Novel variant in HHAT as a cause of different sex development with partial gonadal dysgenesis associated with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs: Case report

Different sexual development; Minigene studiesDesarrollo sexual diferente; Estudios de minigenesDesenvolupament sexual diferent; Estudis minigènicsThe palmitoylation of the Hedgehog (Hh) family of morphogens, named sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH), is crucial for effective short- and long-range signaling. The hedgehog acyltransferase (HHAT) attaches the palmitate molecule to the Hh; therefore, variants in HHAT cause a broad spectrum of phenotypes. A missense HHAT novel variant c.1001T>A/p.(Met334Lys) was described in a patient first referred for a 46,XY different sexual development with partial gonadal dysgenesis but with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs. The in silico analysis of the variant predicted an affectation of the nearest splicing site. Thus, in vitro minigene studies were carried out, which demonstrated that the variant does not affect the splicing. Subsequent protein in silico studies supported the pathogenicity of the variant, and, in conclusion, this was considered the cause of the patient’s phenotype.This study was partly supported by a grant from the Fondo de Investigación Sanitaria (PI15/01647 [to MF-C and SB-S])

TFG 2012/2013

Amb aquesta publicació, EINA, Centre universitari de Disseny i Art adscrit a la Universitat Autònoma de Barcelona, dóna a conèixer el recull dels Treballs de Fi de Grau presentats durant el curs 2012-2013. Voldríem que un recull com aquest donés una idea més precisa de la tasca que es realitza a EINA per tal de formar nous dissenyadors amb capacitat de respondre professionalment i intel·lectualment a les necessitats i exigències de la nostra societat. El treball formatiu s’orienta a oferir resultats que responguin tant a paràmetres de rigor acadèmic i capacitat d’anàlisi del context com a l’experimentació i la creació de nous llenguatges, tot fomentant el potencial innovador del disseny.Con esta publicación, EINA, Centro universitario de diseño y arte adscrito a la Universidad Autónoma de Barcelona, da a conocer la recopilación de los Trabajos de Fin de Grado presentados durante el curso 2012-2013. Querríamos que una recopilación como ésta diera una idea más precisa del trabajo que se realiza en EINA para formar nuevos diseñadores con capacidad de responder profesional e intelectualmente a las necesidades y exigencias de nuestra sociedad. El trabajo formativo se orienta a ofrecer resultados que respondan tanto a parámetros de rigor académico y capacidad de análisis, como a la experimentación y la creación de nuevos lenguajes, al tiempo que se fomenta el potencial innovador del diseño.With this publication, EINA, University School of Design and Art, ascribed to the Autonomous University of Barcelona, brings to the public eye the Final Degree Projects presented during the 2012-2013 academic year. Our hope is that this volume might offer a more precise idea of the task performed by EINA in training new designers, able to speak both professionally and intellectually to the needs and demands of our society. The educational task is oriented towards results that might respond to the parameters of academic rigour and the capacity for contextual analysis, as well as to considerations of experimentation and the creation of new languages, all the while reinforcing design’s innovative potential

Identificación y caracterización de mecanismos moleculares implicados en la dishormonogénesis tiroidea mediante la aplicación de técnicas de secuenciación masiva

