Targeting ATR in Cancer Medicine.

As a key component of the DNA Damage Response, the Ataxia telangiectasia and Rad3-related (ATR) protein is a promising druggable target that is currently widely evaluated in phase I-II-III clinical trials as monotherapy and in combinations with other rational antitumor agents, including immunotherapy, DNA repair inhibitors, chemo- and radiotherapy. Ongoing clinical studies for this drug class must address the optimization of the therapeutic window to limit overlapping toxicities and refine the target population that will most likely benefit from ATR inhibition. With advances in the development of personalized treatment strategies for patients with advanced solid tumors, many ongoing ATR inhibitor trials have been recruiting patients based on their germline and somatic molecular alterations, rather than relying solely on specific tumor subtypes. Although a spectrum of molecular alterations have already been identified as potential predictive biomarkers of response that may sensitize to ATR inhibition, these biomarkers must be analytically validated and feasible to measure robustly to allow for successful integration into the clinic. While several ATR inhibitors in development are poised to address a clinically unmet need, no ATR inhibitor has yet received FDA-approval. This chapter details the underlying rationale for targeting ATR and summarizes the current preclinical and clinical landscape of ATR inhibitors currently in evaluation, as their regulatory approval potentially lies close in sight.

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

Formación profesional y competencias en Enfermería / Professional training and competencies in Nursing

Objetivo: Analizar el proceso de formación profesional y competencias en las prácticas preprofesionales por internos de enfermería de la Universidad Regional Autónoma de los Andes. Método: Tipo observacional descriptiva. Resultados: El 63% considera que su experiencia en las prácticas preprofesionales que brinda la carrera de Enfermería, son pocas satisfactorias. Conclusión: se constató la importancia de atender a la demanda colectiva de atención a disposición del profesional, En lo que se necesita de ingreso del elemento de prevención y promoción de salud en la formación. Se sugiere la realización de actividades de capacitación y actualización en la formación por competencias en Enfermería.

Objective: To analyze the process of professional training and competencies in pre-professional practices by nursing interns of the Universidad Regional Autónoma de los Andes. Method: Descriptive observational type. Results: 63% considered that their experience in the pre-professional internships provided by the Nursing career were not very satisfactory. Conclusion: The importance of attending to the collective demand for care available to the professional was noted, which requires the inclusion of the prevention and health promotion element in the training. It is suggested the realization of training and updating activities in the training by competences in Nursing.

Pediculosis capitis y transmisión potencial de enfermedades infecciosas reemergentes en Colombia. Revisión de la literatura / Pediculosis capitis and potential transmission of re-emerging infectious diseases in Colombia. Literature review

Resumen Introducción. La infestación por piojos de la cabeza en humanos (Pediculus humanus capitis) se conoce como pediculosis capitis. Estos parásitos pueden ser vectores de enfermedades infecciosas con potencial reemergente. Objetivos. Revisar la literatura actual sobre las enfermedades infecciosas transmitidas por piojos de la cabeza y realizar una breve descripción de sus manifestaciones clínicas. Materiales y métodos. Se realizó una revisión de la literatura en Medline, ScienceDirect, Google Scholar y SciELO mediante la siguiente estrategia de búsqueda: años de publicación: 1938 a 2019; idioma: inglés y español; términos de búsqueda: "Pediculus", "lice infestations", "bacteria", "emerging communicable diseases", "Rickettsia", "Bartonella", "Borrelia", "Acinetobacter", "Yersinia", and "Colombia", y sus equivalentes en español. Resultados. De los 110 artículos incluidos, la mayoría correspondió a investigaciones originales (48.2%). A nivel mundial, numerosos estudios han reportado la transmisión de Rickettsia prowazekii, Bartonella quintana, Borrelia recurrentis, Staphylococcus aureus, Acinetobacter bau-manniiy Yersiniapestis, entre otras bacterias, por los piojos de la cabeza y del cuerpo en humanos. Conclusiones. Aunque las enfermedades infecciosas transmitidas por piojos de la cabeza son raras, guardan potencial reemergente en poblaciones afectadas por migraciones humanas, crisis sociopolíticas, indigencia e inmunosupresión. En Colombia no se han realizado investigaciones sobre la transmisión de estas enfermedades por Pediculus spp., por lo que se sugiere que en estudios futuros se determine la prevalencia y los aspectos epidemiológicos de las enfermedades transmitidas por piojos de la cabeza.

