stronger evidence on nature-based solutions for climate change adaptation and mitigation and raise awareness by increasing implementation; (ii) adapt for governance challenges in implementing nature-based solutions by using reflexive approaches, which implies bringing together new networks of society, nature-based solution ambassadors, and practitioners; (iii) consider socio-environmental justice and social cohesion when implementing nature-based solutions by using integrated governance approaches that take into account an integrative and transdisciplinary participation of diverse actors. Taking these needs into account, nature-based solutions can serve as climate mitigation and adaptation tools that produce additional cobenefits for societal well-being, thereby serving as strong investment options for sustainable urban planning.

Community- and population-level effects of chytridiomycosis in a Neotropical amphibian community

As the number of fungal pathogen outbreaks become more frequent worldwide across taxa, so have the number of species extirpations and communities persisting with the pathogen. This phenomenon raises questions, such as: “what leads to host extinction during an outbreak?” and “how are hosts persisting once the pathogen establishes?.” But the data on host populations and communities across life stages before and after pathogen arrival rarely exist to answer these questions. Over the past three to four decades, the amphibian-killing fungus Batrachochytrim dendrobatidis (Bd) spread in a wave-like manner across Central America, leading to rapid species extirpations and population declines. I collected data on tadpole and adult amphibians in El Copé, Panama before, during, and after the Bd outbreak to answer these questions. I used Bayesian statistical approaches to account for imperfect host and pathogen detection of marked and unmarked individuals. In the tadpole community, within 11 months of Bds arrival, density and occupancy rapidly declined. Species losses were phylogenetically correlated, with glass frogs disappearing first, and tree frogs and poison-dart frogs remaining. I found that tadpole communities resembled one another more strongly after the outbreak than they did before Bd invasion. I found no tadpoles within 22 months of the outbreak and limited signs of recovery within 10 years. In contrast, at the same site, for a population of male glass frogs, Espadarana prosopleon, I found that 10 years post-outbreak, the population was consistently half its historic abundance, and that the lack of recruits to the population explained why the population had not rebounded, rather than high pathogen-induced mortality. And finally, examining the entire amphibian community, I found high pathogen prevalence, low infection intensities, and high survival rates of uninfected and infected hosts. Bd transmission risk, i.e., the probability a susceptible host becomes infected, did not relate to host density, pathogen prevalence, or infection intensity– Bd transmission risk was uniform across the study area. My results are especially relevant to conservation biologists aiming to predict the future impacts of Bd outbreaks, those trying to manage persisting populations, and those interested in reintroducing species back into wild amphibian communities.

Influence of magnesium on biochemical parameters of iron and oxidative stress in patients with type 2 diabetes

Introduction: Studies have shown that oxidative stress, found in patients with type 2 diabetes, may be due to changes in the metabolism of minerals, such as magnesium and iron. Data related to compartmentalization of these minerals in diabetes are scarce and controversial. Objective: This study assessed the influence of magnesium on biochemical parameters of iron and oxidative stress in patients with type 2 diabetes. Methods: A case-control study in male and female subjects aged 27-59 years, divided into two groups: type 2 diabetes (n=40) and control (n=48). Intake of magnesium and iron was assessed by three-day food record. Plasma, erythrocyte and urinary levels of magnesium, serum iron, ferritin, total iron binding capacity, fasting glucose, glycated hemoglobin, insulin, creatinine clearance and plasma thiobarbituric acid reactive substances (TBARS) were analyzed. Results and Discussion: Magnesium intake and plasma magnesium were lower in diabetic subjects. There was low urinary magnesium excretion, with no difference between groups. Although normal, the diabetic group had lower serum iron and ferritin concentrations compared to control subjects. Plasma TBARS in diabetic patients was higher than control while creatinine clearance was lower. An inverse correlation between erythrocyte magnesium and serum iron and ferritin was observed in the diabetes group. Conclusions: Diabetes induced hypomagnesemia and this, associated with chronic hyperglycemia, may have enhanced oxidative stress. Erythrocyte magnesium may have contributed to prevent iron overload and worsening of oxidative stress and hyperglycemic status.

