Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

A multiscale orchestrated computational framework to reveal emergent phenomena in neuroblastoma.

Neuroblastoma is a complex and aggressive type of cancer that affects children. Current treatments involve a combination of surgery, chemotherapy, radiotherapy, and stem cell transplantation. However, treatment outcomes vary due to the heterogeneous nature of the disease. Computational models have been used to analyse data, simulate biological processes, and predict disease progression and treatment outcomes. While continuum cancer models capture the overall behaviour of tumours, and agent-based models represent the complex behaviour of individual cells, multiscale models represent interactions at different organisational levels, providing a more comprehensive understanding of the system. In 2018, the PRIMAGE consortium was formed to build a cloud-based decision support system for neuroblastoma, including a multi-scale model for patient-specific simulations of disease progression. In this work we have developed this multi-scale model that includes data such as patient's tumour geometry, cellularity, vascularization, genetics and type of chemotherapy treatment, and integrated it into an online platform that runs the simulations on a high-performance computation cluster using Onedata and Kubernetes technologies. This infrastructure will allow clinicians to optimise treatment regimens and reduce the number of costly and time-consuming clinical trials. This manuscript outlines the challenging framework's model architecture, data workflow, hypothesis, and resources employed in its development.

Comparison of two methods for obtaining and transporting corneal samples in suspected infectious keratitis.

BACKGROUND AND PURPOSE: The purpose of this study is to compare two alternative methods of collecting and transporting media for the diagnosis of corneal ulcers, as not all clinical settings have conventional culture materials and transport media available. METHODS: In this open-label, prospective, comparative, and randomized study, patients with clinical suspicion of infectious keratitis with high risk of loss of vision had corneal specimens collected using two methods and transport media: Eswab scraping with Amies transport medium and 23-gauge needle scraping in BACTEC Peds broth. The order of each collection method was randomized. The samples were processed by standard methods, comparing the positivity frequencies for both by parametric and nonparametric tests, according to normality criteria. RESULTS: Corneal infiltrates from 40 eyes of 40 patients were analyzed. Culture positivity rate was 50% for Eswab and 35% for 23-gauge needle (P=0.258). The overall growth rate of the two methods combined was not higher than with the swab alone. The results obtained with a swab were not influenced by the collection sequence (P=0.112); however, the positivity rate was significantly higher when the sample taken with the needle was performed first (P=0.046). CONCLUSIONS: The single sample Eswab method of collection and transportation for the diagnosis of high risk corneal ulcers is a valid alternative and can be used in cases in which, for various reasons, there is no access to the full set of traditional culture materials.

Effects of different antihypertensive medication groups on cognitive function in older patients: A systematic review.

BACKGROUND: Chronic hypertension has been associated with an increased risk of cognitive decline. Although a link between hypertension and cognitive decline has been established, there is less evidence supported by systematic reviews. The main aim was to compare different antihypertensive drug groups in relation to their effect on cognition in older patients without established dementia using a systematic review. METHOD: A systematic search in Medline and Embase through to January 2017 was used to identify randomized controlled clinical trials (RCTs) studying the impact of different antihypertensives on cognition in older patients without dementia. Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE-Is), beta-blockers (BBs), diuretics, and calcium channel blockers (CCBs) were included in this review. RESULTS: The systematic search identified 358 studies. The full text of 31 RCTs was reviewed and a total of 15 RCTs were included in the review. Most studies reported an improvement in episodic memory in patients treated with ARBs versus placebo or other types of antihypertensive drugs. No study showed an improvement in cognition in patients who received diuretics, BBs, or CCBs. Heterogeneity was high in most trials (predominantly in the blinding of participants and investigators). CONCLUSION: This review suggests that ARBs can improve cognitive functions in the elderly, especially episodic memory. ACE-Is, diuretics, BBs and CCBs did not seem to improve cognitive function in the elderly but were similarly effective in blood pressure lowering as ARBs.

Defining the optimal sequence for the systemic treatment of metastatic breast cancer.