Abstract Introduction: Head lice (Pediculus humanus capitis) infestation in humans is known as pediculosis capitis. These parasites can be vectors of potentially re-emerging infectious diseases. Objective: To review the current literature on infectious diseases transmitted by head lice and provide a brief description of their clinical manifestations. Materials and methods: A literature review was conducted in the Medline, ScienceDirect, Google Scholar and SciELO databases using the following search strategy: Publication time: 1938 to 2019; Publication language: English and Spanish; Search terms: "Pediculus", "lice infestations", "bacteria", "emerging communicable diseases", "Rickettsia", "Bartonella", "Borrelia", "Acinetobacter", "Yersinia", and "Colombia", and their Spanish equivalents. Results: Of the 110 studies included in the review, most of them were original research articles (48.2%). Worldwide, many studies have reported the transmission of Rickettsia prowazekii, Bartonella quintana, Borrelia recurrentis, Staphylococcus aureus, Acinetobacter baumannii and Yersinia pestis, among other bacteria, by head and body lice in humans. Conclusions. Although infectious diseases transmitted by head lice are rare, they have the potential to become re-emerging infectious diseases in population groups affected by human migration processes, socio-political crises, homelessness, and immunosuppression conditions. In Colombia, so far, there are no studies on the transmission of these bacterial diseases by Pediculus spp., so in future studies the prevalence and epidemiological characteristics of human head louse-borne diseases should be determined.

Prevalence, incidence, clinical manifestations and factors associated with pediculosis capitis in nursery school children of a lowincome area from Colombia / Prevalencia, incidencia, manifestaciones clínicas y factores asociados con pediculosis capitis en niños de guardería de un área de bajos ingresos en Colombia

Objectives: epidemiology of pediculosis capitis was determined. The worldwide distributed ectoparasite, Pediculus humanus capitis, causes pediculosis capitis. Although risk factors for children are known, studies about its clinical description are rare. Materials and methods: cross-sectional descriptive study based on a sample (356 children) aged 1 to 5 of a low-income area from Popayán, Colombia. Two observations were practiced: at the beginning and at the end of the year 2017. Hair, scalp, lymphatic nodules and frontotemporal, parietal, occipital, nuchal and retroauricular cutaneous regions were examined. Insects were mechanically removed by wetting the hair and using lice combs. Nits, nymphs and adult lice were gathered and stored for future studies. Results: prevalence and incidence of pediculosis capitis were 5.1 % and 20.2 %, respectively. The associated variables were mainly infestation antecedent, long hair, female sex and eliminating with shampoo (95 % CI: 15-20). Clinical variables: presence of adenopathies, hair scalp inflammation and nuchal adenopathies (25-35 %); nits and lice localized in occipital region, hair scalp itching and retroauricular itching (20-25 %). Conclusions: pediculosis capitis affects those nursery children studied. It is important to know the variables associated for prevention, control and eradication of head lice infestation..(AU)

Objetivo: se determinó la epidemiólogía de la pediculosis capitis. El ectoparásito mundialmente distribuido, Pediculus humanus capitis, causa pediculosis capitis. Aunque los factores de riesgo son conocidos, investigaciones sobre su descripción clínica son pocas. Materiales y métodos: estudio descriptivo de corte transversal con una muestra (356 niños) entre 1 y 5 años de un área de bajos ingresos (Popayán, Colombia). Se realizaron dos observaciones: al inicio y al final del año 2017. Se examinaron el pelo, cuero cabelludo, nódulos linfáticos y las regiones cutáneas frontotemporales, parietales, occipital, nuca y retroauriculares. Los insectos fueron removidos mecánicamente por medio de peines liendrera y humedeciendo el pelo. Las liendres, ninfas y piojos adultos se almacenaron para futuros estudios. Resultados: la prevalencia e incidencia de pediculosis capitis fueron 5,1 % y 20,2 %, respectivamente. Las variables asociadas fueron principalmente antecedentes de infestación, pelo largo, sexo femenino y eliminación con champú (95 % CI: 15-20). Variables clínicas: presencia de adenopatías, inflamación del cuero cabelludo y adenopatías nucales (25-35 %); liendres y piojos localizados en la región occipital, prurito del cuero cabelludo y prurito retroauricular (20-25 %). Conclusiones: la pediculosis capitis está presente y afecta a los niños de guardería. Es importante conocer las variables asociadas a la pediculosis capitis para prevenir, controlar y erradicar la infestación por piojos de la cabeza..(AU)

Epstein-Barr virus infection as a predisposing factor for multiple sclerosis. An update from molecular biology, immunology and epidemiology / Infección por virus de Epstein-Barr como factor predisponente en la esclerosis múltiple. Actualización desde la biología molecular, la inmunología y la epidemiología

