Relevance of Comet Assay and Phosphorylated-Hsp90α in Cancer Patients' Peripheral Blood Leukocytes as Tools to Assess Cisplatin-based Chemotherapy Clinical Response and Disease Outcome.

Cisplatin (cPt) is a commonly used treatment for solid tumors. The main target of its cytotoxicity is the DNA molecule, which makes the DNA damage response (DDR) crucial for cPt-based chemotherapy. Therefore, it is essential to identify biomarkers that can accurately predict the individual clinical response and prognosis. Our goal was to assess the usefulness of alkaline comet assay and immunocytochemical staining of phosphorylated Hsp90α (p-Hsp90α), γH2AX, and 53BP1 as predictive/prognostic markers. Pre-chemotherapy peripheral blood leukocytes were exposed to cPt in vitro and collected at 0, 24 (T24), and 48 (T48) hr post-drug removal. Healthy subjects were also included. Baseline DNA damage was elevated in cancer patients (variability between individuals was observed). After cPt, patients showed increased γH2AX foci/nucleus (T24 and T48). Both in healthy persons and patients, the nuclear p-Hsp90α and N/C (nuclear/cytoplasmic) ratio augmented (T24), decreasing at T48. Favorable clinical response was associated with high DNA damage and p-Hsp90α N/C ratio following cPt. For the first time, p-Hsp90α significance as a predictive marker is highlighted. Post-cPt-DNA damage was associated with longer disease-free survival and overall survival. Our findings indicate that comet assay and p-Hsp90α (a marker of DDR) would be promising prognostic/predictive tools in cP-treated cancer patients.

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Effects of omega-3 supplementation on anxiety-like behaviors and neuroinflammation in Wistar rats following cafeteria diet-induced obesity.

ABSTRACTObjetives: Omega-3 (n3) fatty acids have been studied as an option to alleviate the harmful effects of obesity. However, its role in obesity-related behavioral changes is still controversial. This study aimed to evaluate the effects of n3 on behavior and neuroinflammation in obese animals. Methods: Male Wistar rats were divided into four groups: control diet (CT), CT+n3, cafeteria diet (CAF), and CAF+n3. Diet was administered for 13 weeks, and n3 was supplemented during the last 5 weeks. Metabolic and biochemical parameters were evaluated, as well as anxiety-like behaviors. Immunoblots were conducted in the animals' cerebral cortex and hippocampus to assess changes in neuroinflammatory markers.Results: CAF-fed animals showed higher weight gain, visceral adiposity, fasting glucose, total cholesterol, triglycerides, and insulin levels, and n3 improved the lipid profile and restored insulin sensitivity. CAF-fed rats showed anxiety-like behaviors in the open field and light-dark box tasks but not in the contextual aversive conditioning. Omega-3 did not exert any effect on these behaviors. Regarding neuroinflammation, diet and supplementation acted in a region-specific manner. In the hippocampus, CAF reduced claudin-5 expression with no effect of n3, indicating a brain-blood barrier disruption following CAF. Furthermore, in the hippocampus, the glial fibrillary acidic protein (GFAP) and toll-like receptor 4 (TLR-4) were reduced in treated obese animals. However, n3 could not reverse the TLR-4 expression increase in the cerebral cortex.Discussion: Although n3 may protect against some neuroinflammatory manifestations in the hippocampus, it does not seem sufficient to reverse the increase in anxiolytic manifestations caused by CAF.