Les dishormonogènesis tiroïdals (DT) representen aproximadament el 20% dels casos d’hipotiroïdisme congènit (HC) primari. En aquests pacients s’acostuma a identificar una glàndula tiroide in situ (GIS) normal o augmentada de mida. Les DT es deuen a defectes genètics en la biosíntesi d’hormones tiroïdals que habitualment es transmeten de forma autosòmica recessiva. El coneixement cada vegada més precís dels processos i activitats enzimàtiques que intervenen en la síntesi de les hormones tiroïdals ha permès identificar diferents factors de transcripció i proteïnes específicament implicats en la regulació de l’hormonogènesi tiroïdal. L’expressió clínica de les DT és molt àmplia, amb formes clíniques que van des del hipotiroïdisme subclínic fins al desenvolupament de goll. Molts dels pacients diagnosticats d’HC en el cribratge neonatal presenten un perfil suggestiu de DT, en base a criteris clínics, hormonals i gammagràfics, però pocs estudis han analitzat sistemàticament el defecte molecular en aquests pacients. En aquest treball s’han inclòs 70 pacients amb sospita de DT procedents del programa de cribratge neonatal de l’HC i se’ls ha realitzat, mitjançant tècniques de seqüenciació massiva, un estudi molecular de gens relacionats amb DT. S’ha detectat que un 77.1% (n = 54) d’ells presentava defectes moleculars en algun d’aquests gens. Els gens més freqüentment afectats en els pacients amb un diagnòstic molecular que justifiqués el seu fenotip van ser: TG (n = 18), seguit de TPO (n = 10) i DUOX2 (n = 9). També es van trobar variants genètiques en PAX8 i TSHR (n = 5 i n = 3, respectivament). En total, es van detectar 72 variants genètiques diferents: 28 en TG, 16 a TPO, 15 a DUOX2, 5 a PAX8, 6 a TSHR, 1 a DUOXA2 i 1 a IYD. D’aquestes 72 variants, un total de 31 són noves (43%). Segons la classificació de l’American College of Medical Genetics, 23 d’aquestes variants són patogèniques (32%), 10 probablement patogèniques (13.9%), 35 variants de significat incert (48.6%) i 4 probablement benignes (5.5%). Es va realitzar un estudi per correlacionar el genotip i el fenotip d’aquests pacients. Es va observar que els pacients portadors de variants genètiques presentaven un hipotiroïdisme més sever que els pacients sense variants genètiques. Així mateix, els pacients portadors de variants genètiques van presentar, majoritàriament (91.3%) un HC de caràcter permanent en la revaluació diagnòstica. Per contra, la majoria dels pacients sense variants (83.4%) van presentar un HC de caràcter transitori. Es va realitzar un estudi per relacionar el fenotip clínic amb el gen afecte i la mutació trobada. Així mateix, es va realitzar un estudi de les variables que podien ser útils per predir el caràcter permanent o transitori de l’hipotiroïdisme i es va concloure que l’únic paràmetre que permet diferenciar entre els dos fenotips és la dosi de levotiroxina que necessiten els pacients durant la seva evolució. Els punts de tall òptims de la dosi de levotiroxina, basats en el màxim índex de Youden, van ser els següents: 4 mcg / kg / dia a l’any de vida; 3.1 mcg / kg / dia als 2 anys de vida i 2.4 mcg / kg / dia als 4 anys de vida. Del nostre estudi es pot concloure que la DT és la principal causa de l’HC amb GIS. L’estudi genètic en aquests pacients permet predir l’evolució clínica d’aquests pacients i prendre decisions sobre la necessitat o el moment de realitzar la revaluació diagnòstica. A més, s’ha constatat, mitjançant l’estudi de cosegregació familiar, que les variants són heretades dels progenitors i no de novo, de manera que l’estudi genètic en els progenitors d’aquests pacients és d’utilitat per a realitzar un diagnòstic i tractament precoç en la descendència futura.Las dishormonogénesis tiroideas (DT) representan aproximadamente el 20% de los casos de hipotiroidismo congénito (HC) primario. En estos pacientes se suele identificar una glándula tiroidea in situ (GIS) normal o aumentada de tamaño. Las DT se deben a defectos genéticos en la biosíntesis de hormonas tiroideas que habitualmente se transmiten de forma autosómica recesiva. El conocimiento cada vez más preciso de los procesos y actividades enzimáticas que intervienen en la síntesis de las hormonas tiroideas ha permitido identificar distintos factores de transcripción y proteínas específicamente implicados en la regulación de la hormonogénesis tiroidea. La expresión clínica de las DT es muy amplia, con formas clínicas que van desde el hipotiroidismo subclínico hasta el desarrollo de bocio. Muchos de los pacientes diagnosticados de HC en el cribado neonatal presentan un perfil sugestivo de DT, en base a criterios clínicos, hormonales y gammagráficos, pero pocos estudios han analizado sistemáticamente el defecto molecular en estos pacientes. En este trabajo se han incluido 70 pacientes con sospecha de DT procedentes del programa de cribado neonatal del HC y se les ha realizado, mediante técnicas de secuenciación masiva, un estudio molecular de genes relacionados con DT. Se ha detectado que un 77.1% (n=54) de ellos presentaba defectos moleculares en alguno de estos genes. Los genes más frecuentemente afectados en los pacientes con un diagnóstico molecular que justificara su fenotipo fueron: TG (n=18), seguido de TPO (n=10) y DUOX2 (n=9). También se encontraron variantes genéticas en PAX8 y TSHR (n=5 y n=3, respectivamente). En total, se detectaron 72 variantes genéticas distintas: 28 en TG, 16 en TPO, 15 en DUOX2, 5 en PAX8, 6 en TSHR, 1 en DUOXA2 y 1 en IYD. De estas 72 variantes, un total de 31 son nuevas (43%). Según la