Genes and primary headaches: discovering new potential therapeutic targets

Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache) are multifactorial disorders characterized by a complex interaction between different genes and environmental factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is now emerging for some of these genes. The main purpose of this review is to describe new advances in our knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders. Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders, will be discussed

Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease

Phase separation is a physiological process occurring spontaneously when single-phase molecular complexes separate in two phases, a concentrated phase and a more diluted one. Eukaryotic cells employ phase transition strategies to promote the formation of intracellular territories not delimited by membranes with increased local RNA concentration, such as nucleolus, paraspeckles, P granules, Cajal bodies, P-bodies, and stress granules. These organelles contain both proteins and coding and non-coding RNAs and play important roles in different steps of the regulation of gene expression and in cellular signaling. Recently, it has been shown that most human RNA-binding proteins (RBPs) contain at least one low-complexity domain, called prion-like domain (PrLD), because proteins harboring them display aggregation properties like prion proteins. PrLDs support RBP function and contribute to liquid–liquid phase transitions that drive ribonucleoprotein granule assembly, but also render RBPs prone to misfolding by promoting the formation of pathological aggregates that lead to toxicity in specific cell types. Protein–protein and protein-RNA interactions within the separated phase can enhance the transition of RBPs into solid aberrant aggregates, thus causing diseases. In this review, we highlight the role of phase transition in human disease such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and in cancer. Moreover, we discuss novel therapeutic strategies focused to control phase transitions by preventing the conversion into aberrant aggregates. In this regard, the stimulation of chaperone machinery to disassemble membrane-less organelles, the induction of pathways that could inhibit aberrant phase separation, and the development of antisense oligonucleotides (ASOs) to knockdown RNAs could be evaluated as novel therapeutic strategies for the treatment of those human diseases characterized by aberrant phase transition aggregates

Soft Skills Identification for Guidance and Job Placement. Presentation of the Project UNIMC (Macerata University) for Soft Skills

The issue of recognition, validation and certification of skills, especially those developed in non-formal and informal fields, is becoming a current topic for all educative institutions, including University. Soft skills is a psycho-sociological term relating to a cluster of personality traits, social abilities, communication, language, personal attitudes that characterize relationships with other people. Soft skills complement hard skills which are the occupational requirements of a job and many other activities. In Italy the legal framework on skills is leaded by the Legislative Decree n. 13/13. According to the Decree, University should assure the effective implementation of lifelong learning through guidance and counselling services. The University of Macerata (UNIMC) has been involved from a long time in the field of soft skills with many activities, formal as well as informal and non-formal. A system to recognize and validate them has been experienced in the last years. The objective of the paper is to describe the designed procedures aimed to the recognition and validation of soft skills such as observation, active listening, communication in small group and problem solving. Each skill was operationalized through the identification of specific indicators to recognize three level of expertise: basic, intermediate, advanced. Moreover several tasks were tested in order to identify a set of activities useful for the aim of a kind of formal recognition

MiR-23-TrxR1 as a novel molecular axis in skeletal muscle differentiation

Thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing protein involved in cellular redox homeostasis which is downregulated in skeletal muscle differentiation. Here we show that TrxR1 decrease occurring during myogenesis is functionally involved in the coordination of this cellular process. Indeed, TrxR1 depletion reduces myoblasts growth by inducing an early myogenesis -related gene expression pattern which includes myogenin and Myf5 up-regulation and Cyclin D1 decrease. On the contrary, the overexpression of TrxR1 during differentiation delays myogenic process, by negatively affecting the expression of Myogenin and MyHC. Moreover, we found that miR-23a and miR-23b - whose expression was increased in the early stage of C2C12 differentiation - are involved in the regulation of TrxR1 expression through their direct binding to the 3′ UTR of TrxR1 mRNA. Interestingly, the forced inhibition of miR-23a and miR-23b during C2C12 differentiation partially rescues TrxR1 levels and delays the expression of myogenic markers, suggesting the involvement of miR-23 in myogenesis via TrxR1 repression. Taken together, our results depict for the first time a novel molecular axis, which functionally acts in skeletal muscle differentiation through the modulation of TrxR1 by miR-23

Percepção de doença e distress emocional numa amostra de mulheres brasileiras com e sem histórico familiar de câncer de mama