Incorporación a nivel nacional de tecnología no invasiva para valoración del dolor y/o disconfort neonatal / Incorporation of non-invasive technology for the assessment of neonatal pain and/or discomfort at national level / Incorporação a nível nacional de tecnologia não invasiva para avaliação da dor e/ou desconforto neonatal

Introducción: la exposición a estímulos dolorosos y estrés en la etapa neonatal, sin un correcto tratamiento, tiene consecuencias a corto y largo plazo. El diagnóstico adecuado es un desafío, ya que las escalas clínicas son subjetivas y se requieren herramientas de detección con mejor objetividad y capacidad de interpretación del disconfort/dolor neonatal. Newborn Infant Parasympathetic Evaluation (NIPE™) es una tecnología no invasiva de monitorización continua del dolor en neonatos, desarrollada recientemente dada la dificultad de objetivar el dolor mediante los métodos convencionales en la práctica clínica. Esta tecnología se basa en el análisis de la variabilidad de la frecuencia cardíaca (FC), lo que permite aproximarse a la actividad del sistema parasimpático. Objetivos: el objetivo de esta investigación fue valorar el disconfort en un modelo de cerdo recién nacido (RN) y en humanos neonatos expuestos a maniobras nociceptivas con la utilización de tecnología no invasiva (NIPE), en la maternidad del Hospital Universitario. Material y métodos: se realizó un estudio observacional, longitudinal, en seis cerdos RN, anestesiados, monitorizados hemodinámicamente y sometidos a un procedimiento quirúrgico mayor (toracotomía lateral izquierda con abordaje cardíaco, pericardiostomía y acceso vascular pulmonar transventricular derecho) y 12 procedimientos mínimamente invasivos de la práctica clínica habitual, como vacunación BCG, hemoglucotest y pesquisa, que generan un estímulo nociceptivo en ocho RN de término sanos. Se incluyeron RN sanos de término (EG entre 37-41 semanas más seis días) internados en el alojamiento conjunto madre-hijo, se excluyeron de la muestra los RN que presentaron alguna patología y aquellos cuyos padres no aceptaron la participación en el estudio. Resultados: se comparó la variabilidad de la FC mediante detección automatizada (NIPE™) para estimación objetiva del dolor/disconfort. Se comparó en la clínica con una escala validada y ampliamente utilizada en neonatos: Premature Infant Pain Profile (PIPP). Para valorar la asociación entre variables NIPE™ y FC se utilizaron correlación de Spearman, el test de Kruskall-Wallis o test de chi cuadrado con corrección de Fisher, según correspondiera. Se encontró una correlación negativa entre FC y NIPE™ tanto para el grupo de neonatos humanos (r=-1; p=0,008) como para el modelo animal (r=-0,6; p=0,0004). No se encontró asociación significativa entre NIPE™ y la escala PIPP. La variación entre valores de NIPE™ pre y posestímulo en RN humanos fue significativa (p=0,008). Conclusiones: determinamos que en ambos escenarios explorados los valores de NIPE™ descienden ante estímulos nociceptivos y los cambios en la FC se relacionan con sus valores, independientemente de la especie o la agresividad de la maniobra. Este trabajo es el primero a nivel nacional incorporando el uso de esta tecnología, creemos que tendrá impacto en la forma de evaluar y abordar el dolor por parte de los equipos asistenciales y de experimentación.