Abstract Introduction: Epstein-Barr virus is an infectious agent used to immortalize and induce polyclonal activation of B cells. It has been widely described that this virus produces changes in the cells it infects and in the immune response, and stimulates the development of autoimmune diseases. Objective: To characterize the association between Epstein-Barr virus and multiple sclerosis described in current scientific literature. Materials and methods: A 59-years range literature search was conducted in the PubMed, ScienceDirect, Redalyc and SciELO databases using the following MeSH terms: "Epstein-Barr virus, multiple sclerosis autoimmune diseases, autoimmune diseases of the nervous system". Results: Many studies describe the association between Epstein-Barr virus and multiple sclerosis. It is believed that acute infection and viral reactivation promote the development of multiple sclerosis. Conclusions: It is necessary to conduct further research on the pathogenesis and morphophysiological and neuroimmunological changes -at the ecological, molecular, cellular, tissue, organic and systemic level- induced by the immune response and that favor the development of multiple sclerosis.

Resumen Introducción. El virus de Epstein-Barr (VEB) es un agente inmortalizador y activador policlonal de células B. Es conocido que este virus induce cambios en las células que infecta y en la respuesta inmune, y que favorece la presentación de enfermedades autoinmunes. Objetivo. Caracterizar la asociación entre el VEB y la esclerosis múltiple (EM) descrita en la literatura actual. Materiales y métodos. Se realizó una búsqueda bibliográfica con rango de 59 años mediante los términos DeCS "virus de Epstein-Barr, esclerosis múltiple, enfermedades autoinmunes del sistema nervioso" en las bases de datos PubMed, ScienceDirect, Redalyc y SciELO. Resultados. Hay muchos estudios que describen la asociación del VEB con la EM. Se cree que la infección aguda y la reactivación viral contribuyen al desarrollo de la enfermedad. Conclusiones. Es necesario realizar más estudios que indaguen sobre la patogénesis, los cambios morfofisiológicos y las alteraciones neuroinmunológicas en la ecología molecular, celular, tisular, orgánica y sistémica inducida por la respuesta inmune y que favorecen el desarrollo de la EM.

HIV-1 Tat interactions with cellular 7SK and viral TAR RNAs identifies dual structural mimicry.

The HIV Tat protein competes with the 7SK:HEXIM interaction to hijack pTEFb from 7SK snRNP and recruit it to the TAR motif on stalled viral transcripts. Here we solve structures of 7SK stemloop-1 and TAR in complex with Tat's RNA binding domain (RBD) to gain insights into this process. We find that 7SK is peppered with arginine sandwich motifs (ASM)-three classical and one with a pseudo configuration. Despite having similar RBDs, the presence of an additional arginine, R52, confers Tat the ability to remodel the pseudo configuration, required for HEXIM binding, into a classical sandwich, thus displacing HEXIM. Tat also uses R52 to remodel the TAR bulge into an ASM whose structure is identical to that of the remodeled ASM in 7SK. Together, our structures reveal a dual structural mimicry wherein viral Tat and TAR have co-opted structural motifs present in cellular HEXIM and 7SK for productive transcription of its genome.

El rol de VEGF en la angiogénesis fisiológica y tumoral / The role of VEGF in Physiological and tumoral angiogénesis

El proceso de angiogénesis, en el cual se desarrollan nuevos vasos sanguíneos a partir de una red vascular existente, requiere de la activación de los receptores en la superficie de las células endoteliales. En sus procesos fisiológicos, como la reparación de heridas, se observa un aumento en la permeabilidad vascular que induce el depósito de proteínas plasmáticas en la matriz extracelular y favorece la reparación y la cicatrización. No obstante, en algunas patologías como el cáncer, desempeña un papel importante para el crecimiento y la diseminación de las células tumorales. Su activación en el tumor permite, pero no garantiza, la expansión tumoral y, por ende, la ausencia de angiogénesis puede limitar el crecimiento. Por eso, se han desarrollado varios inhibidores con el propósito de interferir específicamente en diferentes etapas de este proceso, por ejemplo, el bevacizumab (Avastin) que se distingue como un anticuerpo monoclonal que reconoce y se une al Factor de Crecimiento Endotelial Vascular (por sus siglas en inglés VEGF).

