The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?

In recent decades, survival rates in colorectal cancer have improved greatly due to pharmacological treatment. However, many patients end up developing adverse drug reactions that can be severe or even life threatening, and that affect their quality of life. These remain a limitation, as they may force dose reduction or treatment discontinuation, diminishing treatment efficacy. From candidate gene approaches to genome-wide analysis, pharmacogenomic knowledge has advanced greatly, yet there is still huge and unexploited potential in the use of novel technologies such as next-generation sequencing strategies. This review summarises the road of colorectal cancer pharmacogenomics so far, presents considerations and directions to be taken for further works and discusses the path towards implementation into clinical practiceThis research was supported by grant FIS PI 16/01057- ISCIII (to Á.C.), ISCIII PFIS grant FI17/00215 (to A.R.S.) and Fundación Olga Torres (to C.F.-R.)S

Relaciones tróficas entre los macroinvertebrados y peces en un arroyo de la llanura pampeana (Argentina)

The diet and trophic relationships between the macroinvertebrates Phyllogomphoides joaquini Rodrigues Capítulo, 1992 and Coenagrionidae (Odonata), Chironomidae (Diptera), Diplodon delodontus (Lamarck, 1919) (Bivalvia: Hyriidae), and Pomacea canaliculata (Lamarck, 1822) (Gastropoda: Ampulariidae) and the fishes Pimelodella laticeps Eigenmann, 1917 (Heptapteridae) and Bryconamericus iheringii (Boulenger, 1887) (Characidae) in a temperate lowland lotic system in Argentina were assessed on the basis of gut contents and stable-isotope analyses. The feeding strategies were analyzed by the Amundsen method. Relative food items contribution for the taxa studied indicated a generalist-type trophic strategy. In macroinvertebrates, in general, the values of stable isotope confirmed the result of the analysis of gut contents. With the fish, stable-isotope analysis demonstrated that both species are predators, although B. iheringii exhibited a more omnivorous behaviour. These feeding studies allowed us to determine the trophic relationships among taxa studied. Detritus and diatoms were a principal source of food for all the macroinvertebrates studied. In La Choza stream the particulate organic matter is a major no limited food resource, has a significant influence upon the community.Instituto de Limnología "Dr. Raul A. Ringuelet

Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration

Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance.This work was partially supported by the ISCIII (PI17/00940, RETICS Oftared, RD16/0008/0003 and RD12/0034/0017) cofunded by FEDER and by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100)S

Relaciones tróficas entre los macroinvertebrados y peces en un arroyo de la llanura pampeana (Argentina)

The diet and trophic relationships between the macroinvertebrates Phyllogomphoides joaquini Rodrigues Capítulo, 1992 and Coenagrionidae (Odonata), Chironomidae (Diptera), Diplodon delodontus (Lamarck, 1919) (Bivalvia: Hyriidae), and Pomacea canaliculata (Lamarck, 1822) (Gastropoda: Ampulariidae) and the fishes Pimelodella laticeps Eigenmann, 1917 (Heptapteridae) and Bryconamericus iheringii (Boulenger, 1887) (Characidae) in a temperate lowland lotic system in Argentina were assessed on the basis of gut contents and stable-isotope analyses. The feeding strategies were analyzed by the Amundsen method. Relative food items contribution for the taxa studied indicated a generalist-type trophic strategy. In macroinvertebrates, in general, the values of stable isotope confirmed the result of the analysis of gut contents. With the fish, stable-isotope analysis demonstrated that both species are predators, although B. iheringii exhibited a more omnivorous behaviour. These feeding studies allowed us to determine the trophic relationships among taxa studied. Detritus and diatoms were a principal source of food for all the macroinvertebrates studied. In La Choza stream the particulate organic matter is a major no limited food resource, has a significant influence upon the community.Instituto de Limnología "Dr. Raul A. Ringuelet

El juego y el arte como herramientas para la valorización de los ambientes acuáticos urbanos

Los ambientes acuáticos urbanos se ven afectados de manera directa por la ineficiencia en el manejo de los residuos, la contaminación y las inundaciones, problemáticas que han sido reiteradamente identificadas por vecinos/as del Partido de La Plata, y potenciadas luego de las inundaciones de 2008 y 2013. Con la convicción de que el rol de los/as científicos/as es involucrarse en las realidades de otros sectores de la sociedad, en el 2015 creamos el proyecto “Exploracuátic@s: explorando el ambiente acuático y sus habitantes” con el objetivo de re-valorizar los ambientes acuáticos urbanos desde un enfoque lúdico y artístico. Nuestra experiencia trabajando en Centros Comunitarios de Extensión Universitaria (UNLP) nos marca que tanto el juego como el arte han sido las mejores herramientas para lograr un verdadero diálogo de saberes con personas que habitan en barrios atravesados por arroyos en pos de difundir su importancia y su conservación.Instituto de Limnología "Dr. Raúl A. Ringuelet"Centro de Estudios Integrales de la Dinámica Exógen