Introduction: exposure to painful stimuli and stress in the neonatal stage, without correct treatment, has short and long-term consequences. Proper diagnosis is a challenge since clinical scales are subjective, and we require more objective screening tools and a better ability to interpret neonatal discomfort/pain. Newborn Infant Parasympathetic Evaluation (NIPE™) is a non-invasive technology for continuous pain monitoring in neonates, recently developed given the difficulty to objectify pain using conventional methods in clinical practice. This technology is based on the analysis of heart rate variability (HR), which allows us to approximate the activity of the parasympathetic system. Objectives: the objective of this research was to assess discomfort in a newborn pig model (NB) and in human neonates exposed to nociceptive maneuvers with the use of non-invasive technology (NIPE), in the maternity ward of the University Hospital. Material and methods: an observational, longitudinal study was carried out in 6 NB pigs, anesthetized, hemodynamically monitored and subjected to a major surgical procedure (left lateral thoracotomy with cardiac approach, pericardiostomy and right trans ventricular pulmonary vascular access) and 12 minimally invasive procedures, from clinical practice. routine such as BCG vaccination, hemoglucotest and screening, which generate a nociceptive stimulus in 8 healthy term newborns. Healthy term newborns (GA between 37-41 weeks plus 6 days) admitted to the mother-child joint accommodation were included, We excluded those NB patients who presented some pathology or whose parents did not accept participation in the study. Results: HR variability was compared using automated detection (NIPETM) for objective estimation of pain/discomfort. It was compared in the clinic with a validated and widely used scale in neonates: Premature Infant Pain Profile (PIPP). We used the Spearman's correlation, the Kruskall-Wallis test or the Chi square test with Fisher's correction to assess the association between NIPE™ variables and HR, as needed. A negative correlation was found between HR and NIPETM for both the group of neonates. humans (r=-1; p=0.008) and for the animal model (r=-0.6; p=0.0004). No significant association was found between NIPETM and the PIPP scale. The variation between pre- and post-stimulus NIPE™ values in human NBs was significant (p=0.008). Conclusions: we conclude that in both scenarios explored, NIPE™ values decrease when faced with nociceptive stimuli and changes in HR are related to its values, regardless of the species or the aggressiveness of the maneuver. This paper is the first at a national level to incorporate the use of this technology, we believe it will have an impact on the way pain is assessed and addressed by healthcare and experimental teams.

Introdução: a exposição a estímulos dolorosos e ao estresse na fase neonatal, sem tratamento correto, traz consequências a curto e longo prazo. O diagnóstico adequado é um desafio, uma vez que as escalas clínicas são subjetivas e são necessárias ferramentas de triagem com melhor objetividade e capacidade de interpretar o desconforto/dor neonatal. A Avaliação Parassimpática do Recém-Nascido (NIPE™) é uma tecnologia não invasiva para monitoramento contínuo da dor em neonatos, desenvolvida recentemente devido à dificuldade de objetivar a dor usando métodos convencionais na prática clínica. Esta tecnologia baseia-se na análise da variabilidade da frequência cardíaca (FC), o que nos permite aproximar a atividade do sistema parassimpático. Objetivos: o objetivo desta pesquisa foi avaliar o desconforto em recém-nascido modelo suíno (RN) e em neonatos humanos expostos a manobras nociceptivas com uso de tecnologia não invasiva (NIPE), na maternidade do Hospital Universitário. Material e métodos: foi realizado um estudo observacional, longitudinal, em 6 suínos RN, anestesiados, monitorados hemodinamicamente e submetidos a um procedimento cirúrgico de grande porte (toracotomia lateral esquerda com abordagem cardíaca, pericardiostomia e acesso vascular pulmonar transventricular direito) e 12 procedimentos minimamente invasivos, da prática clínica. rotina como vacinação BCG, hemoglicoteste e triagem, que geram estímulo nociceptivo em 8 recém-nascidos a termo saudáveis. Foram incluídos recém-nascidos a termo saudáveis (IG entre 37-41 semanas mais 6 dias) internados no alojamento conjunto mãe-filho, foram excluídos do A amostra incluiu RNs que apresentavam alguma patologia e aqueles cujos pais não aceitaram a participação no estudo. Resultados: a variabilidade da FC foi comparada por meio de detecção automatizada (NIPETM) para estimativa objetiva de dor/desconforto. Foi comparado na clínica com uma escala validada e amplamente utilizada em neonatos: Premature Infant Pain Profile (PIPP). Para avaliar a associação entre as variáveis do NIPE™ e a FC, utilizou-se a correlação de Spearman, o teste de Kruskall-Wallis ou o teste Qui-quadrado com correção de Fisher, conforme apropriado. Foi encontrada correlação negativa entre a FC e o NIPETM para ambos os grupos de neonatos. (r=-1; p=0,008) e para o modelo animal (r=-0,6; p=0,0004). Não foi encontrada associação significativa entre o NIPETM e a escala PIPP. A variação entre os valores de NIPE™ pré e pós-estímulo em RN humanos foi significativa (p=0,008). Conclusões: concluímos que em ambos os cenários explorados, os valores do NIPE™ diminuem diante de estímulos nociceptivos e as alterações na FC estão relacionadas aos seus valores, independente da espécie ou da agressividade da manobra. Este trabalho é o primeiro a nível nacional a incorporar a utilização desta tecnologia, acreditamos que terá impacto na forma como a dor é avaliada e abordada pelas equipas de saúde e experimentais.

