Respect for international humanitarian law (IHL) in the battlefield is contingent on the measures undertaken in peacetime. Indeed, satisfactory compliance with IHL rests in the implementation of ...multiple measures at the domestic level crossing different spheres, including legislative, administrative and educational. In most latitudes, governments and other stakeholders coordinate these measures in what is known as National Committees for the Implementation of International Humanitarian Law. The article addresses the practice of these bodies in Latin America and provides alternatives to enhance their work.
A second-generation tetrathiomolybdate analogue (ATN-224; choline tetrathiomolybdate), which selectively binds copper with high affinity, is currently completing two phase I clinical trials in ...patients with advanced solid and advanced hematologic malignancies. However, there is very little information about the mechanism of action of ATN-224 at the molecular level.
The effects of ATN-224 on endothelial and tumor cell growth were evaluated in cell culture experiments in vitro. The antiangiogenic activity of ATN-224 was investigated using the Matrigel plug model of angiogenesis.
ATN-224 inhibits superoxide dismutase 1 (SOD1) in tumor and endothelial cells. The inhibition of SOD1 leads to inhibition of endothelial cell proliferation in vitro and attenuation of angiogenesis in vivo. The inhibition of SOD1 activity in endothelial cells is dose and time dependent and leads to an increase in the steady-state levels of superoxide anions, resulting in the inhibition of extracellular signal-regulated kinase phosphorylation without apparent induction of apoptosis. In contrast, the inhibition of SOD1 in tumor cells leads to the induction of apoptosis. The effects of ATN-224 on endothelial and tumor cells could be substantially reversed using Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, a catalytic small-molecule SOD mimetic.
These data provide a distinct molecular target for the activity of ATN-224 and provide validation for SOD1 as a target for the inhibition of angiogenesis and tumor growth.
cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the ...clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted ‘third‐generation’ ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats.
TR1801‐ADC is an antibody–drug conjugate with highly potent PBD payload–linker conjugated site‐specifically to our cMet antibody. The ADC is stable in rat circulation with acceptable tolerability. TR1801‐ADC is highly active in MET‐amplified and cMet‐overexpressing cancer cell lines. Patient‐derived xenograft solid tumor models of the stomach, colorectum, and head and neck were highly sensitive to treatment with our anti‐cMet‐ADC.
Small-scale gold mining in Portovelo–Zaruma, Southern Equador, performed by mercury amalgamation and cyanidation, yields 9–10
t of gold/annum, resulting in annual releases of around 0.65
t of ...inorganic mercury and 6000
t of sodium cyanide in the local river system. The release of sediments, cyanide, mercury, and other metals present in the ore such as lead, manganese and arsenic significantly reduces biodiversity downstream the processing plants and enriches metals in bottom sediments and biota. However, methylmercury concentrations in sediments downstream the mining area were recently found to be one order of magnitude lower than upstream or in small tributaries. In this study we investigated cyanide, bacterial activity in water and sediment and mercury methylation potentials in sediments along the Puyango river watershed, measured respectively by in-situ spectrophotometry and incubation with
3H-leucine and
203Hg
2+.
Free cyanide was undetectable (<
1
μg·L
−
1
) upstream mining activities, reached 280
μg·L
−
1
a few km downstream the processing plants area and was still detectable about 100
km downstream. At stations with detectable free cyanide in unfiltered water, 50% of it was dissolved and 50% associated to suspended particles. Bacterial activity and mercury methylation in sediment showed a similar spatial pattern, inverse to the one found for free cyanide in water, i.e. with significant values in pristine upstream sampling points (respectively 6.4 to 22
μgC·mg
wet weight
−
1
·h
−
1
and 1.2 to 19% of total
203Hg·g
dry weight
−
1
·day
−
1
) and undetectable downstream the processing plants, returning to upstream values only in the most distant downstream stations. The data suggest that free cyanide oxidation was slower than would be expected from the high water turbulence, resulting in a long-range inhibition of bacterial activity and hence mercury methylation. The important mercury fluxes resultant from mining activities raise concerns about its biomethylation in coastal areas where many mangrove areas have been converted to shrimp farming.
► Polymetallic and S-rich ore is processed for gold by amalgamation and cyanidation. ► But very low MeHg concentrations are found downstream processing plants. ► Cyanide strongly depressed bacterial activity and mercury methylation along a ~
50
km river stretch. ► Risk for coastal plain: cyanide disappears from ~
110
km on, while Hg does not.