clasificación de la American College of Medical Genetics, 23 de estas variantes son patogénicas (32%), 10 probablemente patogénicas (13.9%), 35 variantes de significado incierto (48.6%) y 4 probablemente benignas (5.5%). Se realizó un estudio para correlacionar el genotipo y el fenotipo de estos pacientes. Se observó que los pacientes portadores de variantes genéticas presentaban un hipotiroidismo más severo que los pacientes sin variantes genéticas. Asimismo, los pacientes portadores de variantes genéticas presentaron, en su mayoría (91.3%) un HC de carácter permanente en la reevaluación diagnóstica. Por el contrario, la mayoría de los pacientes sin variantes (83.4%) presentaron un HC de carácter transitorio. También se realizó un estudio para relacionar el fenotipo clínico con el gen afecto y la mutación encontrada. Asimismo, se realizó un estudio de las variables que podían ser útiles para predecir el carácter permanente o transitorio del hipotiroidismo y se concluyó que el único parámetro que permite diferenciar entre ambos fenotipos es la dosis de levotiroxina que precisan los pacientes durante su evolución. Los puntos de corte óptimos de la dosis de levotiroxina, basados en el máximo índice de Youden, fueron los siguientes: 4 mcg/kg/día al año de vida; 3.1 mcg/kg/día a los 2 años de vida y 2.4 mcg/kg/día a los 4 años de vida. De nuestro estudio se puede concluir que la DT es la principal causa del HC con GIS. El estudio genético en estos pacientes permite predecir la evolución clínica de estos pacientes y tomar decisiones sobre la necesidad o el momento de realizar la reevaluación diagnóstica. Además, se ha constatado, mediante el estudio de cosegregación familiar, que las variantes son heredadas de los progenitores y no de novo, por lo que el estudio genético en los progenitores de estos pacientes es de utilidad para realizar un diagnóstico y tratamiento precoz en la descendencia futura.Thyroid dyshormonogenesis (TD) represent approximately 20% of cases of primary congenital hypothyroidism (CH). In these patients, a normal or enlarged thyroid gland in situ (GIS) is usually identified. TDs are due to genetic defects in the biosynthesis of thyroid hormones that are usually transmitted in an autosomal recessive manner. The increasingly knowledge of the enzymatic processes and activities involved in the synthesis of thyroid hormones has allowed the identification of different transcription factors and proteins specifically involved in the regulation of thyroid hormonegenesis. The clinical expression of TD is very broad, with clinical forms ranging from subclinical hypothyroidism to the development of goiter. Many of the patients diagnosed with CH in neonatal screening have a suggestive TD profile, based on clinical, hormonal and scintigraphic criteria, but few studies have systematically analyzed the molecular defect in these patients. In this study, 70 patients with suspected TD, diagnosed in the neonatal HC screening program, have been included and a molecular study of genes related to TD has been carried out using massive sequencing techniques. We detected that 77.1% (n = 54) of them had molecular defects in any of these genes. The most frequently affected genes in patients with a molecular diagnosis that justified their phenotype were: TG (n = 18), followed by TPO (n = 10) and DUOX2 (n = 9). Genetic variants were also found in PAX8 and TSHR (n = 5 and n = 3, respectively). In total, 72 different genetic variants were detected: 28 in TG, 16 in TPO, 15 in DUOX2, 5 in PAX8, 6 in TSHR, 1 in DUOXA2 and 1 in IYD. Of these 72 variants, a total of 31 are new (43%). According to the American College of Medical Genetics classification, 23 of these variants are pathogenic (32%), 10 probably pathogenic (13.9%), 35 variants of uncertain significance (48.6%), and 4 probably benign (5.5%). A study was conducted in order to know the relationship between the genotype and phenotype of these patients. Patients carrying genetic variants were observed to have more severe hypothyroidism than patients without genetic variants. Likewise, patients with genetic variants presented, in their majority (91.3%) a permanent CH in the diagnostic re-evaluation. On the contrary, the majority of the patients without genetic variants (83.4%) presented a transient HC. A study was also carried out to relate the clinical phenotype with the affected gene and the detected mutation. Likewise, we studied the variables that could be useful to predict the permanent or transitory nature of hypothyroidism and we concluded that the only parameter that allows differentiating between both phenotypes is the dose of levothyroxine that patients require during their evolution. The optimal cut-off points for the levothyroxine dose, based on the maximum Youden index, were as follows: 4 mcg / kg / day at 1 year of age; 3.1 mcg / kg / day at 2 years of age and 2.4 mcg / kg / day at 4 years of age. From our study, we can conclude that TD is the main cause of CH with GIS. The genetic study in these patients allows predicting the clinical evolution of these patients and making decisions about the need or the time to carry out the diagnostic re-evaluation. In addition, we verified, through the family co-segregation study, that the variants are inherited from the parents and not de novo, so that the genetic study in the parents of these patients is useful for making an early diagnosis and treatment in the future offspring.Universitat Autònoma de Barcelona. Programa de Doctorat en Pediatria, Obstetrícia i Ginecologi