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations.

Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.

LuciA-15 - a real-world prospective study of PARP inhibitors for the treatment of patients with HER-2 negative metastatic breast cancer with germline and/or somatic mutation of BRCA genes or homologous recombination repair related genes.

Background: Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) improve progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to chemotherapy (CT). The objective of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods: From September 2019 to April 2023, we analyzed the data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA1 or BRCA2, or in the homologous recombination repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. real-world objective response rate (rwORR), best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analysed with R software and RStudio version 14.0. Results: After a median follow-up of 18.07 months (95% CI 10.53-30.07), 51 patients were treated with PARPi. Mean age at starting treatment was 47.08 years. 62.7% had ER + ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talazoparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT in the (neo)adjuvant/metastatic setting. At the time to starting PARPi treatment, 57.5% had visceral metastasis, the median number of metastatic sites was 2 (range 1-4), the median number of lines was 2 (range 0-8), and 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively.The rwORR was 47.0%, and the median real-world progression-free survival-1 (rwPFS1) was 7.77 months (95% CI 5.67-14.7). There was a tendency of better rwPFS1 in patients with versus without previous CT in the advance setting, 6.37 months (95% CI 5.03-8.73) and 14.30 months (95% CI 6.47-NR), respectively (p 0.084). The median rwOS was 26.97 months (95% CI 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (95% CI 27.0-NR) versus 13.0 (95% CI10.1-NR), respectively (p 0.022). The medium real-world progression-free survival-2 (next treatment after PARPi failure) was 4.00 months (95% CI 3.43-7.13). Treatment was discontinued due to adverse events in 4.0% of patients. Conclusion: This is the first evidence in a Latin-American population that replicates the data already published in randomised clinical trials and other scanty real-world evidence studies in this field, showing positive results in rwORR and rwPFS, and encouraging data in rwOS. Notably, there was a high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, there were similar rwOS results among subgroups (TNBC versus ER + ve/HER2-ve, talazoparib versus olaparib, etc).

The Effects of Probiotics and Prebiotics on Gastrointestinal and Behavioural Symptoms in Autism Spectrum Disorder.

BACKGROUND: Autism Spectrum Disorders (ASDs) are a group of prevalent neuropsychiatric disorders. They present a complex and unknown etiology, which in most cases includes significant peripheral alterations outside the brain such as in the composition of gut microbiota. Because the gut microbiota is involved in modulating the gut-brain axis, several studies have suggested that the microbiome in the gut can modify metabolites which are able to cross the blood-brain barrier and modulate brain function. METHODS: We reviewed the current evidence regarding microbiota alterations in patients with ASD and the effects of the administration of probiotics and prebiotics in these patients, both in terms of gastrointestinal and behavioural symptoms. RESULTS: Administration of a probiotic formulation containing different strains of Lactobacillus (L. acidophilus, L. rhamnosus, and others) and Bifidobacteria had beneficial effects upon these aforementioned symptoms and their use is recommended in a subgroup of ASD patients that present gastrointestinal disturbances. Nonetheless, the types of gastrointestinal disturbances that most benefit from such interventions remain to be elucidated in order to personalize the medical approaches. CONCLUSION: Recent clinical studies have shown that probiotic treatments can regulate the gut microbiota and may result in improvements in some behavioral abnormalities associated with ASD. Trials using prebiotic fibers or synbiotics preparations are still lacking and necessary in order to deep in such therapeutic strategies in ASD with comorbid gastrointestinal disrturbances.

3-aryl-indolinones derivatives as antiplasmodial agents: synthesis, biological activity and computational analysis.

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H2/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC50 < 20 µM. The most active of these compounds was 8c; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.