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of lifeThis project was partially supported by Fundación Española de Farmacia Hospitalaria “Convocatoria de ayudas de proyectos para grupos de trabajo de la SEFH 2021-2022”, Plan Galego de Saude Mental (SERGAS) and Axencia Galega Innovación (Grupos de Potencial Crecimiento IN607B2020/11). Bandín-Vilar E.: Mondelo-García C. and Fernández-Ferreiro A. are grateful to the Carlos III Health Institute for financing their personnel contracts: CM20/00135, JR20/00026 and JR18/00014S

First-line treatment in lymphomatoid papulosis: a retrospective multicentre study

Background: Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. Aim: To assess the daily clinical practice approach to LyP and the response to first-line treatments. Methods: This was a retrospective study enrolling 252 patients with LyP. Results: Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. Conclusions: Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse

La puesta en valor de los servicios ecosistémicos que ofrecen los arroyos de llanura como una medida de mitigación de las inundaciones: el caso del A° del Gato en el partido de La Plata

El concepto de servicios ecosistémicos surge en la década de los 70 como una forma de dar a conocer a la sociedad y a los tomadores de decisiones el vínculo directo que existe entre el bienestar humano y el mantenimiento de las funciones básicas del planeta. Más específicamente los servicios ecosistémicos hidrológicos se relacionan con la conservación de las cuencas hidrográficas entre los que se reconocen la regulación de flujos hidrológicos, reducción del impacto de las inundaciones, de la erosión del suelo, de la sedimentación en los cursos de agua, incluyendo también el mantenimiento o mejoramiento de la calidad del agua, de la recarga de acuíferos y de los hábitats acuáticos, entre otros. Desde el punto de vista del abastecimiento humano se pueden reconocer las principales fuentes de agua para beber, cocinar, asearse y cultivar en zonas donde las precipitaciones son insuficientes, además de generar energía eléctrica para manufacturar diversos productos, como así también ser fuente de alimentos. Asimismo, desde el punto de vista hidrológico, cumplen un rol en el ciclo global del agua ya que junto con los acuíferos subterráneos acumulan la precipitación que es conducida por escurrimientos hacia el mar, desde donde continúa el ciclo hidrológico. Cabe resaltar que los humedales y las planicies de inundación de los ríos absorben el agua de lluvia, reducen el escurrimientos disminuyendo así de los daños por inundaciones y ayudan a la recarga de aguas subterráneas contribuyendo también a mitigar las sequías. Asimismo considerando los aspectos culturales cumplen un importante rol en actividades de recreación, además de proporcionar beneficios estéticos, educativos y espirituales. Atendiendo la conservación de la biodiversidad desempeñan un papel destacado como proveedores de hábitats para diversas especies de flora y fauna, constituyendo reservorios ricos en diversidad genética (Brauman et al., 2007, Brauman, 2015, Thorp et al., 2013).Hydrological ecosystem services involve the regulation of water flows, the reduction of the flooding impact, the soil erosion and the sediment accumulation in the watercourses, also including the maintenance and improvement of the water quality, the aquiferous recharge and the aquatic habitats. The impermeability of the soil due to urbanization, the acceleration of drainings, the building of obstacles to the water flow in streams and rivers together with pollution are recognized as the main causes contributing to magnify the consequences of storms in urban and suburban areas. With the aim of showing the consequences of this type of interferences and the lossesin services and goods of the Pampean plain water flows, the case of the Gato stream is here explained. Its basin is inhabited by over 400,000 people, with approximately 50% of urbanized area and a deficient drainage system. The occupation of the alluvial valley and the lack of an integral plan for flooding risks are acknowleged as the main causes for the recurrent floods in this basin. The extreme expression of these events was observed on 2nd and 3rd April, 2013, as a consequence of a meteorological phenomenon which reached over 301 mm of water in four hours with an average intensity of 100.3 mm/h, causing the death of 89 people and over 2200 evacuated people together with an immense material loss. A study carried out in three areas of the basin, in order to identify the main causes that reduce the ecological quality of the stream, revealed that in sectors of the mid and low basin there is a deficient water quality with habitat destruction and the consequent loss of biodiversity. On the other hand, a detailed analysis of a fluvial overflow swamp, located on the upper basin, demonstrated the capacity of these areas of the basin which contribute to the improvement of water quality functioning as green filters and generating a proper environment to host diverse flora and fauna. They also retain water during storms and favor the regulation of the increase of the downstream flow contributing to alleviate the effects of floods. The review of the draining management techniques of the basin is essential. It is, therefore, necessary to count with the integral knowledge of the structure and functioning of the different areas of the basin. It is also very important to make the population aware of the necessity of their contribution, in order to regain the ecosystem services which have been partially or completely lost