An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: gefitinib (Iressatrade mark)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review)

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have beenreported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a generalagreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstreamof EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However,there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKIefficacy. We recently monitored gene expression profiles andsub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin,epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cellsensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated(up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times)of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second,loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breastcancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells.In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene,oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 functionalso leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands,and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. Therelevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypassthe antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascade

Efficacy, cost-utility and physiological effects of Acceptance and Commitment Therapy (ACT) and Behavioural Activation Treatment for Depression (BATD) in patients with chronic low back pain and depression: study protocol of a randomised, controlled trial including mobile-technology-based ecological momentary assessment (IMPACT study)

Introduction: The IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre-post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the FKBP5 gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes. Methods and analysis: Participants will be 225 patients with CLBP and moderate to severe depression symptoms recruited at Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs TAU+ACT versus TAU+BATD. A comprehensive assessment to collect clinical variables and costs will be conducted pretreatment, post-treatment and at 12 months follow-up, being pain interference the primary outcome measure. The following physiological variables will be considered at pretreatment and post-treatment assessments in 50% of the sample: immune-inflammatory markers, hair cortisol and cortisone, serum cortisol, corticosteroid-binding globulin and vitamin D. Polymorphisms in the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916) will be analysed at baseline assessment. Moreover, we will include mobile-technology-based ecological momentary assessment, through the Pain Monitor app, to track ongoing clinical status during ACT and BATD treatments. Linear mixed-effects models using restricted maximum likelihood, and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed. Ethics and dissemination: This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu and Hospital del Mar. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities. Trial registration number: NCT04140838

Efficacy, cost-utility and physiological effects of Acceptance and Commitment Therapy (ACT) and Behavioural Activation Treatment for Depression (BATD) in patients with chronic low back pain and depression: Study protocol of a randomised, controlled trial including mobile-technology-based ecological momentary assessment (IMPACT study)

Introduction The IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre-post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the FKBP5 gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes. Methods and analysis Participants will be 225 patients with CLBP and moderate to severe depression symptoms recruited at Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs TAU+ACT versus TAU+BATD. A comprehensive assessment to collect clinical variables and costs will be conducted pretreatment, post-treatment and at 12 months follow-up, being pain interference the primary outcome measure. The following physiological variables will be considered at pretreatment and post-treatment assessments in 50% of the sample: immune-inflammatory markers, hair cortisol and cortisone, serum cortisol, corticosteroid-binding globulin and vitamin D. Polymorphisms in the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916) will be analysed at baseline assessment. Moreover, we will include mobile-technology-based ecological momentary assessment, through the Pain Monitor app, to track ongoing clinical status during ACT and BATD treatments. Linear mixed-effects models using restricted maximum likelihood, and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed. Ethics and dissemination This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu and Hospital del Mar. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities. Trial registration number NCT04140838 </p

Efficacy, cost-utility and physiological effects of Acceptance and Commitment Therapy (ACT) and Behavioural Activation Treatment for Depression (BATD) in patients with chronic low back pain and depression : Study protocol of a randomised, controlled trial including mobile-technology-based ecological momentary assessment (IMPACT study)

Introduction The IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre-post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the FKBP5 gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes. Methods and analysis Participants will be 225 patients with CLBP and moderate to severe depression symptoms recruited at Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs TAU+ACT versus TAU+BATD. A comprehensive assessment to collect clinical variables and costs will be conducted pretreatment, post-treatment and at 12 months follow-up, being pain interference the primary outcome measure. The following physiological variables will be considered at pretreatment and post-treatment assessments in 50% of the sample: immune-inflammatory markers, hair cortisol and cortisone, serum cortisol, corticosteroid-binding globulin and vitamin D. Polymorphisms in the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916) will be analysed at baseline assessment. Moreover, we will include mobile-technology-based ecological momentary assessment, through the Pain Monitor app, to track ongoing clinical status during ACT and BATD treatments. Linear mixed-effects models using restricted maximum likelihood, and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed. Ethics and dissemination This study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu and Hospital del Mar. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities. Trial registration number NCT04140838 </p