Craniolateral forearm muscles of the crab-eating raccoon (Procyon cancrivorus) and a comparative review with other carnivorans / Músculos cráneo-laterales del antebrazo del mapache cangrejero (Procyon cancrivorus) y una revisión comparativa con otros carnívoros

The crab-eating raccoon Procyon cancrivorus (Cuvier, 1798) is a species of the order Carnivora and family Procyonidae with a geographical distribution in Central and South America. Although crab-eating raccoons use scansorial locomotion, they also have aquatic habits, displaying greatly developed skills when handling their food. This species can frequently be found in wildlife care centers due to injuries caused by domestic dogs, humans, and car collisions. Having knowledge of the species' gross anatomy and anatomical bases is imperative to perform the most appropriate medical and surgical procedures. Thus, the objective of this investigation was to analyze the interspecific and intraspecific differences of the craniolateral forearm muscles of Procyon cancrivorus. Gross dissections were performed in four specimens describing the origin, insertion, shape, innervation, and arterial supply of the craniolateral forearm muscles. There is a constant and well development of brachioradialis muscle comparatively to that described in strictly cursorial species; the extensor carpi radialis muscle has two bellies that are fused proximally; the extensor digitorum communis muscle can also extend the tendon to the digit I as an anatomical variant, and the extensor digiti I and II muscle also extends the tendon to digit III. All are innervated by the deep branch of the radial nerve, and their arterial supply is mainly by the radial collateral, cubital transverse, and cranial interosseous arteries. The anatomical characteristics observed in this study complement the previous descriptions for Procyon cancrivorus, and the anatomical variants found in this species can also be in other carnivorans. Thus, the intraspecific anatomical variations of the digital extensor muscles in P. cancrivorus are phylogenetic traits that can occur as a common pattern or as anatomical variants in other species of the order Carnivora.

El mapache cangrejero Procyon cancrivorus (Cuvier, 1798) es una especie del orden Carnivora y familia Procyonidae con distribución geográfica en América Central y del Sur. Esta especie tiene hábitos arbóreos y acuáticos. Tiene una alta frecuencia en los centros de rehabilitación de fauna silvestre debido a las lesiones causadas por perros, humanos y colisiones de automóviles, por esto, tener conocimiento de la anatomía macroscópica de la especie es imprescindible para realizar los procedimientos médicos y quirúrgicos más adecuados. Por lo tanto, el objetivo de esta investigación fue analizar las diferencias inter e intraespecíficas de los músculos cráneo-laterales del antebrazo de Procyon cancrivorus. Se realizaron disecciones macroscópicas en cuatro especímenes donde se describió el origen, inserción, forma, inervación y la irrigación arterial de la musculatura cráneo-lateral del antebrazo. Entre los principales hallazgos se pueden mencionar: el músculo braquiorradial es constante y bien desarrollado comparativamente a lo descrito en especies estrictamente cursoriales; el músculo extensor radial del carpo presenta dos vientres fusionados proximalmente; el músculo extensor común de los dedos también puede formar un tendón al dedo I como una variante anatómica, y el músculo extensor de los dedos I y II también extiende un tendón al dedo III. Todos están inervados por el ramo profundo del nervio radial y su irrigación arterial es principalmente por las arterias colateral radial, transversa cubital e interósea craneal. Las características anatómicas encontradas en este estudio complementan las descripciones anteriores para Procyon cancrivorus, y las variantes anatómicas encontradas en esta especie también pueden encontrarse en otros carnívoros. Así, las variaciones anatómicas intraespecíficas de los músculos extensores digitales en P. cancrivorus son rasgos filogenéticos que se puede presentar en el patrón común o como variante anatómica en otras especies del orden Carnivora.

Evaluation of mutagenic activity of platinum complexes in somatic cells of Drosophila melanogaster.