Effects of palmitoylethanolamide in cocaine-induced behaviours

Aims. Cocaine addiction is a chronically relapsing disorder characterized by the compulsion to seek and take the drug. Previous investigations have demonstrated that several drugs of abuse, as cocaine, can alter the levels of lipid-based signalling molecules such as the N-acylethanolamines (NAEs). In addition, NAEs levels in the brain are sensitive to cocaine self-administration and extinction training. In this context, this study aimed to investigate the effect of repeated and acute palmitoylethanolamide (PEA), an endogenous NAE, on the behavioural effects of cocaine using mouse models of conditioned reward and psychomotor activation. Methods. Using male C57BL/6J mice, the ability of repeated PEA injections (1 or 10 mg/kg i.p) to modulate the development of a conditioned place preference (CPP) and behavioural sensitization (BS) induced by cocaine (20 mg/kg i.p.) was evaluated. In addition, the expression of cocaine-induced CPP and BS after acute PEA administration was also studied. Results. PEA (1 and 10 mg/kg i.p) significantly reduced the development of cocaine-induced BS, but did not modify the acquisition of cocaine-induced CPP. Furthermore, both doses of PEA were able to reduce the expression of BS and CPP. Conclusions. Altogether, these findings show that exogenous administration of PEA attenuated psychomotor activation and impaired the expression of CPP induced by cocaine. Our results may be relevant in order to understand the role of NAEs in the development and treatment of cocaine addiction.

Manejo del dolor postoperatorio con morfina en anestesia espinal en cirugía gineco-obstétrica de la Fundación Pablo Jaramillo Crespo

Objetivo: Evaluar la eficacia del tratamiento del dolor postoperatorio con el uso de la morfina en anestesia conductiva en pacientes con cirugía ginecológica, obstétrica. Fundación Pablo Jaramillo Crespo; septiembre- diciembre de 2011. Métodos: Estudio observacional, analítico, prospectivo y cuantitativo. Se incluyeron, con la clasificación de la Sociedad Americana de Anestesiología (ASA) I y II a 231 pacientes, entre 15 y 65 años, hospitalizadas en la Fundación Pablo Jaramillo Crespo, por cirugía ginecológica-obstétrica, realizadas desde septiembre a diciembre de 2011. Se administraron dosis de morfina: 2 mg para epidural y 0,2 mg para anestesia raquídea. El dolor fue evaluado a las 12 y 24 horas, con la escala visual analógica de la intensidad del dolor (EVA). Resultados: La morfina utilizada no tuvo preservantes; se observó que la anestesia raquídea muestra una ligera ventaja a la epidural, con mejor tolerancia al dolor a las 12 y 24 horas (p<0.05) No hubo relación entre la etiología de las cirugías ginecológicas y obstétricas con el dolor a las 12 y 24 horas (p>0.05). En 25.78 % de los casos, la analgesia de la morfina, por administración raquídea, se complementó con el uso de ketorolaco por vía intravenosa. Un 49.2% de las pacientes no mostró efectos secundarios; de estos, los más observados fueron: el prurito (13.14 %), retención urinaria (11.3%), náuseas (9.8%) y vómitos (6.9%). Conclusión: el uso de morfina en dosis: 2 mg para epidural y 0.2 mg para anestesia raquídea, proporciona una favorable recuperación del dolor en las pacientes con cirugía ginecológica y obstétrica. Los efectos secundarios provocados por su administración pueden manejarse de manera eficiente sin alterar la recuperación postoperatoria

Efficacy of Preoperative Chemotherapy in Treatment of Children With Wilms’ Tumor: A Meta-Analysis

Context: To assess the efficacy of preoperative chemotherapy in Wilms’ tumor patients and explore its true value for specific subgroups. Objectives: In the presence of these controversies, a meta-analysis that examines the efficacy of preoperative chemotherapy in Wilms’ tumor patients and specific subgroups is needed to clarify these issues. The objective of this meta-analysis is to assess the efficacy of preoperative chemotherapy in Wilms’ tumor patients and explore its true value for specific subgroups. Data Sources: Computer-based systematic search with “preoperative chemotherapy”, “Neoadjuvant Therapy” and “Wilms’ tumor” as search terms till January 2013 was performed. Study Selection: No language restrictions were applied. Searches were limited to randomized clinical trials (RCTs) or retrospective studies in human participants under 18 years. A manual examination of references in selected articles was also performed. Data Extraction: Relative Risk (RR) and their 95% Confidence Interval (CI) for Tumor Shrinkage (TS), total Tumor Resection (TR), Event-Free Survival (EFS) and details of subgroup analysis were extracted. Meta-analysis was carried out with the help of the software STATA 11.0. Finally, four original Randomized Clinical Trials (RCTs) and 28 retrospective studies with 2375 patients were included. Results: For preoperative chemotherapy vs. up-front surgery (PC vs. SU) group, the pooled RR was 9.109 for TS (95% CI: 5.109 - 16.241; P < 0.001), 1.291 for TR (95% CI: 1.124 - 1.483; P < 0.001) and 1.101 for EFS (95% CI: 0.980 - 1.238; P = 0.106). For subgroup short course vs. long course (SC vs. LC), the pooled RR was 1.097 for TS (95% CI: 0.784 - 1.563; P = 0.587), 1.197 for TR (95% CI: 0.960 - 1.493; P = 0.110) and 1.006 for EFS (95% CI: 0.910 - 1.250; P = 0.430). Conclusions: Short course preoperative chemotherapy is as effective as long course and preoperative chemotherapy only benefits Wilms’ tumor patients in tumor shrinkage and resection but not event-free survival.