Metastatic breast cancer is a heterogeneous disease that presents in varying forms, and a growing number of therapeutic options makes it difficult to determine the best choice in each particular situation. When selecting a systemic treatment, it is important to consider the medication administered in the previous stages, such as acquired resistance, type of progression, time to relapse, tumor aggressiveness, age, comorbidities, pre- and post-menopausal status, and patient preferences. Moreover, tumor genomic signatures can identify different subtypes, which can be used to create patient profiles and design specific therapies. However, there is no consensus regarding the best treatment sequence for each subgroup of patients. During the SABCC Congress of 2014, specialized breast cancer oncologists from referral hospitals in Europe met to define patient profiles and to determine specific treatment sequences for each one. Conclusions were then debated in a final meeting in which a relative degree of consensus for each treatment sequence was established. Four patient profiles were defined according to established breast cancer phenotypes: pre-menopausal patients with luminal subtype, post-menopausal patients with luminal subtype, patients with triple-negative subtype, and patients with HER2-positive subtype. A treatment sequence was then defined, consisting of hormonal therapy with tamoxifen, aromatase inhibitors, fulvestrant, and mTOR inhibitors for pre- and post-menopausal patien ts; a chemotherapy sequence for the first, second, and further lines for luminal and triple-negative patients; and an optimal sequence for treatment with new antiHER2 therapies. Finally, a document detailing all treatment sequences, that had the agreement of all the oncologists, was drawn up as a guideline and advocacy tool for professionals treating patients with this disease.

Infecciones de transmisión sexual: experiencia de una consulta multidisciplinar en un hospital terciario (2010-2013) / Sexually Transmitted Infections: Experience in a Multidisciplinary Clinic in a Tertiary Hospital (2010-2013)

INTRODUCCIÓN: Las infecciones de transmisión sexual son un motivo de consulta creciente en nuestro medio. El objetivo de este trabajo es describir y analizar las características epidemiológicas, conductuales, clínicas y microbiológicas de los pacientes registrados en una unidad de infecciones de transmisión sexual de un hospital terciario. MÉTODOS: Estudio descriptivo, retrospectivo y unicéntrico realizado en una unidad multidisciplinar especializada en infecciones de transmisión sexual de un hospital terciario entre 2010 y 2013. Se recogieron datos epidemiológicos, clínicos y conductuales mediante entrevista oral abierta y cuestionario estandarizado, y se llevó a cabo la obtención de muestras para estudio microbiológico. RESULTADOS: Se estudiaron 546 pacientes, de los cuales fueron 96% varones, 41% infectados por el VIH, 56% hombres que tienen sexo con hombres. Los motivos de consulta más prevalentes fueron: uretritis, úlceras genitales y/o anales/perianales, proctitis, úlceras orales, contacto sexual de persona con ITS conocida y contacto sexual de riesgo. Los diagnósticos microbiológicos más frecuentes fueron: Neisseria gonorrhoeae en uretritis, Treponema pallidum en úlceras genitales y/o anales/perianales y Chlamydia trachomatis serovares de linfogranuloma venéreo en proctitis. Las principales ITS estudiadas fueron más prevalentes en varones homosexuales e infectados por el VIH. CONCLUSIÓN: Se confirma el incremento en la incidencia de las infecciones de transmisión sexual en los últimos años y las características epidemiológicas de la epidemia VIH/ITS de nuestro entorno

INTRODUCTION: The number of consultations for sexually transmitted infections (STIs) is increasing in Spain. The aim of this study was to describe and analyze the epidemiological, behavioral, clinical, and microbiological characteristics of patients registered at the STI unit of a tertiary hospital. METHODS: This was a retrospective, single-center descriptive study carried out between 2010 and 2013 in a multidisciplinary unit specialized in STIs, situated in a tertiary hospital. Epidemiological, clinical, and behavioral data were gathered using a face-to-face interview and a standardized questionnaire. Samples were collected for microbiology analysis. RESULTS: The study included 546 patients: 96% were men, 41% had human immunodeficiency virus (HIV) infection, and 56% were men who have sex with men. The reasons for consultation were the following: urethritis; genital, anal, or perianal ulcers; proctitis; oral ulcers; sexual contact with a person with a known STI; and high-risk sexual contact. The most common microbiological diagnoses were Neisseria gonorrhoeae in urethritis, Treponema pallidum in genital and anal or perianal ulcers, and Chlamydia trachomatis lymphogranuloma venereum serovars in proctitis. The highest prevalences of the main STIs studied occurred in homosexual men with HIV infection. CONCLUSION: This study confirms the increase in the incidence of STIs in recent years and the epidemiological characteristics of the HIV/STI epidemic in Spain

Sexually Transmitted Infections: Experience in a Multidisciplinary Clinic in a Tertiary Hospital (2010-2013).