Cisplatin, carboplatin, and oxaliplatin are some of the most often used alkylating chemotherapeutic agents. In view of the paucity of data on the genotoxicity of oxaliplatin, this study compares the mutagenic activity of cisplatin (0.006, 0.012, 0.025, 0.05 mM), carboplatin (0.1, 0.2, 0,5, 1.0 mM), and oxaliplatin (0.1, 0.2, 0,5, 1.0 mM) using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Standard and high-bioactivation crosses of the drosophilid were used, which present basal and high levels of cytochrome P450 (CYP450) metabolization enzymes, respectively. All concentrations of cisplatin and carboplatin induced lesions in genetic material in both crosses, while oxaliplatin was mutagenic only to high bioactivation flies treated with 0.1, 0.5 and 1 mM of the compound. No significant differences were observed between genotoxicity values of cisplatin and carboplatin. However, CYP450 enzymes may have affected the mutagenic action of oxaliplatin. Carboplatin induced mainly mutation events, while cisplatin triggered mostly mutation and recombination events when low and high doses were used. Most events induced by oxaliplatin were generated by somatic recombination. Important differences were observed in genotoxic potential of platinum chemotherapeutic compounds, possibly due to the origin and type of the lesions induced in DNA and the repair mechanisms involved.

Secure base scripted knowledge and preschoolers' social competence in samples from Mexico and Peru.

A central hypothesis in attachment theory poses that child-mother relationships have implications for children's social competence. A key task for researchers is that of investigating the pathways responsible for the association found between child attachment security and social competence. We studied whether children's secure base representations, defined as scripts, are associated with assessments of social competence in a preschool setting. We tested this association in samples from Mexico and Peru. Preschoolers' attachment representations were assessed via narratives gathered with the Attachment Story Completion Task. Teachers (in Mexico) and mothers (in Peru) provided questionnaire information about social competence. Attachment scripts predicted children's social competence in both samples. Results are discussed in terms of their implications for theory and research.

Effects of the Protonation State of Titratable Residues and the Presence of Water Molecules on Nocodazole Binding to ß-Tubulin.

Regulation of microtubule assembly by antimitotic agents is a potential therapeutic strategy for the treatment of cancer, parasite infections, and neurodegenerative diseases. One of these agents is nocodazole (NZ), which inhibits microtubule polymerization by binding to ß-tubulin. NZ was recently co-crystallized in Gallus gallus tubulin, providing new information about the features of interaction for ligand recognition and stability. In this work, we used state-of-the-art computational approaches to evaluate the protonation effects of titratable residues and the presence of water molecules in the binding of NZ. Analysis of protonation states showed that residue E198 has the largest modification in its pKa value. The resulting E198 pKa value, calculated with pH-REMD methodology (pKa =6.21), was higher than the isolated E amino acid (pKa =4.25), thus being more likely to be found in its protonated state at the binding site. Moreover, we identified an interaction between a water molecule and C239 and G235 as essential for NZ binding. Our results suggest that the protonation state of E198 and the structural water molecules play key roles in the binding of NZ to ß-tubulin.

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies.

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1, 2 and 3) with an I50 value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT.

Structure-based approaches for the design of benzimidazole-2-carbamate derivatives as tubulin polymerization inhibitors.

Microtubules are highly dynamic assemblies of α/ß-tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (ßI) and class III (ßIII) ß-tubulin isotypes in breast and lung cancers and the highly expressed class VI (ßVI) ß-tubulin isotype in normal blood cells have increased the interest for designing specific tubulin-binding anticancer therapies. To this end, we employed our previously proposed model of the ß-tubulin-nocodazole complex, supported by the recently determined X-ray structure, to identify the fundamental structural differences between ß-tubulin isotypes. Moreover, we employed docking and molecular dynamics (MD) simulations to determine the binding mode of a series of benzimidazole-2-carbamete (BzC) derivatives in the ßI-, ßIII-, and ßVI-tubulin isotypes. Our results demonstrate that Ala198 in the ßVI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between ßI- and ßIII-BzC complexes were observed; however, Ser239 in the ßIII isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the ß-tubulin-BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics.