STABILITY ANALYSIS AND HAZARD ASSESSMENT OF THE NORTHERN SLOPES OF SAN VICENTE VOLCANO IN CENTRAL EL SALVADOR

Geologic hazards affect the lives of millions of people worldwide every year. El Salvador is a country that is regularly affected by natural disasters, including earthquakes, volcanic eruptions and tropical storms. Additionally, rainfall-induced landslides and debris flows are a major threat to the livelihood of thousands. The San Vicente Volcano in central El Salvador has a recurring and destructive pattern of landslides and debris flows occurring on the northern slopes of the volcano. In recent memory there have been at least seven major destructive debris flows on San Vicente volcano. Despite this problem, there has been no known attempt to study the inherent stability of these volcanic slopes and to determine the thresholds of rainfall that might lead to slope instability. This thesis explores this issue and outlines a suggested method for predicting the likelihood of slope instability during intense rainfall events. The material properties obtained from a field campaign and laboratory testing were used for a 2-D slope stability analysis on a recent landslide on San Vicente volcano. This analysis confirmed that the surface materials of the volcano are highly permeable and have very low shear strength and provided insight into the groundwater table behavior during a rainstorm. The biggest factors on the stability of the slopes were found to be slope geometry, rainfall totals and initial groundwater table location. Using the results from this analysis a stability chart was created that took into account these main factors and provided an estimate of the stability of a slope in various rainfall scenarios. This chart could be used by local authorities in the event of a known extreme rainfall event to help make decisions regarding possible evacuation. Recommendations are given to improve the methodology for future application in other areas as well as in central El Salvador.

Evidencia sobre la eficacia de cannabinoides en el dolor neuropático oncológico

Contexto: La eficacia de los cannabinoides en el dolor neuropático es desconocida. El control del dolor es determinante en los pacientes ya que genera un impacto negativo en la calidad de vida de los pacientes. Objetivo: El presente trabajo pretende demostrar la evidencia sobre la eficacia de los medicamentos cannabinoides en el control del dolor neuropático oncológico, mediante la evaluación de la literatura disponible. Metodología: Se realizó una revisión sistemática de literatura incluyendo estudios experimentales, observacionales y revisiones sistemáticas en un periodo de 15 años. Se incluyeron todos los estudios desde el años 2000 con evidencia IB según la escala de evidencia de Oxford. Resultados: Cuatro estudios cumplieron criterios para su inclusión, sin embargo la evidencia es baja y no permite recomendar o descartar los cannabinoides como terapia coadyuvante en control del dolor neuropático oncológico. La combinación de THC/CDB (Sativex®) parece ser un medicamento seguro pues no se reportaron muertes asociadas a su uso, sin embargo la presentación de eventos adversos a nivel gastrointestinal y neurológico podría aumentar el riesgo de interacciones medicamentosas y tener un impacto negativo en la calidad de vida de los pacientes oncológicos. Conclusiones: No hay suficiente literatura y la evidencia no es suficiente para recomendar o descartar el uso de los cannabinoides en dolor neuropático oncológico. Futuros estudios deben realizarse para analizar el beneficio de estos medicamentos. Aunque ética y socialmente hay resistencia para el uso de los cannabinoides, actualmente hay una gran discusión política en el mundo y en Colombia para su aceptación como terapia en el control del dolor.