Angiogenesis, the cellular process leading to the development of new blood vessels from an existing vascular network, requires activation of surface receptors of normal endothelial cells by signaling molecules such as the Vascular Endothelial Growth Factor (VEGF). During physiological processes of angiogenesis leading to injury repair, an increase of vascular permeability favors deposits of plasma proteins in the extracellular matrix. However, in pathological processes such as cancer, angiogenesis plays an important role in the growth and proliferation of the tumor cells. The activation of angiogenesis in a tumor induces, but does not guarantee, tumor expansion; hence, the absence of angiogenesis may limit the tumor growth. Angiogenesis inhibitors been developed to interfere with different stages of the process. For example, bevacizumab (Avastin) is recognized as a monoclonal antibody binds specifically to VEGF and inhibits its angiogenic function.

CÁNCER Y MITOCONDRIA: UN ASPECTO CENTRAL PARA EL DESARROLLO Y CRECIMIENTO TUMORAL / Cancer and mitochondria: a central aspect to tumor development and growth

Se sabe que las células tumorales consumen más glucosa que las no tumorales. Además, las células tumorales expresan isoformas embrionarias de enzimas para la glucólisis, permitiendo su mayor actividad y obtención de energía en los diversos procesos cancerígenos. Algunos autores han sugerido que la hipoxia del tumor actúa como regulador del metabolismo energético y que puede redirigir a las células tumorales a utilizar la glucólisis como fuente de provisión de ATP cuando hay limitación de oxígeno. Otros autores sugieren que ese es el resultado de mutaciones en oncogenes, genes supresores y enzimas de la vía glucolítica o del metabolismo oxidativo mitocondrial (Myc, Akt, p53, HIF1-α). La aplicación de la tomografía de emisión de positrones (PET) en los servicios de medicina nuclear y radiología ha permitido usar la mitocondria como un organelo para el diagnóstico de cáncer cuantificando una mayor captación de glucosa por las células tumorales respecto del tejido no tumoral adyacente, mediante el uso del análogo radioactivo no metabolizable de la glucosa (18FDG, 18F-2-desoxiglucosa). Así pues, las investigaciones se han centrado en el metabolismo alterado como parte del desarrollo y crecimiento tumoral con el objetivo de inhibir la progresión a la metástasis de esta patología en los pacientes que no se pueden recuperar recibiendo tratamiento con quimioterapia y la radioterapia. El objetivo de esta revisión documental consiste en resaltar las generalidades e importancia de las mitocondrias en los mecanismos que promueven el cáncer.

Tumor cells consume more glucose than the non-tumor cells. In addition, tumor cells express isoforms of embryonic glycolytic enzymes with higher activity to obtain energy in the various carcinogenic processes. Some authors have suggested that hypoxia of the tumor acts as a regulator of energy metabolism and can redirect to tumor cells to use the glycolysis as source for the supply of ATP when there is limitation of oxygen. In contrast, other authors suggest that this phenomena is the result of mutations in oncogenes, tumor suppressor genes and enzymes of the glycolytic pathway or oxidative metabolism mitochondrial including Myc, Akt, p53, HIF1-α. The application of Positron Emission Tomography (PET) in nuclear medicine services and radiology has allowed the use of mitochondria as an organelle that serves to diagnose cancer, quantify greater uptake of glucose by tumor cells on adjacent non-tumor tissue using analogue radioactive non-metabolizable glucose (18FDG, 18F-2-desoxiglucosa). Such research has focused on altered metabolism as part of development and tumor growth to inhibit the progression of cancer to metastases in patients that cannot be recovered by chemotherapy and radiation therapy. The aim of this review is to highlight the generalities and importance of mitochondria in the mechanisms that promote cancer.

Chemo-enzymatic synthesis of site-specific isotopically labeled nucleotides for use in NMR resonance assignment, dynamics and structural characterizations.

Stable isotope labeling is central to NMR studies of nucleic acids. Development of methods that incorporate labels at specific atomic positions within each nucleotide promises to expand the size range of RNAs that can be studied by NMR. Using recombinantly expressed enzymes and chemically synthesized ribose and nucleobase, we have developed an inexpensive, rapid chemo-enzymatic method to label ATP and GTP site specifically and in high yields of up to 90%. We incorporated these nucleotides into RNAs with sizes ranging from 27 to 59 nucleotides using in vitro transcription: A-Site (27 nt), the iron responsive elements (29 nt), a fluoride riboswitch from Bacillus anthracis(48 nt), and a frame-shifting element from a human corona virus (59 nt). Finally, we showcase the improvement in spectral quality arising from reduced crowding and narrowed linewidths, and accurate analysis of NMR relaxation dispersion (CPMG) and TROSY-based CEST experiments to measure µs-ms time scale motions, and an improved NOESY strategy for resonance assignment. Applications of this selective labeling technology promises to reduce difficulties associated with chemical shift overlap and rapid signal decay that have made it challenging to study the structure and dynamics of large RNAs beyond the 50 nt median size found in the PDB.