Breast cancer often means a concern for women, especially for those with a family history of the disease. Exposure to external stimuli related to the disease may change women’s illness perception such as its symptoms, control and cure assimilation, as well as causes and consequences involved in the possibility of becoming sick. The aim of this study was to examine the relationship between breast cancer perception and emotional distress in women with and without a family history of the disease. Participants of this cross-sectional study were 114 women users of primary health services in the south of Brazil, of which 43 had breast cancer family history (mean age = 48.21, SD = 11.91), and 71 had no such history (mean age = 50.21, SD = 11.44). Instruments were health behaviors questionnaire, illness perceptions questionnaire and distress thermometer. Results suggest that women with breast cancer history believed they had less breast cancer treatment control (U=1088.5; p<0.05) than women without cancer family history. We did not observe differences about distress between groups. We conclude that, in general, illness perception and distress between women with and without cancer family history is similar, although the former believe that breast cancer is difficult to control.Keywords: Illness perception, distress, breast cancer, family history.El cáncer de mama representa una preocupación para las mujeres en general, en especial para las que tienen historia familiar de la enfermedad. La exposición a estimulos externos relacionados a la enfermedad puede cambiar la percepción de la mujer sobre el cáncer de mama como, por ejemplo, sus síntomas, su apreciación de control y cura, y causas y consecuencias relacionadas a la posibilidad de enfermar. El objetivo del estudio fue examinar la relación entre percepción del cáncer de mama y distrés emocional en mujeres con y sin historia familiar de la enfermedad. Participaron de este estudio de delineamiento observacional analítico y transversal 114 mujeres usuarias de servicios de atención básica de salud del sur de Brasil, 43 de ellas con historia de cáncer de mama (edad promedio= 48.21; DP= 11.91) y 71 sin historia familiar (edad promedio =50.21; DP=11.44). Los instrumentos fueron: cuestionarios de comportamientos en salud, de percepción de la enfermedad y termómetro de distrés. Los resultados sugieren que las mujeres con historia familiar creen tener menos control de la enfermedad por medio del tratamiento (U=1088.5; p<0.05) en comparación a las mujeres del grupo sin histórico. No se observaron diferencias entre los grupos con relación al distrés. Se concluye que en general la percepción de la enfermedad y distrés es semejante entre mujeres con y sin historia familiar; sin embargo, mujeres con historia creen que la enfermedad es de más difícil control.Palabras clave: percepción de la enfermedad, distrés, cáncer de mama, historia familiar.O câncer de mama representa uma preocupação entre as mulheres de modo geral, em especial para aquelas com histórico familiar da doença. A exposição a estímulos externos relacionados à doença pode modificar a percepção da mulher sobre o câncer de mama como, por exemplo, seus sintomas, percepção de controle e cura, causas e consequências envolvidas na possibilidade de adoecer. O objetivo do estudo foi examinar a relação entre percepção do câncer de mama e distress emocional em mulheres com e sem histórico familiar da doença. Participaram deste estudo de delineamento observacional analítico e transversal 114 mulheres usuárias de serviços de atenção básica de saúde do sul do Brasil, 43 delas com histórico de câncer de mama (idade média=48.21; DP=11.91) e 71 sem histórico familiar (idade média=50.21; DP=11.44). Os instrumentos foram: questionários de comportamentos em saúde, de percepção da doença e termômetro de distress. Os resultados sugerem que as mulheres com histórico familiar acreditaram ter menos controle da doença por meio do tratamento (U=1088.5; p<0.05) em comparação às mulheres do grupo sem histórico. Não se observaram diferenças entre os grupos em relação ao distress. Conclui-se que em geral a percepção da doença e distress é semelhante entre mulheres com e sem histórico familiar, porém mulheres com histórico acreditam que a doença é de mais difícil controle.Palavras-chave: percepção da doença, distress, câncer de mama, histórico familiar

Comparative Bioavailability Study of Two 81 mg Coated Tablet Formulations of Acetylsalicylic Acid in Fasting Healthy Volunteers

Introduction: Low-dose acetylsalicylic acid is used as antithrombotic agent and the enteric-coated formulations are widely used to minimize the gastrointestinal side effects. Aim: To compare the bioavailability of two acetylsalicylic acid formulations (Ecasil-81®, 81 mg coated tablet) in fasting healthy volunteers. Methods: Healthy volunteers (n=16) were recruited to a monocentric, open label, randomized, two-way crossover pharmacokinetic study, with seven days washout period between the treatments. They received a single 81 mg oral dose of a test (new formulation) or a standard reference formulation of acetylsalicylic acid (Ecasil-81®) after about 8 h fasting. Blood samples were collected over a period of 36 h. The salicylic acid plasma concentration was evaluated by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program. Results: The maximum plasma concentration (Cmax) of salicylic acid was 5433 and 5719 ng/mL reached in 3.66 and 4.02 h (tmax) for the test and the reference formulation, respectively. The 90% confidence interval of the ratios of geometric means of Cmax and area under curve of plasma concentration until the last concentration observed (AUC0- last) were within the interval 80-125%. Conclusion: The new acetylsalicylic acid formulation has a bioavailability equivalent to the reference formulation for the rate and the extent of absorption

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling

Bayesian Machine Learning Techniques for revealing complex interactions among genetic and clinical factors in association with extra-intestinal Manifestations in IBD patients

The objective of the study is to assess the predictive performance of three different techniques as classifiers for extra-intestinal manifestations in 152 patients with Crohn's disease. Na\uefve Bayes, Bayesian Additive Regression Trees and Bayesian Networks implemented using a Greedy Thick Thinning algorithm for learning dependencies among variables and EM algorithm for learning conditional probabilities associated to each variable are taken into account. Three sets of variables were considered: (i) disease characteristics: presentation, behavior and location (ii) risk factors: age, gender, smoke and familiarity and (iii) genetic polymorphisms of the NOD2, CD14, TNFA, IL12B, and IL1RN genes, whose involvement in Crohn's disease is known or suspected. Extra-intestinal manifestations occurred in 75 patients. Bayesian Networks achieved accuracy of 82% when considering only clinical factors and 89% when considering also genetic information, outperforming the other techniques. CD14 has a small predicting capability. Adding TNFA, IL12B to the 3020insC NOD2 variant improved the accuracy