Development and Detailed Characterization of Innovative, High-Performance Membrane Materials for CO2 Capture Processes

The scope of this dissertation is to study the transport phenomena of small molecules in polymers and membranes for gas separation applications, with particular attention to energy efficiency and environmental sustainability. This work seeks to contribute to the development of new competitive selective materials through the characterization of novel organic polymers such as CANALs and ROMPs, as well as through the combination of selective materials obtaining mixed matrix membranes (MMMs), to make membrane technologies competitive with the traditional ones. Kinetic and thermodynamic aspects of the transport properties were investigated in ideal and non-ideal scenarios, such as mixed-gas experiments. The information we gathered contributed to the development of the fundamental understanding related to phenomenon like CO2-induced plasticization and physical aging. Among the most significant results, ZIF-8/PPO MMMs provided materials whose permeability and selectivity were higher than those of the pure materials for He/CO2 separation. The CANALs featured norbornyl benzocyclobutene backbone and thereby introduced a third typology of ladder polymers in the gas separation field, expanding the structural diversity of microporous materials. CANALs have a completely hydrocarbon-based and non-polar rigid backbone, which makes them an ideal model system to investigate structure-property correlations. ROMPs were synthesized by means of the ring opening metathesis living polymerization, which allowed the formation of bottlebrush polymers. CF3-ROMP reveled to be ultrapermeable to CO2, with unprecedented plasticization resistance properties. Mixed-gas experiments in glassy polymer showed that solubility-selectivity controls the separation efficiency of materials in multicomponent conditions. Finally, it was determined that plasticization pressure in not an intrinsic property of a material and does not represent a state of the system, but rather comes from the contribution of solubility coefficient and diffusivity coefficient in the framework of the solution-diffusion model.

Surgery after biological therapy in locally advanced NSCLC with molecular driver: feasibility and effectiveness of a new multidisciplinary approach

Introduction: Surgical outcomes after biological therapy have not been investigated yet and no information about timing, postoperative complications and survival have been recorded. Methods: This is a prospective study which compares a group of stage IIIA and IIIB NSCLC patients treated with biological therapy with patients undergoing standard induction chemotherapy. Data reported are preliminary results on the safety and effectiveness of surgery after target therapy. Results: We compared 22 patients treated with standard chemotherapy (Group 1) and 6 patients who received target therapy (Group 2). No differences were observed with an important bias due to the limited number of cases. The median time of resection was 159.8 ± 62.8 for group 1 and 201 ± 57.8 for group 2 (p=0.194). Complete resection was obtained in all Group 1-cases. Post-operative complication rate was 22% vs 16% (p=1). Pathologists reported necrosis >50% in 13% in group 1, Fibrosis >50% was presents respectively in 27% and 33% of patients (p=1). Residual vital tumor was >50% in 77% of patients undergone CT and in 66% of patients undergone TT (p=0.622). A total of 6 (31%) patients in the CT-group developed recurrence, 3 in the TT- group (64.2%), p was 0.634. No difference was observed both in terms of OS (P=0.29, Figure 3) and in term of DFS (P=0.106, Figure 4). Discussion: There is no consensus in the use of target therapy for advanced tumor in association with surgery. EGFR-tyrosine kinase inhibitors showed higher and more rapid response and our study wants to demonstrate that surgery after target therapy gives full access to the advantage of definitive local treatment. In our series, despite fibrosis, radical surgery has been achieved in all patients operated. The intraoperative blood loss, operation time, postoperative hospital stay and postoperative complication rate seems to be similar.

Acquired and inherited cardiomyopathies: evaluation of cardiotoxic effects in preclinical models

Cardiomyopathies are a heterogeneous group of myocardial disorders defined by structural and functional alterations of the heart. These cardiac diseases can have both non-genetic and genetic origin. Nevertheless, a different etiology can trigger the same phenotype, as in the case of anthracycline-induced cardiotoxicity and desmin-related cardiomyopathy (DRM). Therefore, the aim of this study was to investigate the cellular mechanisms driving the development of these cardiotoxic conditions in in vitro models. Doxorubicin (DOX) is a commonly used antineoplastic drug for the treatment of a wide range of tumors. Besides, its clinical use is restricted because of dose-dependent cardiotoxicity. Our findings provided evidence that phospholipase C Beta 2 (PLCβ2) may have a critical role in DOX-induced cardiotoxicity in undifferentiated and differentiated H9c2 cell line. Interestingly, the results obtained revealed that cardiomyocytes are less sensitive to DOX, following the evaluation of cellular mechanisms such as: oxidative stress, apoptosis and cell proliferation. Nonetheless, the treatment induced a significant upregulation of PLCβ2 associated to morphological changes in both models, demonstrating the implication in a hypertrophic response. On the other hand, a hereditary DRM was associated to a missense mutation of aB crystallin (CRYAB), a chaperone protein involved in the regulation of the intermediate filament network. Since research has only been conducted on transgenic (TG) mice and neonatal rat cardiomyocytes, this study aimed at investigating cellular mechanisms triggered by CRYABR120G mutation in a hiPSC-derived DRM model. Our model confirmed the impairment of the cytoskeletal organization resulting in the formation of desmin and CRYAB aggregates and myofibril misalignment. Moreover, the missense mutation confirmed a hypertrophic cardiomyopathy phenotype, a feature of DRM patients, on cardiac engineered tissues. Lastly, these data obtained suggest that further research on PLCβ2 and CRYAB are needed to comprehend the molecular mechanisms behind the development of these 2 cardiac diseases.

