Jerarquización de zonas de atención prioritaria para la minimización del riesgo biológico en situación de crisis / Ordering areas for priority public health interventions during infectious disease outbreaks

RESUMEN Objetivo Proponer una herramienta para identificar sectores de población que requieren mayor atención por parte de autoridades locales o gubernamentales en situaciones de crisis biológica, considerando los factores que influyen en la adherencia a las normas de minimización de riesgos. Metodología Se implementó un algoritmo de ordenamiento, tomando como referencia las restricciones de julio del 2021 en Ecuador. El contexto del estudio se resume en siete sectores urbanos de la ciudad de Guayaquil, con una población caracterizada por un nivel de educación promedio por debajo de la educación secundaria superior (70%) y más del 50% entre 20-34 años, con alguna ocupación en el medio de una economía popular debilitada. Siete factores de riesgo fueron identificados después de un análisis estructural de la hipótesis de adherencia (x2/gl=3,6; CFI≥0,91; TLI≥0,90; RMSEA≤0,05), basado en una muestra aleatoria de n=515 adultos viviendo en las áreas afectadas. Resultados El seguimiento de las normas está influenciado por la percepción del clima de seguridad, el riesgo percibido y el entendimiento del riesgo. El umbral de ordenamiento (h) permite establecer relaciones unidireccionales entre variables. Conclusiones Los resultados muestran que Vergeles, Norte y Fertisa representan los sectores con mayor prioridad de atención en materia de salud pública {A4,A5,A6}>{A2}>{A3}>{A1}>{A7}. Se requiere identificar más factores para garantizar una diferenciación óptima.

ABSTRACT Objective To propose a tool to identify local communities that require public health work priority, taking into account factors that influence adherence to risk minimization guidelines, especially in lock-down environments and unconventional workplaces. Methodology An ordering algorithm, based on the theory of uncertainty, was applied to classify population zones exhibiting high levels of infection and non-compliance with regulations in Guayaquil, during the last 'weekend' lockdown episode in July 2021. Seven urban sectors showed the highest number of infections (more than 70% of the local population): Vergeles (A1), Samanes (A2), Socio Vivienda (A3), Guasmo Norte (A4), Fertisa (A5), Alborada (A6), Urdesa (A7). Seven risk factors were identified after a path analysis of compliance hypothesis (x2/gl=3,6; CFI≥0,91; TLI≥0,90, RMSEA≤0,05), based on a random sample of n=515 adults living in the affected areas. Results Adherence to norms is influenced by the safety climate, perceived risk and risk understanding. The ordering threshold (h) leaded unidirectional relationships between variables. Conclusions: Adding more factors are believed to increases the differentiation path. The results showed that Vergeles, Norte and Fertisa were the areas with the highest priority for public health care {A4,A5,A6}>{A2}>{A3}>{A1}>{A7}.

KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines.

KRAS is one of the most frequently mutated oncogenes in human cancer, yet remaining undruggable. To explore a new therapeutic strategy, a library of 5-methyl-indolo[3,2-c]quinoline derivatives (IQc) with a range of alkyldiamine side chains was designed to target DNA and RNA G-quadruplexes (G4) in the promoter and 5'-UTR mRNA of the KRAS gene. Biophysical experiments showed that di-substituted IQc compounds are potent and selective KRAS G4 stabilizers. They preferentially inhibit the proliferation of KRAS mutant cancer cell lines (0.22 < IC50 < 4.80 µM), down-regulate KRAS promoter activity in a luciferase reporter assay, and reduce both KRAS mRNA and p21(KRAS) steady-state levels in mutant KRAS colon cancer cell lines. Additionally, IQcs induce cancer cell death by apoptosis, explained in part by their capacity to repress KRAS expression. Overall, the results suggest that targeting mutant KRAS at the gene level with G4 binding small molecules is a promising anticancer strategy.

Indolo[3,2-c]quinoline G-quadruplex stabilizers: a structural analysis of binding to the human telomeric G-quadruplex.

A library of 5-methylindolo[3,2-c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G-quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and two weakly basic side chains are potent and selective human telomeric (HT) and gene promoter G4 stabilizers. Spectroscopic studies with HT G4 as a model showed that an IQc stabilizing complex involves the binding of two IQc molecules (2,9-bis{[3-(diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride, 3 d) per G4 unit, in two non-independent but equivalent binding sites. Molecular dynamics studies suggest that end-stacking of 3 d induces a conformational rearrangement in the G4 structure, driving the binding of a second 3 d ligand to a G4 groove. Modeling studies also suggest that 3 d, with two three-carbon side chains, has the appropriate geometry to participate in direct or water-mediated hydrogen bonding to the phosphate backbone and/or G4 loops, assisted by the terminal nitrogen atoms of the side chains. Additionally, antiproliferative studies showed that IQc compounds 2 d (2-{[3-(diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride) and 3 d are 7- to 12-fold more selective for human malignant cell lines than for nonmalignant fibroblasts.

Interactions of isoniazid with membrane models: implications for drug mechanism of action.

This work focuses on the application of biophysical techniques to assess the interaction of isoniazid (INH) with three-dimensional cell membrane mimetic models. Liposomes made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were used as cell membrane lipids, being the interactions of the drug studied under different pH conditions to mimic the in vivo near neutral physiological pH found in the cytoplasm and the acidic conditions encountered in the protective gastric barrier and in the macrophage intracellular acidic compartments (i.e., phagosomes and phagolysomes). The effect of INH on the biophysical parameters of the cell membrane lipids was assessed by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). The overall results highlighted the importance of the pH for the interactions of INH with biological membranes. A relationship between the effect of INH on the biophysical properties of the membranes and the pH was established. In fact, the experimental results point to a higher affinity of the drug to the acidic environments, which not only explain its sequestration in the infected cells but also some of its side-effects.

Evaluation of the effect of rifampicin on the biophysical properties of the membranes: significance for therapeutic and side effects.

This work aims to study the biophysical interactions of rifampicin (RIF) with three-dimensional macrophage membrane models, under environments with physiological and pathological relevance. The interaction of RIF with liposomes formed by 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in different pH values (i.e., 5.0, 6.2 and 7.4) was investigated by several biophysical techniques. The RIF's membrane concentration was quantified by partition coefficient (Kp) using derivative spectrophotometry. To predict the drug's location across the membrane, fluorescence quenching studies were performed using liposomes labeled with two different fluorescence probes. The effect of the drug on the biophysical parameters of the membrane was carried out by dynamic light scattering (DLS), and small-angle X-ray scattering (SAXS). The overall results confirm that the interactions of RIF with membranes are pH-dependent, being much more pronounced at the acidic pH. A correlation between the effect of RIF on the biophysical properties of the membranes and the pH was found, which may be useful in the development of novel analogs with higher efficacy and fewer side effects, and also to understand the higher selectivity of RIF to the membranes of the infected cells, as well as its side effects.