INTRODUCTION: The number of consultations for sexually transmitted infections (STIs) is increasing in Spain. The aim of this study was to describe and analyze the epidemiological, behavioral, clinical, and microbiological characteristics of patients registered at the STI unit of a tertiary hospital. METHODS: This was a retrospective, single-center descriptive study carried out between 2010 and 2013 in a multidisciplinary unit specialized in STIs, situated in a tertiary hospital. Epidemiological, clinical, and behavioral data were gathered using a face-to-face interview and a standardized questionnaire. Samples were collected for microbiology analysis. RESULTS: The study included 546 patients: 96% were men, 41% had human immunodeficiency virus (HIV) infection, and 56% were men who have sex with men. The reasons for consultation were the following: urethritis; genital, anal, or perianal ulcers; proctitis; oral ulcers; sexual contact with a person with a known STI; and high-risk sexual contact. The most common microbiological diagnoses were Neisseria gonorrhoeae in urethritis, Treponema pallidum in genital and anal or perianal ulcers, and Chlamydia trachomatis lymphogranuloma venereum serovars in proctitis. The highest prevalences of the main STIs studied occurred in homosexual men with HIV infection. CONCLUSION: This study confirms the increase in the incidence of STIs in recent years and the epidemiological characteristics of the HIV/STI epidemic in Spain.

Drug repurposing: far beyond new targets for old drugs.

Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug-target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs.

Linking pharmacology to clinical reports: cyclobenzaprine and its possible association with serotonin syndrome.

The link between cyclobenzaprine (Flexeril) administration and serotonin syndrome (SS) is subject to debate. Establishing such a connection is difficult because of the limited number of case reports available and the almost complete ignorance of its preclinical pharmacology. In this context, evidence is provided here that cyclobenzaprine blocks the serotonin and norepinephrine transporters and binds to another set of five serotonin receptors. SS should be considered when indicative signs occur in the context of cyclobenzaprine use.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

Assessment of in vitro dermal absorption of the kaurenic acid from Coespeletia moriziana extracts.

Espeletiinae are plants which grow above 3000 m of altitude in the Northern Andes and kaurenic acid was extracted from the leaves of Coespeletia moritziana. This compound has shown a wide range of biological activities, including cytotoxicity which is efficient in cancer therapy. The percutaneous penetration of this compound was measured in vitro using Franz cells. At appropriate intervals for up to 24h, diffusion samples were analyzed using HPLC. At the end of the test period, the amount of kaurenic acid was determined in each compartment and approximately 10% of kaurenic acid had been absorbed and was found in the skin layers.

Benzophenone-3 entrapped in solid lipid microspheres: formulation and in vitro skin evaluation.

Solid lipid microspheres (SLM), lipid-in-water formulations made from oil-and-wax mixtures, were studied concerning feasibility. SLMs were then loaded with a benzophenone-3, water insoluble UVAB-filter intended for dermal application. Microspheres were prepared by dispersion with homogenisers and investigated by polarizing micrography and scanning electron micrography. For the selected formulations, investigations on percutaneous penetration of B-3 capacity were performed "in vitro" using Franz cells. Microspheres, 5-50 µm in size, and a spherical shape were obtained from several mixtures. B-3 was added and the loading capacity of this drug in the SLM was obtained for a maximum of 5% when the lipophilic phase was 18%. The lipophilic mixture with non-ionic surfactants in the selected formulation of lipid microspheres has a favorable effect on size. The selected formulation is also cosmetically adapted and it is composed of physiological and biodegradable lipids. B-3 was released and penetrated into skin more quickly and in greater quantity than in SLM form, from vehicles containing free B-3. This work has shown that SLM is an excellent carrier for lipophilic sunscreens like B-3 in order to decrease the release and penetration rate of this UV absorber compared with B-3 in oily solution.