Estudio de alcance de terapia ocupacional y drogodependencias: reflexiones críticas de los contextos, prioridades y miradas en la investigación / A scoping review of occupational therapy literature on drug addiction: critical reflections on contexts, priorities and research perspectives

Introducción: El consumo problemático de drogas representa uno de los problemas de salud más significativos a nivel mundial. La terapia ocupacional es uno de los actores sociales que promueve la participación en la comunidad, mediante la ocupación, contribuyendo a la justicia ocupacional. Sin embargo, se desconoce qué perspectivas y prioridades se están utilizando en la investigación de la terapia ocupacional, lo cual es clave para desarrollar una práctica reflexiva y crítica. Objetivo: Actualizar, identificar y sintetizar las prioridades y perspectivas en la producción científica existente relacionada al consumo de drogas y terapia ocupacional. Método: Se realizó una revisión de la literatura siguiendo el marco de referencia para “Scoping Review” desarrollado por Arksey y O’Malley. Se buscó en las siguientes bases de datos electrónicas: CINAHL, Cochrane Library Plus, Dialnet, EMBASE, ISI Web of Science, OTseeker y Scopus. Se empleó el método descriptivo analítico y la triangulación de investigadores para realizar el análisis de los datos. Resultados: Del análisis de la literatura emergieron tres categorías: “Contextualización”, “Prioridades de investigación” –relación entre el desempeño ocupacional y la calidad de vida, instrumentos de evaluación e intervenciones de terapia ocupacional– y “Miradas teóricas en la investigación” (una mirada positivista: la neurociencia como sustento de la intervención; una mirada empoderadora: construyendo el camino hacia la inclusión, y una mirada sistémica: centrada en la familia como base de la intervención). Conclusión: Es preciso continuar investigando acerca de la problemática del consumo de drogas desde la terapia ocupacional, empleando una perspectiva crítica basada en la ciencia de la ocupación.

Introduction: Drug abuse is one of the most complex global health issues. Occupational therapy is one of the socialactors that promotes community participation, using occupation as a means to contribute to occupational justice. However, it is unknown what theoretical perspectives are being used in occupational therapy research. This knowledge is essential for developing a critical and reflexive practice. Objective: This study aims to update, identify and synthesize the priorities and perspectives employed in the existing scientific literature of occupational therapy related with problematic use of drugs. Method: A scoping literature review based on the methods described by Arksey and O’Malley (2005) was conducted. Literature was identified using the following electronic databases: CINAHL, Cochrane Library Plus, Dialnet, EMBASE, ISI Web of Science, OTseeker, and Scopus. To analyse the data, a descriptive-analytic method and triangulation were used. Results: The literature reviewed reveals information regarding three categories: “Contextualization”, “Research Priorities” –the relationship between occupational performance and quality of life, assessment tools, occupational therapy intervention and “Theoretical Research Perspectives” (a positivist view: neuroscience as base for intervention, an empowering view: paving the way for inclusion, and a systemic view: family as base for intervention). Conclusion: Further research is needed regarding the role of occupational therapy in the field of problematic drug use using a critical perspective based on occupational science.

Gestación heterotópica: dos casos con gestación intrauterina viable a término / Heterotopic pregnancy: two cases with viable intrauterine pregnancy at term

Se presentan dos casos de gestación heterotópica, el primero de ellos espontáneo y el segundo tras técnicas de fecundación in vitro. En ambos la gestación intrauterina evolucionó de forma favorable, con control gestacional normal y llegando a término, con el nacimiento de recién nacidos sanos. La gestación heterotópica se define como la presencia simultánea de gestación en dos lugares de implantación distintos, lo más frecuente una gestación intrauterina acompañada de otra ectópica. Se trata de una situación poco frecuente, con una incidencia de 1/8000 embarazos espontáneos según la bibliografía más reciente.