Abstract Political ecology pushes back against the apolitical and ahistorical ecologies frequently found in mainstream scientific accounts of nature and the environment, and has increasingly focused ...on how scientific knowledge is 'socially constructed.' In this article, we argue for political ecological engagement with the highly influential knowledge-to-action (KTA) movement in science about health and the environment. We introduce KTA using results of a survey conducted under the auspices of a Canada-Latin America-Caribbean 'ecosystem approaches to health' (ecohealth) collaboration, and then narrow our focus to a single illustrative ecohealth project, dealing with the health impacts of small-scale gold mining in southwestern Ecuador. We employ an ecology of knowledge framework for integrating insights from science and technology studies,illustrating the interacting actors, material artifacts, institutions and discourses involved in not only the generation but also the application of health-environment science. The origins of ecohealth research in the Americas reflect interacting epistemological and political factors, as sophisticated, complex systemic analyses of health-environment interactions occurred amidst increasing neoliberalization of knowledge production. Simultaneously, corporate actors such as large mining companies influenced both the distribution of healthdamaging environmental conditions in the Americas, and the ways in which they were studied. This analysis motivates our advocacy of specifically political ecologies of health-environment knowledge, in which inequitable power dynamics and non-human actors are foregrounded in studies of the social production and application of science. The political ecology of knowledge framework that we envision would allow for simultaneous consideration of how societal contexts influence scientific knowledge production, and how the resulting knowledge can be better applied to protect the health of communities facing environmental injustice. Key words: ecohealth; mining; praxis; science and technology studies; knowledge-to-action; Canada; Ecuador
Based on ecosystem approaches to health (Ecohealth), this study sought to identify neurobehavioral disorders in children exposed to several levels of toxic metal pollution from gold mining in the ...Puyango River Basin, Southern Ecuador. Ninety-three children born or living in the study area participated in the study. A neurobehavioral test battery consisting of 12 tests assessing various functions of the nervous system was applied as well as a questionnaire regarding events of exposure of children’s mothers to contaminants during perinatal period. Hair samples were taken from children to determine manganese concentrations. Descriptive and inferential statistics were applied in order to examine possible relationships between exposure events, hair manganese, and neurobehavioral disorders. Having controlled co-variables such as age and educational level, it was found that children with elevated levels of hair manganese (over 2 μg/g) had poor performance in the test of general intelligence (Raven’s Progressive Color Matrices Scale PCM). The Ecohealth approach helped to identify that children in the lower Puyango Basin with very elevated levels of manganese in the river water (970 µg/L) are the ones who have the highest levels of hair manganese and the worst performance in the intelligence test.
Introducción: los anticuerpos anti-ADN doble cadena son un marcador serológico diagnóstico de lupus eritematoso sistémico (LES). El ensayo inmunoenzimático en fase sólida es una técnica rápida y ...rentable para su detección. Objetivo: estandarizar un ELISA que detecte anti ADN doble cadena para el diagnóstico del lupus. Métodos: los pasos que se siguieron para la estandarización incluyeron la preparación de controles, la sensibilización de la fase sólida, la selección de los amortiguadores y conjugado del ensayo, la evaluación de las condiciones de reacción y la determinación del nivel de corte. Además se realizó el estudio de inespecificidades. Se probaron 5 tipos de placas de poliestireno y se compararon ADN plasmídico de E.coli, pUC19 y ADN genómico humano como antígenos de recubrimiento. Se evaluó el efecto de la poli-L-lisina y la irradiación de la placa con luz ultravioleta, en la fijación del antígeno. El valor de corte del ensayo se determinó por el método del valor límite. Resultados: se observó disociación del antígeno cuando no se utilizó poli-L-lisina en el pretratamiento de la placa y la irradiación con luz UV no favoreció la unión del ADN a la fase sólida. No se encontraron diferencias significativas (p=0,710) entre ambos ADN, en el recubrimiento. El valor de corte (K=3) permitió clasificar como positivas 28 muestras (63,6 %) de pacientes con LES. Conclusiones: el método estandarizado, con el empleo de ADN plasmídico, permitió la detección de anticuerpos anti-ADN doble cadena en pacientes con lupus.
Objective
To explore attitudes toward immigrants and refugees living in Ecuador.
Design and Measures
A transnationalism framework informed this qualitative study, which utilized a semi‐structured ...interview guide to elicit responses from participants about their attitudes toward immigrants and refugees. Interviews were conducted in Spanish, audio‐taped, transcribed, coded, and analyzed in Spanish to identify emergent themes. Demographic data were analyzed using SPSS.
Sample
Participants (n = 50) were recruited from five sectors that interact with refugees: health care, the press, the police, nongovernmental organizations, and education. Fifty interviews were conducted with adults in Quito, Ecuador, in 2017.
Results
Participants reported concerns about the health and well‐being of immigrants and refugees, expressed a willingness to assist them, but within limits, noted discrimination and bias against refugees, and cited social policies and human rights as factors that influenced their attitudes.
Conclusions
Our findings indicate that immigrants and refugees face challenges which impact their health and well‐being, according to participants in the study. Social policies can influence attitudes, but are also affected by rapidly shifting immigration patterns. Migration flows in South America is an under‐studied area of research, with opportunity for further public health nursing inquiry.
Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy ...with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine.
We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy
in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level.
We show that MET is highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine
and an improved response to the combination
.
Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.
This study explored factors affecting the health and well being of recent refugees from Colombia in Ecuador. Data collection focused on how sending-country violence and structural violence in a new ...environment affect immigrant health vulnerability and risk behaviors. A qualitative approach included ethnographic observation, media content analysis, focus groups, and individual interviews with refugees (N = 137). The focus groups (5) provided perspectives on the research domains by sex workers; drug users; male and female refugees; and service providers. Social and economic marginalization are impacting the health and well being of this growing refugee population. Data illustrate how stigma and discrimination affect food and housing security, employment and health services, and shape vulnerabilities and health risks in a new receiving environment. Widespread discrimination in Ecuador reflects fears, misunderstanding, and stereotypes about Colombian refugees. For this displaced population, the sequelae of violence, combined with survival needs and lack of support and protections, shape new risks to health and well-being.
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