Phase Segregation at the Liquid-Air Interface Prior to Liquid-Liquid Equilibrium.

Binary systems with partial miscibility segregate into two liquid phases when their overall composition lies within the interval defined by the saturation points; out of this interval, there is one single phase, either solvent-rich or solute-rich. In most systems, in the one-phase regions, surface tension decreases with increasing solute concentration due to solute adsorption at the liquid-air interface. Therefore, the solute concentration at the surface is higher than in the bulk, leading to the hypothesis that phase segregation starts at the liquid-air interface with the formation of two surface phases, before the liquid-liquid equilibrium. This phenomenon is called surface segregation and is a step toward understanding liquid segregation at a molecular level and detailing the constitution of fluid interfaces. Surface segregation of aqueous binary systems of alkyl acetates with partial miscibility was theoretically demonstrated by means of a thermodynamic stability test based on energy minimization. Experimentally, the coexistence of two surface regions was verified through Brewster's angle microscopy. The observations were further interpreted with the aid of molecular dynamics simulations, which show the diffusion of the acetates from the bulk toward the liquid-air interface, where acetates aggregate into acetate-rich domains.

Gibbs excess and the calculation of the absolute surface composition of liquid binary mixtures.

Adsorption at the liquid-vapor interphase of a liquid binary mixture is traditionally quantified by means of the Gibbs solute excess. Despite several theoretical reviews on the meaning of Gibbs excess defined by the Gibbs dividing surface, it is still misinterpreted as the excess concentration under Guggenheim's finite-depth surface layer approach. In this work, both concepts are clarified in a practical way, aided by a graphical representation without loss of generality. The understanding of both quantities led to the development of a thermodynamic procedure for the calculation of the actual number of solute and solvent molecules at a finite-depth surface layer (not a monolayer), what is called the absolute surface composition. From surface tension and density data, the absolute surface composition of the binary aqueous mixtures of methanol, ethanol, 1-propanol, and 1-butanol was calculated. Results show thermodynamic consistency and agree with experimental reports and with an empirical mixing rule. The increasing alcohol surface concentration throughout the entire concentration range casts doubt on the formation of an alcohol monolayer, as was suggested by other authors. Furthermore, the use of Guggenheim's monolayer model does not reproduce the experimental data, nor does it show thermodynamic consistency.

An equilibrium-dependent retroviral mRNA switch regulates translational recoding.

Most retroviruses require translational recoding of a viral messenger RNA stop codon to maintain a precise ratio of structural (Gag) and enzymatic (Pol) proteins during virus assembly. Pol is expressed exclusively as a Gag-Pol fusion either by ribosomal frameshifting or by read-through of the gag stop codon. Both of these mechanisms occur infrequently and only affect 5-10% of translating ribosomes, allowing the virus to maintain the critical Gag to Gag-Pol ratio. Although it is understood that the frequency of the recoding event is regulated by cis RNA motifs, no mechanistic explanation is currently available for how the critical protein ratio is maintained. Here we present the NMR structure of the murine leukaemia virus recoding signal and show that a protonation-dependent switch occurs to induce the active conformation. The equilibrium is such that at physiological pH the active, read-through permissive conformation is populated at approximately 6%: a level that correlates with in vivo protein quantities. The RNA functions by a highly sensitive, chemo-mechanical coupling tuned to ensure an optimal read-through frequency. Similar observations for a frameshifting signal indicate that this novel equilibrium-based mechanism may have a general role in translational recoding.

Analysis of Gibbs adsorption equation and thermodynamic relation between Gibbs standard energies of adsorption and micellization through a surface equation of state.

The calculation of surface molecular areas through Gibbs adsorption equation has been questioned in some early works on the belief that these areas have been obtained from the apparently constant slope of the surface tension vs. logarithm of concentration curve along the entire region at which surface tension declines rapidly as the concentration increases. This premise leads to consider that Gibbs equation predicts that surface saturation is reached at the beginning of this region. However, through an analysis of the forementioned curve in accordance to Gibbs equation, it can be easily shown that surface saturation is attained at the end of the region. On the other hand, based on a thermodynamic model, it is also shown that the adsorption process, and thus, surface saturation, proceeds before micellization.