We report two cases of heterotopic pregnancy, the first one spontaneous and the second one after in vitro fertilization techniques. In both, the intrauterine gestation evolved favorably, normal pregnancy control and coming to terms with the birth of healthy newborns. Heterotopic pregnancy is defined as the simultaneous presence of gestation at two different locations, most often in utero accompanied by another ectopic pregnancy. This is a rare situation, with an incidence of spontaneous pregnancies 1/8000 according to the most recent literature.

Infections and inequalities: anemia in AIDS, the disadvantages of poverty.

OBJECTIVE: To study anemia in AIDS patients and its relation with socioeconomic, employment status and educational levels. METHODS: A total number of 442 patients who visited the Infectious Diseases University Hospital in Buenos Aires, Argentina were included in the study. Patients were dividied into two groups, i.e. one with anemia and the other without anemia. Anemia epidemiology and its relationship with educational level, housing, job situation, monthly income, total daily caloric intake and weekly intake of meat were evaluated. RESULTS: Anemia was found in 228 patients (54%). Comparing patients with or without anemia, a statistically significant difference was found (P<0.000 1) in those whose highest educational level reached was primary school, who lived in a precarious home, who had no stable job or were unable to work, whose income was less than 30 dollars per month, whose meat consumption was less than twice a week or received less than 8 000 calories per day. CONCLUSIONS: The high prevalence of anemia found in poor patients with AIDS suggests that poverty increases the risk to suffer from this hematological complication. The relationship between economic development policies and AIDS is complex. Our results seem to point to the fact that AIDS epidemic may affect economic development and in turn be affected by it. If we consider that AIDS affects the economically active adult population, despite recent medical progress it usually brings about fatal consequences, especially within the poorest sectors of society where the disease reduces the average life expectancy, increases health care demand and tends to exacerbate poverty and iniquity.

A case report of cutaneous larva migrans in Argentina.

Cutaneous larva migrans (CLM) represents the most common tropically acquired dermatosis. CLM is caused by infection with hookworm larvae in tropical and sub-tropical areas, and people who have a history of foreign travel and of walking barefoot on sandy soil or beaches are at a high risk of getting infected with it. The diagnosis is usually made on the basis of the typical appearance of the lesion, intense itching and history of foreign travel. CLM is a common parasitic skin disease that can be easily prevented by wearing 'protective' footwear. A case of CLM is described in this article.

Enfermedades transmitidas por los alimentos: Análisis del riesgo microbiológico / Risk analysis of foodborne diseases: Microbial risk assessment

The basic goals of risk assessment include the following: to identify potentially hazardous situations and apply appropriate methods to estimate the likelihood that a hazard occurs. In The uncertainty in that estimate, to provide alternative solutions to reduce the risk, estimate the effectiveness of those solutions, provide information to base a risk management decision, and estimate the uncertainty associated with the analysis. Risk analysis provides the rational framework for assembling and then analysing the evidence relating to risk and presenting the results in a form that is easy to understand and then act upon fairly and effectively. Progress made is no excuse for arrogance. The present review is definitely not designed as the last word on risk analysis for foodborne diseases. Rather, this review has been designed to continue an evolving and necessary process and to provide a reference point that indicates the state of development in 2010.

Las metas básicas del análisis de riesgo incluyen las siguientes: identificar las situaciones potencialmente peligrosas, aplicar los métodos apropiados para estimar la probabilidad que un peligro ocurra, y en la incertidumbre en esa estimación, proporcionar las soluciones alternativas para reducir el riesgo, estimar la eficacia de esas soluciones, proporcionar la información sobre las que se base una decisión de la gestión de riesgos, y estimar la incertidumbre asociada a la evaluación. El análisis de riesgos constituye un sistema de referencia coherente para reunir y analizar indicios sobre los factores de riesgo, y también para presentar los resultados de modo inteligible y obrar después eficazmente. Pero los progresos realizados no pueden excusar la arrogancia. La presente revisión no pretende sentar cátedra sobre el análisis de riesgo microbiano, más bien está pensado como una etapa más de un proceso necesario y permanente, como un jalón que describe el estado de cosas en 2010.