Long runs of homozygosity are associated with Alzheimer's disease

Altres ajuts: The Genome Research at Fundació ACE project (GR@ACE) is supported by Fundación bancaria "La Caixa," Grifols SA and Fundació ACE. L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (Grant PI-0001/2017).Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [ β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 −5 ; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 −16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 −4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability

La puesta en valor de los servicios ecosistémicos que ofrecen los arroyos de llanura como una medida de mitigación de las inundaciones: el caso del A° del Gato en el partido de La Plata

El concepto de servicios ecosistémicos surge en la década de los 70 como una forma de dar a conocer a la sociedad y a los tomadores de decisiones el vínculo directo que existe entre el bienestar humano y el mantenimiento de las funciones básicas del planeta. Más específicamente los servicios ecosistémicos hidrológicos se relacionan con la conservación de las cuencas hidrográficas entre los que se reconocen la regulación de flujos hidrológicos, reducción del impacto de las inundaciones, de la erosión del suelo, de la sedimentación en los cursos de agua, incluyendo también el mantenimiento o mejoramiento de la calidad del agua, de la recarga de acuíferos y de los hábitats acuáticos, entre otros. Desde el punto de vista del abastecimiento humano se pueden reconocer las principales fuentes de agua para beber, cocinar, asearse y cultivar en zonas donde las precipitaciones son insuficientes, además de generar energía eléctrica para manufacturar diversos productos, como así también ser fuente de alimentos. Asimismo, desde el punto de vista hidrológico, cumplen un rol en el ciclo global del agua ya que junto con los acuíferos subterráneos acumulan la precipitación que es conducida por escurrimientos hacia el mar, desde donde continúa el ciclo hidrológico. Cabe resaltar que los humedales y las planicies de inundación de los ríos absorben el agua de lluvia, reducen el escurrimientos disminuyendo así de los daños por inundaciones y ayudan a la recarga de aguas subterráneas contribuyendo también a mitigar las sequías. Asimismo considerando los aspectos culturales cumplen un importante rol en actividades de recreación, además de proporcionar beneficios estéticos, educativos y espirituales. Atendiendo la conservación de la biodiversidad desempeñan un papel destacado como proveedores de hábitats para diversas especies de flora y fauna, constituyendo reservorios ricos en diversidad genética (Brauman et al., 2007, Brauman, 2015, Thorp et al., 2013).Hydrological ecosystem services involve the regulation of water flows, the reduction of the flooding impact, the soil erosion and the sediment accumulation in the watercourses, also including the maintenance and improvement of the water quality, the aquiferous recharge and the aquatic habitats. The impermeability of the soil due to urbanization, the acceleration of drainings, the building of obstacles to the water flow in streams and rivers together with pollution are recognized as the main causes contributing to magnify the consequences of storms in urban and suburban areas. With the aim of showing the consequences of this type of interferences and the lossesin services and goods of the Pampean plain water flows, the case of the Gato stream is here explained. Its basin is inhabited by over 400,000 people, with approximately 50% of urbanized area and a deficient drainage system. The occupation of the alluvial valley and the lack of an integral plan for flooding risks are acknowleged as the main causes for the recurrent floods in this basin. The extreme expression of these events was observed on 2nd and 3rd April, 2013, as a consequence of a meteorological phenomenon which reached over 301 mm of water in four hours with an average intensity of 100.3 mm/h, causing the death of 89 people and over 2200 evacuated people together with an immense material loss. A study carried out in three areas of the basin, in order to identify the main causes that reduce the ecological quality of the stream, revealed that in sectors of the mid and low basin there is a deficient water quality with habitat destruction and the consequent loss of biodiversity. On the other hand, a detailed analysis of a fluvial overflow swamp, located on the upper basin, demonstrated the capacity of these areas of the basin which contribute to the improvement of water quality functioning as green filters and generating a proper environment to host diverse flora and fauna. They also retain water during storms and favor the regulation of the increase of the downstream flow contributing to alleviate the effects of floods. The review of the draining management techniques of the basin is essential. It is, therefore, necessary to count with the integral knowledge of the structure and functioning of the different areas of the basin. It is also very important to make the population aware of the necessity of their contribution, in order to regain the ecosystem services which have been partially or completely lost.Instituto de Limnología "Dr. Raúl A. Ringuelet