Investigación en cuidados paliativos en España. Una revisión de las comunicaciones presentadas en los congresos de la Sociedad Española de Cuidados Paliativos (2000-2006) / No disponible

Objetivo: analizar la producción científica en el ámbito de los cuidados paliativos basándose en las comunicaciones presentadas en los III, IV,V y VI congresos de la SECPAL. Material y método: se han presentado un total de 1.069 comunicaciones orales o póster. Para cada comunicación se han analizado los siguientes parámetros: comunidad de origen, número de autores, principales centros investigadores, lugar de trabajo, áreas temáticas y tipo de estudio. Las comunicaciones presentadas en los V y VI Congresos se han puntuado en función de 6 parámetros: importancia, interés, relación entre título y contenido, adecuación del diseño y metodología, solidez y relevancia de los resultados y solidez de las conclusiones. Resultados: las comunidades autónomas más activas han sido Cataluña,Valencia, Canarias y Andalucía. El equipo más productivo ha sido el Hospital Dr. Negrín de Las Palmas de Gran Canaria (90 comunicaciones). La mayoría de comunicaciones corresponden a trabajos realizados en unidades de cuidados paliativos (434), seguidas por las efectuadas en equipos de soporte domiciliarios (175). Los temas de organización, otros síntomas excepto dolor, tratamiento complementario y farmacología son las áreas temáticas preponderantes. El 21% son estudios prospectivos. Sobre un máximo de 18 puntos por comunicación, la media ha sido de 7,66 para el V Congreso y de 7,36 para el VI. Conclusiones: el mayor número de aportaciones a los congresos de la SECPAL corresponde a las unidades de cuidados paliativos. El nivel científico es mejorable y es necesario un esfuerzo para la mejora de la calidad de los trabajos presentados (AU)

Objective: to describe the scientific activity in palliative care research in Spain, as measured by the abstracts submitted to four national congresses of the Spanish Society of Palliative Care (SECPAL) (3th-6th, from 2000 to 2006). Material and method: 1,069 abstracts accepted in the four congresses were analyzed. Data collected: autonomic administration source, number of authors, work center, issues, study design. The quality of the abstracts presented to the 5th and 6th congresses was evaluated. Assessments included six items: study importance, interest, connection between title and contents, study design, result and conclusion significance. Results: the most productive autonomic administrations were Catalonia, Valencia, Canary Islands and Andalusia. Mean authors: 5.4 (1-19). Setting: 175 (16%) Home Palliative Care Team, 434 (41%) Palliative CareUnit, 129 (12%) Medical Oncology Department, 154 (14%) other hospital departments, and 179 (17%) others. Topic areas: 234 (22%) organization, 69 (6%) pain, 186 (17%) other symptoms, 106 (10%) complementary therapies/treatment, 101 (9%) pharmacology, 51 (5%) family, 322 (31%) others. Study design: 452 (42%) descriptive, 224 (21%) retrospective, 224 (21%) prospective, 22 (2%) others. Mean total score obtained was 7.66 (5th congress) and 7.36 (6th congress) (range: 0-18). Conclusions: Palliative Care Units presented most of the abstracts. Organization and health system issues were common topics. The mean total score obtained was low. Prospective and multicenter studies should be encouraged to improve research in palliative care, and more stringent criteria for abstract acceptance should be implemented (AU)

In silico pharmacology for drug discovery: applications to targets and beyond.

Computational (in silico) methods have been developed and widely applied to pharmacology hypothesis development and testing. These in silico methods include databases, quantitative structure-activity relationships, similarity searching, pharmacophores, homology models and other molecular modeling, machine learning, data mining, network analysis tools and data analysis tools that use a computer. Such methods have seen frequent use in the discovery and optimization of novel molecules with affinity to a target, the clarification of absorption, distribution, metabolism, excretion and toxicity properties as well as physicochemical characterization. The first part of this review discussed the methods that have been used for virtual ligand and target-based screening and profiling to predict biological activity. The aim of this second part of the review is to illustrate some of the varied applications of in silico methods for pharmacology in terms of the targets addressed. We will also discuss some of the advantages and disadvantages of in silico methods with respect to in vitro and in vivo methods for pharmacology research. Our conclusion is that the in silico pharmacology paradigm is ongoing and presents a rich array of opportunities that will assist in expediting the discovery of new targets, and ultimately lead to compounds with predicted biological activity for these novel targets.

In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling.