Dissecting and resetting SETD2/H3K36ME3 deficiency in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR::ABL1 fusion gene, leading to a constitutively active tyrosine kinase that drives the disease. Genomic instability is a hallmark of CML, contributing to disease progression and treatment resistance. A study identified SETD2, a histone methyltransferase, as frequently dysfunctional in advanced-phase CML, resulting in reduced trimethylation of Histone H3 at lysine 36 (H3K36Me3). This loss is associated with poor prognosis and increased genetic instability. Investigations revealed that SETD2 dysfunction is caused by post-translational modifications mediated by Aurora kinase A and MDM2, leading to proteasome-mediated degradation. Aurora kinase A phosphorylates SETD2, while MDM2 ubiquitinates it, targeting it for degradation. Inhibition of MDM2 and Aurora kinase A restored SETD2 expression and activity, suggesting potential therapeutic targets. Loss of SETD2 and H3K36Me3 impairs DNA repair mechanisms, favoring error-prone repair pathways over faithful ones, exacerbating genetic instability. Reintroduction of SETD2 into deficient cells restored DNA repair pathways, preserving genomic integrity. Analysis of CD34+ progenitor cells from CML patients showed reduced SETD2 levels compared to healthy individuals, correlating with decreased clonogenic capacity. Notably, SETD2 loss is not detectable at diagnosis but emerges during disease progression, indicating its role as an early indicator of CML advancement. Therapeutically, inhibitors targeting Aurora kinase A, MDM2, and the proteasome showed efficacy in cells expressing SETD2, particularly in those with low SETD2 levels. Proteasome inhibitors induced apoptosis and DNA damage in SETD2-deficient cells, highlighting their potential for CML treatment. In conclusion, SETD2 acts as a tumor suppressor in CML, with its dysfunction contributing to genetic instability and disease progression. Targeting the mechanisms of SETD2 loss presents promising therapeutic avenues for controlling CML proliferation and restoring genomic integrity.

Mitigation of Train-Induced waves by resonant filled-trench (RFT)

The increase of railways near the urban areas is a significant cause of discomfort for inhabitants due to train-induced vibration and noise. Vibration characteristics can vary widely according to the train type: for high-speed trains, if train speed becomes comparable to the ground wave speed, the vibration level becomes significant; for freight trains, due to their heavier weight and lower speed, the vibration amplitudes are greater and propagate at a more considerable distance from the track; for urban tramways, although the vibration amplitude is relatively low, they can have a negative structural effect on the closest buildings [51]. Therefore, to dampen the vibration level, it is possible to carry out some interventions both on the track and the transmission path. This thesis aims to propose and numerically investigate a novel method to dampen the train-induced vibrations along the transmission path. The method is called "resonant filled-trench (RFT)" and consists of a combination of expanded polystyrene (EPS) geofoam to stabilize the trench wall against the collapse and drowned cylindrical embedded inclusions inside the geofoam, which act as a resonator, reflector, and attenuator. By means of finite element simulations, we show that up to 50% higher attenuation than the open trench is achievable after overcoming the resonance frequency of the inclusion, i.e., 35Hz, which covers the frequency contents of the train-induced vibration. Moreover, depending on the filling material used for the inclusions, trench depth can be reduced up to 17% compared to the open trench showing the same screening performance as the open trench. Also, an RFT with DS inclusion installed in dense sand soil shows a high hindrance performance (i.e., IL≥6dB) when the trench depth is larger than 0.5λ_R while it is 0.6λ_R for the open trench.