Pharmacology over the past 100 years has had a rich tradition of scientists with the ability to form qualitative or semi-quantitative relations between molecular structure and activity in cerebro. To test these hypotheses they have consistently used traditional pharmacology tools such as in vivo and in vitro models. Increasingly over the last decade however we have seen that computational (in silico) methods have been developed and applied to pharmacology hypothesis development and testing. These in silico methods include databases, quantitative structure-activity relationships, pharmacophores, homology models and other molecular modeling approaches, machine learning, data mining, network analysis tools and data analysis tools that use a computer. In silico methods are primarily used alongside the generation of in vitro data both to create the model and to test it. Such models have seen frequent use in the discovery and optimization of novel molecules with affinity to a target, the clarification of absorption, distribution, metabolism, excretion and toxicity properties as well as physicochemical characterization. The aim of this review is to illustrate some of the in silico methods for pharmacology that are used in drug discovery. Further applications of these methods to specific targets and their limitations will be discussed in the second accompanying part of this review.

The "in vitro" percutaneous penetration of three antioxidant compounds.

Caffeic acid, chlorogenic acid and oraposide, a natural glycoside, are phenyl-propanoid compounds. These natural products have been reported to have antioxidant activities such as the scavenging of superoxide anions and hydroxyl radicals. These compounds could be used in the dermocosmetic field to protect the skin from oxidative stress induced by UV radiation. To this end, the permeation of caffeic acid, chlorogenic acid, and oraposide, through pig-ear skin was evaluated in vitro. The percutaneous permeation of these three compounds through pig skin was measured and compared using Franz diffusion cells. At appropriate intervals, up to 72 h, diffusion samples were analyzed using an HPLC assay. After 48 h of drug contact the permeation was also evaluated with a fluorescent microscope on vertical microtomed pig skin sections. In this study on excised pig skin, the flux value was found to be equal to 0.32 and 0.48 microgcm(-2)h(-1) for caffeic and chlorogenic acids, respectively; for oraposide the levels were below the limit of detection and the flux was not evaluated. These results were corroborated by fluorescent microscopy. Caffeic and chlorogenic acids were found in all skin sections, and these might represent a systemic activity, whereas oraposide remained in the upper superficial layer of the skin. This latter phenomenon seems to be interesting for dermocosmetic applications.

Dopamine transporter binding in Gilles de la Tourette syndrome: a [123I]FP-CIT/SPECT study.

OBJECTIVE: To investigate dopamine transporter binding in Gilles de la Tourette syndrome (GTS) with SPECT and [123I]FP-CIT. METHOD: Ten neuroleptic naïve/free patients with GTS, and 10 age- and gender-matched normal volunteers were studied. Subjects were clinically evaluated. GTS severity and affective symptoms were measured and the presence of GTS-related behaviours were recorded. RESULTS: The GTS group showed significantly higher binding in both caudate and putamen nuclei than the controls. No associations were found between striatal binding ratios and measures of affect or GTS-related behaviours. CONCLUSION: Patients with GTS show higher striatal binding of FP-CIT to the striatum in comparison with age- and gender-matched control subjects, indicating that dopamine transporter abnormalities are involved in the pathophysiology of GTS. These abnormalities appear to be distributed across both caudate and putamen.

Virtual screening: a real screening complement to high-throughput screening.

Virtual screening is being routinely used as an integral part of today's hit-identification strategies for, on one hand, prioritizing large corporate screening collections and, on the other hand, to extend the scope of screening to external databases. A brief description of the essential elements required for virtual screening and an application example to the identification of agonist hits for the oestrogen receptor subtype ER alpha are presented.

Neuropsychiatry of the basal ganglia.

This review aims to relate recent findings describing the role and neural connectivity of the basal ganglia to the clinical neuropsychiatry of basal ganglia movement disorders and to the role of basal ganglia disturbances in "psychiatric"' states. Articles relating to the relevant topics were initially collected through MEDLINE and papers relating to the clinical conditions discussed were also reviewed. The anatomy and connections of the basal ganglia indicate that these structures are important links between parts of the brain that have classically been considered to be related to emotional functioning and brain regions previously considered to have largely motor functions. The basal ganglia have a role in the development and integration of psychomotor behaviours, involving motor functions, memory and attentional mechanisms, and reward processes.